IndraLab

Statements


USP4 is modified
| 3 67 8
USP4 is phosphorylated.
| 41 8
USP4 is phosphorylated. 10 / 41
| 36 5

sparser
"The authors also observed phosphorylation of endogenous USP4 upon the addition of TGF-β."

sparser
"The AKT-mediated phosphorylation of USP4 also affects its stability and DUB activity."

sparser
"However, AKT-mediated USP4 phosphorylation promoted its subcellular localization to the membrane, where USP4 deubiquitinated TβRI."

sparser
"They further showed that USP4 could interact with Akt at endogenous level, and phosphorylate USP4 in vitro and in vivo."

sparser
"We further showed that the phosphorylation of both USP15 and USP4 is regulated by the activity of CDKs, although a question remains on which CDK, or whether more than one CDK, is required for this pho[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"The phosphorylation of USP4 prolongs its half-life on the plasma membrane, and activates TGF-β cell signalling through binding and deubiquitination of TGF-β receptors, which plays a crucial role in tumour cell migration and metastasis."

sparser
"Moreover, AKT-mediated USP4 phosphorylation can abolish the ubiquitination of Rheb and then stabilize it, which activate the mechanistic target of rapamycin complex 1-mediated signaling pathways, thus influenced tumor growth [ xref ]."

sparser
"Direct association of USP4 with TβRI at the plasma membrane and USP4-mediated TβRI deubiquitylation are enhanced in response to Akt activation and Akt-mediated USP4 phosphorylation, and directly oppos[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"TGF-β-induced migration of MDA-MB-231 cells is inhibited by USP4 knockdown and PI (3) K–AKT signalling inhibitors, indicating that phosphorylation of USP4 plays a critical role in AKT-mediated breast cancer cell migration ( xref ; xref )."

sparser
"It has been reported that growth factor could induce the phosphorylation of USP4 by AKT xref ."
USP4 is phosphorylated on S445. 5 / 8
| 5 3

sparser
"AKT-mediated phosphorylation of USP4 at the Ser 445 residue is essential to form a complex with other protein partners such as USP15 or TβRI [ 54 ]."

sparser
"Results have shown that AKT-mediated phosphorylation of USP4 at the Ser445 residue is essential for it to form a complex with itself or with other protein partners, such as USP15 or TβRI ( xref )."

sparser
"To examine whether the phosphorylation of USP4 at Ser445 affects the interaction between USP4 and Rheb, we generated a USP4 dephospho-mimetic mutant (USP4-S445A) and a phospho-mimetic mutant (USP4-S445D)."

sparser
"The study that identified USP4 as a DUB for ALK5 also demonstrated that phosphorylation of USP4 on S445 triggers homomeric and heteromeric complex formation with USP11, USP15 and USP19, suggesting that these DUBs could act as a complex xref ."

sparser
"Taken together, these findings indicate that EGF regulates Rheb deubiquitination by inducing USP4 phosphorylation at S445."
USP4 is ubiquitinated.
| 2 22
USP4 is ubiquitinated. 10 / 24
| 2 22

sparser
"In light of this and our other data, we tested whether we could detect USP4 ubiquitylations that were sensitive to β-mercaptoethanol treatment."

sparser
"In its inactive ubiquitinated form USP4 cannot interact with these factors but due to auto-de-ubiquitination these modifications are removed, enabling interaction with MRN-CtIP."

sparser
"For both cases, the E3 ligases responsible for ubiquitylation of USP4 and NFRKB in the context of HR remain to be identified."

sparser
"For instance, USP4 can be ubiquitinated at multiple sites such as the cysteine residues."

sparser
"Furthermore, we show that USP4 is ubiquitylated on multiple sites including those on cysteine residues and that deubiquitylation of these sites requires USP4 catalytic activity and is required for USP4 to interact with CtIP/MRN and to promote CtIP recruitment and DNA repair."

sparser
"However, if Rho52 ubiquitinates USP4 the DUB may be degraded."

sparser
"More importantly, USP4 ubiquitination can block USP4-CtIP interaction, whereas the USP4CA mutant could not mediate its autodeubiquitination, and sustained ubiquitination of USP4 would block its intera[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"Ubiquitination of USP4 could physically block its interaction with CtIP or induce conformational change of USP4."

sparser
"Together, these findings supported a model in which USP4 ubiquitylations, including those on zinc-binding cysteine residues, are subject to turnover by USP4 catalytic activity."

reach
"Importantly, EVO inhibited USP4 expression and reduced the levels of SOX9, OCT4, and CD133.These results suggest that EVO may relieve the regulation of CRC stemness by inhibiting USP4 deubiquitination and stabilizing SOX9."
USP4 is methylated.
| 2
USP4 is methylated. 2 / 2
| 2

sparser
"Moreover, we identified that METTL3 could methylate USP4 at one m 6 A site within the CDS and around the stop codon, and the m 6 A reader protein YTHDF2 could recognize the m 6 A site and then recruit RNA-binding protein HNRNPD to the mRNA, resulting in degradation of USP4 mRNA."

sparser
"Metformin attenuates multiple myeloma cell proliferation and encourages apoptosis by suppressing METTL3-mediated m6A methylation of THRAP3, RBM25, and USP4."
USP4 is dephosphorylated.
| 2
USP4 is dephosphorylated. 2 / 2
| 2

sparser
"Dephosphorylation of USP4 can cause its nuclear accumulation which enhances its interaction with squamous cell carcinoma antigen recognized by T cells 3 (SART3) and regulate spliceosome dynamics through deubiquitinating precursor RNA processing 3 [ xref ]."

sparser
"For instance, dephosphorylated USP4 accumulates in the nucleus, whereas the AKT-mediated phosphorylated form of USP4 (at residue Ser445) was primarily localized in the cytoplasm and cell membrane."
USP4 is produced.
| 1
USP4 is produced. 1 / 1
| 1

reach
"In addition, the relationship between hsa_circ_0001326 and hsa-miR-136-5p, or between hsa-miR-136-5p and USP4 are also need further verify.In brief, we found luteolin promoted M2 polarization and inhibited M1 polarization by upregulating the expression of hsa_circ_0001326, which then mediated the expression of hsa-miR-136-5p and USP4."

reach
"USP4 and S1P1 were up-regulated in mesenchymal-type liver-tumor cells with miR-148a dysregulation, facilitating migration and proliferation of tumor cells."

reach
"Notably, this study demonstrated that USP4 promotes PTC proliferation by modulating the MAPK and AKT signaling pathways."

reach
"In summary, these data indicate that USP4 enhances HCC cell proliferation, migration, and invasion and suppresses HCC cell apoptosis in vitro."

reach
"TbetaRI stabilized downstream from TGF-beta signaling causes the phosphorylation of Smad2 and 3, the transcription factors responsible for target gene induction [XREF_BIBR], as verified by our result that USP4 fortified Smad2 phosphorylation and promoted migration and proliferation of hepatoma cell."

reach
"As shown in XREF_FIG, the inhibition of cell proliferation that was induced by USP4 overexpression was markedly reversed following PDCD4 knockdown using siRNA."

reach
"By promoting activation of the relaxin and TGF-beta 1/Smad2/matrix metalloproteinase 9 axis and transcriptional repression activity of HDAC2, USP4 induces breast cell invasion, migration, and proliferation both in vitro and in vivo."

reach
"XREF_BIBR also demonstrated that inhibiting USP4 expression in GBM cells both inhibited their proliferation and induced apoptosis via antagonizing USP4 mediated stimulation of the ERK signaling pathway."

reach
"The inhibition of USP4 in vitro significantly enhanced breast cancer cell growth and proliferation, while the overexpression of USP4 inhibited cell growth and proliferation."

eidos
"In addition , USP4 reportedly mediates cell proliferation , survival and metastasis ( 32 , 33 ) ."

reach
"METTL3 elevates the levels of oncogenes such as THRAP3, RBM25, USP4, and BZW2, which accelerate the proliferation of MM cells and inhibit apoptosis [233, 234]."

reach
"As shown in XREF_FIG, the overexpression of USP4 significantly inhibited the proliferation of BT549 cells, whereas USP4 knockdown significantly promoted the proliferation of the MCF7 cells (XREF_FIG)."

reach
"These results indicated that USP4 markedly inhibited breast cancer cell proliferation and colony forming ability."

reach
"In addition, by inducing USP4 overexpression (using a USP4 overexpression plasmid) or the knockdown of USP4 (by transfection with a USP4 shRNA plasmid), we found that USP4 inhibited cell proliferation in vitro."

reach
"We also demonstrate that USP4 inhibits breast cancer cell proliferation."

reach
"USP4 inhibits breast cancer cell proliferation."

reach
"These results indicate that PDCD4 is involved in the USP4 mediated inhibition of the proliferation of breast cancer cells."

reach
"Cai et al. showed that USP4 expression was significantly decreased in tumor tissues and knockdown of USP4 significantly promoted cell proliferation."

reach
"These data demonstrate that USP4 suppresses the proliferation of breast cancer cells through the upregulation of PDCD4."

sparser
"In addition, by inducing USP4 overexpression (using a USP4 overexpression plasmid) or the knockdown of USP4 (by transfection with a USP4 shRNA plasmid), we found that USP4 inhibited cell proliferation in vitro ."

reach
"These results suggest that USP4 inhibits breast cancer cell growth and proliferation in vivo."
USP4 affects MAP3K7
4 1 | 46 14
USP4 binds MAP3K7.
4 | 8 12
4 | 8 12

sparser
"USP4 binds to overexpressed TAK1 with TAB1 and TNFα induces association of USP4 with TAK1."

sparser
"To further determine the molecular interaction of USP4 and TAK1 in TNFα-induced signal transduction, we overexpressed expression vector encoding MYC-USP4 in HEK-293T cells and treated with TNFα for the time points as indicated ( xref )."

reach
"USP4 and USP18 bind with TAK1 and de-ubiquitinate TAK1 to inhibit its activation [10, 12]."

sparser
"Tumour necrosis factor-α (TNFα) promotes the interaction between USP4 and TAK1 and the deubiquitination of TAK1, leading to the attenuation of TAK1-mediated NF-κB activation."

sparser
"Furthermore, unlike CYLD, binding of USP4 with TAK1 is induced by TNFα stimulation in the cells ( xref )."

reach
"To verify the mass spectrometry results, a Co-IP assay was performed to test the reciprocal interaction between USP4 and TAK1 in ESCC cells."

sparser
"TNFα induces association of USP4 with TAK1 to deubiquitinate TAK1 and downregulate TAK1-mediated NF-κB activation."

sparser
"In conclusion, our results provide evidence that TNFα induces association of USP4 with TAK1 which leads to TAK1 deubiquitination in the TNFα-mediated NF-κB activation."

sparser
"In view of the data presented here and previous reports, we propose a working model ( xref ), in which that TNFα rapidly induces Lys63-linked TAK1 polyubiquitnation and binding of USP4 to TAK1, Lys63-linked TAK1 would be rapidly deubiquitinated by USP4 to attenuate the magnitude of TNFα-induced Lys63-linked TAK1 polyubiquitination and TAK1-mediated IKK/NF-κB activation."

sparser
"In addition, USP4-TAK1 interaction and subsequent TAK1 deubiquitination were required for the amelioration of metabolic dysfunctions."
USP4 deubiquitinates MAP3K7.
1 | 24
USP4 deubiquitinates MAP3K7. 10 / 21
1 | 20

reach
"However, it is not known whether USP4 also deubiquitinates TAK1 in rainbow trout through a similar mechanism."

reach
"Mechanistically, p38IP dynamically interacts with TAK1 and promotes USP4 dependent deubiquitination of TAK1."

reach
"USP4 deubiquitinates TAK1 in vitro and in vivo."

reach
"Moreover, p38IP scaffolds the deubiquitinase USP4 to deubiquitinate TAK1 once TAK1 is activated."

reach
"We then analyzed the effect of USP4 knockdown on the TNFalpha induced TAK1 polyubiquitination."

reach
"In agreement with a previous study showing that USP4 acts as a deubiquitinase for TAK1 [33], the present study also indicated that USP4 knockdown suppressed TAK1 deubiquitination, but overexpression enhanced its deubiquitination."

reach
"USP4 deubiquitinates TAK1 and negatively regulats the IL-1β-, LPS-, and TGF-β-induced NF-κB activation [ 36 ]."

reach
"Although it has been reported that USP4 deubiquitinates TAK1 and negatively regulates TNF- and IL-1-induced activation of NF-kappaB, how TAK1 ubiquitination is regulated in adaptive immune cells such as T cells and whether such a regulation regulates T cell mediated immune response remain unknown."

reach
"After TAK1 is activated with Lys63 linked polyubiquitination by Dox, USP4 deubiquitinates TAK1 and inhibits TAK1 mediated signaling."

reach
"These results indicate that USP4 mainly inhibits inducible TAK1 polyubiquitination and activation whereas CYLD mainly inhibits basal level of TAK1 polyubiquitination and activation."
Modified USP4 leads to the deubiquitination of MAP3K7. 2 / 2
| 2

reach
"Overexpression of USP4 wild-type, but not deuibiquitinase deficient C311A mutant, inhibits both TNFalpha- and TAK1 and TAB1 co-overexpression-induced TAK1 polyubiquitination and NF-kappaB activation."

reach
"As shown in XREF_FIG, overexpression of USP4 wild-type but not deubiquitinase deficient C311A mutant abrogated TAK1 and TAB1 co-overexpression-induced TAK1 polyubiquitination."
USP4 deubiquitinates MAP3K7 on K63. 2 / 2
| 2

reach
"USP4 deubiquitinates TAK1 with Lys63 linked polyubiquitination and inhibits Dox induced NF-kappaB activation."

reach
"Ubiquitin-specific protease 4 (USP4) inhibited pathological cardiac hypertrophy and dysfunction by hydrolyzing the K63 ubiquitination of TAK1, resulting in the suppression of TAK1-JNK1/2/p38 signaling[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 inhibits MAP3K7.
| 3 2
USP4 inhibits MAP3K7. 5 / 11
| 3 2

reach
"XREF_BIBR showed that USP4 could block Dox induced activation of NF-kappaB at the early stage of the treatment by preventing TAK1 from conjugating K63 linked polyubiquitin chains."

sparser
"We also found that overexpression of USP4 inhibited TAK1 but not IKKβ-induced NF-κB activation in a reporter assay ( xref )."

sparser
"We also found that overexpression of USP4 inhibited TAK1 but not IKKβ-induced NF-κB activation in a reporter assay ( xref )."

reach
"USP4 inhibits TAK1 and TAB1 co-overexpression-mediated NF-kappaB activation."

reach
"The positive impact of USP4 is based on its capacity to deubiquitinate TAK1 and inhibit TAK1/JNK signaling activation."
USP4 activates MAP3K7.
| 8
USP4 activates MAP3K7. 8 / 8
| 8

reach
"Previous study also showed that USP4 targets TAK1 by removing K63 linked polyubiquitination and then recruit IkappaB kinase (IKK) complex to simulate TNF-alpha -induced NF-kappaB activation 49."

reach
"Taken together, these results indicate that USP4 accelerates ESCC cell progression by targeting TAK1."

reach
"USP4 directly deubiquitinated transforming growth factor-β activated kinase 1 (TAK1), resulting in TAK1 dephosphorylation [109]."

reach
"USP4 promotes the proliferation, migration, and invasion of esophageal squamous cell carcinoma by targeting TAK1."

reach
"In addition, USP4 promotes the proliferation, migration, and invasion of esophageal squamous cell carcinoma by targeting TAK1."

reach
"The protein expression of USP4 in liver tissue samples from patients with NAFLD was significantly lower than that of healthy controls, and mechanistically, USP4 inhibits TAK1 degradation by removing the K48-linked ubiquitinated chain, leading to inhibition of signaling activation of the downstream NF-κB and JNK cascades, which in turn reverses the disruption of IRS-AKT-GSK3β signaling, inhibits IR, and thus attenuates hepatic steatosis and inflammation (35)."

reach
"Molecular analysis revealed that USP4 deficiency augmented the activation of the transforming growth factor beta activated kinase 1 (TAK1)-(JNK1/2)/P38 signaling in response to hypertrophic stress, and blockage of TAK1 activation abolished the pathological effects of USP4 deficiency in vivo."

reach
"Importantly, USP4 dramatically accelerates the malignant phenotype of ESCC cells by targeting TAK1 in ESCC, suggesting that the USP4TAK1 axis plays an important role in ESCC malignant progression."
USP4 ubiquitinates MAP3K7.
| 2
USP4 ubiquitinates MAP3K7. 2 / 2
| 2

reach
"Overexpression of wild-type USP4 in Hela cells can inhibit TAK1 polyubiquitination and NF-κB activation, whereas its knockdown can enhance polyubiquitination of TAK1 and phosphorylated IκBα and negatively regulate NF-κB activation induced by IL-1β, LPS and TGFβ (154)."

reach
"It has been reported that USP4 acts as a negative regulator to inhibit IL-1β-, LPS- and TGF-β-induced NF-κB activation by deubiquitinating TAK1 [45]."
USP4 dephosphorylates MAP3K7.
| 1
USP4-C311A leads to the dephosphorylation of MAP3K7. 1 / 1
| 1

reach
"USP4 (C311A) mutation did not inhibit the TAK1 polyubiquitination, and phosphorylation of TAK1, = JNK1/2, and p38 in angiotensin treated myocytes."
USP4 affects HDAC2
4 1 | 31 19
USP4 binds HDAC2.
4 | 14 19
4 | 13 15

reach
"We found that the interaction between endogenous USP4 and HDAC2 did not change after etoposide and TNFalpha treatment (XREF_SUPPLEMENTARY)."

reach
"29 We detected the interaction between USP4 and HDAC2 after treatment with VPA."

reach
"Remarkably, the interaction between endogenous USP4 and HDAC2 is significantly decreased upon VPA treatment."

sparser
"Remarkably, the interaction between endogenous USP4 and HDAC2 is significantly decreased upon VPA treatment.( xref )."

sparser
"We found that TRPS1 scaffolding recruits and enhances interaction between USP4 and HDAC2 leading to HDAC2 de-ubiquitination and H4K16 deacetylation."

reach
"USP4 's interaction with HDAC2 likely also emerged after WGD as a small region of USP4 (a.a. 188-302), which encompasses its unique alternatively spliced exon, interacts with this HDAC1 derived ohnolog."

reach
"We found that TRPS1 scaffolding recruits and enhances interaction between USP4 and HDAC2 leading to HDAC2 de-ubiquitination and H4K16 deacetylation."

reach
"It has recently been reported that USP4 directly interacts and de-ubiquitinates HDAC2 resulting in its stability in colon cancer cells [22]."

reach
"It appeared that both TRPS1 and USP4 interacted with and stabilized HDAC2 in a UDPD-dependent fashion."

sparser
"Our results indicated that the GATA domain of TRPS1 alone was unable to interact with HDAC2 and USP4 (Fig. xref )."
HDAC2 binds USP4 and TRPS1. 5 / 5
| 1 4

reach
"Similarly, trichorhinophalangeal syndrome type I (TRPS1) functions as a scaffold protein involved in the USP4 induced stabilization of HDAC2 through bringing them together to form the TRPS1, USP4, and HDAC2 complex."

sparser
"We hypothesized that TRPS1, USP4, and HDAC2 formed a complex, used Co-IP to test this notion, and found that TRPS1 co-immunoprecipitated with USP4 and HDAC2 (Fig. xref )."

sparser
"To further confirm the interaction between TRPS1, USP4, and HDAC2, we generated serial TRPS1 truncates based on the domain structure of TRPS1 consisting of an N-terminal domain and GATA and C-terminal domains (Fig. xref )."

sparser
"The results indicated that N-terminal or C-terminal domains of TRPS1 together with the GATA domain were sufficient to interact with HDAC2 and USP4 while neither TRPS1 N-terminal or C-terminal domain alone interacted with HDAC2 and USP4 (Fig. xref )."

sparser
"Similarly, trichorhinophalangeal syndrome type I (TRPS1) functions as a scaffold protein involved in the USP4-induced stabilization of HDAC2 through bringing them together to form the TRPS1-USP4-HDAC2 complex ( xref )."
USP4 deubiquitinates HDAC2.
1 | 12
USP4 deubiquitinates HDAC2. 10 / 12
1 | 11

reach
"USP4 suppresses HDAC2 ubiquitination."

reach
"Taken together, our results suggested that TRPS1 stabilized HDAC2 by functioning as a scaffold protein to bring UPS4 and HDAC2 together forming the TRPS1-UPS4-HDAC2 complex to enhance USP4-directed HDAC2 de-ubiquitination."

reach
"Although USP4 alone could reduce HDAC2 ubiquitination level, additional overexpression of TRPS1 significantly enhanced the reduction of HDAC2 ubiquitination (Fig. 3l)."

reach
"As we demonstrated that USP4 deubiquitinates HDAC2, it is possible that USP4 can stabilize HDAC2."

reach
"Collectively, our data indicate that USP4 deubiquitinates and stabilizes HDAC2 protein."

reach
"Significantly, our results revealed the scaffolding function of TPRS1 in USP4-directed HDAC2 de-ubiquitination and provided new mechanistic insights into the crosstalk between TRPS1, ubiquitin, and histone modification systems leading to tumor growth."

reach
"Furthermore, our results identified the novel non-transcription factor scaffolding function of the GATA family member TRPS1 in USP4-directed HDAC2 de-ubiquitination."

reach
"Nonetheless, USP4 might deubiquitinate and stabilize both ARF-BP1 and its substrate HDAC2."

reach
"XREF_BIBR, XREF_BIBR Of note, our studies show that USP4 deubiquitinates and stabilizes HDAC2 and the expression of USP4 correlates with that of HDAC2 in cancer tissues (XREF_FIG)."

reach
"However, the mechanism by which USP4 mediates HDAC2 de-ubiquitination contributing to cancer remains unclear.In this study, we show that the TRPS1-USP4-HDAC2 regulatory axis is involved in tumor cell proliferation."
Modified USP4 leads to the deubiquitination of HDAC2. 1 / 1
| 1

reach
"As shown in XREF_FIG, overexpression of USP4-WT but not C311A mutant abrogated HDAC2 polyubiquitination."
USP4 activates HDAC2.
| 4
USP4 activates HDAC2. 4 / 9
| 4

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"By promoting activation of the relaxin and TGF-beta 1/Smad2/matrix metalloproteinase 9 axis and transcriptional repression activity of HDAC2, USP4 induces breast cell invasion, migration, and proliferation both in vitro and in vivo."

reach
"In fact, expression of USP4 significantly prolonged the half-life of HDAC2 (XREF_FIG)."

reach
"Furthermore, when we silenced USP4 with siRNAs with or without HDAC2 overexpression in MCF7, we consistently found that USP4 silencing led to decreased HDAC2 and increased H4K16ac, whereas additional HDAC2 overexpression restored the H4K16ac level (Fig. 4c, d)."

reach
"Moreover, we found that USP4 targets HDAC2 to downregulate tumor necrosis factor-alpha (TNFalpha)-induced NF-kappaB activation."
USP4 inhibits HDAC2.
| 1
USP4 inhibits HDAC2. 1 / 7
| 1

reach
"Therefore, our studies reveal USP4 suppresses p53 and NF-kappaB activation by stabilizing HDAC2."
USP4 affects RBBP8
6 | 22 34
USP4 binds RBBP8.
6 | 18 34
6 | 18 30

sparser
"USP4 interacts with the retinoblastoma binding protein 8 (CtIP, also known as RBBP8) and the MRE11RAD50-NBS1 (MRN) complex [ xref , xref ]."

sparser
"Because USP4 autodeubiquitination did not affect its levels, the next question we asked was whether USP4 autodeubiquitination could affect USP4-CtIP interaction."

sparser
"As shown in Figure 7 B, USP4 catalytic activity is essential for the USP4-CtIP interaction."

sparser
"USP4-CtIP interaction is a little increased after IR treatment, but in the USP4CA mutant cells, USP4-CtIP interaction is almost gone, even in IR-treated cells."

sparser
"This result suggests that USP4 promotes USP4-CtIP interaction specifically through its deubiquitinase activity and likely through its autodeubiquitination."

reach
"They both demonstrated that USP4 interacts with CtIP and MRN and regulates the recruitment of CtIP to DSBs."

sparser
"These are consistent with our results; CtIP N-terminal could interact with USP4, and this interaction is essential for DNA end resection."

sparser
"USP4 interacts with CtIP and MRN via the C-terminal insert domain (residues 572–773) and intact catalytic domain of USP4, respectively."

sparser
"More importantly, USP4 ubiquitination can block USP4-CtIP interaction, whereas the USP4CA mutant could not mediate its autodeubiquitination, and sustained ubiquitination of USP4 would block its intera[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"Of note, USP4 can deubiquitinate itself, and this autodeubiquitination function is crucial for the USP4-CtIP interaction, which occurs in HR ( xref ; xref )."
USP4 binds RBBP8 and foci. 2 / 2
| 2

sparser
"As USP4 directly interacts with CtIP, we also checked CtIP foci formation in USP4-depleted cells."

sparser
"Because USP4 interacts with the N-terminal of CtIP through its insert domain, CtIP N-terminal is essential for its foci formation and depletion of USP4 decreased CtIP foci formation."
| 2

sparser
"We and others report that USP4 interacts with CtIP and the MRE11RAD50NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites and DNA end resection ( xref , xref )."

sparser
"We also report that USP4 interacts with CtIP and the MRE11-RAD50-NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites."
USP4 activates RBBP8.
| 4
USP4 activates RBBP8. 4 / 4
| 4

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"As shown in Figures 5 A-5D, WT USP4, but not the insert domain deletion mutant, restored CtIP and downstream RAD51 and RPA foci in USP4 depleted cells after IR."

reach
"In addition, auto-deubiquitination of USP4 has been shown to stimulate homologous recombination and its interaction with CtIP to recruit CtIP to DNA damage sites, suggesting ubiquitination-dependent regulation of DUB enzyme interaction and function."

reach
"Existing studies have shown that auto-deubiquitylation of USP4 enhances its interaction with CtIP/MRN, thereby promoting homologous recombination (33)."

reach
"Rather, there are additional routes for the initiation of HR via enhancing DSB end resection, wherein p75 (50), USP4 (51) or AUNIP (52) interacts with CtIP, promoting CtIP accumulation at DSBs for efficient end resection and HR."
USP4 affects CTNNB1
5 1 | 41 11
USP4 activates CTNNB1.
| 15 2
USP4 activates CTNNB1. 10 / 21
| 15 2

reach
"These results confirm that USP4 knockdown suppresses the transcriptional activity of beta-catenin, thereby supporting the suggestion that USP4 functions as a positive regulator of the WNT and beta-cat[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Therefore, it can be speculated that USP4 promotes brain metastasis of LUAD cells by stabilizing the β-catenin protein74."

reach
"If p values were < 0.05, the differences were considered statistically significant and labeled in the following ways: * p < 0.05, ** p < 0.01, and *** p < 0.001, in the corresponding graph.Because USP[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"In addition to these newly identified nuclear functions, both USP4 and USP15 are well known to function in the cytosol, i.e. USP4 modulates the Wnt and beta-catenin, NF-kappaB, p53 and TGF-beta signaling pathways while USP15 performs functions in the TGF-beta receptor and NF-kappaB signaling pathways."

reach
"Interestingly, it was also found that knockdown of USP4 decreased the level of beta-catenin protein without changes in its mRNA level (XREF_FIG)."

reach
"USP20 and USP4 induce drug resistance in breast cancer and colorectal cancer cells by stabilizing β-catenin, the key modulator of the Wnt pathway [249, 250]."

reach
"In colon cancer and neuroblastoma cells, it had been revealed that USP4 activates the Wnt pathway by stabilizing β-catenin as a deubiquitinase [12,38] ."

reach
"For example, the β-catenin degradation through ubiquitin-dependent proteolysis is prevented by several deubiquitinating enzymes including USP6N, USP4 and USP7 [ 167–169 ]."

sparser
"However, stabilized β-catenin was partially affected by the USP4 expression level ( Figure 2 F), and the catalytically defective C311A USP4 was able to activate β-catenin to some extent ( Figure 2 A)."

reach
"This observation raised the possibility that USP4 dependent activation of beta-catenin is not only caused by the catalytic activity of USP4 but also mediated by another mechanism such as a nuclear tra[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 binds CTNNB1.
5 | 4 9
5 | 3 9

sparser
"USP4 was detected in β-catenin IP materials ( xref ), and β-catenin was found in USP4 IP materials ( xref ), suggesting that USP4 and β-catenin directly bind to each other."

sparser
"We further investigated the physical interaction between β-catenin and USP4 through co-immunoprecipitation."

sparser
"Taken these results together, it was concluded that β-catenin activity is primarily associated with the C-terminal catalytic domain of USP4."

sparser
"These results suggest the association of the C-terminus of USP4(261–963) with a subset of β-catenin in the nucleus as evidenced by the observed binding ( Figure 4 B)."

reach
"We further investigated the physical interaction between beta-catenin and USP4 through co-immunoprecipitation."

sparser
"The interaction of endogenous β-catenin and USP4 was confirmed in 293T and HCT116 cells, a colon cancer cell line harboring stable β-catenin that has a mutation at S45 phosphorylation site ( Figure 1 [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"To further investigate the association of USP4 and β-catenin in colon cancers, we examined 30 human colon specimens (cancer and normal)."

sparser
"Immunohistochemical analysis of colon cancer tissues supported the idea that the expression of β-catenin and USP4 are closely associated with colorectal cancer."

sparser
"We observed that both USP4(140–572) and USP4(261–963) bind to β-catenin, thus the second UBL domain (483–571) seems to have a major role in interaction with β-catenin ( Figure 4 )."

reach
"Thus, we examined the direct interaction between USP4 and beta-catenin in our metastatic model system."
USP4 binds CTNNB1 and UBL domain. 1 / 1
| 1

reach
"We observed that both USP4 (140-572) and USP4 (261-963) bind to beta-catenin, thus the second UBL domain (483-571) seems to have a major role in interaction with beta-catenin."
USP4 deubiquitinates CTNNB1.
1 | 10
USP4 deubiquitinates CTNNB1. 10 / 11
1 | 10

reach
"In addition, β-catenin is deubiquitinated by USP15 and USP4 [ 38 , 39 ]."

reach
"In addition, USP4 enhances the Wnt signaling pathway and regulates osteogenic differentiation by deubiquitinating and stabilizing β-catenin [43]."

reach
"In a colon cancer cell line, USP4 deubiquitinates beta-catenin and mediates its nuclear transportation, thus promoting Wnt and beta-catenin signaling and cancer cells growth, migration, and invasion."

reach
"USP4 activates the Wnt/β-catenin signaling pathway by promoting the deubiquitination of β-catenin (Yun et al., 2015)."

reach
"Moreover, a Korean study also indicated that USP4 was a positive modulator of Wnt/β-catenin signaling pathway by deubiquitinating and facilitating nucleus localization of β-catenin and then promoted i[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"We showed that USP4 deubiquitinates beta-catenin."

reach
"Moreover, USP4 contributes to the progression of CRC by deubiquitinating and controlling the stability of β-catenin, a key component of the Wnt/β-catenin pathway[56]."

reach
"Ubiquitin-specific protease 4 (USP4) is highly overexpressed in colon cancer and acts as a potent protooncogenic protein by deubiquitinating β-catenin."

reach
"USP4 deubiquitinates and stabilizes β-catenin to drive colon cancer cell migration [29]."

reach
"Deubiquitination of beta-catenin by USP4 reverses the ubiquitination mediated degradation of beta-catenin, upregulating Wnt signalling."
USP4 increases the amount of CTNNB1.
| 7
USP4 increases the amount of CTNNB1. 7 / 7
| 7

reach
"The current study provides evidence that USP4 increases the protein levels of Twist1 and β-catenin, subsequently promoting stemness and drug resistance in CRC."

reach
"beta-Catenin protein stability was significantly lower in USP4 silenced PC14PE6 and LvBr4 cells than in PC14PE6 cells (XREF_FIG), demonstrating that USP4 positively regulated beta-catenin expression in metastatic lung cancer cells."

reach
"Knockdown of USP4 reduces the level of β-catenin protein without affecting the level of mRNA expression."

reach
"Based on the above results, we found that beta-catenin was involved in the metastatic potential of PC14PE6 and LvBr4 cells and that USP4 upregulated the expression of beta-catenin by deubiquitinylating beta-catenin."

reach
"To verify that USP4 induces EMT process by upregulating beta-catenin expression, we checked the expression level of ZEB1 and E-cadherin in USP4 overexpressing PC14PE6 cells (XREF_FIG)."

reach
"As expected, knockdown of USP4 significantly downregulated the expression of beta-catenin (XREF_FIG) and suppressed the invasiveness of PC14PE6 and LvBr5-Luc cells (XREF_FIG)."

reach
"USP4 increased the level of beta-catenin by inducing its deubiquitinylation."
USP4 inhibits CTNNB1.
| 5
USP4 inhibits CTNNB1. 4 / 4
| 4

reach
"In this study, we found ubiquitin specific peptidase 4 (USP4) to strongly inhibit the Wnt and beta-catenin signaling by removing Lysine 63 linked poly-ubiquitin chain from Dishevelled (Dvl)."

reach
"As shown in Fig 3J, restoration of USP4 effectively reversed FBXO3 knockdown-mediated down-regulation of Twist1 and β-catenin."

reach
"Furthermore, silencing of USP4 rescued p110α -mediated up-regulation of Twist1 and β-catenin, accompanied with reduced cell migration (Figs 6F–6H, S5C, and S5D)."

reach
"Consistently, wild-type FBXO3- or FBXO3 - mediated the up-regulation of Twist1 and β-catenin could be rescued by silencing of USP4 in MDA-MB-231 or Hs578T cells (Figs 3K and S2D)."
Modified USP4 inhibits CTNNB1. 1 / 1
| 1

reach
"Ectopic expression of USP4 promoted beta-catenin poly-ubiquitination and thus inhibited Wnt induced accumulation of cytosolic beta-catenin and counteracted Wnt induced transcriptional activity."
RBBP8 affects USP4
6 | 18 34
6 | 18 30

sparser
"USP4 interacts with the retinoblastoma binding protein 8 (CtIP, also known as RBBP8) and the MRE11RAD50-NBS1 (MRN) complex [ xref , xref ]."

sparser
"Because USP4 autodeubiquitination did not affect its levels, the next question we asked was whether USP4 autodeubiquitination could affect USP4-CtIP interaction."

sparser
"As shown in Figure 7 B, USP4 catalytic activity is essential for the USP4-CtIP interaction."

sparser
"USP4-CtIP interaction is a little increased after IR treatment, but in the USP4CA mutant cells, USP4-CtIP interaction is almost gone, even in IR-treated cells."

sparser
"This result suggests that USP4 promotes USP4-CtIP interaction specifically through its deubiquitinase activity and likely through its autodeubiquitination."

reach
"They both demonstrated that USP4 interacts with CtIP and MRN and regulates the recruitment of CtIP to DSBs."

sparser
"These are consistent with our results; CtIP N-terminal could interact with USP4, and this interaction is essential for DNA end resection."

sparser
"USP4 interacts with CtIP and MRN via the C-terminal insert domain (residues 572–773) and intact catalytic domain of USP4, respectively."

sparser
"More importantly, USP4 ubiquitination can block USP4-CtIP interaction, whereas the USP4CA mutant could not mediate its autodeubiquitination, and sustained ubiquitination of USP4 would block its intera[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"Of note, USP4 can deubiquitinate itself, and this autodeubiquitination function is crucial for the USP4-CtIP interaction, which occurs in HR ( xref ; xref )."
USP4 binds RBBP8 and foci. 2 / 2
| 2

sparser
"As USP4 directly interacts with CtIP, we also checked CtIP foci formation in USP4-depleted cells."

sparser
"Because USP4 interacts with the N-terminal of CtIP through its insert domain, CtIP N-terminal is essential for its foci formation and depletion of USP4 decreased CtIP foci formation."
| 2

sparser
"We and others report that USP4 interacts with CtIP and the MRE11RAD50NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites and DNA end resection ( xref , xref )."

sparser
"We also report that USP4 interacts with CtIP and the MRE11-RAD50-NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites."
SART3 affects USP4
15 | 20 18
SART3 binds USP4.
15 | 17 18
15 | 16 13

sparser
"The interaction analysis showed that USP4 and SART3 form a complex with the majority of the U4/U6-snRNP components such as PRP31, PRP3 and PRP4 ( xref )."

sparser
"However, when ALAL-1 was depleted, the SART3-mediated nuclear translocation of USP4 was partially impaired ( xref ), while the interaction between SART3 and USP4 was not affected by depletion of ALAL-1 ( xref ), indicating that ALAL-1 is involved in USP4 relocalization without impairing SART3-USP4 interaction in bulk."

sparser
"To have a better understanding of the interaction between ALAL-1 and SART3 and USP4, we performed coimmuno-FISH experiments coupled with confocal microscopy."

reach
"USP4 binds SART3 at the opposite surface of the HAT-C dimer interface utilizing the beta structured linker between the DUSP and the UBL domains."

reach
"Moreover, as a substrate recruiting factor of USP15 either, SART3 can simultaneously bind USP4 and USP15, serving as a platform to deubiquitinate PRP31 and PRP3."

sparser
"In this process, USP15 makes a complex with USP4 and SART3 that serves as a platform for the efficient splicing of chromosome segregation-related genes, such as Bub1 and α-tubulin, by stabilizing the U4/U6."

sparser
"Interestingly, the pathways found to be affected by either ALAL-1 or SART3 depletion were previously reported in different studies to be modulated by SART3 directly or indirectly through its interacting partner USP4 ( xref ; xref ; xref ; xref ), suggesting that the interaction of ALAL-1 with SART3 could be regulating the SART3USP4 complex."

reach
"In order to verify the importance of the beta-hairpin linker between the DUSP and UBL domains as seen in the crystal structure of SART3 and USP4 complex, we generated a series of mutants, e.g. the linkers of USP4 (124 HGLFVKHC 131) and USP15 (124 QGMFVKHC 131) replaced by the USP11 linker (186 LPNIQ 190) and vice versa, denoted as USP4 L11 and USP15 L11, USP11 L4 and USP11 L15."

reach
"In order to identify the exact NLS required for the nuclear import of SART3 as well as the SART3 and USP4 complex, we have co-purified NLS of SART3 with ImpA (residues 70-498 of mouse importin-alpha) and the complex was crystallized."

sparser
"A similarly unified DUSP-UBL interaction surface was also suggested for the USP4 interaction with the U4/U6 recycling protein SART3 ( xref )."
USP15 binds SART3 and USP4. 6 / 6
| 1 5

sparser
"We next examined whether SART3 forms a complex with USP15 and USP4 simultaneously using sequential immunoprecipitation."

reach
"Deubiquitination of PRP31 and PRP3 by the USP15, SART3, and USP4 complex decreases the affinity towards PRP8 and this regulation is important for the proper splicing of chromosome segregation related genes such as Bub1 and alpha-tubulin."

sparser
"Drugs interfering with the interaction between USP4 and USP15 and SART3 may selectively inhibit the DUB functions in the nucleus."
| PMC

sparser
"Moreover, as a substrate recruiting factor of USP15 either ( xref ; xref ), SART3 can simultaneously bind USP4 and USP15, serving as a platform to deubiquitinate PRP31 and PRP3 ( xref )."

sparser
"PRP31, a component of the U4 snRNP, is modified with K63-linked ubiquitin chains by the PRP19 complex and is deubiquitinated by the ternary complex of USP15, SART3, and USP4."

sparser
"Consistent with our prediction, SART3 interacted with endogenous USP4 and USP15 (Figure xref )."
SART3 inhibits USP4.
| 2
SART3 inhibits USP4. 2 / 3
| 2

reach
"The complex structure of SART3 nuclear localization signal (NLS) and importin-alpha reveals bipartite binding, and removal of SART3 NLS prevents the entry of USP4 (and USP15) into the nucleus and abrogates the subsequent deubiquitinase activity of USP4."

reach
"The complex structure of the NLS on Tip110 and importin 2α is involved a bipartite binding, and removal of Tip110 NLS prevents the entry of USP4 or USP15 in the nucleus and abrogates their subsequent deubiquitinase activity (12, 55), which may explain the detection of a higher ubiquitinated form of cytoplasmic expressed Tip110ΔNLS mutant ( Figures 2D , 4C, E )."
SART3 activates USP4.
| 1
SART3 activates USP4. 1 / 2
| 1

reach
"While it has been reported that overexpressed SART3 causes nuclear localization of exogenously expressed USP4, we found that SART3 depletion from U2OS cells did not detectably affect the nuclear and cytoplasmic distribution of endogenous USP4 (data not shown), suggesting that USP4 nuclear targeting might be mediated by multiple mechanisms."
USP4 affects TRAF6
8 1 | 36 9
USP4 binds TRAF6.
8 | 8 9
8 | 8 6

sparser
"As previously reported, TRAF6 is a key adaptor molecule for the activation of the NF-κB pathway xref , therefore it was speculated that USP4 indeed interacts with TRAF6."

sparser
"Flag-TRAF6 and HA-USP4 plasmids were co-transfected into HEK293T cells and after 48 h, further IP experiments were performed with anti-HA antibody, and it was established that USP4 interacted with TRAF6 (Fig.  xref )."

sparser
"As shown in Fig.  xref , the interaction between USP4 and TRAF6 was not impaired by the mutation of the Cys-311 to Alanine (‘CA mutant’) of USP4 molecule."

sparser
"To further map the functional domain that interacts with TRAF6, we generated two truncated constructs based on the structural domains of USP4 and as shown in Fig.  xref , only the C-terminal domain (C) of USP4 was able to interact with TRAF6."

reach
"USP4 interacts with and deubiquitinates TRAF6, thereby preventing the activation of NF-kappaB and AP-1 transcription factors and subsequent immune responses."

reach
"Xiao et al. 's study added on to this by demonstrating USP4 's interaction and deubiquitination of TRAF2 and TRAF6, but not TRAF3, both in vivo, in HEK293T cells, and in vitro [XREF_BIBR]."

reach
"As previously reported, TRAF6 is a key adaptor molecule for the activation of the NF-kappaB pathway 31, therefore it was speculated that USP4 indeed interacts with TRAF6."

reach
"Flag-TRAF6 and HA-USP4 plasmids were co-transfected into HEK293T cells and after 48h, further IP experiments were performed with anti-HA antibody, and it was established that USP4 interacted with TRAF6."

reach
"XREF_FIG, the interaction between USP4 and TRAF6 was not impaired by the mutation of the Cys 311 to Alanine (' CA mutant ') of USP4 molecule."

reach
"We found that USP4 specifically interacts with TRAF2 and TRAF6, but not TRAF3."
USP4 binds TRAF2 and TRAF6. 3 / 3
| 3

sparser
"Xiao et al.’s study added on to this by demonstrating USP4’s interaction and deubiquitination of TRAF2 and TRAF6, but not TRAF3, both in vivo, in HEK293 T cells, and in vitro [ xref ]."

sparser
"We found that USP4 specifically interacts with TRAF2 and TRAF6, but not TRAF3."

sparser
"It was confirmed that USP4 associates with TRAF2 and TRAF6, consistent with our results."
USP4 deubiquitinates TRAF6.
1 | 12
USP4 deubiquitinates TRAF6. 10 / 13
1 | 12

reach
"USP4 deubiquitinates TRAF2 and TRAF6, but not TRAF3, and it also rescues IkappaBalpha from degradation in TNFalpha induced HEK cells [XREF_BIBR]."

reach
"However, there is no evidence of how USP4 deubiquitinates TRAF6 and TRAF2 proteins; our results prove that USP4 targets TRAF6 for K48 linked deubiquitination."

reach
"For example, TNFAIP3, CYLD, USP3, USP4, USP15, USP25, and OTUD5 deubiquitinate key components of the IFN production pathway, including RIG-I, TRAF2, TRAF3, TRAF6, RIP1, and TRIF (reviewed in [93,94])."

reach
"These findings suggest that USP4 deubiquitinates TRAF6 largely in a noncatalytic manner."

reach
"Taken together, these findings suggest that USP4 decreases the polyubiquitination of TRAF6 in a ubiquitin specific domain dependent manner."

reach
"In colon cancer, a deubiquitinating enzyme USP4 suppressed anti-tumor immune responses by deubiquitinating TRAF6 and IRF3, hindering the nuclear localization of the latter protein and thus inhibiting cellular interferon responses and antigen presentation (Zhou et al., 2024)."

reach
"Animal studies have shown that USP4 expression in microglia cells decreases after SCI, leading to microglial activation and subsequent neuronal inflammation through NF-kB by attenuating the deubiquitination of TRAF6 [44]."

reach
"The results indicated that USP4 suppresses the nuclear localization of IRF3 by deubiquitinating IRF3 in CRC cells.It has been reported that USP4 interacted with and deubiquitinates TRAF6 [ 25 ], which[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"USP4 interacts with and deubiquitinates TRAF6, thereby preventing the activation of NF-kappaB and AP-1 transcription factors and subsequent immune responses."

reach
"USP4 interacts with and deubiquitinates Lys-63-linked polyubiquitination of TRAF6, thereby suppressing the activation of NF-κB and TLR/IL-1R-mediated innate immune responses [ 21 ]."
USP4 activates TRAF6.
| 8
USP4 activates TRAF6. 8 / 8
| 8

reach
"Recently, Xiao et al reported that USP4 targeted TRAF2 and TRAF6 for deubiquitination and inhibited the migration of tumor necrosis factor-alpha (TNF-alpha)-stimulated cancer cells."

reach
"However, when the RD cells were transfected with a plasmid bearing USP4, the results show that USP4 could decrease the degradation of TRAF6 and also inhibit the replication of EV71."

reach
"USP4 has also been shown to target TRAF2 and TRAF6 inhibiting nuclear factor-kappaB (NF-kB) signalling and antagonizing lung cancer cell migration XREF_BIBR XREF_BIBR XREF_BIBR, suggesting a context dependent role in cancer."

reach
"USP4 targets TRAF6 through its USP domain."

reach
"USP4-mediated TRAF6 stabilization was studied in pancreatic cancer models (MIA PaCa-2 and AsPC-1) (31)."

reach
"However, in breast cancer, USP4 was also recognized as a tumour suppressor for its up-regulatory effect on programmed cell death 4 (PDCD4) to restrain tumour growth.20 Moreover, USP4 was able to target TRAF2 and TRAF6 for deubiquitination and thereafter inhibited TNFalpha induced cancer cell migration.34 In the present study, we proved that USP4 expression was drastically increased in melanoma."

reach
"USP4 has previously been confirmed to target TRAF2 and TRAF6 for deubiquitination and it has been established that USP4 inhibits TNFalpha induced cancer cell migration 35."

reach
"However, there is no evidence of how USP4 deubiquitinates TRAF6 and TRAF2 proteins; our results prove that USP4 targets TRAF6 for K48 linked deubiquitination."
USP4 inhibits TRAF6.
| 4
USP4 inhibits TRAF6. 4 / 4
| 4

reach
"Overexpression of USP4 inhibits EV71 replication by stabilizing TRAF6 to activate NF-kappaB inflammatory signaling."

reach
"Mechanistically, USP4 can directly bind to the TRAF domain to inhibit TRAF2/TRAF6 activity through deubiquitination in an activity-dependent manner and negatively regulate IL-1β and TNF-α-induced NF-κB activation, thereby inhibiting lung cancer metastasis (46)."

reach
"USP4 (ubiquitin specific peptidase 4) also negatively regulates TRAF6, by a mechanism that involves removal of polyubiquitin chains."

reach
"55 Ubiquitin specific peptidase 4 (USP4) negatively regulates TRAF6, suppressing IL-1beta-induced NF-kappaB activation by removing polyubiquitin chains on TRAF6 in a deubiquitin activity dependent manner."
USP4 increases the amount of TRAF6.
| 2
USP4 increases the amount of TRAF6. 2 / 2
| 2

reach
"Secondly, although we indicated USP4 may promote the malignant biological behaviors of PC through NF-κB signaling pathway by stabilizing TRAF6 protein expression, there is no evidence to directly conf[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"However, USP4 overexpression in MIA PaCa-2 cells elevated the level of remaining TRAF6 ( Fig. 7 D)."
USP4 decreases the amount of TRAF6.
| 2
USP4 decreases the amount of TRAF6. 2 / 2
| 2

reach
"Moreover, although USP4 downregulation can decrease the expression of TRAF6, knockdown TRAF6 expression did not affect USP4 protein level which implied a unidirectional action between USP4 and TRAF6 ([MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"USP4 silencing in LPS induced activation of microglia promoted the expression of p-p65 and TRAF6 and the secretion of TNF-alpha and IL-1beta."
USP4 affects SART3
15 | 17 18
15 | 16 13

sparser
"The interaction analysis showed that USP4 and SART3 form a complex with the majority of the U4/U6-snRNP components such as PRP31, PRP3 and PRP4 ( xref )."

sparser
"However, when ALAL-1 was depleted, the SART3-mediated nuclear translocation of USP4 was partially impaired ( xref ), while the interaction between SART3 and USP4 was not affected by depletion of ALAL-1 ( xref ), indicating that ALAL-1 is involved in USP4 relocalization without impairing SART3-USP4 interaction in bulk."

sparser
"To have a better understanding of the interaction between ALAL-1 and SART3 and USP4, we performed coimmuno-FISH experiments coupled with confocal microscopy."

reach
"USP4 binds SART3 at the opposite surface of the HAT-C dimer interface utilizing the beta structured linker between the DUSP and the UBL domains."

reach
"Moreover, as a substrate recruiting factor of USP15 either, SART3 can simultaneously bind USP4 and USP15, serving as a platform to deubiquitinate PRP31 and PRP3."

sparser
"In this process, USP15 makes a complex with USP4 and SART3 that serves as a platform for the efficient splicing of chromosome segregation-related genes, such as Bub1 and α-tubulin, by stabilizing the U4/U6."

sparser
"Interestingly, the pathways found to be affected by either ALAL-1 or SART3 depletion were previously reported in different studies to be modulated by SART3 directly or indirectly through its interacting partner USP4 ( xref ; xref ; xref ; xref ), suggesting that the interaction of ALAL-1 with SART3 could be regulating the SART3USP4 complex."

reach
"In order to verify the importance of the beta-hairpin linker between the DUSP and UBL domains as seen in the crystal structure of SART3 and USP4 complex, we generated a series of mutants, e.g. the linkers of USP4 (124 HGLFVKHC 131) and USP15 (124 QGMFVKHC 131) replaced by the USP11 linker (186 LPNIQ 190) and vice versa, denoted as USP4 L11 and USP15 L11, USP11 L4 and USP11 L15."

reach
"In order to identify the exact NLS required for the nuclear import of SART3 as well as the SART3 and USP4 complex, we have co-purified NLS of SART3 with ImpA (residues 70-498 of mouse importin-alpha) and the complex was crystallized."

sparser
"A similarly unified DUSP-UBL interaction surface was also suggested for the USP4 interaction with the U4/U6 recycling protein SART3 ( xref )."
USP15 binds SART3 and USP4. 6 / 6
| 1 5

sparser
"We next examined whether SART3 forms a complex with USP15 and USP4 simultaneously using sequential immunoprecipitation."

reach
"Deubiquitination of PRP31 and PRP3 by the USP15, SART3, and USP4 complex decreases the affinity towards PRP8 and this regulation is important for the proper splicing of chromosome segregation related genes such as Bub1 and alpha-tubulin."

sparser
"Drugs interfering with the interaction between USP4 and USP15 and SART3 may selectively inhibit the DUB functions in the nucleus."
| PMC

sparser
"Moreover, as a substrate recruiting factor of USP15 either ( xref ; xref ), SART3 can simultaneously bind USP4 and USP15, serving as a platform to deubiquitinate PRP31 and PRP3 ( xref )."

sparser
"PRP31, a component of the U4 snRNP, is modified with K63-linked ubiquitin chains by the PRP19 complex and is deubiquitinated by the ternary complex of USP15, SART3, and USP4."

sparser
"Consistent with our prediction, SART3 interacted with endogenous USP4 and USP15 (Figure xref )."
USP4 affects TA
| 52
USP4 binds TA. 10 / 52
| 52

sparser
"These results indicate that Ta-UnP was mainly localized in the cell membrane."

sparser
"A wheat full-length cDNA sequence ( Ta-UnP ) with a complete coding region was cloned via gene splicing."

sparser
"The Cl − levels increased by 3.61-fold in the CK plants, by 3.39-fold in the Ta-UnP overexpressing rice and by 4.60-fold in RNAi lines compared with the levels before salt treatment ( Fig. 3 F)."

sparser
"Detection of seed germination: The transgenic plants and WT control plants presented similar seed germination on the 0 mM NaCl MS plate, whereas the germination of Ta-UnP homozygous seeds was much bet[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"Following NaCl treatment, the Na + levels increased by 1.77-fold in the CK plants, by 1.34-fold in the Ta-UnP overexpressing rice and by 2.99-fold in RNAi lines compared with the levels before salt tr[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"Although both lines showed some increase in Na + and Cl − content after salt treatment, the content of Na + and Cl − in the Ta-UnP overexpressing rice plants was significantly lower than that in the C[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"In particular, the genes like TaMKP1, TaECS, TaGGT, TaYqgF, TaGBF1, TaCML11, TaEXPB23, TaWRKY2, SR3WRSI5, TaMYB19, TdSHN1, TaTPS1, TaNHX2, TaWNK1, TaRSL4 A-homeolog, TaAPX7, TaAQP8, TaBIERF3, TaAOX1a, TaPP2C1, PI4K, TaAPXb, TaHsfA7, TaCIPK29, TaMYB30-B, TaHAP2E, TaWRKY19, TaC3H50, TaCLC-1, TaSAMDC, TaSRG, TaSnRK2.7, TaERF4, TaCRT1, TaSOS1, TaHBP1b, TaTPC1, TaSOS2, TaST, TaPUB15, TaAIDFa, TaSIP, TaDi19A, TaRab7, TaCML8, TaMYB3R1, TaSNAC2, TaBADH1, TaMyb3R-2, TaSnRK2.4, TaP5CR, TaCBSX4, TaCIPK14, W69, TaWRKY44, TaMAPK44, TaSDIR1, TaSOD2, TNHXS1, TaNAC, TaRINO1, TaPEX11-1, TaCIPK15, TaSnRK2.8, TaNAC2, TaCML5, TaPOP5, TaSC, TaglyII, TaNAC5, Ta-sro1, TaACA6, TabZIP71, TaSK5, TaNAC47, TaWRKY93, TaABL1, TaSRZ1, Tamyb4, TaMGD, TaNOA1, TaRacB, TaMSRMK3, TaiSAP8, TaDSM1, TaSKIPa, TaAOC1, TaSRWD3, TaCIPK25, TaMIOX, TVP1, TaERF1, Ta-UnP, TaSRWD2, TaABP, TaMSRB, TaWRKY79, TaNIP and TaMAPK1 were expressed in most of the tissues and in all ten developmental stages, as well (Figs.  xref , xref )."
| PMC

sparser
"Ta-UnP was cloned by taking cDNA as the template, and the sequence was deposited in GenBank (accession No."

sparser
"The cloned Ta-UnP sequence was subcloned into the expression vector pCAMBIA2300-35S-GFP-OCS (abbrev."

sparser
"The cloned Ta-UnP cDNA was subcloned into the expression vector pCAMBIA1300."
USP4 affects USP15
7 | 13 26
USP4 binds USP15.
7 | 11 26
7 | 10 14

sparser
"USP15 and USP4 form a complex with SART3."

sparser
"However, Tip110 was found to interact with and promote nuclear translocation of USP4 and USP15 but not USP11, and this is due to β-hairpin of the linker region of the DUSP and UBL domains of both USP4 and USP15 proteins that were associated with the HAT domain of Tip110 ( xref , xref , xref , xref ) In addition, the binding of USP15 to Tip110 is 20-fold stronger than USP4 ( xref )."

sparser
"We further investigated the possibility of USP15 interacting with other parts of USP4 using a GST-pull down assay."

sparser
"However, when full length USP4 synthesized with IVT/T was used, there was no binding ( xref ) suggesting that the interaction between USP15 and USP4 is indirect."

sparser
"To examine the effect of endogenous SART3, the interaction between USP4 and USP15 was examined by immunoprecipitation after depletion of SART3 using siRNA."

sparser
"The depletion of SART3 hampered the interaction between USP15 and USP4 (Figure xref and  xref )."

sparser
"For example, SART3 has been shown to form a complex with USP4 and USP15 by binding their DUSPs through its C-terminal region."

reach
"We found that USP15 interacts with both overexpressed and endogenous USP4."

reach
"To examine whether USP15 interact with USP4 directly, we first carried out an ITC experiment using the DUSP-UBL domains of the two proteins."

reach
"Moreover, it was reported that Sart3, Usp4 and Usp15 form a complex in order to de-ubiquitinate Prp3 and Prp31 simultaneously."
| PMC
USP15 binds SART3 and USP4. 6 / 6
| 1 5

sparser
"We next examined whether SART3 forms a complex with USP15 and USP4 simultaneously using sequential immunoprecipitation."

reach
"Deubiquitination of PRP31 and PRP3 by the USP15, SART3, and USP4 complex decreases the affinity towards PRP8 and this regulation is important for the proper splicing of chromosome segregation related genes such as Bub1 and alpha-tubulin."

sparser
"Drugs interfering with the interaction between USP4 and USP15 and SART3 may selectively inhibit the DUB functions in the nucleus."
| PMC

sparser
"Moreover, as a substrate recruiting factor of USP15 either ( xref ; xref ), SART3 can simultaneously bind USP4 and USP15, serving as a platform to deubiquitinate PRP31 and PRP3 ( xref )."

sparser
"PRP31, a component of the U4 snRNP, is modified with K63-linked ubiquitin chains by the PRP19 complex and is deubiquitinated by the ternary complex of USP15, SART3, and USP4."

sparser
"Consistent with our prediction, SART3 interacted with endogenous USP4 and USP15 (Figure xref )."
USP4 binds USP11 and USP15. 3 / 3
| 3

sparser
"USP15 forms a subfamily with USP4 and USP11 related through a shared presence of N-terminal &quot;domain present in ubiquitin specific proteases&quot; (DUSP) and &quot;ubiquitin-like&quot; (UBL) domains (DU subfamily)."

sparser
"Human deubiquitinase Usp15 forms a small subfamily with its close relatives Usp11 and Usp4, which all share a common domain architecture."

sparser
"USP4 can form stable homodimers and can also interact with USP11 and USP15 ( Fig. 4 )."
USP4 binds USP15 and BRAP. 3 / 3
| 3

sparser
"This reinforces the notion that although both USP4 and USP15 can interact with BRAP under certain experimental conditions, the USP15:BRAP rather than USP4:BRAP interaction may be of most relevance within a physiological setting."

sparser
"In summary, USP4 and USP15 interact with the coiled-coil domain of BRAP through their N-terminal regions, requiring a combination of DUSP and UBL domains ( xref C )."

sparser
"We turned to expression of epitope-tagged proteins to confirm the interactions of USP4 and USP15 with BRAP in the context of a mammalian cell system."
USP4 binds USP7 and USP15. 1 / 1
| 1

sparser
"For example, USP11 has been found to interact with USP4, USP7 and USP15; and PSMD7 interacts with USP15 and PSMD14 [ xref ]."
USP4 activates USP15.
| 2
USP4 activates USP15. 2 / 3
| 2

reach
"The overexpression of USP4 has been immunohistochemically detected in small cell tumors and adenocarcinomas, supporting the oncogenic potential of USP15 [XREF_BIBR]."

reach
"These data suggest that complex formation of USP15 and USP4 stimulates the enzymatic activity of USP15 and possibly USP4."
USP15 affects USP4
7 | 13 26
USP15 binds USP4.
7 | 11 26
7 | 10 14

sparser
"USP15 and USP4 form a complex with SART3."

sparser
"However, Tip110 was found to interact with and promote nuclear translocation of USP4 and USP15 but not USP11, and this is due to β-hairpin of the linker region of the DUSP and UBL domains of both USP4 and USP15 proteins that were associated with the HAT domain of Tip110 ( xref , xref , xref , xref ) In addition, the binding of USP15 to Tip110 is 20-fold stronger than USP4 ( xref )."

sparser
"We further investigated the possibility of USP15 interacting with other parts of USP4 using a GST-pull down assay."

sparser
"However, when full length USP4 synthesized with IVT/T was used, there was no binding ( xref ) suggesting that the interaction between USP15 and USP4 is indirect."

sparser
"To examine the effect of endogenous SART3, the interaction between USP4 and USP15 was examined by immunoprecipitation after depletion of SART3 using siRNA."

sparser
"The depletion of SART3 hampered the interaction between USP15 and USP4 (Figure xref and  xref )."

sparser
"For example, SART3 has been shown to form a complex with USP4 and USP15 by binding their DUSPs through its C-terminal region."

reach
"We found that USP15 interacts with both overexpressed and endogenous USP4."

reach
"To examine whether USP15 interact with USP4 directly, we first carried out an ITC experiment using the DUSP-UBL domains of the two proteins."

reach
"Moreover, it was reported that Sart3, Usp4 and Usp15 form a complex in order to de-ubiquitinate Prp3 and Prp31 simultaneously."
| PMC
USP15 binds SART3 and USP4. 6 / 6
| 1 5

sparser
"We next examined whether SART3 forms a complex with USP15 and USP4 simultaneously using sequential immunoprecipitation."

reach
"Deubiquitination of PRP31 and PRP3 by the USP15, SART3, and USP4 complex decreases the affinity towards PRP8 and this regulation is important for the proper splicing of chromosome segregation related genes such as Bub1 and alpha-tubulin."

sparser
"Drugs interfering with the interaction between USP4 and USP15 and SART3 may selectively inhibit the DUB functions in the nucleus."
| PMC

sparser
"Moreover, as a substrate recruiting factor of USP15 either ( xref ; xref ), SART3 can simultaneously bind USP4 and USP15, serving as a platform to deubiquitinate PRP31 and PRP3 ( xref )."

sparser
"PRP31, a component of the U4 snRNP, is modified with K63-linked ubiquitin chains by the PRP19 complex and is deubiquitinated by the ternary complex of USP15, SART3, and USP4."

sparser
"Consistent with our prediction, SART3 interacted with endogenous USP4 and USP15 (Figure xref )."
USP4 binds USP11 and USP15. 3 / 3
| 3

sparser
"USP15 forms a subfamily with USP4 and USP11 related through a shared presence of N-terminal &quot;domain present in ubiquitin specific proteases&quot; (DUSP) and &quot;ubiquitin-like&quot; (UBL) domains (DU subfamily)."

sparser
"Human deubiquitinase Usp15 forms a small subfamily with its close relatives Usp11 and Usp4, which all share a common domain architecture."

sparser
"USP4 can form stable homodimers and can also interact with USP11 and USP15 ( Fig. 4 )."
USP4 binds USP15 and BRAP. 3 / 3
| 3

sparser
"This reinforces the notion that although both USP4 and USP15 can interact with BRAP under certain experimental conditions, the USP15:BRAP rather than USP4:BRAP interaction may be of most relevance within a physiological setting."

sparser
"In summary, USP4 and USP15 interact with the coiled-coil domain of BRAP through their N-terminal regions, requiring a combination of DUSP and UBL domains ( xref C )."

sparser
"We turned to expression of epitope-tagged proteins to confirm the interactions of USP4 and USP15 with BRAP in the context of a mammalian cell system."
USP4 binds USP7 and USP15. 1 / 1
| 1

sparser
"For example, USP11 has been found to interact with USP4, USP7 and USP15; and PSMD7 interacts with USP15 and PSMD14 [ xref ]."
USP15 activates USP4.
| 2
USP15 activates USP4. 2 / 3
| 2

reach
"Furthermore, they demonstrate that AKT phosphorylation of USP4 enhances the binding of USP4 to USP15 and that overexpression of USP15 increases USP4 stability."

reach
"These data suggest that complex formation of USP15 and USP4 stimulates the enzymatic activity of USP15 and possibly USP4."
| 1 47
| 1 40

reach
"USP4 promotes the migration and invasion of lung adenocarcinoma cells by regulating cellular EMT processes."

reach
"Collectively, these data demonstrated that USP4 promotes melanoma cell migration and invasion by promoting EMT."

reach
"Transwell assays showed that USP4 knockdown inhibited cell migration and invasion in MHCC97H and LM3 cells."

reach
"Moreover, USP4 upregulation promoted Huh7 and PLC/PRF/5 cell migration and invasion ability (P < 0.01 for all)."

reach
"Transwell invasion assay further confirmed USP4 expression significantly accelerated invasion ( Fig. 5 A and B)."

reach
"In summary, these data indicate that USP4 enhances HCC cell proliferation, migration, and invasion and suppresses HCC cell apoptosis in vitro."

reach
"By promoting activation of the relaxin and TGF-beta 1/Smad2/matrix metalloproteinase 9 axis and transcriptional repression activity of HDAC2, USP4 induces breast cell invasion, migration, and proliferation both in vitro and in vivo."

reach
"Further experiments found that overexpression of USP4 could significantly enhance the migration and invasion of CRC and promote the expression of stemness-related genes such as SOX9, OCT4, and CD133."

reach
"Decreased level of USP4 protein leads to increased ubiquitination of ELAV-like RNA-binding protein 1 (ELAVL1), which in turn increases Rho GDP dissociation inhibitor alpha (ARHGDIA) expression, ultimately promoting migration and invasion of PCa cell.23 METTL3 was also found to affect lymphoid enhancer-binding factor 1 (LEF1) protein levels by affecting m A methylation of LEF1 mRNA, thereby downregulating the activity of wingless/integrated (Wnt) signaling to affect PCa progression."

reach
"USP4 accelerates the growth, invasion, and metastasis of colorectal cancer [XREF_BIBR, XREF_BIBR]."
| 7

reach
"Interestingly, we were also able to observe that USP4 knockdown in SW480 cells increased invasion activity under the same experimental conditions as used in HCT116 cells, suggesting that the role of U[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"USP4 can inhibit NF-κB activation through deubiquitination of TRAF2 and TRAF6, thereby promoting cell migration and invasion in lung cancer (46)."

reach
"Results Showed that MMP2, VEGF after silencing USP4 expression The expression of e-cadherin was decreased, while the expression of N-cadherin was increased, indicating that downregulation of USP4 expression inhibited the invasion ability of cells (Fig. 4D)."

reach
"Then we confirmed that USP4 downregulation inhibited malignant biological behaviors, such as cell proliferation, migration and invasion in PC."

reach
"These results indicated that USP4 inhibits antitumor immunity and that inhibition of USP4 may reshape the TME into an immunostimulatory microenvironment.Given the data indicating that USP4 inhibits th[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"In contrast, overexpression of wild-type USP4 suppressed the infiltration of total T cells and CD8 + T cells while increasing the infiltration of Treg populations ( Fig. 6 H, Fig. S5C )."

reach
"In addition, Overexpression of USP4 reduced hepatic inflammatory infiltration and apoptosis upon HIR stimulation."
AKT affects USP4
| 26 21 1
AKT phosphorylates USP4.
| 15 18 1
AKT phosphorylates USP4. 10 / 31
| 14 16 1

sparser
"AKT phosphorylates USP4, leading to USP4 relocalization to the membrane, reinforcing the pro-tumorigenic functions of TGFβ [ xref ]."

sparser
"EGF enhances the deubiquitination of Rheb through AKT-dependent USP4 phosphorylation, leading to the release of Rheb from the TSC complex."

sparser
"Similarly, phosphorylation of USP4 by AKT also leads to its redistribution from the nucleus to the cytoplasm, where it ultimately reaches the cell membrane to deubiquitylate the TFG-β receptor I [85] [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"USP4 also directly associated with AKT and became phosphorylated by AKT on a conserved Ser445 motif."

sparser
"Phosphorylation of USP4 by AKT enhances the association of USP4 with cell surface TβRI, and USP4-mediated TβRI de-ubiquitylation ( xref )."

reach
"Furthermore, they demonstrate that AKT phosphorylation of USP4 enhances the binding of USP4 to USP15 and that overexpression of USP15 increases USP4 stability."

sparser
"Upon growth factor stimulation, deubiquitinase USP4 was phosphorylated by AKT, resulting in the release of the inhibitory TSC complex from Rheb, which is essential for the activation of both Rheb and mTORC1."

reach
"Further, a genome-wide gain-of-function study revealed that AKT acts as a kinase for USP4 phosphorylation and phosphorylated USP4 moves into the cytoplasm from the nucleus."
| PMC

sparser
"USP4 is phosphorylated by AKT and translocated to the cytoplasm and membrane, where USP4 binds TβRI to deubiquitinate and protect it from damage ( xref )."

reach
"Moreover, this report showed that USP4 was phosphorylated by AKT, leading to increased USP4 membrane localization and promoting USP4 self association, leading to enhanced TGF-beta signalling."
AKT phosphorylates USP4 on S445. 3 / 3
| 1 2

sparser
"Further study showed that USP4 can be phosphorylated at its Ser 445 by activated protein kinase B (AKT) and bind to 14-3-3 isoforms to be exported from nucleus to cytoplasm and subsequently exert its deubiquitination capacity [ xref ]."

sparser
"AKT directly phosphorylates USP4 at Ser445, relocating nuclear USP4 to the cytoplasm and membrane with the help of 14-3-3 protein, as well as enhancing its stability and deubiquitinating activity."

reach
"AKT directly phosphorylates USP4 at Ser445, relocating nuclear USP4 to the cytoplasm and membrane with the help of 14-3-3 protein, as well as enhancing its stability and deubiquitinating activity."
AKT binds USP4.
| 5 3
| 5 3

reach
"Conceivably, AKT directly interacts with USP4 for its phosphorylation and translocates nuclear USP4 to the membrane and thus maintains TbetaRI stability and possibly modulates TGF-beta induced EMT and MMT."

reach
"Interestingly, it was also found that Akt directly associates and phosphorylates USP4, and then induces the translocation of USP4 from the nucleus to the cytoplasm and plasmalemma for maintaining TbetaRI stability [XREF_BIBR]."

reach
"They further showed that USP4 could interact with Akt at endogenous level, and phosphorylate USP4 in vitro and in vivo."

sparser
"Conceivably, AKT directly interacts with USP4 for its phosphorylation and translocates nuclear USP4 to the membrane and thus maintains TβRI stability and possibly modulates TGF-β induced EMT/MMT."

sparser
"They further showed that USP4 could interact with Akt at endogenous level, and phosphorylate USP4 in vitro and in vivo."

sparser
"USP4 also directly associated with AKT and became phosphorylated by AKT on a conserved Ser445 motif."

reach
"As mentioned above, USP4 binds to and deubiquitinates the TGF-beta type I receptor and associates with AKT, leading to enhanced TGF-beta signalling and AKT induced breast cancer cell migration (Zhang [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Interestingly, AKT directly interacts and phosphorylates USP4, which then translocates from the nucleus to the plasma membrane where it stabilizes TGFbeta receptor I through direct interaction [XREF_BIBR]."
AKT activates USP4.
| 6
AKT activates USP4. 6 / 6
| 6

reach
"Based on this study, it would be interesting to investigate whether USP4 function, which is also modulated by AKT as described above, is also affected in CYLD knockout mice XREF_BIBR."

reach
"According to a previous study by Iyengar [XREF_BIBR], Akt promotes USP4 to enter the cell membrane and cytoplasm to phosphorylate USP4 and regulate its subcellular localization, and Akt phosphorylation of USP4 occurs by combining with other de-ubiquitinating enzymes (DUBs) to de-ubiquitinate the TGF-beta receptor [XREF_BIBR]."

reach
"A recent study has demonstrated that AKT mediates the nuclear-to-cytoplasmic transport of USP4, leading USP4 to interact with and deubiquitinate TGF-β type I receptor (TβRI), which indicates USP4 as a[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Here, Akt phospho-activated the deubiquitylating enzyme USP4, resulting in reduced ubiquitylation-mediated degradation of TβR-I and thus enhanced Smad signaling ( Zhang et al., 2012 )."

reach
"These results suggest that the USP4 effect on myogenesis is possibly mediated by AKT and p38 signalings.We found that USP4 performs a function in myogenesis, but not as a deubiquitinase."

reach
"This study suggests that Akt activation in breast cancer cells induces USP4 to relocate and stabilize TbetaRI in the plasma membrane, and thereby enforces TGF-beta-induced pro tumorigenic responses."
USP4 affects TP53
1 | 1 1 30 3
USP4 inhibits TP53.
| 1 1 12 3
USP4 inhibits TP53. 10 / 22
| 1 1 12 3

trips
"USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1."

reach
"USP4 inhibits p53 and NF-kappaB through deubiquitinating and stabilizing HDAC2."

reach
"Previous study has also demonstrated that USP4 inhibits p53 functions by deubiquitinating HDAC [80]."

reach
"USP4 inhibits p53 transcriptional activation via stabilizing HDAC2 and ARF-BP1, which acts as a deacetylase and E3 ubiquitin ligase of p53, respectively."

reach
"Therefore, our studies reveal USP4 suppresses p53 and NF-kappaB activation by stabilizing HDAC2."

reach
"USP4 can inhibit the tumor suppressor effect of p53, thus acting as a potential oncogene."

sparser
"Because USP4 inhibits ubiquitination-mediated HDAC2 degradation, we hypothesized that USP4 inhibits p53 functions through HDAC2."

sparser
"USP4 inhibits p53- and p53-mediated apoptosis, regulates NF-κB signaling pathway and modulates TGFβ signaling, xref , xref , xref , xref promoting breast cancer xref and lung adenocarcinoma invasiveness. xref We demonstrate here that both USP17 and USP4 are expressed at higher levels in breast and lung cancer cell lines compared to normal cells."

reach
"Recently, it has been reported that USP4 could antagonize p53 signalling through its deubiquitinating activity.15, 18 Given that Bax and Bcl2 are 2 canonical downstream regulators of p53 in mediating cell apoptosis and were regulated by USP4 in response to cisplatin treatment, we speculated that pro survival effect of USP4 in response to cisplatin treatment may be associated with p53 signalling pathway."

reach
"Furthermore, we demonstrated that USP4 inhibited p53 mediated transcriptional activity in wild-type but not HDAC2 knockdown U2OS cells in response to DNA damage or not (XREF_FIG)."
USP4 activates TP53.
| 7
USP4 activates TP53. 7 / 7
| 7

reach
"Another example is that USP4 expression increases p53 transcriptional activity by stabilizing ARF-BP1, which is an E3 ubiquitin ligase of p53 [ 24 ]."

reach
"In addition to these newly identified nuclear functions, both USP4 and USP15 are well known to function in the cytosol, i.e. USP4 modulates the Wnt and beta-catenin, NF-kappaB, p53 and TGF-beta signaling pathways while USP15 performs functions in the TGF-beta receptor and NF-kappaB signaling pathways."

reach
"However, in response to cisplatin treatment, USP4 deficiency significantly augmented melanoma cells apoptosis by activating p53 signalling."

reach
"However, in response to cisplatin induced stress, the knockdown of USP4 could markedly increase the apoptotic rate of melanoma cells, and USP4 deficiency sensitized melanoma cell to cisplatin induced apoptosis by activating p53 pathway."

reach
"Similarly, knockdown of USP4 significantly decreases cell viability in a p53 dependent manner after treating GMB cells with temozolomide."

reach
"In contrast, silencing USP4 by shRNA remarkably increased the p53 activity in response to DNA damage or not (XREF_FIG)."

reach
"USP4 regulates the cell cycle and apoptosis and promotes tumor cell proliferation by regulating the p53 and downstream protein expression."
USP4 decreases the amount of TP53.
| 3
USP4 decreases the amount of TP53. 3 / 4
| 3

reach
"Previous studies have found that USP4 can inhibit p53 transcription and pro-apoptotic functions by stabilizing HDAC2 [17], whereas the deubiquitinase USP4 stabilizes Twist1 protein to promote lung cancer stemness [18]."

reach
"In fact, our data show that USP4 inhibited the levels of acetylation but not protein expression of p53 (XREF_FIG)."

reach
"For instance, USP4 was shown to reduce p53 levels via deubiquitination of ARF-BP1 XREF_BIBR."
USP4 deubiquitinates TP53.
1 | 2
USP4 deubiquitinates TP53. 2 / 3
1 | 2

reach
"In the cytosol, USP4 deubiquitinates the member of many vital cell signaling pathways, e.g., NF-κB [77], TGF-β [54], Wnt/β-catenin [78], and p53 [79] as well as adenosine A2A receptor [80] and the E3 ligase TRIM21 [81]."

reach
"USP4 is a deubiquitinating enzyme which may inhibit p53 by deubiquitinating an important p53 ubiquitin ligase ARF-BP1 [35]."
USP4 increases the amount of TP53.
| 2
USP4 increases the amount of TP53. 2 / 2
| 2

reach
"More importantly, in response to cisplatin treatment, USP4 deficiency resulted in up-regulation of p53 expression both at transcriptional level and translational level."

reach
"Previous studies have found that USP4 can inhibit p53 transcription and pro-apoptotic functions by stabilizing HDAC2 [17], whereas the deubiquitinase USP4 stabilizes Twist1 protein to promote lung cancer stemness [18]."
USP4 deacetylates TP53.
| 2
USP4 leads to the deacetylation of TP53. 2 / 2
| 2

reach
"USP4 inhibits p53 acetylation and its transcriptional activity."

reach
"USP4 inhibits p53 acetylation and transcriptional activity."
USP4 binds TP53.
| 2
| 2

reach
"ARF-BP1 is a p53-specific E3 ligase that binds to USP4."
| PMC

reach
"USP4, for example, interacts directly with end resection factors CtIP and MRN [172], USP21 deubiquitinates and stabilizes BRCA2 to promote RAD51 binding and successful HR [173], and USP10 deubiquitinates and stabilizes p53 to promote its nuclear localization and apoptosis in response to DSBs [174]."
HDAC2 affects USP4
4 | 15 19
HDAC2 binds USP4.
4 | 14 19
4 | 13 15

reach
"We found that the interaction between endogenous USP4 and HDAC2 did not change after etoposide and TNFalpha treatment (XREF_SUPPLEMENTARY)."

reach
"29 We detected the interaction between USP4 and HDAC2 after treatment with VPA."

reach
"Remarkably, the interaction between endogenous USP4 and HDAC2 is significantly decreased upon VPA treatment."

sparser
"Remarkably, the interaction between endogenous USP4 and HDAC2 is significantly decreased upon VPA treatment.( xref )."

sparser
"We found that TRPS1 scaffolding recruits and enhances interaction between USP4 and HDAC2 leading to HDAC2 de-ubiquitination and H4K16 deacetylation."

reach
"USP4 's interaction with HDAC2 likely also emerged after WGD as a small region of USP4 (a.a. 188-302), which encompasses its unique alternatively spliced exon, interacts with this HDAC1 derived ohnolog."

reach
"We found that TRPS1 scaffolding recruits and enhances interaction between USP4 and HDAC2 leading to HDAC2 de-ubiquitination and H4K16 deacetylation."

reach
"It has recently been reported that USP4 directly interacts and de-ubiquitinates HDAC2 resulting in its stability in colon cancer cells [22]."

reach
"It appeared that both TRPS1 and USP4 interacted with and stabilized HDAC2 in a UDPD-dependent fashion."

sparser
"Our results indicated that the GATA domain of TRPS1 alone was unable to interact with HDAC2 and USP4 (Fig. xref )."
HDAC2 binds USP4 and TRPS1. 5 / 5
| 1 4

reach
"Similarly, trichorhinophalangeal syndrome type I (TRPS1) functions as a scaffold protein involved in the USP4 induced stabilization of HDAC2 through bringing them together to form the TRPS1, USP4, and HDAC2 complex."

sparser
"We hypothesized that TRPS1, USP4, and HDAC2 formed a complex, used Co-IP to test this notion, and found that TRPS1 co-immunoprecipitated with USP4 and HDAC2 (Fig. xref )."

sparser
"To further confirm the interaction between TRPS1, USP4, and HDAC2, we generated serial TRPS1 truncates based on the domain structure of TRPS1 consisting of an N-terminal domain and GATA and C-terminal domains (Fig. xref )."

sparser
"The results indicated that N-terminal or C-terminal domains of TRPS1 together with the GATA domain were sufficient to interact with HDAC2 and USP4 while neither TRPS1 N-terminal or C-terminal domain alone interacted with HDAC2 and USP4 (Fig. xref )."

sparser
"Similarly, trichorhinophalangeal syndrome type I (TRPS1) functions as a scaffold protein involved in the USP4-induced stabilization of HDAC2 through bringing them together to form the TRPS1-USP4-HDAC2 complex ( xref )."
HDAC2 activates USP4.
| 1
HDAC2 activates USP4. 1 / 1
| 1

reach
"Moreover, we found that USP4 targets HDAC2 to downregulate tumor necrosis factor-alpha (TNFalpha)-induced NF-kappaB activation."
USP4 affects NFkappaB
| 1 26 4
USP4 inhibits NFkappaB.
| 18 2
| 18 2

reach
"Consistent with this, the results of Hou et al. 28 showed that USP4 promotes apoptosis and inhibits NF-kappaB activation in head and neck squamous cell carcinoma."

sparser
"USP4 deubiquitinates TRAF6 and inhibits the TRAF6-stimulated NF-κB reporter gene and regulates the activation of NF-κB ( xref ) ( xref )."

reach
"USP4 inhibits p53 and NF-kappaB through deubiquitinating and stabilizing HDAC2."

reach
"Studies focused on the other USPs demonstrated that USP14 overexpression regulates IkappaB polyubiquitination to stimulate its degradation 26, and ectopic expression of USP4 inhibits the TRAF2- and TRAF6 stimulated NF-kappaB reporter gene and negatively regulates the TNF-alpha-induced IkappaB-alpha degradation and NF-kappaB activation 27."

reach
"In addition, USP4 inhibits TNF-alpha-induced activation of NF-kappaB through USP4 deubiquitination of TAK1 XREF_BIBR."

reach
"Therefore, our studies reveal USP4 suppresses p53 and NF-kappaB activation by stabilizing HDAC2."

reach
"XREF_BIBR showed that USP4 could block Dox induced activation of NF-kappaB at the early stage of the treatment by preventing TAK1 from conjugating K63 linked polyubiquitin chains."

reach
"USP4 inhibits NF-kappaB transcriptional activity through HDAC2."

reach
"USP4 inhibits TAK1 and TAB1 co-overexpression-mediated NF-kappaB activation."

reach
"238 Recently, USP4 has been identified as a new DUB of TRAF6 and can negatively regulate the NF-kappaB signaling pathway."
USP4 activates NFkappaB.
| 1 8 2
| 1 8 2

reach
"However, we found that EV71 infection inhibit the expression of USP4 to attenuate the activation of the NF-kappaB pathway, an example of an evolved mechanism through which EV71 antagonizes host defences."

reach
"USP4 positively regulates the antiviral NF-kappaB pathway."

reach
"Our findings provide novel insights into the molecular mechanisms by which USP4 positively regulates NF-kappaB signalling and thus plays a critical role in maintaining the balance between innate immune responses and immune tolerance."

reach
"Therefore, to further confirm USP4 induced NF-kappaB activation, we designed and synthesized two siRNAs to knock down the intrinsic expression of USP4."

reach
"Hence, USP4 positively regulates NF-kappaB signaling by deubiquitinating K48-ubiquitin chains of TRAF6 in EV71 infection [XREF_BIBR]."

sparser
"Therefore, to further confirm USP4-induced NF-κB activation, we designed and synthesized two siRNAs to knock down the intrinsic expression of USP4."

eidos
"Although USP4 / UNP is associated with the TNF response and activates NF-kappaB as shown with USP2a , it has a different role , wherein USP4 regulates TAK-1 stability upon TNF response ."
| PMC

sparser
"These results suggest that deubiquitinating enzyme activity is responsible for the suppression of TNFα-mediated NF-κB activation by USP4."

reach
"Knockdown of USP4 promoted IL-1beta, LPS, and TGF-beta-induced NF-kappaB activation (Fan et al., 2011)."

reach
"It was also found that USP4 inhibited NF-kappaB activation, but in this study we confirmed that USP4 positively regulates the NF-kappaB signalling pathway during EV71 infection."
USP4 affects BRCA1
| 18 14
USP4 binds BRCA1.
| 6 14
| 6 14

sparser
"Based on this, we then examined whether USP4 and BRCA1 could interact with each other in the absence of CtIP."

sparser
"To investigate the physiological significance of USP4-BRCA1 association, we analyzed the protein level and interaction between BRCA1 and USP4 during cell cycle."

sparser
"Immunoprecipitation result showed that the interaction between USP4 and BRCA1 is almost undetectable at early G1, and increases from late G1 through S, and peaks at G2/M, which concomitantly correlates with the levels of BRCA1 at these phases (Fig. xref )."

sparser
"This result is consistent with a role of USP4 in stabilizing BRCA1, suggesting that USP4 physiologically interacts with BRCA1 to control BRCA1 protein level during the progression of cell cycle."

sparser
"The Co-IP assay indicated that endogenous BRCA1 could interact with USP4 in a manner that is independent of its DUB activity (Supplementary Fig. xref )."

sparser
"This result indicates that USP4 can interact with both BARD1-unbound BRCA1(“free” BRCA1) and may also bind BRCA1/BARD1 heterodimer."

sparser
"This result suggests that USP4 can interact with BRCA1 in a manner independent of CtIP."

sparser
"Interestingly, the interaction between USP4 and BRCA1 was enhanced with IR/ doxorubicin treatment (Fig. xref ), suggesting their interactions might be DNA damage inducible."

sparser
"To further confirm the in vivo interaction between USP4 and BRCA1, Co-IP of endogenous USP4 and BRCA1 from MCF-10A cells were performed and the results showed that USP4 was efficiently co-immunoprecipitated with BRCA1, and vice versa (Fig. xref )."

reach
"USP4 physically interacts with and deubiquitinates BRCA1, thus saving BRCA1 from UPS-meditated ubiquitination and degradation."
USP4 deubiquitinates BRCA1.
| 8
USP4 deubiquitinates BRCA1. 6 / 6
| 6

reach
"USP4 physically interacts with and deubiquitinates BRCA1, thus saving BRCA1 from UPS-meditated ubiquitination and degradation."

reach
"USP4 deubiquitinates BRCA1."

reach
"Indeed, ectopic expression of USP4 WT, but not the C311A mutant, which is still capable of interacting with BRCA1, reduced both endogenous BRCA1 ubiquitylation (Fig. 3a, mostly polyubiquitinated BRCA1 species at high MW) and exogenous-overexpressed BRCA1 ubiquitylation in cells (Fig. 3b), suggesting that the DUB catalytic activity of USP4 is critical for USP4-dependent deubiquitylation of BRCA1."

reach
"Conversely, silencing USP4 expression increased endogenous BRCA1 ubiquitylation level in cells after MG132 treatment (Fig. 3c)."

reach
"As expected, USP4 WT efficiently deubiquitinated BRCA1."

reach
"We demonstrate that USP4 act as BRCA1 deubiquitinating enzyme to antagonize BRCA1 ubiquitination."
Mutated USP4 deubiquitinates BRCA1. 2 / 2
| 2

reach
"Clinical USP4 mutations from human breast cancer are defective in deubiquitinating and stabilizing BRCA1."

reach
"Interestingly, like L310R and S315C, R559W mutant still can destabilize BRCA1 despite of its ability to interact with BRCA1.Next, we asked whether these USP4 mutants could deubiquitinate BRCA1."
USP4 increases the amount of BRCA1.
| 2
USP4 increases the amount of BRCA1. 2 / 2
| 2

reach
"Conversely, silencing USP4 expression increased endogenous BRCA1 ubiquitylation level in cells after MG132 treatment (Fig. 3c)."

reach
"Importantly, we further demonstrate that USP4 mutants (L301R, S315C and R559W) that are defective either in DUB activity or in interacting with BRCA1 can cause significant decrease in BRCA1 protein level and hence confer increased sensitivity to IR or anticancer drugs such as DOX, ETO or PARPi."
USP4 activates BRCA1.
| 2
USP4 activates BRCA1. 2 / 2
| 2

reach
"The results showed that overexpression of USP4 induced significant upregulation of BRCA1 protein, whereas other DUBs including USP9X had little effect (Fig. 1a and Supplementary Fig. 1a–d)."

reach
"Overexpression of wild-type USP4 prolonged the half-life of BRCA1, whereas the catalytic-inactive mutant of USP4 (C311A) had no such effects (Fig. 1f)."
USP4 affects TGFBR1
5 1 | 1 22 1
USP4 deubiquitinates TGFBR1.
1 | 12
USP4 deubiquitinates TGFBR1. 10 / 13
1 | 12

reach
"This phosphorylation promotes USP4 localization in membrane and cytoplasm, where USP4 deubiquitylates TbetaRI."

reach
"USP4 directly interacts with and deubiquitinates TGF-beta type I receptor (TbetaRI), regulating TGF-beta signaling by controlling TbetaRI levels at the plasma membrane."

reach
"USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-beta type I receptor [XREF_BIBR]."

reach
"After phosphorylation by AKT, USP4 associates with and deubiquitinates ALK5, leading to upregulation of TGFβ signal [84]."

reach
"Mechanistically, we revealed that USP4 interacted directly with and deubiquitinated TGF-beta receptor type I (TGFR-1) to activate the TGF-beta signaling pathway, and subsequently induced the Epithelial-Mesenchymal Transition (EMT) in HCC cells."

reach
"USP4 can also deubiquitinate TGF-beta type I receptor (TbetaRI) and sustain its plasma membrane expression in a SMAD7 independent fashion, leading to hyperactivation of the TGF-beta pathway."

reach
"Taken together, our results elucidate that USP4 is highly expressed in HCC and promotes the tumor invasion and metastasis, the underlying mechanism is that USP4 directly interacts with and deubiquitinates TGFR-1 to increase TGF-beta signaling Induced EMT."

reach
"USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-beta type I receptor."

reach
"USP4 is regulated by AKT phos phorylation and directly deubiquitylates TGF-beta type I receptor."

reach
"As mentioned above, USP4 binds to and deubiquitinates the TGF-beta type I receptor and associates with AKT, leading to enhanced TGF-beta signalling and AKT induced breast cancer cell migration (Zhang [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 binds TGFBR1.
5 | 7 1
5 | 7 1

reach
"Likewise USP4 as a deubiquitylating enzyme also interacts with TbetaRI at the plasma membrane and reverses its ubiquitination and thus regulates the TbetaRI levels [XREF_BIBR]."

reach
"USP4 directly interacts with and deubiquitinates TGF-beta type I receptor (TbetaRI), regulating TGF-beta signaling by controlling TbetaRI levels at the plasma membrane."

sparser
"Co-immunoprecipitation assay showed that exogenous USP4 and TGFR-1 directly bound to each other ( xref )."

reach
"Deubiquitinating TbetaRI and stimulation of TGF-beta signaling pathway also associate USP4 with liver fibrosis and cirrhosis where it facilitates activation of hepatic stellate cell and EMT in hepatocytes."

reach
"Mechanistically, we revealed that USP4 interacted directly with and deubiquitinated TGF-beta receptor type I (TGFR-1) to activate the TGF-beta signaling pathway, and subsequently induced the Epithelial-Mesenchymal Transition (EMT) in HCC cells."

reach
"Taken together, our results elucidate that USP4 is highly expressed in HCC and promotes the tumor invasion and metastasis, the underlying mechanism is that USP4 directly interacts with and deubiquitinates TGFR-1 to increase TGF-beta signaling Induced EMT."

reach
"As mentioned above, USP4 binds to and deubiquitinates the TGF-beta type I receptor and associates with AKT, leading to enhanced TGF-beta signalling and AKT induced breast cancer cell migration (Zhang [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"For instance, USP4 directly interacts with and deubiquitinates TGF-beta type I receptor (TbetaRI), thereby determining the levels of TGF-beta signaling."
USP4 activates TGFBR1.
| 1 3
USP4 activates TGFBR1. 4 / 4
| 1 3

reach
"Therefore, USP4 mediates TbetaRI regulation via PI3K and Akt pathway, which is a strong modulator of TGF-beta pathway and plays a critical role in the crosstalk between TGF-beta and AKT signaling."

eidos
"Published studies revealed that , unlike USP15 , USP4 directly binds , stabilizes , and activates TbetaRI in the plasma membrane rather than via SMAD7-mediated recruitment to the active receptor as USP15 does ."

reach
"As we have discussed above, USP4 can target the TGF-beta type I receptor and promote invasion and metastasis of breast cancer and high USP15 expression correlated with enhanced pSmad2 expression in ti[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"In particular, USP4 pre-activates and/or persistently increases TbetaRI stabilization."
USP4 affects HUWE1
4 1 | 20 2
USP4 binds HUWE1.
4 | 7 2
4 | 7 2

reach
"USP4 interacts directly with and deubiquitinates ADP-ribosylatibon factor binding protein 1 (ARFBP1), which results in the stabilization of ARF-BP1 and the subsequent reduction of p53 levels."

reach
"USP4 negatively regulates p53 by binding to ARF-BP1 and deubiquitinates it thereby promoting ARF-BP1-dependent ubiquitination and degradation of p53."

reach
"USP4 interacts directly with and deubiquitinates ARF-BP1, leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels."

reach
"For example, USP4 interacts directly with and deubiquitinates ARF binding protein 1 (ARF-BP1), leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels."

reach
"USP4 interacts directly with and deubiquitinates ADP-ribosylatibon factor-binding protein 1 (ARF-BP1), leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels [12] ."

reach
"Furthermore, USP4 interacts directly with and deubiquitinates ARF-BP1, leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels [XREF_BIBR]."

sparser
"This regulation depends on the binding of USP4 to ARF-BP1 through deubiquitination, promoting ARF-BP1-dependent ubiquitination and degradation of p53, which indicates its tumor-promoting role [ xref ]."

sparser
"In human osteosarcoma cells, USP4 can directly bind to and deubiquitinate ARF-BP1, which stabilises ARF-BP1 and reduces p53 levels, thereby promoting cancer cell proliferation ( xref )."

reach
"USP4 also interacts directly with and deubiquitinates ARF-BP1, leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels."
USP4 deubiquitinates HUWE1.
1 | 12
USP4 deubiquitinates HUWE1. 10 / 13
1 | 12

reach
"USP4 interacts directly with and deubiquitinates ARF-BP1, leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels."

reach
"USP4 interacts directly with and deubiquitinates ADP-ribosylatibon factor-binding protein 1 (ARF-BP1), leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels [12] ."

reach
"For instance, USP4 is reported to participate in the control of p53-related signaling through deubiquitinating ARF-BP1 , the suppression of canonical Wnt signaling pathway through deubiquitinating TCF4 , the activation of TGF-β signaling through deubiquitinating substrates like TβR-I and SMAD4 and the inhibition of NF-κB pathway through deubiquitinating mediators like TRAF2, TRAF6 and TAK1 ."

reach
"USP2 deubiquitinates both MDM2 and MDMX [XREF_BIBR, XREF_BIBR] whereas USP4 deubiquitinates ARF-BP1 [XREF_BIBR], another ubiquitin ligase for p53, thus indirectly destabilizing p53 and inhibiting its function."

reach
"Furthermore, USP4 interacts directly with and deubiquitinates ARF-BP1, leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels [XREF_BIBR]."

reach
"USP4 also interacts directly with and deubiquitinates ARF-BP1, leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels."

reach
"USP4 also regulates p53 stability via direct deubiquitination of the E3 ARF-BP1 [179] ."

reach
"For example, USP4 interacts directly with and deubiquitinates ARF binding protein 1 (ARF-BP1), leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels."

reach
"Recently, ARF-BP1 was reported to specifically target HDAC2 for ubiquitination and degradation and USP4 deubiquitinates and stabilizes ARF-BP1."

reach
"Nonetheless, USP4 might deubiquitinate and stabilize both ARF-BP1 and its substrate HDAC2."
USP4 inhibits HUWE1.
| 1
USP4 inhibits HUWE1. 1 / 2
| 1

reach
"Conversely, whereas USP4 and USP15 target p53 inhibiting ligases ARF-BP1 [XREF_BIBR] and MDM2 [XREF_BIBR], respectively, USP11 stabilizes p53 [XREF_BIBR] as well as several other tumor suppressors including PML [XREF_BIBR], BRCA2 [XREF_BIBR] and Mre11 complex members MRE11 & RAD50 [XREF_BIBR]."
MAP3K7 affects USP4
4 | 12 12
MAP3K7 binds USP4.
4 | 8 12
4 | 8 12

sparser
"USP4 binds to overexpressed TAK1 with TAB1 and TNFα induces association of USP4 with TAK1."

sparser
"To further determine the molecular interaction of USP4 and TAK1 in TNFα-induced signal transduction, we overexpressed expression vector encoding MYC-USP4 in HEK-293T cells and treated with TNFα for the time points as indicated ( xref )."

reach
"USP4 and USP18 bind with TAK1 and de-ubiquitinate TAK1 to inhibit its activation [10, 12]."

sparser
"Tumour necrosis factor-α (TNFα) promotes the interaction between USP4 and TAK1 and the deubiquitination of TAK1, leading to the attenuation of TAK1-mediated NF-κB activation."

sparser
"Furthermore, unlike CYLD, binding of USP4 with TAK1 is induced by TNFα stimulation in the cells ( xref )."

reach
"To verify the mass spectrometry results, a Co-IP assay was performed to test the reciprocal interaction between USP4 and TAK1 in ESCC cells."

sparser
"TNFα induces association of USP4 with TAK1 to deubiquitinate TAK1 and downregulate TAK1-mediated NF-κB activation."

sparser
"In conclusion, our results provide evidence that TNFα induces association of USP4 with TAK1 which leads to TAK1 deubiquitination in the TNFα-mediated NF-κB activation."

sparser
"In view of the data presented here and previous reports, we propose a working model ( xref ), in which that TNFα rapidly induces Lys63-linked TAK1 polyubiquitnation and binding of USP4 to TAK1, Lys63-linked TAK1 would be rapidly deubiquitinated by USP4 to attenuate the magnitude of TNFα-induced Lys63-linked TAK1 polyubiquitination and TAK1-mediated IKK/NF-κB activation."

sparser
"In addition, USP4-TAK1 interaction and subsequent TAK1 deubiquitination were required for the amelioration of metabolic dysfunctions."
MAP3K7 activates USP4.
| 4
MAP3K7 activates USP4. 4 / 4
| 4

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"TAK1 was required for USP4 function in hepatic I/R injury as TAK1 inhibition abolished USP4 function in vitro In conclusion, our study demonstrates that USP4 deficiency plays a detrimental role in hepatic I/R injury by promoting activation of the TAK1 and JNK signalling pathways."

reach
"USP4 binds to overexpressed TAK1 with TAB1 and TNFalpha induces association of USP4 with TAK1."

reach
"Previous study also showed that USP4 targets TAK1 by removing K63 linked polyubiquitination and then recruit IkappaB kinase (IKK) complex to simulate TNF-alpha -induced NF-kappaB activation 49."

reach
"Molecular analysis revealed that USP4 deficiency augmented the activation of the transforming growth factor beta activated kinase 1 (TAK1)-(JNK1/2)/P38 signaling in response to hypertrophic stress, and blockage of TAK1 activation abolished the pathological effects of USP4 deficiency in vivo."
USP4 affects TGFB
| 1 28
USP4 activates TGFB.
| 1 20
USP4 activates TGFB. 10 / 19
| 1 18

reach
"The DUBs USP4, USP11, USP15, and UCH37 have previously been demonstrated to modulate TGF-beta pathway activity by directly deubiquitinating the TbetaRI, resulting in increased TbetaRI stability (XREF_FIG) XREF_BIBR XREF_BIBR XREF_BIBR XREF_BIBR."

eidos
"USP4 can enhance TGF-beta signaling by directly interacting with TbetaRI / ALK5 ."

reach
"USP4 promotes TGF-beta signals by stabilizing TGF-betatype I rceptor (TbetaRIota) [XREF_BIBR]."

reach
"In addition to these newly identified nuclear functions, both USP4 and USP15 are well known to function in the cytosol, i.e. USP4 modulates the Wnt and beta-catenin, NF-kappaB, p53 and TGF-beta signaling pathways while USP15 performs functions in the TGF-beta receptor and NF-kappaB signaling pathways."

reach
"By promoting activation of the relaxin and TGF-beta 1/Smad2/matrix metalloproteinase 9 axis and transcriptional repression activity of HDAC2, USP4 induces breast cell invasion, migration, and proliferation both in vitro and in vivo."

reach
"Collectively, our results support the concept that dysregulation of miR-148a is associated with the poor prognosis of HCC and may account for the tumor progression to advanced stages, and that, of the newly identified targets, USP4 overexpression may contribute to HCC progression towards more aggressive feature presumably by facilitating TGF-beta signaling pathways, growth advantage and migrating capability."

reach
"USP4, when overexpressed, potently enhanced TGF-beta signaling."

reach
"However, when it comes to tumor metastasis, USP4 can promote breast cancer cells metastasis by activating TGF-β1/Smad2/matrix metalloproteinase-9 signaling pathway [ 33 ]."

reach
"USP4 can serve as a double-edged sword in tumor progression because it functions as a tumor suppressor in lung cancer by indirectly circumventing stemness [56], while USP4 promotes TNBC metastasis by enhancing TGF-β signaling and inducing the suppressive activity of Tregs [87, 119]."

reach
"USP4 promotes invasion of breast cancer cells via Relaxin and TGF-beta 1/Smad2/MMP -9 signal."
USP4 bound to TGFBR1 activates TGFB. 2 / 2
| 2

reach
"Taken together, our results elucidate that USP4 is highly expressed in HCC and promotes the tumor invasion and metastasis, the underlying mechanism is that USP4 directly interacts with and deubiquitinates TGFR-1 to increase TGF-beta signaling Induced EMT."

reach
"Mechanistically, we revealed that USP4 interacted directly with and deubiquitinated TGF-beta receptor type I (TGFR-1) to activate the TGF-beta signaling pathway, and subsequently induced the Epithelial-Mesenchymal Transition (EMT) in HCC cells."
USP4 deubiquitinates TGFB.
| 6
USP4 deubiquitinates TGFB. 6 / 6
| 6

reach
"Mechanically, USP4 influences the TGFβ/BMP pathway by deubiquitinating the TGFβ1 receptor, thereby stabilizing TGFβ signaling [35]."

reach
"In the cytosol, USP4 deubiquitinates the member of many vital cell signaling pathways, e.g., NF-κB [77], TGF-β [54], Wnt/β-catenin [78], and p53 [79] as well as adenosine A2A receptor [80] and the E3 ligase TRIM21 [81]."

reach
"The authors further go on to show that USP4 was able to deubiquitylate the TGF-beta receptor I (TbetaRI) directly and rescue it from proteasome mediated degradation."

reach
"USP4 has been reported to enhance TGFbeta signalling by directly interacting with and deubiquitylating type I TGFbeta receptor, ALK5 XREF_BIBR."

reach
"For example, USP4 directly interacts with and deubiquitylates transforming growth factor-β (TGF-β) type I receptor (TβRI), thereby determining the levels of TGF-β signaling [13] ."

reach
"Mechanistically, hepatocyte USP4 directly bound to and deubiquitinated transforming growth factor-beta activated kinase 1 (TAK1), leading to a suppression of the activation of downstream NF-kappaB and JNK cascades, which in turn reversed the disruption of the IRS-AKT-GSK3beta signaling."
USP4 inhibits TGFB.
| 2
USP4 inhibits TGFB. 2 / 2
| 2

reach
"In this context, to achieve a certain biological outcome, the same DUB can regulate the pathway at different levels (e.g., USP15 and USP4 promote signaling by targeting the TGF-beta receptor and the effector SMADs) or multiple DUBs can act on the same target (e.g., USP15 and OTUB1 promote signaling through stabilizing R-SMADs)."

reach
"H19 functions as a competing endogenous RNA (ceRNA) by sponging miR-148a and maintaining the expression levels of ubiquitin specific protease 4 (USP4), a key miR-148a target that stabilizes TGFbetaRI and promotes TGF-beta signalling."
TRIM21 affects USP4
4 1 1 | 7 8
TRIM21 binds USP4.
4 1 | 3 3
4 1 | 3 3

reach
"Another possibility is that the Ro52 and Usp4 complex regulates the movements of the cytoplasmic bodies by ubiquitination and deubiquitination."

sparser
"The proteasome has both ubiquitin ligases and DUBs that associate with it (Crosas et al., 2006) , and several DUB-ligase pairs interact directly, including BRCC36-BRCA1, BAP1-BRCA1, USP4-Ro52, USP7-MDM2, USP8-GRAIL, USP20-pVHL, USP33-pVHL and USP44-APC (Kee and Huibregtse, 2007; Marfany and Denuc, 2008; Ventii and Wilkinson, 2008) ."

sparser
"For example, USP4 associates with the E3 ligase Ro52 forming, as observed here for dUSP36-D and AGO, a DUB/E3 ligase pair that transregulates each other by ubiquitination and deubiquitination ( xref )."

reach
"USP4 was shown to self-deubiquitinate after being ubiquitinated by E3 ligase Ro52, and it was suggested that USP4 forms a heterodimeric protein complex with Ro52 in which both proteins transregulate each other."

sparser
"The two proteins were shown to co-localize to cytoplasmic rod-like structures in HEK293 cells, suggesting that Ro52 interacts with USP4 in mammalian cells to form a heteromeric protein complex that mediates both ubiquitination and deubiquitination of substrates [ xref ]."

reach
"The two proteins were shown to co-localize to cytoplasmic rod like structures in HEK293 cells, suggesting that Ro52 interacts with USP4 in mammalian cells to form a heteromeric protein complex that mediates both ubiquitination and deubiquitination of substrates [XREF_BIBR]."
TRIM21 ubiquitinates USP4.
1 | 4 5
TRIM21 ubiquitinates USP4. 9 / 14
1 | 4 5

reach
"Conversely, USP4 can be ubiquitylated by Ro52 and subsequently degraded."

sparser
"Ro52 is an E3 ubiquitin ligase that can ubiquitinate itself (self-ubiquitination) as well as ubiquitinate USP4 in vitro and in vivo ."

sparser
"Conversely, USP4 can be ubiquitylated by Ro52 and subsequently degraded."

reach
"Conversely, USP4 can be ubiquitylated by Ro52 and subsequently degraded."

sparser
"Conversely, USP4 can be ubiquitylated by Ro52 and subsequently degraded."

sparser
"USP4 is ubiquitinated by the ubiquitin ligase Ro52, whose deubiquitination, in turn, is facilitated by USP4 ( xref ; xref )."

sparser
"Finally, recent studies reported reciprocal activities between USP4 and the E3 ubiquitin ligase Ro52 with an USP4-mediated de-ubiquitination of Ro52 and a Ro52-induced ubiquitination of USP4 but preci[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Finally, recent studies reported reciprocal activities between USP4 and the E3 ubiquitin ligase Ro52 with an USP4-mediated de-ubiquitination of Ro52 and a Ro52-induced ubiquitination of USP4 but preci[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"USP4 is ubiquitinated by the ubiquitin ligase Ro52, whose deubiquitination, in turn, is facilitated by USP4."
TRAF6 affects USP4
8 | 10 9
TRAF6 binds USP4.
8 | 8 9
8 | 8 6

sparser
"As previously reported, TRAF6 is a key adaptor molecule for the activation of the NF-κB pathway xref , therefore it was speculated that USP4 indeed interacts with TRAF6."

sparser
"Flag-TRAF6 and HA-USP4 plasmids were co-transfected into HEK293T cells and after 48 h, further IP experiments were performed with anti-HA antibody, and it was established that USP4 interacted with TRAF6 (Fig.  xref )."

sparser
"As shown in Fig.  xref , the interaction between USP4 and TRAF6 was not impaired by the mutation of the Cys-311 to Alanine (‘CA mutant’) of USP4 molecule."

sparser
"To further map the functional domain that interacts with TRAF6, we generated two truncated constructs based on the structural domains of USP4 and as shown in Fig.  xref , only the C-terminal domain (C) of USP4 was able to interact with TRAF6."

reach
"USP4 interacts with and deubiquitinates TRAF6, thereby preventing the activation of NF-kappaB and AP-1 transcription factors and subsequent immune responses."

reach
"Xiao et al. 's study added on to this by demonstrating USP4 's interaction and deubiquitination of TRAF2 and TRAF6, but not TRAF3, both in vivo, in HEK293T cells, and in vitro [XREF_BIBR]."

reach
"As previously reported, TRAF6 is a key adaptor molecule for the activation of the NF-kappaB pathway 31, therefore it was speculated that USP4 indeed interacts with TRAF6."

reach
"Flag-TRAF6 and HA-USP4 plasmids were co-transfected into HEK293T cells and after 48h, further IP experiments were performed with anti-HA antibody, and it was established that USP4 interacted with TRAF6."

reach
"XREF_FIG, the interaction between USP4 and TRAF6 was not impaired by the mutation of the Cys 311 to Alanine (' CA mutant ') of USP4 molecule."

reach
"We found that USP4 specifically interacts with TRAF2 and TRAF6, but not TRAF3."
USP4 binds TRAF2 and TRAF6. 3 / 3
| 3

sparser
"Xiao et al.’s study added on to this by demonstrating USP4’s interaction and deubiquitination of TRAF2 and TRAF6, but not TRAF3, both in vivo, in HEK293 T cells, and in vitro [ xref ]."

sparser
"We found that USP4 specifically interacts with TRAF2 and TRAF6, but not TRAF3."

sparser
"It was confirmed that USP4 associates with TRAF2 and TRAF6, consistent with our results."
TRAF6 activates USP4.
| 2
TRAF6 activates USP4. 2 / 2
| 2

reach
"USP4 targets TRAF6 through its USP domain."

reach
"However, there is no evidence of how USP4 deubiquitinates TRAF6 and TRAF2 proteins; our results prove that USP4 targets TRAF6 for K48 linked deubiquitination."
USP4 affects IRF4
3 1 | 16 8
USP4 binds IRF4.
3 | 7 8
3 | 7 8

reach
"To conclude, this study indicated that USP4 interacts with and deubiquitinates IRF4, and also stabilizes IRF4 protein and promotes IRF4 function to facilitate IL-4 expression in Th2 cells, which may be associated with the pathological process of RHD."

sparser
"These results demonstrated that USP4 and IRF4 interact directly with each other."

sparser
"The association of USP4 and IRF4 was corroborated by reverse co-immunoprecipitation experiment using the anti-Myc antibody to immunoprecipitate IRF4 and anti-Ha to detect the associated Ha-IRF4 by western blot analysis ( xref )."

sparser
"We found that immunoprecipitation of USP4 using the anti-USP4 antibody resulted in the co-immunoprecipitation of Myc-IRF4 as detected by immunoblotting with anti-Myc antibodies, indicating that USP4 interacts with IRF4 in Th2 cells ( xref )."

sparser
"In this study, we not only found an interaction between USP4 and IRF4, but also proved the effect of USP4 on the stabilization and deubiquitination of IRF4."

reach
"Here, the interaction between USP4 and IRF4 were analyzed by co-immunoprecipitation assay."

reach
"Our results validated the interaction between USP4 and IRF4, and effects of USP4 on stabilization and deubiquitination of IRF4 were also found."

reach
"On the whole, our data indicate that USP4 interacts with and deubiquitinates IRF4, and also stabilizes IRF4 protein and promotes IRF4 function to facilitate IL-4 expression in Th2 cells, which may be related to the pathological process of RHD."

reach
"In this study, we not only found an interaction between USP4 and IRF4, but also proved the effect of USP4 on the stabilization and deubiquitination of IRF4."

reach
"Interaction between USP4 and IRF4."
USP4 deubiquitinates IRF4.
1 | 5
USP4 deubiquitinates IRF4. 5 / 6
1 | 5

reach
"Therefore, USP4 deubiquitinates and stabilizes IRF4 protein and facilitates Th2-related cytokine expression [51] ."

reach
"On the whole, our data indicate that USP4 interacts with and deubiquitinates IRF4, and also stabilizes IRF4 protein and promotes IRF4 function to facilitate IL-4 expression in Th2 cells, which may be related to the pathological process of RHD."

reach
"Here, we speculated that USP4 may deubiquitinate IRF4, and affect Th2 cell function and may be associated with the pathogenesis of RHD."

reach
"USP4 deubiquitinates IRF4."

reach
"To conclude, this study indicated that USP4 interacts with and deubiquitinates IRF4, and also stabilizes IRF4 protein and promotes IRF4 function to facilitate IL-4 expression in Th2 cells, which may be associated with the pathological process of RHD."
USP4 increases the amount of IRF4.
| 2
USP4 increases the amount of IRF4. 2 / 2
| 2

reach
"USP4 knockdown not only decreased the expression level of IRF4, but also affected the expression level of Th2 related cytokines."

reach
"USP4 knockdown reduces IRF4 expression level and mRNA level of Th2-related cytokines, such as IL-4, IL-10 and IL-13."
USP4 activates IRF4.
| 2
USP4 bound to IRF4 activates IRF4. 2 / 2
| 2

reach
"To conclude, this study indicated that USP4 interacts with and deubiquitinates IRF4, and also stabilizes IRF4 protein and promotes IRF4 function to facilitate IL-4 expression in Th2 cells, which may be associated with the pathological process of RHD."

reach
"On the whole, our data indicate that USP4 interacts with and deubiquitinates IRF4, and also stabilizes IRF4 protein and promotes IRF4 function to facilitate IL-4 expression in Th2 cells, which may be related to the pathological process of RHD."
| 26
USP4 activates apoptotic process.
| 15

reach
"However, in response to cisplatin treatment, USP4 deficiency significantly augmented melanoma cells apoptosis by activating p53 signalling."

reach
"The silencing of USP4 can inhibit the apoptosis of cancer cells and increase the persistent survival rate of HNSCC, as immunosuppressive diseases, UXP9X, CYLD1, and BPLF1 accelerate the development of HNSCC through the escape inhibition mechanism of immune cells or promoting the spread of virus infection."

reach
"Consistent with this, the results of Hou et al. 28 showed that USP4 promotes apoptosis and inhibits NF-kappaB activation in head and neck squamous cell carcinoma."

reach
"Apoptosis related protein Bax, Cleaved caspase-3 expression was increased, and Bcl2, caspase-3 expression was decreased (Fig. 3D), indicating that USP4 could promote cell apoptosis and inhibit cell proliferation."

reach
"However, in response to cisplatin induced stress, the knockdown of USP4 could markedly increase the apoptotic rate of melanoma cells, and USP4 deficiency sensitized melanoma cell to cisplatin induced apoptosis by activating p53 pathway."

reach
"USP4 might negatively regulates RIP1-mediated NF-κB activation and promotes TNF-α-induced apoptosis in FaDu cells, as well as directly interacted with receptor-interacting protein 1 (RIP1) and deubiquitinated K63-linked ubiquitination from RIP142."

reach
"We subsequently showed that USP4 regulated cisplatin induced cell apoptosis via p53 signalling."

reach
"The overexpression of USP4 in HNSCC tissues may be modulated by host immune cells to promote apoptosis of cancer cells and attenuate cancer progression."

reach
"The findings showed that the expression of TGF-betaR1 and USP4 were increased in hypertrophic scar tissues and fibroblasts, and that down-regulating USP4 inhibited hypertrophic scar fibroblast proliferation and migration and induced cell apoptosis in vitro."

reach
"As shown in Fig. 2 B, USP4 overexpression significantly promotes cell apoptosis in FaDu cells in responses to TNF-α with CHX."
| 11

reach
"In summary, these data indicate that USP4 enhances HCC cell proliferation, migration, and invasion and suppresses HCC cell apoptosis in vitro."

reach
"XREF_BIBR also demonstrated that inhibiting USP4 expression in GBM cells both inhibited their proliferation and induced apoptosis via antagonizing USP4 mediated stimulation of the ERK signaling pathway."

reach
"In this study, we demonstrated that USP4 negatively regulated RIP1-mediated NF-κB activation and promoted TNF-α-induced apoptosis through interacting with RIP1 and deubiquitinating K63-linked ubiquiti[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Recent findings indicate that USP4, upregulated in TMZ-resistant GBM cells, inhibits apoptosis in a p53-dependent manner, and this resistance is further amplified by p53-specific inhibitors [103]."

reach
"In addition, Overexpression of USP4 reduced hepatic inflammatory infiltration and apoptosis upon HIR stimulation."

reach
"We then tested whether USP4 expression inhibits cell apoptosis upon DNA damage."

reach
"It was found that over-expression of USP4 enhanced the ability of RD cells to fight against invading EV71, and also reduced cell apoptosis."

reach
"Additionally, USP4 overexpression inhibited hepatocyte inflammation and apoptosis on hepatic I/R stimulation."

reach
"The results demonstrated that stable knockdown of USP4 significantly enhanced the ability of poly (I:C) to induce apoptosis ( Fig. 4 B–C), while stable overexpression of USP4 markedly attenuated the p[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"METTL3 elevates the levels of oncogenes such as THRAP3, RBM25, USP4, and BZW2, which accelerate the proliferation of MM cells and inhibit apoptosis [233, 234]."
USP4 affects PKM2
| 1 15 11
USP4 binds PKM2.
| 3 11
| 3 11

reach
"This conclusion is supported by the following evidence: First, we confirmed the interaction between USP4 and PKM2."

reach
"Taken together, our biochemical assay revealed that USP4 was specifically bound to PKM2."

sparser
"This conclusion is supported by the following evidence: First, we confirmed the interaction between USP4 and PKM2."

sparser
"The results showed that USP4 is associated with PKM2, and they are co-localized in the cytosol and nucleus."

sparser
"The available information generally supports the interaction between PKM2 and USP4, although it is not specific to PKM2's ubiquitin state."

sparser
"We demonstrated the interaction between USP4 and PKM2 by co-expressing these proteins in 293T cells."

sparser
"Our results showing the interaction using both overexpressed and endogenous proteins across multiple cell lines provide strong evidence for a direct physical interaction between USP4 and PKM2."

sparser
"USP4 interacts with PKM2 and catalyzes the de-ubiquitination of PKM2."

sparser
"In this study, we found that USP4 interacts with PKM2 and catalyzes PKM2 de-ubiquitination."

sparser
"Furthermore, we sought to determine whether USP4 interacts with PKM2 in vivo."
USP4 activates PKM2.
| 1 6
USP4 activates PKM2. 7 / 7
| 1 6

reach
"These results indicated that USP4 can upregulate PKM2, and the regulatory capability of USP4 is related to its enzyme activity."

reach
"We already found that USP4 can increase PKM2 expression, and the upregulation of PKM2 by USP4 is associated with its enzymatic activity."

reach
"Because USP4 upregulates PKM2, we thought that USP4 might be able to change the cell’s proliferation."

reach
"This result clearly indicates that PKM2 is a mediator for USP4 function in gastric cancer cells.Similarly, the colony formation assay results (Fig 3D–3F) indicated that USP4 promotes gastric cancer proliferation by regulating PKM2."

reach
"USP4 established its tumor-promoting function (enhancing cell proliferation and the Warburg effect) in gastric cancer cells by upregulating PKM2."

reach
"USP4 promotes the proliferation and glucose metabolism of gastric cancer cells by upregulating PKM2."

eidos
"Knockdown of USP4 reduces PKM2 levels and results in a reduction in cell proliferation and the glycolysis rate ."
USP4 increases the amount of PKM2.
| 4
USP4 increases the amount of PKM2. 4 / 4
| 4

reach
"We already found that USP4 can increase PKM2 expression, and the upregulation of PKM2 by USP4 is associated with its enzymatic activity."

reach
"Because USP4 upregulates PKM2 expression, we speculate that USP4 may increase these gene expressions due to its upregulation of PKM2."

reach
"Knockdown of USP4 reduces PKM2 levels and results in a reduction in cell proliferation and the glycolysis rate."

reach
"Second, USP4 increased the level of PKM2 in gastric cancer cells."
USP4 deubiquitinates PKM2.
| 2
USP4 leads to the deubiquitination of PKM2. 2 / 2
| 2

reach
"In addition, both USP20 [20] and HAUSP [44] can bind to PKM2 to regulate PKM2’s ubiquitination.The present study identified USP4 as a PKM2 interaction protein and found that USP4 can decrease the ubiquitination of PKM2."

reach
"USP4 upregulates PKM2 by promoting PKM2 de-ubiquitination."
| 2 23
| 2 20

reach
"Therefore, it can be speculated that USP4 promotes brain metastasis of LUAD cells by stabilizing the β-catenin protein74."

reach
"Mechanistically, USP4 can directly bind to the TRAF domain to inhibit TRAF2/TRAF6 activity through deubiquitination in an activity-dependent manner and negatively regulate IL-1β and TNF-α-induced NF-κB activation, thereby inhibiting lung cancer metastasis (46)."

reach
"Using bioluminescence imaging, we found that knockdown of USP4 suppressed brain metastasis in vivo and significantly increased overall survival and brain metastasis-free survival."

reach
"USP4 accelerates the growth, invasion, and metastasis of colorectal cancer [XREF_BIBR, XREF_BIBR]."

eidos
"In addition , USP4 reportedly mediates cell proliferation , survival and metastasis ( 32 , 33 ) ."

eidos
"53 USP4 interacts with cyclophilin A and TGF-beta receptor type I and promotes the progression and metastasis of HCC ."

reach
"USP4 promotes proliferation and metastasis in human lung adenocarcinoma."

reach
"Studies have shown that USP4 plays an important role in rectal cancer bladder cancer melanoma The high expression of USP4 in liver cancer and cervical squamous cell carcinoma implies that USP4 may be a potential oncogene, and it has been confirmed that the abnormal expression of USP4 promotes the occurrence, development, invasion and metastasis of rectal cancer ."

reach
"In vivo, we also found that USP4 knockdown obviously blocked HCC cell metastasis."

reach
"Hematoxylin-eosin (H&E) staining was carried out to assess lung nodules in mice based on the tissue structure and nuclei, and the staining results also showed that USP4 knockdown inhibited the lung metastasis of KYSE150 cells, while USP4 overexpression in KYSE180 cells promoted lung metastasis in vivo (Fig. 3G, H)."
| 3

reach
"Knockdown of USP4 dramatically suppressed the metastasis of PC14PE6 and LvBr5-Luc cells to the whole body and brain, as reflected by bioluminescence signals at 19 and 22 days post-injection (XREF_FIG)."

reach
"Further, the effect of USP4 on biological function investigated in HCC cell lines showed that USP4 knockdown significantly impaired HCC cell proliferation, colony formation, migration, and invasion in vitro and inhibited tumor growth and intrahepatic metastasis in vivo."

reach
"Consistently, USP4 silencing repressed tumor growth and metastasis in an ESCC nude mouse model in vivo."
USP4 affects PRPF3
1 7 1 | 15
USP4 deubiquitinates PRPF3.
1 1 | 14
USP4 deubiquitinates PRPF3. 10 / 15
1 1 | 13

reach
"PRP3 was deubiquitinated by USP4 consistent with a previous report but not by USP15."

reach
"In particular, non proteolytic ubiquitylation of the U4/U6 protein Prp3, promoted by the Prp19 complex, is required for stabilization of the U4/U6 * U5 tri-snRNP, while de-ubiquitylation of Prp3 by Usp4 and Sart3 is required for U4 dissociation and recycling."

reach
"Moreover, we found that USP15 and USP4 deubiquitinated substrates PRP31 and PRP3 simultaneously."

reach
"On the other hand, Usp4 and Sart3 promote de-ubiquitination and recycling of Prp3, and this modification weakens its interaction with Prp8 and allows for the dissociation of U4 during activation of the spliceosome [49]."
| PMC

reach
"The result shows that USP4 no longer deubiquitinates Prp3 in the presence of SART3 DeltaNLS."

reach
"As the splicing cycle progresses, PRPF3 and PRPF31 are deubiquitinated by USP4 and USP15, respectively (Song et al., 2010; Das et al., 2017)."

reach
"Prp3 is deubiquitinated by Usp4 and its substrate targeting factor, the U4/U6 recycling protein Sart3, which likely facilitates ejection of U4 proteins from the spliceosome during maturation of its active site."

reach
"Moreover, it was reported that Sart3, Usp4 and Usp15 form a complex in order to de-ubiquitinate Prp3 and Prp31 simultaneously."
| PMC

reach
"U5 tri-snRNP has joined the spliceosome, Usp4 deubiquitinates Prp3, decreasing its affinity for Prp8."

reach
"In addition, the other study reports that USP4, the USP15 homolog, binds to Tip110 and deubiquitinates Prp3, component of the U4 snRNP, during the spilceosome cycle ( Song et al., 2010 )."
USP4 deubiquitinates ubiquitinated PRPF3. 1 / 1
| 1

reach
"For progression of the splicing cycle, ubiquitinated PRP3 and PRP31 get deubiquitinated by the ubiquitin-specific proteases USP4 and USP15, respectively [28,29] ( Figure 1 )."
USP4 binds PRPF3.
7 | 1
7 | 1

reach
"In addition, the other study reports that USP4, the USP15 homolog, binds to Tip110 and deubiquitinates Prp3, component of the U4 snRNP, during the spilceosome cycle ( Song et al., 2010 )."
USP4 affects Nmdar1
| 24
| 24

sparser
"It has a kinase domain near the C-terminus that is homologous to the catalytic domain of MLCK 1 Abbreviations used: NMR, unique N-terminal domain of myorod; NMR-unP and NMR-P, synthetic unphosphorylat[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"AJ249993 , [7] ) were chemically synthesized by ShineGene Molecular Biotech (Shanghai, China) with phosphorylated Thr141 (NMR-P) and a substitution of Thr residue for Ala141 (NMR-unP) to represent the[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"This peptide corresponding to the unique N-terminal region of the amino acid sequence of myorod was synthesized either in phosphorylated (NMR-P) or unphosphorylated (NMR-unP) form (see Materials and m[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"The concentration of myosin held constant and increasing amount of NMR-P and NMR-unP were used in a co-sedimentation assay to determine the binding affinity for the peptides."

sparser
"We found that the peptides were able to bind to myosin and the binding affinity of NMR-P to myosin was higher ( K app = 0.055 μM) than that of NMR-unP ( K app = 0.116 μM)."

sparser
"Only NMR-unP peptide caused the sedimentation of F-actin; the amount of F-actin detected in low-speed pellets increased with increasing concentrations of NMR-unP peptide in the assay mixture ( Fig. 2 [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"NMR-unP can also interact with molluscan thin filaments."

sparser
"However, we note a distinctive feature of this binding: the NMR-unP peptide co-sedimentes with thin filaments only in the presence of Ca 2+ ( Fig. 2 B, lanes 3–6), while interaction of NMR-unP with F-[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"As shown in Fig. 3 , the viscosity of F-actin decreased in the presence of NMR-unP in a concentration-dependent manner, indicating that aggregates or bundles of F-actin have formed."

sparser
"To explore the bundling activity of the NMR-unP peptide further, we analyzed the structural arrangement of fluorescently labeled actin filaments after incubation with increasing concentrations of NMR-[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 affects RIPK1
3 1 | 15 2
USP4 binds RIPK1.
3 | 3 2
3 | 3 2

reach
"Taken together, these data indicate RIP1 and USP4 form a complex through the USP domain of USP4.To test the role of USP4 in RIP1 ubiquitination, RIP1 was co-expressed with HA-ubiquitin and USP4 expres[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"An association between USP4 and RIP1 was reported to impair NF-kappaB activation and exacerbate TNF-alpha-induced apoptosis in head and neck squamous cell carcinoma (HNSCC)."

sparser
"Co-immunoprecipitation showed that USP4 interacted with receptor-interacting protein 1 (RIPI) to remove K63-connected ubiquitin molecules to stabilize RIPI expression."

reach
"Furthermore, TNFalpha induced recruitment of USP4, TAK1 and RIPK1 to TNFR1 (XREF_FIG)."

sparser
"Coimmunoprecipitation experiments showed that RIP1 interacted with USP4 WT and C261, but not with N260, indicating the C-terminal USP domain is required for the interaction with RIP1 ( Fig. 3 F)."
USP4 deubiquitinates RIPK1.
1 | 5
USP4 deubiquitinates RIPK1. 5 / 6
1 | 5

reach
"For example, TNFAIP3, CYLD, USP3, USP4, USP15, USP25, and OTUD5 deubiquitinate key components of the IFN production pathway, including RIG-I, TRAF2, TRAF3, TRAF6, RIP1, and TRIF (reviewed in [93,94])."

reach
"Given the deubiquitinating K63-linked ubiquitination function of USP4, receptor-interacting protein 1 can be deubiquitylated and inactivated by USP4 and then promotes tumor necrosis factor-α induced a[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"In head and neck squamous cell carcinoma, USP4 inhibits carcinogenesis by deubiquitinating receptor-interacting protein 1 (RIP1) and promoting apoptosis induced by tumour necrosis factor-α (TNF-α) (48)."

reach
"USP4 WT remarkably decreased polyubiquitination of RIP1 with and without TNF-α stimulation and USP4-C311S mutant failed to do so ( Fig. 4 A), indicating USP4 has the deubiquitination ability towards R[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"As shown in Fig. 4 D, USP4 knockdown greatly increased TNF-α-induced polyubiquitination of RIP1."
USP4 inhibits RIPK1.
| 5
USP4 inhibits RIPK1. 5 / 5
| 5

reach
"USP4 might negatively regulates RIP1-mediated NF-κB activation and promotes TNF-α-induced apoptosis in FaDu cells, as well as directly interacted with receptor-interacting protein 1 (RIP1) and deubiquitinated K63-linked ubiquitination from RIP142."

reach
"In this study, we demonstrated that USP4 negatively regulated RIP1-mediated NF-κB activation and promoted TNF-α-induced apoptosis through interacting with RIP1 and deubiquitinating K63-linked ubiquiti[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Furthermore, we found USP4 negatively regulated RIP1-induced NF-κB activation ( Fig. 3 B)."

reach
"But, cotransfection of USP4 greatly decreased the polyubiqutination of RIP1 in the setting of ubiquitin WT or K63 transfected cells ( Fig. 4 B), but not in the K48-transfected cells ( Fig. 4 B), indic[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"In this study, we demonstrate that de-ubiquitinating protease USP4 negatively regulates RIP1-mediated NF-κB activation and promotes TNF-α-induced apoptosis through interacting with RIP1 and deubiquiti[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 ubiquitinates RIPK1.
| 2
USP4 ubiquitinates RIPK1. 2 / 2
| 2

reach
"In head and neck squamous cell carcinoma, USP4 inhibits carcinogenesis by deubiquitinating receptor-interacting protein 1 (RIP1) and promoting apoptosis induced by tumour necrosis factor-α (TNF-α) (48)."

reach
"In head and neck squamous cell carcinoma, USP4 inhibits carcinogenesis by deubiquitinating receptor-interacting protein 1 (RIP1) and promoting apoptosis induced by tumour necrosis factor-α (TNF-α) (48)."
USP4 affects RHEB
4 1 | 4 11 1
USP4 binds RHEB.
4 | 1 10
4 | 1 10

sparser
"Interestingly, our data showed that USP4-S445A barely bound to Rheb (Fig.  xref )."

reach
"This finding was further validated in TDSCs, wherein MA significantly inhibited the interaction between USP4 and Rheb mediated by IL‐1β, in the presence of MG132 (Figure 5D)."

sparser
"Furthermore, interaction of USP4 and Rheb was examined by immunoprecipitation assay (Figure  xref )."

sparser
"Since our data showed that Rheb ubiquitination was inhibited by EGF treatment (Fig.  xref ), we examined whether the interaction between USP4 and Rheb was affected by EGF treatment and found that EGF treatment promoted their interaction at both endogenous and exogenous level (Fig.  xref and Supplementary information, Fig.  xref )."

sparser
"Further investigation found that MA significantly inhibited the interaction between Rheb and USP4 in HEK293T cells (Figure  xref )."

sparser
"This finding was further validated in TDSCs, wherein MA significantly inhibited the interaction between USP4 and Rheb mediated by IL‐1β, in the presence of MG132 (Figure  xref )."

sparser
"To examine whether the phosphorylation of USP4 at Ser445 affects the interaction between USP4 and Rheb, we generated a USP4 dephospho-mimetic mutant (USP4-S445A) and a phospho-mimetic mutant (USP4-S445D)."

sparser
"However, our data showed that only USP4 interacted with Rheb (Supplementary information, Fig. S xref )."

sparser
"Moreover, AKT inhibitor (MK2206) disrupted the interaction between USP4 and Rheb (Supplementary information, Fig.  xref ), and promoted Rheb ubiquitination (Supplementary information, Fig.  xref )."

sparser
"The interaction between USP4 and Rheb in cells was confirmed by both in vivo co-IP assay and in vitro GST pull down assay (Fig.  xref )."
USP4 phosphorylates RHEB.
| 1 1
USP4 phosphorylates RHEB. 1 / 2
| 1 1

reach
"Moreover, in LPS treated AML12 cells, LPS induced USP4, inflammatory and fibrotic cytokines, phosphorylated mTOR and Rheb."
USP4 deubiquitinates RHEB.
1 | 1
USP4 leads to the deubiquitination of RHEB. 1 / 2
1 | 1

reach
"Thus, we propose a mechanistic model whereby Rheb mediated mTORC1 activation is dictated by a dynamic opposing act between Rheb ubiquitination and deubiquitination that are catalyzed by RNF152 and USP4 respectively."
USP4 activates RHEB.
| 1 1
USP4 activates RHEB. 2 / 2
| 1 1

sparser
"During growth factor deficiency, the E3 ubiquitin ligase RNF152 promotes the mono-ubiquitination and inactivation of Rheb, while upon growth factor stimulation, USP4 deubiquitinates and activates Rheb."

reach
"USP4 promotes the activation of Rheb by removing ubiquitin from it."
| 1 19
USP4 activates cell migration.
| 1 11
| 1 11

reach
"Collectively, these data demonstrated that USP4 promotes melanoma cell migration and invasion by promoting EMT."

reach
"USP15 enhances the tumorigenic effects of TGF-β in glioblastoma (80), while USP4 promotes TGF-β-induced EMT and cell migration in breast cancer."

reach
"USP4 has also been shown to target TRAF2 and TRAF6 inhibiting nuclear factor-kappaB (NF-kB) signalling and antagonizing lung cancer cell migration XREF_BIBR XREF_BIBR XREF_BIBR, suggesting a context dependent role in cancer."

reach
"Transwell assays showed that USP4 knockdown inhibited cell migration and invasion in MHCC97H and LM3 cells."

eidos
"Subsequently , Cao et al. further confirmed that USP4 can promote cell migration and invasion through relaxin / TGF-beta1 / smad2 / matrix metalloprotein-9 signaling pathway [ 92 ] ."

reach
"The migration and invasion assays showed that USP4 promotes human breast cancer cell migration and invasion by USP4 overexpression, and knockdown of USP4 by siRNA inhibits human breast cancer cell migration and invasion."

reach
"Moreover, USP4 upregulation promoted Huh7 and PLC/PRF/5 cell migration and invasion ability (P < 0.01 for all)."

reach
"In addition, USP4 depletion inhibits breast cancer cell migration, which is induced by AKT [13]."
| PMC

reach
"Using gene interference, we demonstrated that USP4 knockdown significantly inhibited HCC cell migration and invasion in vitro, and USP4 overexpression had the opposite results."

reach
"USP4 promotes ESCC cell migration and invasion."
USP4 inhibits cell migration.
| 8

reach
"Furthermore, silencing of USP4 significantly rescued FBXO3- or FBXO3 -induced cell migration in MDA-MB-231 cells (Figs 3L, S2E, and S2F)."

reach
"USP4 has previously been confirmed to target TRAF2 and TRAF6 for deubiquitination and it has been established that USP4 inhibits TNFalpha induced cancer cell migration 35."

reach
"AKT induced breast cancer cell migration could be inhibited by depletion of USP4 (Zhang et al., 2012)."

reach
"However, in breast cancer, USP4 was also recognized as a tumour suppressor for its up-regulatory effect on programmed cell death 4 (PDCD4) to restrain tumour growth.20 Moreover, USP4 was able to target TRAF2 and TRAF6 for deubiquitination and thereafter inhibited TNFalpha induced cancer cell migration.34 In the present study, we proved that USP4 expression was drastically increased in melanoma."

reach
"USP4 can inhibit NF-κB activation through deubiquitination of TRAF2 and TRAF6, thereby promoting cell migration and invasion in lung cancer (46)."

reach
"Moreover, AKT induced breast cancer cell migration was inhibited by USP4 depletion and TbetaRI kinase inhibition."

reach
"Also, the in vitro wound healing assay for cell migration showed that low expression of USP4 reduced cell migration."

reach
"USP4 can detach the K63-linked polyubiquitin chains from all these proteins to downregulate the p65/p50 activity in multiple cell lines and inhibit cell migration of pulmonary carcinoma (22,38,39)."
BRCA1 affects USP4
| 6 14
| 6 14

sparser
"Based on this, we then examined whether USP4 and BRCA1 could interact with each other in the absence of CtIP."

sparser
"To investigate the physiological significance of USP4-BRCA1 association, we analyzed the protein level and interaction between BRCA1 and USP4 during cell cycle."

sparser
"Immunoprecipitation result showed that the interaction between USP4 and BRCA1 is almost undetectable at early G1, and increases from late G1 through S, and peaks at G2/M, which concomitantly correlates with the levels of BRCA1 at these phases (Fig. xref )."

sparser
"This result is consistent with a role of USP4 in stabilizing BRCA1, suggesting that USP4 physiologically interacts with BRCA1 to control BRCA1 protein level during the progression of cell cycle."

sparser
"The Co-IP assay indicated that endogenous BRCA1 could interact with USP4 in a manner that is independent of its DUB activity (Supplementary Fig. xref )."

sparser
"This result indicates that USP4 can interact with both BARD1-unbound BRCA1(“free” BRCA1) and may also bind BRCA1/BARD1 heterodimer."

sparser
"This result suggests that USP4 can interact with BRCA1 in a manner independent of CtIP."

sparser
"Interestingly, the interaction between USP4 and BRCA1 was enhanced with IR/ doxorubicin treatment (Fig. xref ), suggesting their interactions might be DNA damage inducible."

sparser
"To further confirm the in vivo interaction between USP4 and BRCA1, Co-IP of endogenous USP4 and BRCA1 from MCF-10A cells were performed and the results showed that USP4 was efficiently co-immunoprecipitated with BRCA1, and vice versa (Fig. xref )."

reach
"USP4 physically interacts with and deubiquitinates BRCA1, thus saving BRCA1 from UPS-meditated ubiquitination and degradation."
USP4 affects USP4
| 15 1
USP4 activates USP4.
| 5
USP4 activates USP4. 5 / 7
| 5

reach
"Ectopic expression of sh-RNA-resistant USP4 reverses the effect of USP4 knockdown."

reach
"Ubiquitination of USP4 could physically block its interaction with CtIP or induce conformational change of USP4."

reach
"Furthermore, gastrodin significantly upregulated the expression of USP4 and increased the binding of USP4 to the insulin receptor.Considering the importance of the PI3K-Akt pathway in the pathogenesis of T2DM, we detected the effects of gastrodin on the PI3K-Akt pathway to further explore the underlying mechanism of gastrodin in ameliorating insulin resistance."

reach
"In contrast, USP4 overexpression increased USP4 mRNA and protein levels in KYSE180 cells (all P < 0.001) (Fig. 2B and Supplementary Fig. 1C, D)."

reach
"Together, these findings provided support for USP4 interactions with CtIP and MRN being critical for its DDR functions and for a model wherein USP4 auto-deubiquitylation promotes these interactions and thereby USP4 functions in DSB repair."
USP4 increases the amount of USP4.
| 4
USP4 increases the amount of USP4. 4 / 4
| 4

reach
"The results of IHC staining demonstrated that USP4 expression in xenograft tumors was decreased by USP4 downregulation but increased by USP4 overexpression (Supplementary Fig. 1E)."

reach
"Specific inhibitory siRNA of USP4 reduced USP4 level and the parameters mentioned above."

reach
"By inhibiting the expression of USP4, down-regulation of USP4 inhibited the proliferation, migration, and apoptosis of hypertrophic scar fibroblasts through the TGF-beta and Smad7 signaling pathway."

reach
"Reduced USP4 expression by si-USP4, verified by immunoblotting (Fig. 3C), led to a clear downregulation in KLF2 protein level in MM1.S/BTZ and NCI-H929/BTZ cells (Fig. 3D)."
USP4 phosphorylates USP4.
| 3
USP4 phosphorylates USP4. 3 / 3
| 3

reach
"They further showed that USP4 could interact with Akt at endogenous level, and phosphorylate USP4 in vitro and in vivo."

reach
"However, upon growth factor stimulation, AKT will phosphorylate both TSC2 and the deubiquitinase ubiquitin specific peptidase 4 (USP4), resulting in the release of Rheb from the inhibitory effect of the TSC complex [44]."

reach
"Direct association of USP4 with TβRI at the plasma membrane and USP4-mediated TβRI deubiquitylation are enhanced in response to Akt activation and Akt-mediated USP4 phosphorylation, and directly oppos[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 inhibits USP4.
| 1 1
USP4 inhibits USP4. 2 / 3
| 1 1

sparser
"These results indicated that USP4 inhibits antitumor immunity and that inhibition of USP4 may reshape the TME into an immunostimulatory microenvironment."

reach
"Of note, the overexpression of USP4 suppressed microglia proliferation, NO production, and the expression of the microglial marker IBA-1, indicating the adverse effects of USP4 on microglia activation."
USP4 decreases the amount of USP4.
| 2
USP4 decreases the amount of USP4. 2 / 2
| 2

reach
"Transient transfection of USP4 siRNA effectively reduced the expression of USP4 protein (XREF_FIG)."

reach
"The results of IHC staining demonstrated that USP4 expression in xenograft tumors was decreased by USP4 downregulation but increased by USP4 overexpression (Supplementary Fig. 1E)."
USP4 affects TRAF2
2 1 | 10 4
USP4 binds TRAF2.
2 | 2 4
2 | 2 1

reach
"We found that USP4 specifically interacts with TRAF2 and TRAF6, but not TRAF3."

sparser
"A study in the pulmonary carcinoma model reveals that USP4 interacts with K63-linked TRAF2 and deubiquitinates it to inhibit TNF-α-induced p65/p50 activation ( xref )."

reach
"Xiao et al. 's study added on to this by demonstrating USP4 's interaction and deubiquitination of TRAF2 and TRAF6, but not TRAF3, both in vivo, in HEK293T cells, and in vitro [XREF_BIBR]."
USP4 binds TRAF2 and TRAF6. 3 / 3
| 3

sparser
"Xiao et al.’s study added on to this by demonstrating USP4’s interaction and deubiquitination of TRAF2 and TRAF6, but not TRAF3, both in vivo, in HEK293 T cells, and in vitro [ xref ]."

sparser
"We found that USP4 specifically interacts with TRAF2 and TRAF6, but not TRAF3."

sparser
"It was confirmed that USP4 associates with TRAF2 and TRAF6, consistent with our results."
USP4 deubiquitinates TRAF2.
1 | 4
USP4 deubiquitinates TRAF2. 4 / 5
1 | 4

reach
"However, there is no evidence of how USP4 deubiquitinates TRAF6 and TRAF2 proteins; our results prove that USP4 targets TRAF6 for K48 linked deubiquitination."

reach
"For example, TNFAIP3, CYLD, USP3, USP4, USP15, USP25, and OTUD5 deubiquitinate key components of the IFN production pathway, including RIG-I, TRAF2, TRAF3, TRAF6, RIP1, and TRIF (reviewed in [93,94])."

reach
"Interestingly, USP4 deubiquitinates not only TRAF2 but also TRAF6 and leads to the regulation of cell migration [12]."
| PMC

reach
"USP4 deubiquitinates TRAF2 and TRAF6, but not TRAF3, and it also rescues IkappaBalpha from degradation in TNFalpha induced HEK cells [XREF_BIBR]."
USP4 activates TRAF2.
| 4
USP4 activates TRAF2. 4 / 4
| 4

reach
"However, in breast cancer, USP4 was also recognized as a tumour suppressor for its up-regulatory effect on programmed cell death 4 (PDCD4) to restrain tumour growth.20 Moreover, USP4 was able to target TRAF2 and TRAF6 for deubiquitination and thereafter inhibited TNFalpha induced cancer cell migration.34 In the present study, we proved that USP4 expression was drastically increased in melanoma."

reach
"Recently, Xiao et al reported that USP4 targeted TRAF2 and TRAF6 for deubiquitination and inhibited the migration of tumor necrosis factor-alpha (TNF-alpha)-stimulated cancer cells."

reach
"USP4 has also been shown to target TRAF2 and TRAF6 inhibiting nuclear factor-kappaB (NF-kB) signalling and antagonizing lung cancer cell migration XREF_BIBR XREF_BIBR XREF_BIBR, suggesting a context dependent role in cancer."

reach
"USP4 has previously been confirmed to target TRAF2 and TRAF6 for deubiquitination and it has been established that USP4 inhibits TNFalpha induced cancer cell migration 35."
USP4 affects RIGI
2 1 | 10 4
USP4 binds RIGI.
2 | 2 4
2 | 1 4

sparser
"Several USPs can modulate both K63 and K48-linked polyubiquitination while USP4 can interact with RIG-I and target its K48-linked polyubiquitination and stabilize its expression to upregulate IFN-β expression then modify antiviral innate immune responses [ xref – xref ]."

reach
"Furthermore, whereas our results showed that USP15 efficiently interacted with TRIM25 specifically in infected cells, USP4 constitutively interacts with RIG-I."

sparser
"USP4 can directly target RIG-I and interact with RIG-I ( Wang et al., 2013 )."

sparser
"USP4 interacts with RIG-I to remove the K48-linked polyubiquitination conjugate from RIG-I, thereby maintaining RIG-I stability and then acting antiviral functions [ 15 ]."

sparser
"USP4 interacts with RIG-I and removes K48-linked polyubiquitination chains resulting in the stabilization of RIG-I ( Wang et al., 2013 )."
USP4 binds RIGI and DUSP domain. 1 / 1
| 1

reach
"Moreover, whereas USP4 binds through its N-terminal DUSP domain to RIG-I, our study showed that the C-terminal His Box of USP15 interacted with the B-boxes of TRIM25."
USP4 activates RIGI.
| 5
USP4 activates RIGI. 5 / 5
| 5

reach
"In contrast, USP4 and USP15 enhance the stability of RIG-I by reducing K48-linked ubiquitylation."

reach
"On the other hand, USP4 and USP15 enhance the stability of RIG-I and TRIM25, respectively, by proteolytically cleaving K48 linked ubiquitylation from these molecules XREF_BIBR, XREF_BIBR."

reach
"In contrast, USP4 and USP15 enhance the stability of RIG-I by hydrolyzing the K48-linked ubiquitin chain and exerting a positive regulatory effect ."

reach
"Ubiquitin-specific protease (USP4), a key modulator of RLR signaling pathway, increases the stability of RIG-I protein through deubiquitination and further promotes the production of IFN-I (57)."

reach
"Deubiquitinase USP4 and USP15 can increase the stability of RIG-I and TRIM25 by decreasing their K48-linked ubiquitination (Wang et al., 2013; Pauli et al., 2014)."
USP4 deubiquitinates RIGI.
1 | 3
USP4 deubiquitinates RIGI. 3 / 4
1 | 3

reach
"For example, TNFAIP3, CYLD, USP3, USP4, USP15, USP25, and OTUD5 deubiquitinate key components of the IFN production pathway, including RIG-I, TRAF2, TRAF3, TRAF6, RIP1, and TRIF (reviewed in [93,94])."

reach
"USP4 deubiquitinates and stabilizes RIG-I to promote type I IFN induction after viral infection [83]."

reach
"RIG-I can be ubiquitinated and degraded by RNF125 (Ring Finger Protein 125) and deubiquitinated and stabilized by USP4."
USP4 affects PPIA
5 1 | 8 4
USP4 binds PPIA.
5 | 7 4
5 | 7 4

reach
"Subsequently, the USP4 and CypA complex activated the MAPK signaling pathway and prevented CrkII phosphorylation."

reach
"An endogenous Co-IP assay was performed in MHCC97H cells, and the results showed that endogenous USP4 forms a complex with endogenous CypA in MHCC97H cells."

sparser
"The results revealed that USP4 forms a complex with CypA, both endogenously and exogenously, and is responsible for CypA stabilization via deubiquitination."

reach
"To determine whether USP4 regulates cell pathways depends on CypA in HCC, we next examined the USP4 and CypA complex and related protein levels in MHCC97H and Huh7 cells using western blotting."

reach
"The results revealed that USP4 forms a complex with CypA, both endogenously and exogenously, and is responsible for CypA stabilization via deubiquitination."

sparser
"We observed that USP4 interacted with CypA and inhibited CypA degradation via deubiquitination in HCC cells."

reach
"To find the downstream mechanism of the USP4 and CypA complex in HCC development, the MAPK and CrkII signaling pathways were chosen to test in the current study."

reach
"We presumed that might be because the USP4 and CypA complex does not increase the active form of CrkII directly in HCC cells, but inhibits the formation of its inactive form and disrupts the balance between the two molecules."

sparser
"An endogenous Co-IP assay was performed in MHCC97H cells, and the results showed that endogenous USP4 forms a complex with endogenous CypA in MHCC97H cells (Fig.  xref )."

reach
"We observed that USP4 interacted with CypA and inhibited CypA degradation via deubiquitination in HCC cells."
USP4 deubiquitinates PPIA.
1 | 1
USP4 deubiquitinates PPIA. 1 / 2
1 | 1

reach
"Consistently, deubiquitylation of CYPA by USP4 promotes a poor prognosis of hepatocellular carcinoma [276]."
USP4 affects CENPF
| 1 17
| 1 17

sparser
"Taken together, our data showed that a novel USP4-CENPF axis played an important regulatory role in CRC metastasis and may serve as a potential target for CRC treatment."

sparser
"Mechanically, USP4 interacts with CENPF and decreases CENPF ubiquitination levels, thus stabilizing it."

sparser
"Among the candidates, USP4 could interact with CENPF."

sparser
"These data demonstrated that USP4 interacts with CENPF and facilitates ubiquitination of CENPF, stabilizing it and prolonging its lifespan when overexpressed."

sparser
"Expanding on previous discoveries linking CENPF and USP4 to CRC patient prognosis and their involvement in CRC metastasis regulation, we explored the prognostic relevance of USP4-CENPF association."

sparser
"To confirm the relevance of the USP4-CENPF interaction, we first analyzed protein expression of USP4 and CENPF in our clinical samples from two different Cohort."

sparser
"Second, the role of the CENPF-USP4 axis in CRC metastasis has been identified, but the specific downstream molecular mechanisms remain unclear and require further investigation, In particular, the role of autophagy activation in mediating CRC metastasis through CENPF requires more in-depth exploration."

sparser
"In summary, our groundbreaking research, for the first time, has unveiled CENPF as a novel promoter of CRC metastasis and elucidate the molecular mechanism of the interaction between CENPF and USP4 in inducing migration and invasion of colorectal cancer cells, evidenced from molecular, cellular, animal models, and clinical specimens."

sparser
"After identifying the interaction between USP4 and CENPF, we further examined the effectiveness of USP4 on the CENPF mediated enhanced CRC migration, invasion, and metastasis capacity."

sparser
"Taken together, this study describes a novel USP4-CENPF signaling axis which is crucial for CRC metastasis, potentially serving as a therapeutic target and a promising prognostic biomarker for CRC."
IRF4 affects USP4
3 | 7 8
3 | 7 8

reach
"To conclude, this study indicated that USP4 interacts with and deubiquitinates IRF4, and also stabilizes IRF4 protein and promotes IRF4 function to facilitate IL-4 expression in Th2 cells, which may be associated with the pathological process of RHD."

sparser
"These results demonstrated that USP4 and IRF4 interact directly with each other."

sparser
"The association of USP4 and IRF4 was corroborated by reverse co-immunoprecipitation experiment using the anti-Myc antibody to immunoprecipitate IRF4 and anti-Ha to detect the associated Ha-IRF4 by western blot analysis ( xref )."

sparser
"We found that immunoprecipitation of USP4 using the anti-USP4 antibody resulted in the co-immunoprecipitation of Myc-IRF4 as detected by immunoblotting with anti-Myc antibodies, indicating that USP4 interacts with IRF4 in Th2 cells ( xref )."

sparser
"In this study, we not only found an interaction between USP4 and IRF4, but also proved the effect of USP4 on the stabilization and deubiquitination of IRF4."

reach
"Here, the interaction between USP4 and IRF4 were analyzed by co-immunoprecipitation assay."

reach
"Our results validated the interaction between USP4 and IRF4, and effects of USP4 on stabilization and deubiquitination of IRF4 were also found."

reach
"On the whole, our data indicate that USP4 interacts with and deubiquitinates IRF4, and also stabilizes IRF4 protein and promotes IRF4 function to facilitate IL-4 expression in Th2 cells, which may be related to the pathological process of RHD."

reach
"In this study, we not only found an interaction between USP4 and IRF4, but also proved the effect of USP4 on the stabilization and deubiquitination of IRF4."

reach
"Interaction between USP4 and IRF4."
DNPEP affects USP4
1 1 | 9 7
DNPEP binds USP4.
1 | 6 7
1 | 6 7

sparser
"Mechanistically, FBXO3 disrupts the interaction between USP4 and aspartyl aminopeptidase (DNPEP), thereby protecting USP4 from DNPEP-mediated degradation."

reach
"FBXO3 binds to USP4 and disrupts the interaction between USP4 and DNPEP, leading to stabilization of USP4 and Twist1."

sparser
"FBXO3 binds to USP4 and disrupts the interaction between USP4 and DNPEP, leading to stabilization of USP4 and Twist1."

sparser
"It has been reported that aspartyl aminopeptidase (DNPEP) can bind to and degrade USP4 [ xref ]."

sparser
"Thus, we suspected that FBXO3 may act to block DNPEP interaction with USP4."

reach
"Furthermore, knockdown of FBXO3-induced down-regulation of USP4 could not be rescued by either lysosome inhibitor (chloroquine) or proteasome inhibitor (MG132) (Fig 4A and 4B), suggesting that knockdown of FBXO3-induced down-regulation of USP4 is unlikely to be at the transcriptional levels or at the levels of the proteasome-/lysosome-mediated protein stability.It has been reported that aspartyl aminopeptidase (DNPEP) can bind to and degrade USP4 [38]."

sparser
"Importantly, the elevation of FBXO3 expression significantly reduced complex formation between USP4 and DNPEP, whereas silencing of FBXO3 increased endogenous DNPEP binding to USP4 in MDA-MB-231 cells ( xref )."

sparser
"Together, these results indicate that FBXO3 binds USP4 to interfere with the interaction between USP4 and DNPEP, leading to stabilization of the USP4 protein."

reach
"Notably, aspartyl aminopeptidase (DNPEP) can bind to, hydrolyze, and destabilize USP4 [38]."

reach
"Importantly, the elevation of FBXO3 expression significantly reduced complex formation between USP4 and DNPEP, whereas silencing of FBXO3 increased endogenous DNPEP binding to USP4 in MDA-MB-231 cells (Fig 4H and 4I)."
DNPEP inhibits USP4.
| 2
DNPEP inhibits USP4. 2 / 2
| 2

reach
"DNPEP negatively regulates USP4."

reach
"As shown in Fig 4D, knockdown of FBXO3-mediated down-regulation of USP4 could be effectively rescued by treatment of Tosedostat, an aminopeptidase inhibitor, suggesting that FBXO3 may stabilize USP4 protein by preventing DNPEP-induced USP4 degradation."
DNPEP decreases the amount of USP4.
1 | 1
DNPEP decreases the amount of USP4. 1 / 2
1 | 1

reach
"Our results showed that knockdown of DNPEP indeed prolonged the half-life of USP4 protein and increased USP4 and Twist1 expression (Figs 4C, S3C, and S3D)."
CTNNB1 affects USP4
5 | 4 9
5 | 3 9

sparser
"USP4 was detected in β-catenin IP materials ( xref ), and β-catenin was found in USP4 IP materials ( xref ), suggesting that USP4 and β-catenin directly bind to each other."

sparser
"We further investigated the physical interaction between β-catenin and USP4 through co-immunoprecipitation."

sparser
"Taken these results together, it was concluded that β-catenin activity is primarily associated with the C-terminal catalytic domain of USP4."

sparser
"These results suggest the association of the C-terminus of USP4(261–963) with a subset of β-catenin in the nucleus as evidenced by the observed binding ( Figure 4 B)."

reach
"We further investigated the physical interaction between beta-catenin and USP4 through co-immunoprecipitation."

sparser
"The interaction of endogenous β-catenin and USP4 was confirmed in 293T and HCT116 cells, a colon cancer cell line harboring stable β-catenin that has a mutation at S45 phosphorylation site ( Figure 1 [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"To further investigate the association of USP4 and β-catenin in colon cancers, we examined 30 human colon specimens (cancer and normal)."

sparser
"Immunohistochemical analysis of colon cancer tissues supported the idea that the expression of β-catenin and USP4 are closely associated with colorectal cancer."

sparser
"We observed that both USP4(140–572) and USP4(261–963) bind to β-catenin, thus the second UBL domain (483–571) seems to have a major role in interaction with β-catenin ( Figure 4 )."

reach
"Thus, we examined the direct interaction between USP4 and beta-catenin in our metastatic model system."
USP4 binds CTNNB1 and UBL domain. 1 / 1
| 1

reach
"We observed that both USP4 (140-572) and USP4 (261-963) bind to beta-catenin, thus the second UBL domain (483-571) seems to have a major role in interaction with beta-catenin."
CENPF affects USP4
| 1 17
| 1 17

sparser
"Taken together, our data showed that a novel USP4-CENPF axis played an important regulatory role in CRC metastasis and may serve as a potential target for CRC treatment."

sparser
"Mechanically, USP4 interacts with CENPF and decreases CENPF ubiquitination levels, thus stabilizing it."

sparser
"Among the candidates, USP4 could interact with CENPF."

sparser
"These data demonstrated that USP4 interacts with CENPF and facilitates ubiquitination of CENPF, stabilizing it and prolonging its lifespan when overexpressed."

sparser
"Expanding on previous discoveries linking CENPF and USP4 to CRC patient prognosis and their involvement in CRC metastasis regulation, we explored the prognostic relevance of USP4-CENPF association."

sparser
"To confirm the relevance of the USP4-CENPF interaction, we first analyzed protein expression of USP4 and CENPF in our clinical samples from two different Cohort."

sparser
"Second, the role of the CENPF-USP4 axis in CRC metastasis has been identified, but the specific downstream molecular mechanisms remain unclear and require further investigation, In particular, the role of autophagy activation in mediating CRC metastasis through CENPF requires more in-depth exploration."

sparser
"In summary, our groundbreaking research, for the first time, has unveiled CENPF as a novel promoter of CRC metastasis and elucidate the molecular mechanism of the interaction between CENPF and USP4 in inducing migration and invasion of colorectal cancer cells, evidenced from molecular, cellular, animal models, and clinical specimens."

sparser
"After identifying the interaction between USP4 and CENPF, we further examined the effectiveness of USP4 on the CENPF mediated enhanced CRC migration, invasion, and metastasis capacity."

sparser
"Taken together, this study describes a novel USP4-CENPF signaling axis which is crucial for CRC metastasis, potentially serving as a therapeutic target and a promising prognostic biomarker for CRC."
USP4 affects TUT1
2 | 11 4
USP4 binds TUT1.
2 | 4 4
2 | 4 4

reach
"Next, we investigated whether SART3 affects the binding of USP4 to TUT1."

sparser
"In this study, our findings indicate that USP4 binds to and deubiquitinates TUT1."

reach
"We presumed that SART3 regulates the binding of USP4 with TUT1 similar to the USP15-TUT1 interaction."

reach
"Intriguingly, unlike in the case of USP15-TUT1, we did not observe a strong binding between USP4 and TUT1 in the presence of SART3."

sparser
"Since U6-snRNA plays an important role in regulating spliceosome cascade, it is likely that the USP4-TUT1 axis participates in the regulation of splicing, either in coordination with or complementary [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Taken together, our data suggest that USP4, similarly to USP15, regulates TUT1 subnuclear localization together with SART3 and increases the U6-snRNA level.In this study, our findings indicate that US[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"Next, we investigated whether SART3 affects the binding of USP4 to TUT1."

sparser
"We presumed that SART3 regulates the binding of USP4 with TUT1 similar to the USP15-TUT1 interaction."
USP4 deubiquitinates TUT1.
| 5
USP4 deubiquitinates TUT1. 5 / 5
| 5

reach
"Since USP4 shares several substrates with USP15, TUT1 is a potent candidate to be deubiquitinated by USP4.In this study, we report that USP4 deubiquitinates TUT1."

reach
"Therefore, SART3 predominantly binds to USP15, and this complex may exhibit a higher preference for binding to TUT1 compared to USP4 alone.Next, we examined whether USP4 deubiquitinates TUT1."

reach
"Next, we investigated whether USP4 and USP15 additively deubiquitinate TUT1."

reach
"Moreover, the co-expression of USP4 and USP15 led to an additive enhancement of deubiquitination, despite the effect not being dramatic ( Fig. 3 B), indicating that both enzymes control TUT1 deubiquit[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Taken together, our data suggest that USP4, similarly to USP15, regulates TUT1 subnuclear localization together with SART3 and increases the U6-snRNA level.In this study, our findings indicate that US[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 activates TUT1.
| 2
USP4 activates TUT1. 2 / 2
| 2

reach
"As a result of SART3 co-expression with USP4, the efficiency of TUT1 translocation was increased ( Fig. 4 E and F), demonstrating that USP4 induces TUT1 subnuclear redistribution in a similar manner o[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"In addition, co-expression of USP4 augmented TUT1-dependent U6-snRNA upregulation ( Fig. 4 G)."
USP4 affects TRIM21
4 1 1 | 4 3
USP4 binds TRIM21.
4 1 | 3 3
4 1 | 3 3

reach
"Another possibility is that the Ro52 and Usp4 complex regulates the movements of the cytoplasmic bodies by ubiquitination and deubiquitination."

sparser
"The proteasome has both ubiquitin ligases and DUBs that associate with it (Crosas et al., 2006) , and several DUB-ligase pairs interact directly, including BRCC36-BRCA1, BAP1-BRCA1, USP4-Ro52, USP7-MDM2, USP8-GRAIL, USP20-pVHL, USP33-pVHL and USP44-APC (Kee and Huibregtse, 2007; Marfany and Denuc, 2008; Ventii and Wilkinson, 2008) ."

sparser
"For example, USP4 associates with the E3 ligase Ro52 forming, as observed here for dUSP36-D and AGO, a DUB/E3 ligase pair that transregulates each other by ubiquitination and deubiquitination ( xref )."

reach
"USP4 was shown to self-deubiquitinate after being ubiquitinated by E3 ligase Ro52, and it was suggested that USP4 forms a heterodimeric protein complex with Ro52 in which both proteins transregulate each other."

sparser
"The two proteins were shown to co-localize to cytoplasmic rod-like structures in HEK293 cells, suggesting that Ro52 interacts with USP4 in mammalian cells to form a heteromeric protein complex that mediates both ubiquitination and deubiquitination of substrates [ xref ]."

reach
"The two proteins were shown to co-localize to cytoplasmic rod like structures in HEK293 cells, suggesting that Ro52 interacts with USP4 in mammalian cells to form a heteromeric protein complex that mediates both ubiquitination and deubiquitination of substrates [XREF_BIBR]."
USP4 deubiquitinates TRIM21.
1 | 1
USP4 deubiquitinates TRIM21. 1 / 2
1 | 1

reach
"In the cytosol, USP4 deubiquitinates the member of many vital cell signaling pathways, e.g., NF-κB [77], TGF-β [54], Wnt/β-catenin [78], and p53 [79] as well as adenosine A2A receptor [80] and the E3 ligase TRIM21 [81]."
USP4 affects Neoplasms
| 1 16
USP4 activates Neoplasms.
| 1 12
| 1 12

reach
"Studies of USP4 knockout mice revealed that USP4 upregulates tumor growth in an mTORC1-dependent manner."

reach
"In contrast, depletion of USP4 significantly inhibited proliferation, migration, and invasion abilities in vitro and suppressed tumor growth and metastasis in vivo."

reach
"USP4 induces ESCC cell proliferation and tumor growth."

eidos
"Meanwhile , knockdown of USP4 led to reduced tumor size , as well as reduced expression level of p-S6 , which could be rescued by the expression of Rheb-K8R ( Fig. 7d-f ; Supplementary information , Fig. S7b ) ."

reach
"Knockdown of USP4 significantly inhibited tumor growth in C57BL/6 mice ( Fig. 6 A–C)."

reach
"Together, these findings indicate that USP4 promotes cell proliferation and tumor growth in ESCC."

reach
"Furthermore, IRF3 knockdown rescued the reduced tumor growth caused by USP4 inhibition ( Fig. 6 I–K), and also decreased total T cells and CD8 + T cells infiltration while increased Tregs infiltration[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"USP4 modulates tumor growth factor TGF-β signaling to regulate immunosuppressive pathways in the tumor microenvironment."

reach
"In vivo, treatment with U0126 further enhanced the suppression of tumor growth induced by downregulation of USP4 (Fig. 7D–F)."

reach
"In our study, we indicated that the tumor-promoting role of USP4 in PC relied on interacting with TRAF6 and the activation of NF-κB signaling pathway."
USP4 inhibits Neoplasms.
| 4
| 4

reach
"In addition, Ye et al. suggested that USP4 had anti-cancer effect in breast cancer, and found that USP4 could inhibited the growth of tumors in a mouse tumor xenograft model45."

reach
"In contrast, knockdown of USP4 markedly inhibited gastric cancer cell growth, and suppressed the tumor growth of gastric cancer."

reach
"Consistently, USP4 silencing repressed tumor growth and metastasis in an ESCC nude mouse model in vivo."

reach
"Further research has demonstrated that USP4 suppresses tumor growth by interacting with RIP1, deubiquitinating K63-linked RIP1 and inhibiting NF-κB activation, resulting in tumor suppressor effects (58)."
PPIA affects USP4
5 | 7 4
5 | 7 4

reach
"Subsequently, the USP4 and CypA complex activated the MAPK signaling pathway and prevented CrkII phosphorylation."

reach
"An endogenous Co-IP assay was performed in MHCC97H cells, and the results showed that endogenous USP4 forms a complex with endogenous CypA in MHCC97H cells."

sparser
"The results revealed that USP4 forms a complex with CypA, both endogenously and exogenously, and is responsible for CypA stabilization via deubiquitination."

reach
"To determine whether USP4 regulates cell pathways depends on CypA in HCC, we next examined the USP4 and CypA complex and related protein levels in MHCC97H and Huh7 cells using western blotting."

reach
"The results revealed that USP4 forms a complex with CypA, both endogenously and exogenously, and is responsible for CypA stabilization via deubiquitination."

sparser
"We observed that USP4 interacted with CypA and inhibited CypA degradation via deubiquitination in HCC cells."

reach
"To find the downstream mechanism of the USP4 and CypA complex in HCC development, the MAPK and CrkII signaling pathways were chosen to test in the current study."

reach
"We presumed that might be because the USP4 and CypA complex does not increase the active form of CrkII directly in HCC cells, but inhibits the formation of its inactive form and disrupts the balance between the two molecules."

sparser
"An endogenous Co-IP assay was performed in MHCC97H cells, and the results showed that endogenous USP4 forms a complex with endogenous CypA in MHCC97H cells (Fig.  xref )."

reach
"We observed that USP4 interacted with CypA and inhibited CypA degradation via deubiquitination in HCC cells."
USP4 affects Wnt
| 5 9
USP4 activates Wnt.
| 3 4
USP4 activates Wnt. 7 / 8
| 3 4

reach
"In addition to these newly identified nuclear functions, both USP4 and USP15 are well known to function in the cytosol, i.e. USP4 modulates the Wnt and beta-catenin, NF-kappaB, p53 and TGF-beta signaling pathways while USP15 performs functions in the TGF-beta receptor and NF-kappaB signaling pathways."

eidos
"However , later studies demonstrated that USP4 enhanced Wnt signaling through stabilizing and facilitating nuclear localization of beta-catenin , especially in cancer ( Yun et al ., 2015 ; Hwang et al ., 2016 ) ."

eidos
"According to a study , USP4 activates Wnt signaling by deubiquitinating and stabilizing beta-catenin ( Yun et al ., 2015 ) ."

reach
"In colon cancer and neuroblastoma cells, it had been revealed that USP4 activates the Wnt pathway by stabilizing β-catenin as a deubiquitinase [12,38] ."

reach
"However, in contrast to the previous work RNAi depletion of USP4 caused an up-regulation of Wnt signalling."

reach
"However, later studies demonstrated that USP4 enhanced Wnt signaling through stabilizing and facilitating nuclear localization of beta-catenin, especially in cancer."

eidos
"( D ) Wnt signaling : USP4 enhances Wnt signaling through deubiquitinating and stabilizing P-catenin ."
USP4 inhibits Wnt.
| 2 4
USP4 inhibits Wnt. 6 / 6
| 2 4

eidos
"By contrast , USP4 was reported to inhibit Wnt signaling by deubiquitinating the polyubiquitin chains on dishevelled ( Dvl / Dsh ) and blocking Wnt3a-induced osteoblast differentiation and bone formation ( Zhou et al ., 2016 ) ."

reach
"USP4 negatively regulates Wnt by interacting with Nemo-like kinases [40]."

reach
"In this study, we found ubiquitin specific peptidase 4 (USP4) to strongly inhibit the Wnt and beta-catenin signaling by removing Lysine 63 linked poly-ubiquitin chain from Dishevelled (Dvl)."

reach
"In contrast, USP4 was also reported to inhibit Wnt signaling."

reach
"USP4 negatively regulates Wnt signaling by interacting with Nemolike kinase [XREF_BIBR] and USP15 promotes beta-catenin degradation through the stabilization of adenomatous polyposis coli (APC), a negative regulator of Wnt mediated transcription [XREF_BIBR]."

eidos
"Conversely , USP4 inhibits Wnt signaling by deubiquitinating Dvl ."
USP4 deubiquitinates Wnt.
| 1
USP4 deubiquitinates Wnt. 1 / 1
| 1

reach
"USP4 also deubiquitinates other Wnt signaling components such as Nik and TCF4 [81]."
USP4 affects TWIST1
1 1 | 7 6
USP4 binds TWIST1.
1 | 6
1 | 6

sparser
"To this end, we first asked whether USP4 can form a stable protein complex with Twist1."

sparser
"Co-Immunoprecipitation assay showed that USP4 interacted with Twist1 ( xref D)."

sparser
"Our data indicate that USP4 stabilizes Twist1 to promote lung cancer cell stemness, which prompted us to verify the clinical relevance of USP4Twist1 in human lung cancer."

sparser
"Together, these results indicate that the USP4Twist1 axis plays a critical role in lung cancer stemness and clinical prognoses ( xref E)."

sparser
"In this study, we uncover that USP4 is a novel deubquitinase of Twist1 and that silencing of Twist dramatically inhibits USP4-induced stemness of lung cancer cells, suggesting that the USP4Twist1 axis plays a critical role in lung cancer stemness."

sparser
"Thus, targeting the USP4Twist1 axis may represent a novel therapeutic approach for lung cancer treatment."
USP4 increases the amount of TWIST1.
| 3
USP4 increases the amount of TWIST1. 3 / 3
| 3

reach
"Li et al. revealed that USP4 promoted lung cancer cell stemness by stabilizing Twist1 protein expression [22]."

reach
"These results indicate that FBXO3 increases Twist1 and USP4 protein expression in an E3 ligase activity-independent manner, in which the FBXO3-ApaG domain is indispensable.To investigate the causal effects of USP4 on FBXO3-induced Twist1 expression and cell migration, we performed rescuing experiments."

reach
"The current study provides evidence that USP4 increases the protein levels of Twist1 and β-catenin, subsequently promoting stemness and drug resistance in CRC."
USP4 deubiquitinates TWIST1.
1 | 2
USP4 deubiquitinates TWIST1. 2 / 3
1 | 2

reach
"Moreover, TWIST1 is deubiquitinated by USP4 in NSCLC cells, resulting in an increased stemness of NSCLC cells [18]."

reach
"We have previously shown that USP4 can deubiquitinate and stabilize Twist1 protein [23], so we then asked whether USP4 is involved in FBXO3-induced Twist1 stabilization."
USP4 inhibits TWIST1.
| 2
USP4 inhibits TWIST1. 2 / 2
| 2

reach
"As shown in Fig 3J, restoration of USP4 effectively reversed FBXO3 knockdown-mediated down-regulation of Twist1 and β-catenin."

reach
"Furthermore, silencing of USP4 rescued p110α -mediated up-regulation of Twist1 and β-catenin, accompanied with reduced cell migration (Figs 6F–6H, S5C, and S5D)."
USP4 affects TNF
| 12
USP4 inhibits TNF.
| 9
USP4 inhibits TNF. 9 / 11
| 9

reach
"USP4 has been shown to inhibit TNFα-induced cancer cell migration and breast cancer cell growth through upregulation of programmed cell death 4 (PCD4) [31] ."

reach
"In another study, USP4 was shown to negatively regulate TNF-induced NF-κB activation by de-ubiquitinating TRAF2 [114] ."

reach
"USP4 was identified by studies to negatively regulate both TNF-alpha- and IL-1beta-induced NF-kappaB activation [XREF_BIBR, XREF_BIBR, XREF_BIBR]."

reach
"Moreover, we found that USP4 targets HDAC2 to downregulate tumor necrosis factor-alpha (TNFalpha)-induced NF-kappaB activation."

reach
"Notably, USP4 overexpression antagonized OGD/R-induced IL-1β, IL-6, and TNF-α transcriptional levels (Fig. 3A–C)."

reach
"Recently, also USP4 was shown to downregulate TNF-induced NF-κB activation in two independent studies."

reach
"Consequently, knockdown of USP4 enhanced TNF-induced NF-κB activation."

reach
"USP4 negatively regulates TNFalpha induced, K63 linked TAK1 polyubiquitination and TAK1 mediated IKK and NF-kappaB activation [XREF_BIBR]."

reach
"Additionally, the overexpression of USP4 suppressed the release of microglia activation-induced pro-inflammatory cytokines, including IL-1beta, IL-6, and TNF-alpha."
USP4 activates TNF.
| 3
USP4 activates TNF. 3 / 4
| 3

reach
"Ubiquitin specific protease 4 (USP4) targets TRAF2 and TRAF6 for deubiquitination and inhibits TNFalpha induced cancer cell migration."

reach
"Notably, USP4 overexpression antagonized OGD/R-induced IL-1β, IL-6, and TNF-α transcriptional levels (Fig. 3A–C)."

reach
"As shown in Fig. 2 B, USP4 overexpression significantly promotes cell apoptosis in FaDu cells in responses to TNF-α with CHX."
USP4 affects PTP4A3
2 1 | 2 8 1
USP4 binds PTP4A3.
2 | 1 2 1
2 | 1 2 1

sparser
"In addition, USP4, which is elevated in gastric and rectal cancer, interacts with PRL-3 and increases the stability of PRL-3, promoting NF-κB signaling and cell viability [ xref , xref ]."

reach
"Mechanistically, we observed that USP4 interacted with and stabilized PRL-3 via deubiquitination."

reach
"Xing et al. reported that USP4 interacted with and catalytically stabilized PRL-3."

trips
"Mechanistically, we observed that USP4 interacted with and stabilized PRL-3 via deubiquitination."
USP4 deubiquitinates PTP4A3.
1 | 1 4
USP4 deubiquitinates PTP4A3. 5 / 6
1 | 1 4

trips
"Mechanistically, we observed that USP4 interacted with and stabilized PRL-3 via deubiquitination."

reach
"USP4 can also deubiquitylate PRL-3 to lead to AKT activation, E-cadherin reduction, and distant metastasis [30]."

reach
"Deubiquitinating PRL-3 by USP4 leads to AKT activation and E-cadherin reduction in colorectal cancer, where an elevated level of USP4 is associated with tumor size, differentiation, distant metastasis, and poor survival."

reach
"In CRC tissues, USP4 has been found to stabilize PRL-3 by deubiquitinating PRL-3, activating PI3K/AKT pathway and down-regulating E-cadherin, thereby promoting tumor proliferation and metastasis (Xing et al., 2016)."

reach
"Specifically, up-regulated USP4 potentiated the growth and invasion of colorectal cancer though deubiquitination and stabilization of PRL-3.19 In addition, USP4 transduced Akt activation to TGF-beta signalling by deubiquitinating and stabilizing TGF-beta type I receptor, thus augmented breast cancer cell invasion and migration.33 These studies demonstrate USP4 as a powerful tumour promoter and an important determinant for canonical oncogenic signalling."
USP4 activates PTP4A3.
| 2
USP4 activates PTP4A3. 2 / 2
| 2

reach
"It was recently found that deubiquitinating enzyme USP4 promotes PRL-3 stabilization in colon cancer cells."

reach
"In addition, USP4, which is elevated in gastric and rectal cancer, interacts with PRL-3 and increases the stability of PRL-3, promoting NF-κB signaling and cell viability [51,60]."
USP4 affects NBN
| 8 6
| 8 4

reach
"USP4, for example, interacts directly with end resection factors CtIP and MRN [172], USP21 deubiquitinates and stabilizes BRCA2 to promote RAD51 binding and successful HR [173], and USP10 deubiquitinates and stabilizes p53 to promote its nuclear localization and apoptosis in response to DSBs [174]."

sparser
"The results that CtIP interacts with MRN complex and works together in DNA end resection prompt us to think whether USP4 could bind NBS1, which is indeed the case ( Figure 2 A)."

sparser
"In cells, NBS1 and USP4 can form a complex, and the interaction between USP4 and NBS1 was upregulated by IR ( Figure 2 B)."

reach
"In light of the above findings, we tested whether USP4 might physically interact with CtIP and/or MRN."

reach
"As shown in Figure 1 G, knockdown of CtIP by two different shRNAs did not affect USP4 recruitment to the DNA damage sites.The results that CtIP interacts with MRN complex and works together in DNA end[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"In cells, NBS1 and USP4 can form a complex, and the interaction between USP4 and NBS1 was upregulated by IR."

reach
"These results indicated that MRN complex binds USP4 and recruits USP4 to the DNA damage sites upon DNA damage."

reach
"USP4 binds CtIP and MRN complexes to regulate DDR and thereby promotes homologous recombination [42]."

sparser
"To further confirm that NBS1-USP4 interaction is indeed involved in NBS1-mediated USP4 recruitment, we stably transfected DR-GFP cells with NBS1 shRNA and reconstituted these cells with shRNA-resistan[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"The above results indicated that USP4-NBS1 interaction is indeed involved in USP4 recruitment."
| 2

sparser
"We and others report that USP4 interacts with CtIP and the MRE11RAD50NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites and DNA end resection ( xref , xref )."

sparser
"We also report that USP4 interacts with CtIP and the MRE11-RAD50-NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites."
USP4 affects AKT
| 12 3
USP4 binds AKT.
| 5 3
| 5 3

reach
"Conceivably, AKT directly interacts with USP4 for its phosphorylation and translocates nuclear USP4 to the membrane and thus maintains TbetaRI stability and possibly modulates TGF-beta induced EMT and MMT."

reach
"Interestingly, it was also found that Akt directly associates and phosphorylates USP4, and then induces the translocation of USP4 from the nucleus to the cytoplasm and plasmalemma for maintaining TbetaRI stability [XREF_BIBR]."

reach
"They further showed that USP4 could interact with Akt at endogenous level, and phosphorylate USP4 in vitro and in vivo."

sparser
"Conceivably, AKT directly interacts with USP4 for its phosphorylation and translocates nuclear USP4 to the membrane and thus maintains TβRI stability and possibly modulates TGF-β induced EMT/MMT."

sparser
"They further showed that USP4 could interact with Akt at endogenous level, and phosphorylate USP4 in vitro and in vivo."

sparser
"USP4 also directly associated with AKT and became phosphorylated by AKT on a conserved Ser445 motif."

reach
"As mentioned above, USP4 binds to and deubiquitinates the TGF-beta type I receptor and associates with AKT, leading to enhanced TGF-beta signalling and AKT induced breast cancer cell migration (Zhang [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Interestingly, AKT directly interacts and phosphorylates USP4, which then translocates from the nucleus to the plasma membrane where it stabilizes TGFbeta receptor I through direct interaction [XREF_BIBR]."
USP4 activates AKT.
| 3
USP4 activates AKT. 3 / 3
| 3

reach
"AKT regulation of mesothelial-to-mesenchymal transition in peritoneal dialysis is modulated by smurf2 and deubiquitinating enzyme USP4."

reach
"The deubiquitinating enzyme USP4 modulates AKT regulation of mesothelial-to-mesenchymal transition in peritoneal dialysis (Xiao et al., 2015)."

reach
"These data implied that Akt mediated MMT in PD via Smurf2 modulation and and or Smad7 degradation while conceivably maintaining the TbetaRI stability, most likely by the USP4."
USP4 inhibits AKT.
| 2
USP4 inhibits AKT. 2 / 2
| 2

reach
"Considering current results and previous known mechanism of USP, it can be hypothesized that USP4 is likely to regulate the function of key signaling proteins in myogenesis via protein-protein interac[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"We also found that the effect of USP4 knockdown enhances the AKT and p38 signaling that are known to be involved in myogenesis by activating transcription-regulatory activity of MyoD through a direct [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 dephosphorylates AKT.
| 2
USP4 leads to the dephosphorylation of AKT. 2 / 2
| 2

reach
"We observed that the USP4 knockdown significantly increased the phosphorylation of AKT and p38 ( Figs."

reach
"These data collectively suggest that USP4 inhibits the phosphorylation of AKT and consequently AKT signaling."
RHEB affects USP4
4 | 1 10
4 | 1 10

sparser
"Interestingly, our data showed that USP4-S445A barely bound to Rheb (Fig.  xref )."

reach
"This finding was further validated in TDSCs, wherein MA significantly inhibited the interaction between USP4 and Rheb mediated by IL‐1β, in the presence of MG132 (Figure 5D)."

sparser
"Furthermore, interaction of USP4 and Rheb was examined by immunoprecipitation assay (Figure  xref )."

sparser
"Since our data showed that Rheb ubiquitination was inhibited by EGF treatment (Fig.  xref ), we examined whether the interaction between USP4 and Rheb was affected by EGF treatment and found that EGF treatment promoted their interaction at both endogenous and exogenous level (Fig.  xref and Supplementary information, Fig.  xref )."

sparser
"Further investigation found that MA significantly inhibited the interaction between Rheb and USP4 in HEK293T cells (Figure  xref )."

sparser
"This finding was further validated in TDSCs, wherein MA significantly inhibited the interaction between USP4 and Rheb mediated by IL‐1β, in the presence of MG132 (Figure  xref )."

sparser
"To examine whether the phosphorylation of USP4 at Ser445 affects the interaction between USP4 and Rheb, we generated a USP4 dephospho-mimetic mutant (USP4-S445A) and a phospho-mimetic mutant (USP4-S445D)."

sparser
"However, our data showed that only USP4 interacted with Rheb (Supplementary information, Fig. S xref )."

sparser
"Moreover, AKT inhibitor (MK2206) disrupted the interaction between USP4 and Rheb (Supplementary information, Fig.  xref ), and promoted Rheb ubiquitination (Supplementary information, Fig.  xref )."

sparser
"The interaction between USP4 and Rheb in cells was confirmed by both in vivo co-IP assay and in vitro GST pull down assay (Fig.  xref )."
NBN affects USP4
| 8 6
| 8 4

reach
"USP4, for example, interacts directly with end resection factors CtIP and MRN [172], USP21 deubiquitinates and stabilizes BRCA2 to promote RAD51 binding and successful HR [173], and USP10 deubiquitinates and stabilizes p53 to promote its nuclear localization and apoptosis in response to DSBs [174]."

sparser
"The results that CtIP interacts with MRN complex and works together in DNA end resection prompt us to think whether USP4 could bind NBS1, which is indeed the case ( Figure 2 A)."

sparser
"In cells, NBS1 and USP4 can form a complex, and the interaction between USP4 and NBS1 was upregulated by IR ( Figure 2 B)."

reach
"In light of the above findings, we tested whether USP4 might physically interact with CtIP and/or MRN."

reach
"As shown in Figure 1 G, knockdown of CtIP by two different shRNAs did not affect USP4 recruitment to the DNA damage sites.The results that CtIP interacts with MRN complex and works together in DNA end[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"In cells, NBS1 and USP4 can form a complex, and the interaction between USP4 and NBS1 was upregulated by IR."

reach
"These results indicated that MRN complex binds USP4 and recruits USP4 to the DNA damage sites upon DNA damage."

reach
"USP4 binds CtIP and MRN complexes to regulate DDR and thereby promotes homologous recombination [42]."

sparser
"To further confirm that NBS1-USP4 interaction is indeed involved in NBS1-mediated USP4 recruitment, we stably transfected DR-GFP cells with NBS1 shRNA and reconstituted these cells with shRNA-resistan[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"The above results indicated that USP4-NBS1 interaction is indeed involved in USP4 recruitment."
| 2

sparser
"We and others report that USP4 interacts with CtIP and the MRE11RAD50NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites and DNA end resection ( xref , xref )."

sparser
"We also report that USP4 interacts with CtIP and the MRE11-RAD50-NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites."
HUWE1 affects USP4
4 | 7 2
4 | 7 2

reach
"USP4 interacts directly with and deubiquitinates ADP-ribosylatibon factor binding protein 1 (ARFBP1), which results in the stabilization of ARF-BP1 and the subsequent reduction of p53 levels."

reach
"USP4 negatively regulates p53 by binding to ARF-BP1 and deubiquitinates it thereby promoting ARF-BP1-dependent ubiquitination and degradation of p53."

reach
"USP4 interacts directly with and deubiquitinates ARF-BP1, leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels."

reach
"For example, USP4 interacts directly with and deubiquitinates ARF binding protein 1 (ARF-BP1), leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels."

reach
"USP4 interacts directly with and deubiquitinates ADP-ribosylatibon factor-binding protein 1 (ARF-BP1), leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels [12] ."

reach
"Furthermore, USP4 interacts directly with and deubiquitinates ARF-BP1, leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels [XREF_BIBR]."

sparser
"This regulation depends on the binding of USP4 to ARF-BP1 through deubiquitination, promoting ARF-BP1-dependent ubiquitination and degradation of p53, which indicates its tumor-promoting role [ xref ]."

sparser
"In human osteosarcoma cells, USP4 can directly bind to and deubiquitinate ARF-BP1, which stabilises ARF-BP1 and reduces p53 levels, thereby promoting cancer cell proliferation ( xref )."

reach
"USP4 also interacts directly with and deubiquitinates ARF-BP1, leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels."
USP4 affects SMAD4
4 1 | 7 2
USP4 binds SMAD4.
4 | 1 2
4 | 1 2

reach
"The binding of USP4 to SMAD4 prevents its monoubiquitination in the cytoplasm and subsequently enhances SMAD4 mediated activin and bone morphogenetic protein (BMP) pathways."

sparser
"The binding of USP4 to SMAD4 prevents its monoubiquitination in the cytoplasm and subsequently enhances SMAD4-mediated activin and bone morphogenetic protein (BMP) pathways."

sparser
"GST pull-down in vitro exhibited that USP4 interacted with SMAD4 ( xref E)."
USP4 deubiquitinates SMAD4.
1 | 3
USP4 deubiquitinates SMAD4. 3 / 4
1 | 3

reach
"Interestingly, these speculations have been confirmed that HECW1 can promote the proliferation, migration and invasion of cancer cells by inducing the ubiquitination and degradation of SMAD4 (34), while USP4 can mediate the deubiquitination of SMAD4, leading to the expression of apoptotic proteins (35)."

reach
"However, USP4 was also identified to regulate deubiquitination of Smad4 and was excluded in this study as the content of USP4 in HUVECs was much lower than USP10."

reach
"USP4 inhibits SMAD4 monoubiquitination and promotes activin and BMP signaling."
USP4 ubiquitinates SMAD4.
| 2
USP4 ubiquitinates SMAD4. 2 / 2
| 2

reach
"The ubiquitin ligase Ectodermin/TIF1γ promotes, while the deubiquitinases USP9X and USP4 antagonize SMAD4 monoubiquitination [28,85,86]."

reach
"It may be noted that USP4 modulates the pathways of various TGF-β family members, such as BMPs (Bone morphogenetic proteins) and activin, by directly ubiquitinating Smad4 and, thus, preventing its deg[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 decreases the amount of SMAD4.
| 1
USP4 decreases the amount of SMAD4. 1 / 1
| 1

reach
"Moreover, downregulated USP4 inhibited the expression of SMAD4 by its deubiquitination and promoted EC progression [26]."
USP4 affects DNPEP
1 | 6 7
1 | 6 7

sparser
"Mechanistically, FBXO3 disrupts the interaction between USP4 and aspartyl aminopeptidase (DNPEP), thereby protecting USP4 from DNPEP-mediated degradation."

reach
"FBXO3 binds to USP4 and disrupts the interaction between USP4 and DNPEP, leading to stabilization of USP4 and Twist1."

sparser
"FBXO3 binds to USP4 and disrupts the interaction between USP4 and DNPEP, leading to stabilization of USP4 and Twist1."

sparser
"It has been reported that aspartyl aminopeptidase (DNPEP) can bind to and degrade USP4 [ xref ]."

sparser
"Thus, we suspected that FBXO3 may act to block DNPEP interaction with USP4."

reach
"Furthermore, knockdown of FBXO3-induced down-regulation of USP4 could not be rescued by either lysosome inhibitor (chloroquine) or proteasome inhibitor (MG132) (Fig 4A and 4B), suggesting that knockdown of FBXO3-induced down-regulation of USP4 is unlikely to be at the transcriptional levels or at the levels of the proteasome-/lysosome-mediated protein stability.It has been reported that aspartyl aminopeptidase (DNPEP) can bind to and degrade USP4 [38]."

sparser
"Importantly, the elevation of FBXO3 expression significantly reduced complex formation between USP4 and DNPEP, whereas silencing of FBXO3 increased endogenous DNPEP binding to USP4 in MDA-MB-231 cells ( xref )."

sparser
"Together, these results indicate that FBXO3 binds USP4 to interfere with the interaction between USP4 and DNPEP, leading to stabilization of the USP4 protein."

reach
"Notably, aspartyl aminopeptidase (DNPEP) can bind to, hydrolyze, and destabilize USP4 [38]."

reach
"Importantly, the elevation of FBXO3 expression significantly reduced complex formation between USP4 and DNPEP, whereas silencing of FBXO3 increased endogenous DNPEP binding to USP4 in MDA-MB-231 cells (Fig 4H and 4I)."
PKM2 affects USP4
| 3 11
| 3 11

reach
"This conclusion is supported by the following evidence: First, we confirmed the interaction between USP4 and PKM2."

reach
"Taken together, our biochemical assay revealed that USP4 was specifically bound to PKM2."

sparser
"This conclusion is supported by the following evidence: First, we confirmed the interaction between USP4 and PKM2."

sparser
"The results showed that USP4 is associated with PKM2, and they are co-localized in the cytosol and nucleus."

sparser
"The available information generally supports the interaction between PKM2 and USP4, although it is not specific to PKM2's ubiquitin state."

sparser
"We demonstrated the interaction between USP4 and PKM2 by co-expressing these proteins in 293T cells."

sparser
"Our results showing the interaction using both overexpressed and endogenous proteins across multiple cell lines provide strong evidence for a direct physical interaction between USP4 and PKM2."

sparser
"USP4 interacts with PKM2 and catalyzes the de-ubiquitination of PKM2."

sparser
"In this study, we found that USP4 interacts with PKM2 and catalyzes PKM2 de-ubiquitination."

sparser
"Furthermore, we sought to determine whether USP4 interacts with PKM2 in vivo."
| 13
| 10

reach
"In 2019, Zhang et al. showed that USP4 inhibition prevented the activity of the TGF-β/Smad signaling pathway (40)."

reach
"USP20 and USP4 promote the stability of β-catenin, thus continuously activating the Wnt-β-catenin signaling pathway and mediating drug resistance in breast cancer and CRC ( Fig. 3 )."

reach
"Western blot analyses showed that TRAF6 knockdown in USP4 overexpression PC cell lines can change the protein levels of cell proliferation molecules and also reverse the activation of NF-κB signaling [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"As shown in previous studies [XREF_BIBR], USP4 is an effective inducer of TGF-beta signal transduction, which interacts directly with TGF-betaR1 and acts as a de-ubiquitinase enzyme to maintain the level of TGF-betaR1 on the plasma membrane."

reach
"The hypothesis that drove this study was that USP4 might also mediate the TGF-beta signal transduction pathway in hypertrophic scar fibroblasts."

reach
"However, when it comes to tumor metastasis, USP4 can promote breast cancer cells metastasis by activating TGF-β1/Smad2/matrix metalloproteinase-9 signaling pathway [ 33 ]."

reach
"LncRNA H19 targets miR-148a, increases deubiquitinating enzyme USP4 expression, activates the TGF-β signaling pathway in hepatic stellate cells and hepatocytes, and exacerbates hepatic fibrosis 180."

reach
"USP4 can target the TGF-β receptor for deubiquitination and enhance the activation of the TGF-β/BMP signaling pathway to promote the proliferation and differentiation of MSCs (69)."

reach
"It was also found that USP4 inhibited NF-kappaB activation, but in this study we confirmed that USP4 positively regulates the NF-kappaB signalling pathway during EV71 infection."

reach
"Our results showed that USP4 positively regulates the MER/ERK signaling pathway via a TAK1-dependent process."
| 3

reach
"This study demonstrates that inhibition of USP4 to activate Keap1-Nrf2-ARE signaling pathway may represent a mechanism by which vialinin A conferred protection against cerebral ischaemia‒reperfusion injury and sheds light on its promising prospects as a therapeutic intervention for ischaemic stroke."

reach
"By removing the lysine-63-linked polyUb chain from Dvl, USP4 strongly inhibits Wnt/β-catenin signal transduction to weaken osteogenic differentiation (67)."

reach
"Conversely, USP4 may negatively regulate the NF-κB signaling pathway by targeting multiple signaling molecules, including TRAF2 and TRAF6 [28]."
| 1 12
| 1 6

reach
"Additionally, USP4 overexpression inhibited hepatocyte inflammation and apoptosis on hepatic I/R stimulation."

reach
"The intervention using Vialinin A and liver X receptor α (LXRα)-induced cannabinoid receptor 2 (CB2) has been found to reduce the level of USP4, leading to alleviate inflammation and fibrosis in the liver (74)."

reach
"USP4 overexpression antagonized microglia activation-evoked inflammatory response."

eidos
"In conclusion , USP4 was significantly elevated in autoimmune hepatitis mice and Vialinin A reduced USP4 level and attenuate inflammation and fibrosis in the liver ."

reach
"Notably, this study found that reactivating the TRAF6 pathway negated the effects of USP4 on microglial inflammation and subsequent neuron injuries.Collectively, this study highlighted that the USP4 elevation suppressed microglia activation-evoked inflammation and neuron injury by inhibiting the TRAF6-NF-κB pathway."

reach
"164 Since FoxP3-driven gene expression patterns can largely determine Treg regulatory function,165 USP4 can lead to impaired Treg cell suppressive function by down-regulating Foxp3, thereby promoting further inflammation development."

reach
"In conclusion, USP4 was significantly elevated in autoimmune hepatitis mice and Vialinin A reduced USP4 level and attenuate inflammation and fibrosis in the liver."
| 6

reach
"The intervention using Vialinin A and liver X receptor α (LXRα)-induced cannabinoid receptor 2 (CB2) has been found to reduce the level of USP4, leading to alleviate inflammation and fibrosis in the liver (74)."

reach
"We next elucidated the function of USP4 in the microglia activation-induced inflammation."

reach
"In a model of autoimmune hepatitis in mice, the expression of USP4 was found to be reduced upon treatment with Vi-A, thereby reducing inflammation and fibrosis in the liver [31]."

reach
"Here the downregulation of USP4 promotes microglial activation and subsequent neuronal inflammation through attenuating the deubiquitination of K63 linked TRAF6 and reversing its suppressor role in the NF-kappaB signaling pathway."

reach
"In experimental animal, there were increases in inflammation and fibrosis as well as USP4, and which were reduced after treatment of Vialinin A. Vialinin A also reduced Rheb and phosphorylated mTOR."

reach
"Notably, the cessation of USP4 induces microglial activation and subsequent inflammation through NF-κB in secondary spinal cord injury."

reach
"9 , 10 For example, USP4 enhances the invasive and migratory capabilities of melanoma cells by facilitating EMT."

reach
"Collectively, these data demonstrated that USP4 promotes melanoma cell migration and invasion by promoting EMT."

reach
"Our study showed that after interfering with USP4 expression, lung adenocarcinoma cells changed from a long spindle shape to round, the migration and invasion abilities of cells decreased, N-cadherin expression decreased, and E-cadherin expression increased, indicating that USP4 promoted the invasion and migration of lung adenocarcinoma cells by promoting the EMT of cancer cells."

reach
"Moreover, USP4 is recently showed to enhance EMT and metastasis by stabilizing TbetaRI [XREF_BIBR]."

eidos
"Recently , USP4 was found to mediate deubiquitination of the epithelial-mesenchymal transition ( EMT ) transcriptional factor Twist1 to promote lung cancer cell stemness ( Li et al ., 2020 ) ."

reach
"3.4 USP4 up-regulation contributes to melanoma invasion and migration by promoting EMT."

reach
"For example, USP4 drives breast cancer cell invasion via Relaxin/TGF-β1/Smad2/MMP-9 (matrix metallopeptidase 9) signalling [93] and promotes hepatocellular carcinoma metastasis by enhancing TGF-β sign[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"USP15 enhances the tumorigenic effects of TGF-β in glioblastoma (80), while USP4 promotes TGF-β-induced EMT and cell migration in breast cancer."

reach
"LOXL3-promoted hepatocellular carcinoma progression via promotion of Snail1/USP4-mediated epithelial-mesenchymal transition."

reach
"USP4 promotes the migration and invasion of lung adenocarcinoma cells by regulating cellular EMT processes."

reach
"Through the immunoblotting analysis, we found that the knockdown of USP4 induced drastic down-regulation of N-cadherin and up-regulation of E-cadherin, indicating that USP4 deficiency could reverse the process of EMT."

reach
"USP4 deubiquitination maintains ACE2 stability and thus inhibits EMT and fibrosis in LUAD."

reach
"Researchers discovered that deubiquitinating USP4 (Ubiquitin-specific protease 4) keeps ACE2 stable, which in turn prevents EMT and fibrosis in LUAD."
USP4 affects SOX9
| 9 4
USP4 increases the amount of SOX9.
| 4
USP4 increases the amount of SOX9. 4 / 4
| 4

reach
"Next we intend to further investigate the mechanism by which USP4 modulating SOX9 expression."

reach
"Conversely, silencing of USP4 dramatically reduced SOX9, OCT4 and CD133 levels in SW480 cells and HCT116 cells."

reach
"Ectopic expression of USP4 in CRC cells induced SOX9, OCT4 and CD133 expression significantly."

reach
"Silencing USP4 significantly decreased SOX9 expression, whereas this effect was evidently reversed by proteasome inhibitor MG132 (Fig. 3B)."
USP4 binds SOX9.
| 4
| 4

sparser
"These data indicate that USP4 interacts with SOX9 and stabilizes its function via proteasome pathway."

sparser
"EVO inhibites CRC stemness via affecting USP4-SOX9 axis."

sparser
"These findings suggest that EVO decreases SOX9 level by inducing USP4 degradation, thus further inhibits CRC cell stemness by impairing USP4-SOX9 axis."

sparser
"Next, we observed physical interactions between USP4 and SOX9 by immunoprecipitation assay (Fig.  xref D)."
USP4 deubiquitinates SOX9.
| 3
USP4 leads to the deubiquitination of SOX9. 3 / 3
| 3

reach
"Moreover, USP4 promotes the progression of CRC by mediating the deubiquitination and stabilization of SOX9 protein."

reach
"USP4 mediates SOX9 deubiquitination and stabilization."

reach
"Immunoblotting assay showed the ubiquitination of SOX9 were strongly inhibited by USP4."
USP4 inhibits SOX9.
| 2
USP4 inhibits SOX9. 2 / 2
| 2

reach
"Interestingly, downregulation of SOX9 in CRC cells that were induced by USP4 siRNA was rescued by MG132 treatment, which is a well-known proteasome inhibitor (Fig. 3B)."

reach
"Mechanistically, EVO directly interacts with USP4, thereby disrupting the protein stability of SOX9.In this study, we demonstrated that evodiamine inhibits colorectal cancer (CRC) stemness by disrupting USP4-mediated SOX9 stabilization, providing novel insights into the molecular mechanisms of CRC progression."
USP4 affects RB1
5 2 | 2 3
5 2 | 2 3

reach
"The de-ubiquitinating enzyme Unp interacts with the retinoblastoma protein."

reach
"The de-ubiquitinating enzyme Unp interacts with the retinoblastoma protein."

sparser
"DeSalle LM, Latres E, Lin D, Graner E, Montagnoli A, Baker RT, et al. The de-ubiquitinating enzyme Unp interacts with the retinoblastoma protein."

sparser
"The de-ubiquitinating enzyme Unp interacts with the retinoblastoma protein."

sparser
"We conclude that within cells UNP does physically associate with pRb, and can also associate with p107 and p130."
TGFBR1 affects USP4
5 | 7 1
5 | 7 1

reach
"Likewise USP4 as a deubiquitylating enzyme also interacts with TbetaRI at the plasma membrane and reverses its ubiquitination and thus regulates the TbetaRI levels [XREF_BIBR]."

reach
"USP4 directly interacts with and deubiquitinates TGF-beta type I receptor (TbetaRI), regulating TGF-beta signaling by controlling TbetaRI levels at the plasma membrane."

sparser
"Co-immunoprecipitation assay showed that exogenous USP4 and TGFR-1 directly bound to each other ( xref )."

reach
"Deubiquitinating TbetaRI and stimulation of TGF-beta signaling pathway also associate USP4 with liver fibrosis and cirrhosis where it facilitates activation of hepatic stellate cell and EMT in hepatocytes."

reach
"Mechanistically, we revealed that USP4 interacted directly with and deubiquitinated TGF-beta receptor type I (TGFR-1) to activate the TGF-beta signaling pathway, and subsequently induced the Epithelial-Mesenchymal Transition (EMT) in HCC cells."

reach
"Taken together, our results elucidate that USP4 is highly expressed in HCC and promotes the tumor invasion and metastasis, the underlying mechanism is that USP4 directly interacts with and deubiquitinates TGFR-1 to increase TGF-beta signaling Induced EMT."

reach
"As mentioned above, USP4 binds to and deubiquitinates the TGF-beta type I receptor and associates with AKT, leading to enhanced TGF-beta signalling and AKT induced breast cancer cell migration (Zhang [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"For instance, USP4 directly interacts with and deubiquitinates TGF-beta type I receptor (TbetaRI), thereby determining the levels of TGF-beta signaling."
RB1 affects USP4
5 2 | 2 3
5 2 | 2 3

reach
"The de-ubiquitinating enzyme Unp interacts with the retinoblastoma protein."

reach
"The de-ubiquitinating enzyme Unp interacts with the retinoblastoma protein."

sparser
"DeSalle LM, Latres E, Lin D, Graner E, Montagnoli A, Baker RT, et al. The de-ubiquitinating enzyme Unp interacts with the retinoblastoma protein."

sparser
"The de-ubiquitinating enzyme Unp interacts with the retinoblastoma protein."

sparser
"We conclude that within cells UNP does physically associate with pRb, and can also associate with p107 and p130."
METTL3 affects USP4
| 13
METTL3 activates USP4.
| 8
METTL3 activates USP4. 8 / 8
| 8

reach
"In prostate cancer, METTL3 remains the most studied m6A modification regulators, and METTL3 mediates m6A modification of USP4 mRNA at A2696 to promote prostate cancer invasion and metastasis (Chen et al., 2021[31])."

reach
"For example, metformin has been reported to improve the prognosis of patients with malignant tumours by inhibiting METTL3-mediated m A modification of THRAP3, RBM25, and USP4 mRNAs to repress their expression, hamper cell proliferation, and promote apoptosis (103)."

reach
"In androgen treatment-sensitive prostate cancer, METTL3 mediates m6A modification of USP4 mRNA at A2696, and m6A reader protein YTHDF2 binds to and induces degradation of USP4 mRNA, increasing the expression of Rho GDP dissociation inhibitor alpha (ARHGDIA) protein and promoting migration and invasion [182]."

reach
"METTL3 mediates m A modification of ubiquitin-specific peptidase 4 (USP4) mRNA at A2696, and m A reader protein YTHDF2 binds to and induces the degradation of USP4 mRNA by recruiting RNA-binding protein heterogeneous nuclear ribonucleoprotein D (HNRNPD) to the mRNA."

reach
"METTL3 promotes tumorigenesis and progression by m A modification of HDGF and ZMYM1 in GC, USP4 in GC, YAP in NSCLC, Notch1 in ESCC, Myc in BCa, BMI1 in OSCC, and CRB3 in CRC."

reach
"Mechanistically, METTL3 mediates the m A modification of the deubiquitinating enzyme USP4 RNA at A2696, which in turn promotes the binding of YTHDF2 and HNRNPD to USP4 RNA, leading to USP4 degradation."

reach
"It has been supposed that METTL3 writes m A modification at A2696 of USP4 mRNA, which is read by YTHDF2 and induces ubiquitin-specific peptidase 4 (USP4) mRNA degradation by recruiting the RNA-binding protein heterogeneous nuclear ribonucleoprotein D [HNRNPD]."

reach
"Chen et al. (Chen et al., 2021a) reported that YTHDF2 could recognize and degrade the abundance of m A-modified Ubiquitin Specific peptidase 4 (USP4) mRNA promoted by METTL3 in the PCa cells."
METTL3 decreases the amount of USP4.
| 5
METTL3 decreases the amount of USP4. 5 / 5
| 5

reach
"And thus, we chose USP4, USP8, USP11, USP25 and USP28 for further analyses, and western blotting revealled that METTL3 knockdown markedly increased USP4 protein levels."

reach
"We next found that METTL3 knockdown significantly upregulated USP4 mRNA levels in PCa cells."

reach
"Given the key role of m 6 A mRNA methylation in affecting mRNA stability, it was reasonable to speculate that METTL3 knockdown reduces the m 6 A modification levels in USP4 mRNA and thus increase USP4 mRNA levels by atenuating the inhibitory effect of m 6 A modification on USP4 mRNA stability."

reach
"The present study demonstrates that metformin can repress the expression of THRAP3, RBM25, and USP4 by inhibiting METTL3-mediated m6A modification, which in turn hamper cell proliferation and promotes cell apoptosis."

reach
"Moreover, USP4 promoter transcriptional activity was not affected upon METTL3 knockdown, excluding the possibility that METTL3 downregulation inhibited USP4 transcription."
FBXO3 affects USP4
| 6 7
FBXO3 binds USP4.
| 4 7
| 4 7

sparser
"Rather, the ApaG domain of FBXO3 is indispensable for FBXO3 interaction with USP4."

sparser
"FBXO3 can bind to and stabilize USP4, leading to Twist1 protein stabilization and increased breast cancer cell migration and tumor metastasis."

sparser
"This study reveals a non-canonical function of the E3 ubiquitin ligase FBXO3 in PI3K-induced breast cancer metastasis, showing that FBXO3 binds to and protects USP4 from aspartyl aminopeptidase (DNPEP)-mediated degradation, resulting in Twist1 protein stabilization and increased tumor metastasis."

reach
"FBXO3 can bind to and stabilize USP4, leading to Twist1 protein stabilization and increased breast cancer cell migration and tumor metastasis."

sparser
"FBXO3 binds to USP4 and disrupts the interaction between USP4 and DNPEP, leading to stabilization of USP4 and Twist1."

reach
"FBXO3 binds to USP4 and disrupts the interaction between USP4 and DNPEP, leading to stabilization of USP4 and Twist1."

sparser
"Indeed, the co-immunoprecipitation assays showed that wild-type FBXO3 or FBXO3 ΔF , but not FBXO3 ΔApaG , could form stable complexes with USP4 ( xref )."

reach
"Together, these results indicate that FBXO3 binds USP4 to interfere with the interaction between USP4 and DNPEP, leading to stabilization of the USP4 protein."

reach
"Rather, the ApaG domain of FBXO3 is indispensable for FBXO3 interaction with USP4."

sparser
"Together, these results indicate that FBXO3 binds USP4 to interfere with the interaction between USP4 and DNPEP, leading to stabilization of the USP4 protein."
FBXO3 increases the amount of USP4.
| 2
FBXO3 increases the amount of USP4. 2 / 2
| 2

reach
"We further investigated the molecular basis by which FBXO3 up-regulates USP4 expression."

reach
"In keeping with this observation, ectopic expression of FBXO3 or FBXO3 , but not FBXO3 , led to increased USP4 expression in both nucleus and cytoplasm (Fig 3I)."
USP4 affects Flag
| 12
| 12

sparser
"Flag-USP4 and Myc-PKM2 were co-transfected into cells, and then either immunoprecipitated with Myc and blotted with Flag, or immunoprecipitated with Flag and blotted with Myc."

sparser
"RE: Our Co-IP assay results showed that Flag-USP4 and Myc-PKM2 co-immunoprecipitated with each other."

sparser
"We carried out ubiquitination assays by co-transfecting HEK293T cells with a Myc-HDAC2 expression plasmid plus His and Flag empty vectors, His-Ubiquitin and Flag empty vectors, His-Ubiquitin, Flag-USP4 and Flag empty vectors,or His-Ubiquitin, Flag-USP4 and Flag-TRPS1 vectors and compared them with cells transfected with Myc plus His vector and Flag-empty vectors."

sparser
"The result showed that BRCA1 were pulled down by Flag-USP4 from 293 T cells expressing either BRCA1 alone, or BRCA1 plus BARD1."

sparser
"Notably, BRCA1 C61G was also pulled down by Flag-USP4 (Fig. xref )."

sparser
"For analysis of the ubiquitination of RIP1, HEK293 cells were transfected with Myc-RIP1, HA-Ub (WT) or HA-Ub mutants and Flag-USP4, and then whole-cell extracts were immunoprecipitated with anti-Myc a[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"We found that the anti-Myc antibody co-precipitated Flag-USP4, whereas the control serum did not ( xref )."

sparser
"To further validate this point, we co-transfected Flag-USP4, Myc-HDAC2, and Flag-TRPS1 in HEK293T cells and performed Co-IP using anti-Myc antibody and found that TRPS1, USP4, and HDAC2 were co-purified as a complex (Fig. xref )."

sparser
"293 T cells were transfected with Flag-USP4, together with either BARD1 alone, BRCA1 alone, BARD1 plus BRCA1, or BARD1 plus BRCA1 C61G, a mutant of BRCA1 that does not interact with BARD1, and Flag IPs were performed."

sparser
"Similarly, BARD1 was pulled down by Flag-USP4 from cells expressing BARD1 alone, or BARD1 plus either BRCA1 Wt or C61G (Fig. xref )."
DUSP affects USP4
| 2 10
DUSP binds USP4.
| 10
| 6

sparser
"We were successful in producing the USP4-DUSP, USP11-DUSP, USP15-DUSP, USP20-DUSP2 and USP33-DUSP2 recombinant proteins in Escherichia coli and purified them to near homogeneity from the soluble fract[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"DNA sequences encoding the following residues from each USP were cloned into a pET-21b vector using Gibson Assembly 45 : USP4-DUSP, 8–129; USP15-DUSP, 1–125; USP11-DUSP, 71–191; USP20-DUSP1, 687–780; [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"For USP4-DUSP, none of the 11 UbVs selected for binding exhibited non-specific binding to SAV but nine UbVs (4D."

sparser
"1 and 2) were absolutely specific for USP4-DUSP."

sparser
"1 bound to its target USP4-DUSP with an affinity in the high nanomolar range (K D ∼ 500 nM)."

sparser
"Another protein, NBS1, which is a part of the MRN complex, interacts with the DUSP domain of USP4 and recruits the enzyme to DNA damage sites where it colocalizes with CtIP ( xref )."
USP4 binds UBL and DUSP. 4 / 4
| 4

sparser
"The crystal structure of USP4 DUSP-UBL shows a dimer formation where the subunits are packed against each other in an antiparallel orientation ( xref ) ( xref )."

sparser
"The binding of USP4 N-terminal DUSP-Ubl domain promotes a change of a switching loop near the active site, and hence enhances ubiquitin dissociation and makes it achieve full catalytic activity xref ."

sparser
"Indeed, surface plasmon resonance (SPR) shows an interaction of DUSPUbl with immobilized USP4 CD ( xref )."

sparser
"By binding to the linker between the DUSP and UBL domain of USP4, SART3 can shuttle USP4 to the nucleus from the cytosol through its NLS."
DUSP activates USP4.
| 2
DUSP activates USP4. 2 / 2
| 2

reach
"The structure of USP4 and USP15 DUSP-Ubl has shown some degree of flexibility between the two domains XREF_BIBR XREF_BIBR, suggesting that the movement of the DUSP relative to the Ubl domain may be required to activate USP4."

reach
"In USP4, the tandem N-terminal DUSP (domain in USP) and Ubl domains augment catalytic turnover by promoting substrate release (6)."
USP4 affects FBXO3
| 4 7
| 4 7

sparser
"Rather, the ApaG domain of FBXO3 is indispensable for FBXO3 interaction with USP4."

sparser
"FBXO3 can bind to and stabilize USP4, leading to Twist1 protein stabilization and increased breast cancer cell migration and tumor metastasis."

sparser
"This study reveals a non-canonical function of the E3 ubiquitin ligase FBXO3 in PI3K-induced breast cancer metastasis, showing that FBXO3 binds to and protects USP4 from aspartyl aminopeptidase (DNPEP)-mediated degradation, resulting in Twist1 protein stabilization and increased tumor metastasis."

reach
"FBXO3 can bind to and stabilize USP4, leading to Twist1 protein stabilization and increased breast cancer cell migration and tumor metastasis."

sparser
"FBXO3 binds to USP4 and disrupts the interaction between USP4 and DNPEP, leading to stabilization of USP4 and Twist1."

reach
"FBXO3 binds to USP4 and disrupts the interaction between USP4 and DNPEP, leading to stabilization of USP4 and Twist1."

sparser
"Indeed, the co-immunoprecipitation assays showed that wild-type FBXO3 or FBXO3 ΔF , but not FBXO3 ΔApaG , could form stable complexes with USP4 ( xref )."

reach
"Together, these results indicate that FBXO3 binds USP4 to interfere with the interaction between USP4 and DNPEP, leading to stabilization of the USP4 protein."

reach
"Rather, the ApaG domain of FBXO3 is indispensable for FBXO3 interaction with USP4."

sparser
"Together, these results indicate that FBXO3 binds USP4 to interfere with the interaction between USP4 and DNPEP, leading to stabilization of the USP4 protein."
| 1 7

reach
"USP4 Auto-Deubiquitylation Promotes Homologous Recombination."

reach
"USP4 promotes DNA-end resection and HR by recruiting CtIP to DSB sites [94,95]."

reach
"USP4 auto-deubiquitination stabilizes its interaction with CtIP and MRN complex and stimulates HR repair [151,152]."

reach
"So far, however, we only have a relatively limited understanding of the DDR roles for deubiquitylation enzymes (DUBs), which mediate the processing of DNA end resection.In this study, we show that the[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

eidos
"USP4 was found to enhance DNA double-strand breaks repairment , DNA-end resection and homologous recombination via a conversed and specific domain to form a complex with CtIP and the MRE11-RAD50-NBS1 complex which can be abrogated by USP4 auto-deubiquitination on several specific cysteine residues ."

reach
"USP4 can also be self-deubiquitylated to promote homologous recombination [44]."

reach
"Existing studies have shown that auto-deubiquitylation of USP4 enhances its interaction with CtIP/MRN, thereby promoting homologous recombination (33)."
USP4 bound to RBBP8 activates homologous recombination. 1 / 1
| 1

reach
"USP4 binds CtIP and MRN complexes to regulate DDR and thereby promotes homologous recombination [42]."
USP4 phosphorylates homologous recombination.
| 2
USP4 leads to the phosphorylation of homologous recombination. 2 / 2
| 2

reach
"We also found that WT USP4, but not the insert domain deletion mutant, restored the HR efficiency and CHK1 phosphorylation to their level in the wild-type cells."

reach
"As shown in Figures 6 A-6G, WT USP4, but not the CA mutant, restored HR efficiency, CtIP, RAD51, RPA foci, and CHK1 phosphorylation in USP4 depleted cells after IR."
| 10
| 5

reach
"Naive CD4 + T cells were sorted using flow cytometry based analysis and were induced for Th2 cell differentiation, and were treated with the inhibitor of USP4, vialinin A, and then processed by flow cytometry."

reach
"Accordingly, unlike our initial hypothesis on the role of USP4 in C2C12 cells, we found that USP4 suppresses differentiation of C2C12 myoblasts by reducing β-catenin stability.To investigate how USP4 [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"USP4 suppresses Wnt3a induced osteoblast differentiation and mineralization by cleaving K63 linked polyubiquitin chains from disheveled (Dvl) and inhibiting the accumulation of beta-catenin and activation of its downstream cascades."

reach
"Inhibition of the catalytic activity of USP4 with vialinin A, an inhibitor of USP4 isolated from the Chinese mushroom, impairs Th17 differentiation, suggesting that USP4 promotes Th17 differentiation."

reach
"The role of USP4 in many pathological and physiological processes has been reported; USP4 promotes breast cancer invasive migration through the relaxin2-mediated TGF-β1/Smad2/MMP-9 pathway [31]; USP4 inhibits myogenic cell differentiation by catalyzing MyoD activity [32]; The H19/miR-148a/USP4 axis promotes hepatic stellate cells by enhancing and TGF-β signaling in hepatocytes to promote liver fibrosis [33]."
| 5

reach
"19 A recent study has demonstrated that USP4 could promote osteoblast differentiation via Activation of Wnt and beta-catenin signalling by inducing Runx2."

reach
"Conversely, deubiquitination of the K48 linked polyubiquitination of RORgammat by the deubiquitinase ubiquitinspecific protease USP4 stabilizes RORgammat and promotes its activation of Th17 associated genes, whereas inhibition of USP4 activity diminishes Th17 differentiation."

reach
"USP4 can target the TGF-β receptor for deubiquitination and enhance the activation of the TGF-β/BMP signaling pathway to promote the proliferation and differentiation of MSCs (69)."

reach
"USP4, USP15 and USP17 stabilize RORγt, and promote Th17 cell differentiation and function."

reach
"Inhibition of the catalytic activity of USP4 with vialinin A, an inhibitor of USP4 isolated from the Chinese mushroom, impairs Th17 differentiation, suggesting that USP4 promotes Th17 differentiation."
USP4 affects Ubiquitin
| 7 1
USP4 activates Ubiquitin.
| 6
| 6

reach
"The knockdown of the deubiquitinating enzyme USP4 (ubiquitin specific peptidase 4) reduced the numbers of P-bodies, adding further evidence for ubiquitin chains as critical regulators of P-bodies [195]."

reach
"USP4 DUSP-Ubl promotes ubiquitin release."

reach
"USP4 promotes the activation of Rheb by removing ubiquitin from it."

reach
"Like other USPs, USP4 also mediates the removal and processing of ubiquitin."

reach
"The DUSP-Ubl domain of USP4 enhances its catalytic efficiency by promoting ubiquitin exchange."

reach
"Pulse-chase analysis of Y-betagal degradation in yeast revealed that Y-betagal is degraded at wild-type rates when Unp is expressed (results not shown), consistent with the ONPG assay and reinforcing [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 inhibits Ubiquitin.
| 1
| 1

reach
"Mutation of the conserved Cys residue of Unp to Ala (UnpC311A-FLAG and UnpDelta1-168 : C311A, Fig. 2, lanes 5 and 7) abolished the ubiquitin cleaving activity of Unp, as did the mutation of both conse[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 binds Ubiquitin.
| 1

sparser
"The ubiquitin peptidase inactive form of USP4 (USP4-C311A) abolished its ability to stabilize HDAC2 ( xref and xref )."
USP4 affects USP11
5 | 2 3
5 | 2

reach
"USP4 can form stable homodimers and can also interact with USP11 and USP15."

reach
"Importantly, USP4 could bind to itself and also interact with USP11 and USP15, and thus may be part of a DUB complex when exerting its function."
USP4 binds USP11 and USP15. 3 / 3
| 3

sparser
"USP15 forms a subfamily with USP4 and USP11 related through a shared presence of N-terminal &quot;domain present in ubiquitin specific proteases&quot; (DUSP) and &quot;ubiquitin-like&quot; (UBL) domains (DU subfamily)."

sparser
"Human deubiquitinase Usp15 forms a small subfamily with its close relatives Usp11 and Usp4, which all share a common domain architecture."

sparser
"USP4 can form stable homodimers and can also interact with USP11 and USP15 ( Fig. 4 )."
USP4 affects RAB7A
| 7 3
USP4 binds RAB7A.
| 2 3
| 2 3

sparser
"In conclusion, these findings highlight the interaction between USP4 and RAB7A as a promising target for therapeutic intervention in managing periodontal diseases."

sparser
"Through co-immunoprecipitation (co-IP) and rigid protein-protein docking, we observed an interaction between USP4 and RAB7A in THP-1 cells (Figure S5A; xref )."

sparser
"These findings highlight the RAB7A-USP4 interaction as a promising target for potential therapeutic interventions in periodontal disease."

reach
"In conclusion, these findings highlight the interaction between USP4 and RAB7A as a promising target for therapeutic intervention in managing periodontal diseases.Abbreviation: 3-MA: 3-methyladenine; Baf A1:bafilomycin A 1 ; BECN1: beclin 1, autophagy related; CEJ-ABC: cementoenamel junctionto alveolar bone crest; IL1B/IL-1beta: interleukin 1 beta; KD:knockdown; LPS: lipopolysaccharide; MOI: multiplicity of infection;OE: overexpression; P.g."

reach
"Through co-immunoprecipitation (co-IP) and rigid protein-protein docking, we observed an interaction between USP4 and RAB7A in THP-1 cells (Figure S5A; Figure 5B,C)."
USP4 deubiquitinates RAB7A.
| 3
USP4 leads to the deubiquitination of RAB7A. 3 / 3
| 3

reach
"In summary, our findings collectively suggest that reduced USP4 levels mediate RAB7A ubiquitination, disrupting lysosomal trafficking and autophagosome-lysosome fusion, which contributes to the development and progression of periodontitis.As evidenced by numerous studies, autophagy plays a dual and complex role in the preservation of periodontal homeostasis [46–48]."

reach
"USP4 depletion-driven RAB7A ubiquitylation impairs autophagosome-lysosome fusion and aggravates periodontitis."

reach
"In this study, our investigation revealed that the ubiquitination of RAB7A, mediated by reduced levels of the deubiquitinating enzyme USP4 (ubiquitin specific peptidase 4), disrupts normal lysosomal trafficking and autophagosome-lysosome fusion, thereby contributing significantly to periodontitis progression."
USP4 ubiquitinates RAB7A.
| 2
USP4 leads to the ubiquitination of RAB7A. 2 / 2
| 2

reach
"Last, by proteomics analysis, we revealed that the ubiquitination of RAB7A was mediated by USP4 and validated that upregulation of USP4 could attenuate periodontitis in vivo."

reach
"Additionally, we discovered that USP4 insufficiency leads to increased RAB7A ubiquitination and confirmed reduced USP4 expression in vivo."
USP4 affects IRF3
| 9 1
USP4 inhibits IRF3.
| 5
USP4 inhibits IRF3. 5 / 5
| 5

reach
"As shown in Fig. 5 A and B, the knockdown of USP4 dramatically increased the nuclear accumulation of IRF3."

reach
"Western blot analysis also revealed that knockdown of USP4 facilitated the translocation of IRF3 to the nucleus, whereas overexpression of USP4 impeded the nuclear translocation of IRF3 ( Figs."

reach
"These results suggest that USP4 suppresses IRF3 activation, probably indirectly through the deubiquitination of IRF3."

reach
"Overall, these data suggest that USP4 suppresses IRF3 activation and the IFN response, at least partially, by deubiquitinating the K63-linked polyubiquitination of IRF3 either through TRAF6 or by dire[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Moreover, IHC staining in MC38 tumors confirmed the in vitro data that USP4 suppressed the nuclear accumulation of IRF3 ( Fig. S5A )."
USP4 binds IRF3.
| 2 1
| 2 1

reach
"Coimmunoprecipitation (Co-IP) experiments confirmed the interaction between USP4 and IRF3 in CRC cells ( Fig. 5 F)."

sparser
"Therefore, it is hypothesized that USP4 may interact with IRF3 to modulate its ubiquitination status."

reach
"In addition, USP4 binds and deubiquitinates K63-linked polyubiquitination of IRF3."
USP4 ubiquitinates IRF3.
| 2
USP4 ubiquitinates IRF3. 2 / 2
| 2

reach
"In colon cancer, a deubiquitinating enzyme USP4 suppressed anti-tumor immune responses by deubiquitinating TRAF6 and IRF3, hindering the nuclear localization of the latter protein and thus inhibiting cellular interferon responses and antigen presentation (Zhou et al., 2024)."

reach
"The results indicated that USP4 suppresses the nuclear localization of IRF3 by deubiquitinating IRF3 in CRC cells.It has been reported that USP4 interacted with and deubiquitinates TRAF6 [ 25 ], which[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 affects DUSP
| 10
| 6

sparser
"We were successful in producing the USP4-DUSP, USP11-DUSP, USP15-DUSP, USP20-DUSP2 and USP33-DUSP2 recombinant proteins in Escherichia coli and purified them to near homogeneity from the soluble fract[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"DNA sequences encoding the following residues from each USP were cloned into a pET-21b vector using Gibson Assembly 45 : USP4-DUSP, 8–129; USP15-DUSP, 1–125; USP11-DUSP, 71–191; USP20-DUSP1, 687–780; [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"For USP4-DUSP, none of the 11 UbVs selected for binding exhibited non-specific binding to SAV but nine UbVs (4D."

sparser
"1 and 2) were absolutely specific for USP4-DUSP."

sparser
"1 bound to its target USP4-DUSP with an affinity in the high nanomolar range (K D ∼ 500 nM)."

sparser
"Another protein, NBS1, which is a part of the MRN complex, interacts with the DUSP domain of USP4 and recruits the enzyme to DNA damage sites where it colocalizes with CtIP ( xref )."
USP4 binds UBL and DUSP. 4 / 4
| 4

sparser
"The crystal structure of USP4 DUSP-UBL shows a dimer formation where the subunits are packed against each other in an antiparallel orientation ( xref ) ( xref )."

sparser
"The binding of USP4 N-terminal DUSP-Ubl domain promotes a change of a switching loop near the active site, and hence enhances ubiquitin dissociation and makes it achieve full catalytic activity xref ."

sparser
"Indeed, surface plasmon resonance (SPR) shows an interaction of DUSPUbl with immobilized USP4 CD ( xref )."

sparser
"By binding to the linker between the DUSP and UBL domain of USP4, SART3 can shuttle USP4 to the nucleus from the cytosol through its NLS."
USP11 affects USP4
5 | 2 3
5 | 2

reach
"USP4 can form stable homodimers and can also interact with USP11 and USP15."

reach
"Importantly, USP4 could bind to itself and also interact with USP11 and USP15, and thus may be part of a DUB complex when exerting its function."
USP4 binds USP11 and USP15. 3 / 3
| 3

sparser
"USP15 forms a subfamily with USP4 and USP11 related through a shared presence of N-terminal &quot;domain present in ubiquitin specific proteases&quot; (DUSP) and &quot;ubiquitin-like&quot; (UBL) domains (DU subfamily)."

sparser
"Human deubiquitinase Usp15 forms a small subfamily with its close relatives Usp11 and Usp4, which all share a common domain architecture."

sparser
"USP4 can form stable homodimers and can also interact with USP11 and USP15 ( Fig. 4 )."
TUT1 affects USP4
2 | 4 4
2 | 4 4

reach
"Next, we investigated whether SART3 affects the binding of USP4 to TUT1."

sparser
"In this study, our findings indicate that USP4 binds to and deubiquitinates TUT1."

reach
"We presumed that SART3 regulates the binding of USP4 with TUT1 similar to the USP15-TUT1 interaction."

reach
"Intriguingly, unlike in the case of USP15-TUT1, we did not observe a strong binding between USP4 and TUT1 in the presence of SART3."

sparser
"Since U6-snRNA plays an important role in regulating spliceosome cascade, it is likely that the USP4-TUT1 axis participates in the regulation of splicing, either in coordination with or complementary [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Taken together, our data suggest that USP4, similarly to USP15, regulates TUT1 subnuclear localization together with SART3 and increases the U6-snRNA level.In this study, our findings indicate that US[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"Next, we investigated whether SART3 affects the binding of USP4 to TUT1."

sparser
"We presumed that SART3 regulates the binding of USP4 with TUT1 similar to the USP15-TUT1 interaction."
RIGI affects USP4
2 | 3 4
RIGI binds USP4.
2 | 2 4
2 | 1 4

sparser
"Several USPs can modulate both K63 and K48-linked polyubiquitination while USP4 can interact with RIG-I and target its K48-linked polyubiquitination and stabilize its expression to upregulate IFN-β expression then modify antiviral innate immune responses [ xref – xref ]."

reach
"Furthermore, whereas our results showed that USP15 efficiently interacted with TRIM25 specifically in infected cells, USP4 constitutively interacts with RIG-I."

sparser
"USP4 can directly target RIG-I and interact with RIG-I ( Wang et al., 2013 )."

sparser
"USP4 interacts with RIG-I to remove the K48-linked polyubiquitination conjugate from RIG-I, thereby maintaining RIG-I stability and then acting antiviral functions [ 15 ]."

sparser
"USP4 interacts with RIG-I and removes K48-linked polyubiquitination chains resulting in the stabilization of RIG-I ( Wang et al., 2013 )."
USP4 binds RIGI and DUSP domain. 1 / 1
| 1

reach
"Moreover, whereas USP4 binds through its N-terminal DUSP domain to RIG-I, our study showed that the C-terminal His Box of USP15 interacted with the B-boxes of TRIM25."
RIGI activates USP4.
| 1
RIGI activates USP4. 1 / 1
| 1

reach
"Similarly, in vesicular stomatitis virus (VSV) infection, removing K48 linked polyubiquitin chains from RIG-I allows USP4 to enhance RIG-I-triggered IFN-beta signaling, thereby inducing an antiviral immune response."
USP4 affects cell growth
| 7 2
USP4 inhibits cell growth.
| 3 2
| 3 2

sparser
"Studies have reported that USP4 could inhibit breast cancer cell growth by upregulating PDCD4 [ xref ]."

reach
"In 2016, Li et al. showed that USP4 could inhibit BC cell growth through the upregulation of PDCD4 (21)."

reach
"USP4 has been shown to inhibit TNFα-induced cancer cell migration and breast cancer cell growth through upregulation of programmed cell death 4 (PCD4) [31] ."

sparser
"Previous studies have shown that USP4 expression was significantly decreased in breast cancer tissue and that USP4 inhibited breast cancer cell growth through inhibiting PDCD4 degradation. xref USP4 was downregulated in lung adenocarcinoma and served as an independent predictor. xref Some other studies claimed that USP4 might have oncogenic properties."

reach
"These results suggest that USP4 inhibits breast cancer cell growth and proliferation in vivo."
USP4 activates cell growth.
| 4
| 4

reach
"Using in vitro and in vivo assays, we demonstrated that USP4 overexpression enhanced HCC cell growth, migration, and invasion."

reach
"In contrast, knockdown of USP4 markedly inhibited gastric cancer cell growth, and suppressed the tumor growth of gastric cancer."

reach
"This study indicated that elevated USP4 predicted a poor index for gastric cancer patients, and mediated gastric cancer cell growth by regulating PRL-3/NF-κB signaling, which suggested USP4 may be a novel therapeutic target for gastric cancer."

reach
"The inhibition of USP4 in vitro significantly enhanced breast cancer cell growth and proliferation, while the overexpression of USP4 inhibited cell growth and proliferation."
USP4 affects TRPS1
1 | 3 5
HDAC2 binds USP4 and TRPS1. 5 / 5
| 1 4

reach
"Similarly, trichorhinophalangeal syndrome type I (TRPS1) functions as a scaffold protein involved in the USP4 induced stabilization of HDAC2 through bringing them together to form the TRPS1, USP4, and HDAC2 complex."

sparser
"We hypothesized that TRPS1, USP4, and HDAC2 formed a complex, used Co-IP to test this notion, and found that TRPS1 co-immunoprecipitated with USP4 and HDAC2 (Fig. xref )."

sparser
"To further confirm the interaction between TRPS1, USP4, and HDAC2, we generated serial TRPS1 truncates based on the domain structure of TRPS1 consisting of an N-terminal domain and GATA and C-terminal domains (Fig. xref )."

sparser
"The results indicated that N-terminal or C-terminal domains of TRPS1 together with the GATA domain were sufficient to interact with HDAC2 and USP4 while neither TRPS1 N-terminal or C-terminal domain alone interacted with HDAC2 and USP4 (Fig. xref )."

sparser
"Similarly, trichorhinophalangeal syndrome type I (TRPS1) functions as a scaffold protein involved in the USP4-induced stabilization of HDAC2 through bringing them together to form the TRPS1-USP4-HDAC2 complex ( xref )."
1 | 2 1

reach
"We hypothesized that TRPS1, USP4, and HDAC2 formed a complex, used Co-IP to test this notion, and found that TRPS1 co-immunoprecipitated with USP4 and HDAC2 (Fig. 3a, b)."

sparser
"It appeared that both TRPS1 and USP4 interacted with and stabilized HDAC2 in a UDPD-dependent fashion."

reach
"To further confirm the interaction between TRPS1, USP4, and HDAC2, we generated serial TRPS1 truncates based on the domain structure of TRPS1 consisting of an N-terminal domain and GATA and C-terminal domains (Fig. 3f)."
USP4 affects HAS2
1 1 | 3 4
USP4 binds HAS2.
1 | 1 4
| 3

sparser
"HAS2 interacts with USP17 and USP4."

sparser
"To confirm complex formation of endogenous components, proximity ligation assay (PLA) was performed using the breast cancer cell line MDA-231-BM, known to produce high levels of hyaluronan. xref Using antibodies against HAS2 and USP4 or USP17, reactive signals in the form of red dots indicating interactions between endogenous HAS2 and USP17, and HAS2 and USP4, were observed; only a low background level of dots was seen when each antibody was used alone, or in the fixation control without antibody ( xref )."

sparser
"Thus, both co-immunoprecipitation and PLA analyses supported the notion that HAS2 forms complexes with USP17 and USP4."
1 | 1 1

sparser
"The analysis revealed bands of 113 and 55 kDa, i.e., the expected sizes of USP4 and USP17 ( xref ), and of ~70 kDa ( xref ), which is the expected size of 6myc-HAS2, suggesting the formation of complexes between HAS2 and USP4, as well as between HAS2 and USP17."

reach
"HAS2 interacts with USP17 and USP4."
USP4 deubiquitinates HAS2.
1 | 2
USP4 deubiquitinates HAS2. 2 / 3
1 | 2

reach
"The de-ubiquitinase USP17 preferentially deconjugated polyubiquitin chains from HAS2, whereas USP4 significantly reduced the monoubiquitination of HAS2; thus, the two DUBs were found to selectively affect the activity and stability of HAS2."

reach
"For example, USP4 targets and deubiquitinates hyaluronan synthase 2 (HAS2), but USP4 does not maintain the stability of HAS, and, rather, loss of USP4 increases hyaluronan synthesis [33]."
| PMC
TRPS1 affects USP4
1 | 3 5
HDAC2 binds USP4 and TRPS1. 5 / 5
| 1 4

reach
"Similarly, trichorhinophalangeal syndrome type I (TRPS1) functions as a scaffold protein involved in the USP4 induced stabilization of HDAC2 through bringing them together to form the TRPS1, USP4, and HDAC2 complex."

sparser
"We hypothesized that TRPS1, USP4, and HDAC2 formed a complex, used Co-IP to test this notion, and found that TRPS1 co-immunoprecipitated with USP4 and HDAC2 (Fig. xref )."

sparser
"To further confirm the interaction between TRPS1, USP4, and HDAC2, we generated serial TRPS1 truncates based on the domain structure of TRPS1 consisting of an N-terminal domain and GATA and C-terminal domains (Fig. xref )."

sparser
"The results indicated that N-terminal or C-terminal domains of TRPS1 together with the GATA domain were sufficient to interact with HDAC2 and USP4 while neither TRPS1 N-terminal or C-terminal domain alone interacted with HDAC2 and USP4 (Fig. xref )."

sparser
"Similarly, trichorhinophalangeal syndrome type I (TRPS1) functions as a scaffold protein involved in the USP4-induced stabilization of HDAC2 through bringing them together to form the TRPS1-USP4-HDAC2 complex ( xref )."
1 | 2 1

reach
"We hypothesized that TRPS1, USP4, and HDAC2 formed a complex, used Co-IP to test this notion, and found that TRPS1 co-immunoprecipitated with USP4 and HDAC2 (Fig. 3a, b)."

sparser
"It appeared that both TRPS1 and USP4 interacted with and stabilized HDAC2 in a UDPD-dependent fashion."

reach
"To further confirm the interaction between TRPS1, USP4, and HDAC2, we generated serial TRPS1 truncates based on the domain structure of TRPS1 consisting of an N-terminal domain and GATA and C-terminal domains (Fig. 3f)."
TRAF2 affects USP4
2 | 2 4
2 | 2 1

reach
"We found that USP4 specifically interacts with TRAF2 and TRAF6, but not TRAF3."

sparser
"A study in the pulmonary carcinoma model reveals that USP4 interacts with K63-linked TRAF2 and deubiquitinates it to inhibit TNF-α-induced p65/p50 activation ( xref )."

reach
"Xiao et al. 's study added on to this by demonstrating USP4 's interaction and deubiquitination of TRAF2 and TRAF6, but not TRAF3, both in vivo, in HEK293T cells, and in vitro [XREF_BIBR]."
USP4 binds TRAF2 and TRAF6. 3 / 3
| 3

sparser
"Xiao et al.’s study added on to this by demonstrating USP4’s interaction and deubiquitination of TRAF2 and TRAF6, but not TRAF3, both in vivo, in HEK293 T cells, and in vitro [ xref ]."

sparser
"We found that USP4 specifically interacts with TRAF2 and TRAF6, but not TRAF3."

sparser
"It was confirmed that USP4 associates with TRAF2 and TRAF6, consistent with our results."
RIPK1 affects USP4
3 | 3 2
3 | 3 2

reach
"Taken together, these data indicate RIP1 and USP4 form a complex through the USP domain of USP4.To test the role of USP4 in RIP1 ubiquitination, RIP1 was co-expressed with HA-ubiquitin and USP4 expres[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"An association between USP4 and RIP1 was reported to impair NF-kappaB activation and exacerbate TNF-alpha-induced apoptosis in head and neck squamous cell carcinoma (HNSCC)."

sparser
"Co-immunoprecipitation showed that USP4 interacted with receptor-interacting protein 1 (RIPI) to remove K63-connected ubiquitin molecules to stabilize RIPI expression."

reach
"Furthermore, TNFalpha induced recruitment of USP4, TAK1 and RIPK1 to TNFR1 (XREF_FIG)."

sparser
"Coimmunoprecipitation experiments showed that RIP1 interacted with USP4 WT and C261, but not with N260, indicating the C-terminal USP domain is required for the interaction with RIP1 ( Fig. 3 F)."
| 3 5
USP4 translocates to the membrane. 4 / 4
| 2 2

sparser
"In this study, it was reported that upon phosphorylation by AKT, USP4 translocates to the membrane, where it associates with ALK5, deubiquitylates it and protects it from destruction ( xref A)."

reach
"Conceivably, AKT directly interacts with USP4 for its phosphorylation and translocates nuclear USP4 to the membrane and thus maintains TbetaRI stability and possibly modulates TGF-beta induced EMT and MMT."

sparser
"Conceivably, AKT directly interacts with USP4 for its phosphorylation and translocates nuclear USP4 to the membrane and thus maintains TβRI stability and possibly modulates TGF-β induced EMT/MMT."

reach
"In this study, it was reported that upon phosphorylation by AKT, USP4 translocates to the membrane, where it associates with ALK5, deubiquitylates it and protects it from destruction (XREF_FIG A)."
USP4 translocates to the nucleus. 3 / 3
| 1 2

sparser
"Since SART3 appears to be a targeting factor of USP4 for substrate Prp3, we examined whether USP4 co-localizes with Prp3 in the presence of SART3 ΔNLS , and as expected, USP4 does not translocate to the nucleus, and therefore no longer co-localizes with Prp3 (Figure xref )."

sparser
"Confocal microscopy analysis clearly demonstrates that the NLS is required for SART3 to relocate to the nucleus and both USP4 and USP15 are recruited to the nucleus in the presence of SART3."

reach
"Confocal microscopy analysis clearly demonstrates that the NLS is required for SART3 to relocate to the nucleus and both USP4 and USP15 are recruited to the nucleus in the presence of SART3."
USP4 translocates from the nucleus. 1 / 1
| 1

sparser
"Interestingly, it was also found that Akt directly associates and phosphorylates USP4, and then induces the translocation of USP4 from the nucleus to the cytoplasm and plasmalemma for maintaining TβRI stability [ xref ]."
USP4 affects PRPF31
1 | 7
USP4 deubiquitinates PRPF31. 7 / 8
1 | 7

reach
"For progression of the splicing cycle, ubiquitinated PRP3 and PRP31 get deubiquitinated by the ubiquitin-specific proteases USP4 and USP15, respectively [28,29] ( Figure 1 )."

reach
"When PRP31 was ubiquitinated by PRP19, PRP31 was deubiquitinated by USP4."

reach
"Moreover, we found that USP15 and USP4 deubiquitinated substrates PRP31 and PRP3 simultaneously."

reach
"Moreover, it was reported that Sart3, Usp4 and Usp15 form a complex in order to de-ubiquitinate Prp3 and Prp31 simultaneously."
| PMC

reach
"As the splicing cycle progresses, PRPF3 and PRPF31 are deubiquitinated by USP4 and USP15, respectively (Song et al., 2010; Das et al., 2017)."

reach
"Deubiquitination of PRP31 and PRP3 by the USP15, SART3, and USP4 complex decreases the affinity towards PRP8 and this regulation is important for the proper splicing of chromosome segregation related genes such as Bub1 and alpha-tubulin."

reach
"It is possible that localization of USP15 and USP4 may be regulated by phosphorylation or a nuclear signal such as NLS and NES depending on the cellular conditions.USP15 and USP4 are required for the [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 affects IRF8
2 1 | 5
USP4 binds IRF8.
2 | 2
2 | 2

reach
"We found that USP4 promoted the suppressive function of Treg cells by stabilizing interferon regulatory factor (IRF)8. USP4 interacts with and stabilizes IRF8 by deubiquitination of K48-linked polyubi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Taken together, our results suggest that USP4 interacts with and stabilizes IRF8 to promote the suppressive function of Treg cells."
USP4 deubiquitinates IRF8.
1 | 1
USP4 leads to the deubiquitination of IRF8. 1 / 2
1 | 1

reach
"USP4 deficiency promotes K48-linked polyubiquitination of IRF8 and upregulates the gene expression levels of type 2 inflammatory cytokines in Treg cells, such as IL-4, IL-5 and IL-13."
USP4 activates IRF8.
| 2
USP4 activates IRF8. 2 / 2
| 2

reach
"USP4 interacts and positively regulates IRF8 function via K48 linked deubiquitination in regulatory T cells."

reach
"Deconjugation of polyubiquitin chains from IRF8 mediated by USP4 is vital for maintaining the function of regulatory T cells, which negatively regulate many different immune reactions."
USP4 affects INS
| 7 1
USP4 deubiquitinates INS.
| 4
USP4 deubiquitinates INS. 4 / 4
| 4

reach
"USP4 is a deubiquitinating enzyme and may deubiquitinate insulin receptors to inhibit their degradation, which maintains the expression level of insulin receptors on the membrane surface and improves insulin resistance."

reach
"USP4 further reduces the ubiquitination of insulin receptors and increases their expression."

reach
"Upregulation of USP4 reduces the ubiquitination and degradation of insulin receptors, upregulates the level of insulin receptors, and ultimately improves insulin resistance."

reach
"Additionally, USP4 decreases the ubiquitination and degradation of insulin receptors, consequently leading to reduced insulin resistance (118)."
USP4 binds INS.
| 1 1
| 1 1

reach
"Dexamethasone did not affect the binding of USP4 to insulin receptors compared with the control group, but the expression of USP4 and the binding of USP4 to insulin receptors increased after the addition of gastrodin."

sparser
"Furthermore, Gastrodin has been shown to upregulate the expression of USP4 and enhance the interaction between USP4 and insulin receptors to treat diabetes ( xref )."
USP4 activates INS.
| 2
USP4 activates INS. 2 / 2
| 2

reach
"Liver-specific USP4 overexpression increased insulin sensitivity and attenuated steatosis and inflammatory injury."

reach
"Furthermore, gastrodin significantly upregulated the expression of USP4 and increased the binding of USP4 to the insulin receptor.Considering the importance of the PI3K-Akt pathway in the pathogenesis of T2DM, we detected the effects of gastrodin on the PI3K-Akt pathway to further explore the underlying mechanism of gastrodin in ameliorating insulin resistance."
USP4 affects IL1B
| 5 3
USP4 inhibits IL1B.
| 2 3
USP4 inhibits IL1B. 5 / 5
| 2 3

reach
"Notably, USP4 overexpression antagonized OGD/R-induced IL-1β, IL-6, and TNF-α transcriptional levels (Fig. 3A–C)."

sparser
"USP4 inhibits IL-1β-, LPS-and TGFβ-induced NF-κB activation."

sparser
"Similarly, USP4 inhibited IL-1β-, LPS- and TGFβ-induced NF-κB production xref ."

sparser
"They showed that endogenous USP4 inhibits IL-1β- and LPS-induced IκBα phosphorylation and pro-inflammatory cytokine expression in various cell types, including HeLa, macrophages (RAW264.7), and mouse [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Additionally, the overexpression of USP4 suppressed the release of microglia activation-induced pro-inflammatory cytokines, including IL-1beta, IL-6, and TNF-alpha."
USP4 activates IL1B.
| 3
USP4 activates IL1B. 3 / 3
| 3

reach
"Knockdown of USP4 promoted IL-1beta, LPS, and TGF-beta-induced NF-kappaB activation (Fan et al., 2011)."

reach
"Mechanistically, USP4 can directly bind to the TRAF domain to inhibit TRAF2/TRAF6 activity through deubiquitination in an activity-dependent manner and negatively regulate IL-1β and TNF-α-induced NF-κB activation, thereby inhibiting lung cancer metastasis (46)."

reach
"Notably, USP4 overexpression antagonized OGD/R-induced IL-1β, IL-6, and TNF-α transcriptional levels (Fig. 3A–C)."
USP4 affects CRC
| 8
USP4 activates CRC. 8 / 8
| 8

reach
"Knockdown of USP4 suppresses CRC stemness and inhibits resistance to oxaliplatin."

reach
"Further experiments found that overexpression of USP4 could significantly enhance the migration and invasion of CRC and promote the expression of stemness-related genes such as SOX9, OCT4, and CD133."

reach
"Given that CSCs are implicated in drug resistance, we hypothesized that USP4 might enhance chemoresistance in CRC."

reach
"These data indicates that USP4 facilitates the migration and invasion of CRC, and further promotes CRC development."

reach
"USP4 promotes CRC stemness via upregulating SOX9 expression."

reach
"These data indicates a relevant role of USP4 in CRC stemness via modulating SOX9 expression.Rescuing experiment was performed to verify the critical role of SOX9 in mediating USP4 induced CRC stemness."

reach
"Taken together, these data demonstrate that SOX9 is a critical downstream element in USP4-induced CRC stemness."

reach
"Moreover, USP4 markedly promoted CRC stemness via upregulating SOX9 (Fig. 2B)."
USP4 affects AQP2
| 8
| 8

sparser
"To investigate if USP4 interacts with AQP2, co-immunoprecipitation studies were initially performed on lysates from cultured cells."

sparser
"Supporting this, AQP2 and USP4 interacted in vitro, with USP4 being able to directly deubiquitylate AQP2."

sparser
"In mpkCCD14 cells, USP4 could be immunoprecipitated with an anti-AQP2 antibody, and prior treatment with dDAVP had no clear effect on the interaction, as shown in xref A. Similar results were obtained in MDCK-hAQP2 cells, as shown in xref B, with an interaction between AQP2 and USP4 observed under control conditions, or after treatment of cells with the adenylate cyclase activator forskolin (MDCK-hAQP2 cells have limited response to VP)."

sparser
"To examine if USP4 and AQP2 interact in vivo, co-immunoprecipitation studies were performed on lysates from mouse kidney tubule suspensions treated with vehicle or dDAVP for 30 min."

sparser
"USP4 and AQP2 were detected in samples immunoprecipitated using either anti-AQP2 or anti-USP4, confirming that a USP4 and AQP2 interaction occurs in vivo, as shown in xref C. Similar to the cultured cell experiments, prior stimulation of the tubule suspensions with dDAVP had no clear effect on the USP4-AQP2 interaction, as shown in xref C."

sparser
"The characteristic pattern [ xref ] of ubiquitylated AQP2 was observed in the immunoprecipitated samples, as shown in xref A. Incubation of immunoprecipitated AQP2 with enzymatically active USP4, but not active USP30, significantly decreased the levels of ubiquitylated AQP2 compared to the control condition, as shown in xref B. This data indicates that a direct and functional interaction between USP4 and AQP2 can occur in vitro to modulate AQP2 ubiquitylation."

sparser
"Co-immunoprecipitations of AQP2 with USP4 from a collecting duct cell model (mpkCCD14) and mouse kidney tubules indicated an interaction between AQP2 and USP4."

sparser
"USP4 Interacts with AQP2 in Cultured Kidney Epithelial Cells and In Vivo."
PRPF3 affects USP4
7 | 1
7 | 1

reach
"In addition, the other study reports that USP4, the USP15 homolog, binds to Tip110 and deubiquitinates Prp3, component of the U4 snRNP, during the spilceosome cycle ( Song et al., 2010 )."
Gastrodin affects USP4
| 8
Gastrodin increases the amount of USP4. 8 / 8
| 8

reach
"Furthermore, gastrodin significantly upregulated the expression of USP4 and increased the binding of USP4 to the insulin receptor.Considering the importance of the PI3K-Akt pathway in the pathogenesis of T2DM, we detected the effects of gastrodin on the PI3K-Akt pathway to further explore the underlying mechanism of gastrodin in ameliorating insulin resistance."

reach
"Thus, these results indicate that gastrodin promotes the phosphorylation of GATA1 and upregulate its transcriptional activity via the PI3K-Akt pathway, promotes USP4 gene transcription, and upregulates USP4 expression."

reach
"Furthermore, Gastrodin has been shown to upregulate the expression of USP4 and enhance the interaction between USP4 and insulin receptors to treat diabetes (118)."

reach
"Gastrodin, a compound derived from Gastrodia elata, has been reported to enhance the expression of USP4 and may represent a novel targeted treatment for T2D (118)."

reach
"Our results indicate that gastrodin promotes the phosphorylation of GATA1 via the PI3K/AKT pathway, enhances the transcriptional activity of GATA1, and then increases the expression level of USP4, thereby reducing the ubiquitination and degradation of insulin receptors and ultimately improving insulin resistance."

reach
"Bai et al. [1] indicated that gastrodin promotes the phosphorylation of GATA1, upregulates its transcriptional activity via the PI3K/AKT pathway, and promotes USP4 expression."

reach
"The results of the study showed that gastrodin promotes the phosphorylation of GATA1 via the PI3K/AKT pathway, increases the transcriptional activity of GATA1, and subsequently increases the expression level of USP4, thereby reducing the ubiquitination and degradation of insulin receptors, and ultimately improving insulin resistance."

reach
"Compared to the IR group, gastrodin upregulated the ratio of p-Akt/total Akt by 50.09, 153.81, and 155.27% and upregulated USP4 expression by 15.66, 84.50, and 143.24% at 10, 30, and 100 μg/ml, respectively."
AQP2 affects USP4
| 8
| 8

sparser
"To investigate if USP4 interacts with AQP2, co-immunoprecipitation studies were initially performed on lysates from cultured cells."

sparser
"Supporting this, AQP2 and USP4 interacted in vitro, with USP4 being able to directly deubiquitylate AQP2."

sparser
"In mpkCCD14 cells, USP4 could be immunoprecipitated with an anti-AQP2 antibody, and prior treatment with dDAVP had no clear effect on the interaction, as shown in xref A. Similar results were obtained in MDCK-hAQP2 cells, as shown in xref B, with an interaction between AQP2 and USP4 observed under control conditions, or after treatment of cells with the adenylate cyclase activator forskolin (MDCK-hAQP2 cells have limited response to VP)."

sparser
"To examine if USP4 and AQP2 interact in vivo, co-immunoprecipitation studies were performed on lysates from mouse kidney tubule suspensions treated with vehicle or dDAVP for 30 min."

sparser
"USP4 and AQP2 were detected in samples immunoprecipitated using either anti-AQP2 or anti-USP4, confirming that a USP4 and AQP2 interaction occurs in vivo, as shown in xref C. Similar to the cultured cell experiments, prior stimulation of the tubule suspensions with dDAVP had no clear effect on the USP4-AQP2 interaction, as shown in xref C."

sparser
"The characteristic pattern [ xref ] of ubiquitylated AQP2 was observed in the immunoprecipitated samples, as shown in xref A. Incubation of immunoprecipitated AQP2 with enzymatically active USP4, but not active USP30, significantly decreased the levels of ubiquitylated AQP2 compared to the control condition, as shown in xref B. This data indicates that a direct and functional interaction between USP4 and AQP2 can occur in vitro to modulate AQP2 ubiquitylation."

sparser
"Co-immunoprecipitations of AQP2 with USP4 from a collecting duct cell model (mpkCCD14) and mouse kidney tubules indicated an interaction between AQP2 and USP4."

sparser
"USP4 Interacts with AQP2 in Cultured Kidney Epithelial Cells and In Vivo."
USP4 affects activation
| 7
USP4 inhibits activation. 7 / 7
| 7

sparser
"It was also found that USP4 inhibited NF-κB activation, but in this study we confirmed that USP4 positively regulates the NF-κB signalling pathway during EV71 infection."

sparser
"In addition, USP4 inhibits TNF-α-induced activation of NF-κB through USP4 deubiquitination of TAK1 xref ."

sparser
"USP4 acts as a TAK1 Lys63-specific deubiquitinase to deubiquitinate TAK1 and inhibit Dox-induced NF-κB activation."

sparser
"USP4 inhibits TAK1/TAB1 co-overexpression-mediated NF-κB activation."

sparser
"USP4 deubiquitinates TAK1 with Lys63-linked polyubiquitination and inhibits Dox-induced NF-κB activation."

sparser
"USP4 inhibits TNFα-induced NF-κB activation by acting as a TAK1 deubiquitinase [ xref ]."

sparser
"Taken together, these results suggest that USP4 inhibits TNFα-induced IKK/NF-κB activation through suppressing TAK1 polyubiquitination."
USP4 affects PDCD4
| 6 1
USP4 activates PDCD4.
| 3
USP4 activates PDCD4. 3 / 3
| 3

reach
"To determine whether PDCD4 is involved in the anti-proliferative function of USP4, we further examined the role of PDCD4 in the USP4 induced inhibition of proliferation by knocking down PDCD4 using siRNA."

reach
"The physical interaction between USP4 and PDCD4 indicated that USP4 targets PDCD4 for deubiquitination and subsequent inhibition of its degradation."

reach
"In addition, proteasome inhibition by the addition of MG132 induced a significant increase in the PDCD4 expression level (XREF_FIG), suggesting that USP4 inhibits PDCD4 degradation."
USP4 increases the amount of PDCD4.
| 2
USP4 increases the amount of PDCD4. 2 / 2
| 2

reach
"USP4 upregulates PDCD4 expression in breast cancer cells."

reach
"Furthermore, the knockdown of USP4 significantly decreased the endogenous PDCD4 protein expression level (XREF_FIG)."
USP4 binds PDCD4.
| 1 1
| 1 1

reach
"The physical interaction between USP4 and PDCD4 indicated that USP4 targets PDCD4 for deubiquitination and subsequent inhibition of its degradation."

sparser
"The physical interaction between USP4 and PDCD4 indicated that USP4 targets PDCD4 for deubiquitination and subsequent inhibition of its degradation."
USP4 affects Fibrosis
| 1 6
USP4 inhibits Fibrosis.
| 1 3
| 1 3

eidos
"In conclusion , USP4 was significantly elevated in autoimmune hepatitis mice and Vialinin A reduced USP4 level and attenuate inflammation and fibrosis in the liver ."

reach
"Researchers discovered that deubiquitinating USP4 (Ubiquitin-specific protease 4) keeps ACE2 stable, which in turn prevents EMT and fibrosis in LUAD."

reach
"USP4 deubiquitination maintains ACE2 stability and thus inhibits EMT and fibrosis in LUAD."

reach
"The intervention using Vialinin A and liver X receptor α (LXRα)-induced cannabinoid receptor 2 (CB2) has been found to reduce the level of USP4, leading to alleviate inflammation and fibrosis in the liver (74)."
USP4 activates Fibrosis.
| 3
USP4 activates Fibrosis. 3 / 3
| 3

reach
"LncRNA H19 180 acts as a ceRNA to downregulate the expression of miR-148a and upregulate the expression of USP4, which stabilizes the TGFβRⅠ and activates the TGF-β/smad signaling pathway and promotes the development of liver fibrosis."

reach
"In a model of autoimmune hepatitis in mice, the expression of USP4 was found to be reduced upon treatment with Vi-A, thereby reducing inflammation and fibrosis in the liver [31]."

reach
"The intervention using Vialinin A and liver X receptor α (LXRα)-induced cannabinoid receptor 2 (CB2) has been found to reduce the level of USP4, leading to alleviate inflammation and fibrosis in the liver (74)."
USP4 affects ELAVL1
| 1 4 2
USP4 binds ELAVL1.
| 1 2
| 1 2

sparser
"The results showed that METL3 knockdown markedly enhanced the interaction between USP4 and ELAVL1(Figure xref S and xref N)."

sparser
"In this study, we examined that METTL3 knockdown significantly decreased the binding of HNRNPD to USP4 pre-mRNA(Figure xref N and xref B); however, the interaction between ELAVL1 and USP4 pre-mRNA were not significantly changed(Figure xref O and xref C)."

reach
"The results showed that METL3 knockdown markedly enhanced the interaction between USP4 and ELAVL1."
USP4 increases the amount of ELAVL1.
| 2
USP4 increases the amount of ELAVL1. 2 / 2
| 2

reach
"The reduction in USP4 expression decreases the level of ELAVL1 protein deubiquitination, leading to decreased ELAVL1 protein expression and increased ARHGDIA expression, promoting bladder cancer cell migration and invasion [98]."

reach
"Taken together, our results demonstrated that USP4 upregulates ELAVL1 expression by removing the ubiquitin group from ELAVL1 protein."
USP4 activates ELAVL1.
| 1 1
USP4 activates ELAVL1. 2 / 2
| 1 1

eidos
"Taken together , our results demonstrated that USP4 upregulates ELAVL1 expression by removing the ubiquitin group from ELAVL1 protein ."

reach
"Consistently, USP4 knockdown markedly reduced protein stability of ELAVL1."
USP4 affects E3_Ub_ligase
| 6 1
USP4 deubiquitinates E3_Ub_ligase.
| 4
USP4 deubiquitinates E3_Ub_ligase. 4 / 4
| 4

reach
"USP4 interacts with and deubiquitylates another E3 ubiquitin ligase for p53, ARF-BP1/Mule/HUWE, leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels."

reach
"In contrast to USP2a, USP4 deubiquitinates and stabilizes a different E3 that ubiquitinates p53 called ARF-BP1, thereby destabilizing p53 [XREF_BIBR]."

reach
"USP4 also regulates p53 stability via direct deubiquitination of the E3 ARF-BP1 [179] ."

reach
"In the cytosol, USP4 deubiquitinates the member of many vital cell signaling pathways, e.g., NF-κB [77], TGF-β [54], Wnt/β-catenin [78], and p53 [79] as well as adenosine A2A receptor [80] and the E3 ligase TRIM21 [81]."
| 2 1

sparser
"ARF-BP1 is a p53-specific E3 ligase that binds to USP4."
| PMC

reach
"ARF-BP1 is a p53-specific E3 ligase that binds to USP4."
| PMC

reach
"USP4 interacts with and deubiquitylates another E3 ubiquitin ligase for p53, ARF-BP1/Mule/HUWE, leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels."
TWIST1 affects USP4
1 | 6
1 | 6

sparser
"To this end, we first asked whether USP4 can form a stable protein complex with Twist1."

sparser
"Co-Immunoprecipitation assay showed that USP4 interacted with Twist1 ( xref D)."

sparser
"Our data indicate that USP4 stabilizes Twist1 to promote lung cancer cell stemness, which prompted us to verify the clinical relevance of USP4Twist1 in human lung cancer."

sparser
"Together, these results indicate that the USP4Twist1 axis plays a critical role in lung cancer stemness and clinical prognoses ( xref E)."

sparser
"In this study, we uncover that USP4 is a novel deubquitinase of Twist1 and that silencing of Twist dramatically inhibits USP4-induced stemness of lung cancer cells, suggesting that the USP4Twist1 axis plays a critical role in lung cancer stemness."

sparser
"Thus, targeting the USP4Twist1 axis may represent a novel therapeutic approach for lung cancer treatment."
TNF affects USP4
| 6
TNF activates USP4. 6 / 7
| 6

reach
"To further determine the molecular interaction of USP4 and TAK1 in TNFalpha induced signal transduction, we overexpressed expression vector encoding MYC-USP4 in HEK-293T cells and treated with TNFalpha for the time points as indicated (XREF_FIG)."

reach
"To determine whether USP4 inhibits TNFalpha induced TAK1 polyubiquitination, we overexpressed MYC-USP4-WT and -C311A mutant with HA-Ub in HEK293T cells and treated with TNFalpha for the time points indicated."

reach
"We found that TNFalpha induced co-immunoprecipitation of MYC-USP4 and TAK1 as well as IKKbeta and RIPK1 within 10 min of stimulation (XREF_FIG)."

reach
"Consistently, we also found that TNFalpha induced co-immunoprecipitation of endogenous USP4 and TAK1 as well as IKKbeta and RIPK1 (XREF_FIG)."

reach
"These results suggest that TNFalpha induces association of USP4 with TAK1."

reach
"It was shown that TNFalpha induces the association of USP4 with TAK1 and deubiquitylation of K63 linked ubiquitin chains from TAK1, leading to the inhibition of NF-kappaB production."
SMAD4 affects USP4
4 | 1 2
4 | 1 2

reach
"The binding of USP4 to SMAD4 prevents its monoubiquitination in the cytoplasm and subsequently enhances SMAD4 mediated activin and bone morphogenetic protein (BMP) pathways."

sparser
"The binding of USP4 to SMAD4 prevents its monoubiquitination in the cytoplasm and subsequently enhances SMAD4-mediated activin and bone morphogenetic protein (BMP) pathways."

sparser
"GST pull-down in vitro exhibited that USP4 interacted with SMAD4 ( xref E)."
PTP4A3 affects USP4
2 | 1 2 1
2 | 1 2 1

sparser
"In addition, USP4, which is elevated in gastric and rectal cancer, interacts with PRL-3 and increases the stability of PRL-3, promoting NF-κB signaling and cell viability [ xref , xref ]."

reach
"Mechanistically, we observed that USP4 interacted with and stabilized PRL-3 via deubiquitination."

reach
"Xing et al. reported that USP4 interacted with and catalytically stabilized PRL-3."

trips
"Mechanistically, we observed that USP4 interacted with and stabilized PRL-3 via deubiquitination."
USP4 affects SRSF1
| 6
USP4 activates SRSF1.
| 4
USP4 activates SRSF1. 4 / 4
| 4

reach
"Depletion of USP15 and USP4 impair SRSF1 splicing characterized by the replacement of exon 4 with non-coding intron sequences retained at its C-terminus, resulting in an alternative isoform SRSF1-3."

reach
"On the other hand, SRSF1 is upregulated by high USP15 and USP4 that enhance cell proliferation and invasion (Fig. 7D)."

reach
"Overexpression of USP15 and USP4 upregulated SRSF1 (Fig. 3A), while the knockdown caused its downregulation (Fig. 3B)."

reach
"Deubiquitination enzyme USP15 and its similar parallel gene USP4 were overexpressed and promoted the proliferation of lung cancer cells by regulating SRSF1 alternative splicing (67)."
USP4 increases the amount of SRSF1.
| 2
USP4 increases the amount of SRSF1. 2 / 2
| 2

reach
"Also, the subsequent overexpression of SRSF1 restored the decreased invasion by USP15 (Fig. 5C, D) and USP4 (Fig. 5F, G) knockdown in H157 cells, as well as in A549 cells (Supplementary Fig. 5A, B)."

reach
"Collectively, our current study demonstrates USP15 and USP4 mediated lung cancer cell proliferation and migration by increasing the expression of functional full-length SRSF1 protein."
USP4 affects RNPS1
4 | 1
4 | 1

reach
"USP4 binds to a variety of effectors, including RNA-binding protein with serine-rich domain 1 (RNPS1) [6], the A2a adenosine receptor [7] and diverse components of the spliceosome assembly [8,9]."
USP4 affects RI
| 6
USP4 deubiquitinates RI.
| 4
USP4 deubiquitinates RI. 4 / 4
| 4

reach
"USP4 can directly deubiquitylates TβRI, stabilizing it in the plasma membrane [61]."

reach
"Little is known about microenvironmental stimuli and the signaling pathways that control TGF-β receptor stability and degradation, besides the already mentioned stimulation of USP4-mediated TβRI deubi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"In breast cancer, USP4 directly interacts with and deubiquitinates TβRI and promotes the proliferation of tumor cells (44)."

reach
"However, AKT-mediated USP4 phosphorylation promoted its subcellular localization to the membrane, where USP4 deubiquitinated TβRI."
USP4 increases the amount of RI.
| 2
USP4 increases the amount of RI. 2 / 2
| 2

reach
"The deubiquitinating enzyme USP4 upregulates the expression of TGFβRI by deubiquitinating it and the ability to respond to TGF-β signaling 56."

reach
"Finally, glioblastoma patients express high levels of USP4, which in turn can enhance the expression of TβRI, resulting in increased phospho-SMAD2 [64]."
USP4 affects P-Inter
| 6
USP4 binds P-Inter. 6 / 6
| 6

sparser
"In Experiment 2, comparing responding to X in Group F-Block-Unp ABB with Group P-Inter-Unp ABB could assess overshadowing as a result of Phase 2 containing training of YX compound and X alone, respectively."

sparser
"An outlier analysis, as in Experiment 1, eliminated one subject from Group P-Inter-P ABB, two from Group P-Inter-Unp ABC, and two from Group F-Block-Unp ABB."

sparser
"Data from seven subjects were lost due to malfunctioning of the equipment (two subjects from each from Groups F-Block-Unp ABB and F-Block-Unp ABC, and one subject from each from Groups P-Inter-Unp ABB, F-Block-P ABC, and F-Block-Unp ABC)."

sparser
"Four additional subjects were eliminated for failing to complete an initial 5 cumulative seconds of drinking by the end of the first minute (i.e., before CS onset) (one from each Groups P-Inter-Unp ABB, P-Inter-P ABC, F-Block-Unp ABC, and F-Block-P ABC)."

sparser
"Contrasts revealed no differences in suppression between Group P-Inter-Unp ABB and Group P-Inter-P ABB, F (1, 72) = 1.51, p = ."

sparser
"Lastly, a comparison of F-Block-Unp ABB (effectively an overshadowing treatment) with P-Inter-Unp ABB (effectively an overshadowing control condition) detected no appreciable difference, which indicates that with the present parameters no appreciable overshadowing of X by Y occurred when testing occurred in Context B, F (1, 72) = 1.72, p = ."
USP4 affects Interferon
| 6
USP4 inhibits Interferon.
| 4
| 4

reach
"Overall, these data suggest that USP4 suppresses IRF3 activation and the IFN response, at least partially, by deubiquitinating the K63-linked polyubiquitination of IRF3 either through TRAF6 or by dire[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"These results suggest that USP4 inhibits the IFN response by suppressing the nuclear localization of IRF3.It has been demonstrated that K63-linked polyubiquitination enhances the activation of IRF3, w[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"In the current study, we demonstrated that USP4 suppresses the IFN response and antigen presentation process in CRC cells, suggesting that USP4 negatively regulates cytosolic PRR-mediated signaling an[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"In addition, USP4 suppressed IFN response and antigen presentation process, thus impeding the antitumor immune response in CRC cells and a syngeneic mouse model."
USP4 activates Interferon.
| 2
| 2

reach
"We found that USP4 promoted the suppressive function of Treg cells by stabilizing interferon regulatory factor (IRF)8. USP4 interacts with and stabilizes IRF8 by deubiquitination of K48-linked polyubi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Congruently, the overexpression of USP4 or USP17 significantly promotes virus-induced IFN production and thereby restricts virus replication, whereas the knockdown of USP4 or USP17 has the opposite effect (77, 87)."
USP4 affects CTTN
4 | 1 1
4 | 1 1

reach
"Binding of USP4 to cortactin enhances cell migration in HCT116 human colon cancer cells."

sparser
"Binding of USP4 to cortactin enhances cell migration in HCT116 human colon cancer cells."
USP4 affects CDH1
| 5 1
USP4 inhibits CDH1.
| 2 1
USP4 inhibits CDH1. 3 / 3
| 2 1

reach
"Through the immunoblotting analysis, we found that the knockdown of USP4 induced drastic down-regulation of N-cadherin and up-regulation of E-cadherin, indicating that USP4 deficiency could reverse the process of EMT."

sparser
"Neither transient nor stable overexpression of USP4 inhibited E-cadherin in Huh7 cells (Figure xref )."

reach
"Neither transient nor stable overexpression of USP4 inhibited E-cadherin in Huh7 cells."
USP4 decreases the amount of CDH1.
| 3
USP4 decreases the amount of CDH1. 3 / 3
| 3

reach
"We found that knockdown of both USP4 and beta-catenin downregulated the expression of ZEB1 and thereby increased the level of E-cadherin, indicating that the USP4 and beta-catenin axis is required for the EMT process and involves the regulation of ZEB1."

reach
"In line with previous studies, we also showed that USP4 promoted melanoma metastasis by suppressing E-cadherin expression and increasing N-cadherin expression, indicating the ubiquitous existence of the crosstalk between USP4 and EMT in different kinds of cancer."

reach
"Surprisingly, USP4 knockdown also reduces the levels of SKP2 and CDH1 pointing to distortions in the dynamic equilibrium between APC/C and SCF ."
USP15 affects SART3
| 1 5
USP15 binds SART3 and USP4. 6 / 6
| 1 5

sparser
"We next examined whether SART3 forms a complex with USP15 and USP4 simultaneously using sequential immunoprecipitation."

reach
"Deubiquitination of PRP31 and PRP3 by the USP15, SART3, and USP4 complex decreases the affinity towards PRP8 and this regulation is important for the proper splicing of chromosome segregation related genes such as Bub1 and alpha-tubulin."

sparser
"Drugs interfering with the interaction between USP4 and USP15 and SART3 may selectively inhibit the DUB functions in the nucleus."
| PMC

sparser
"Moreover, as a substrate recruiting factor of USP15 either ( xref ; xref ), SART3 can simultaneously bind USP4 and USP15, serving as a platform to deubiquitinate PRP31 and PRP3 ( xref )."

sparser
"PRP31, a component of the U4 snRNP, is modified with K63-linked ubiquitin chains by the PRP19 complex and is deubiquitinated by the ternary complex of USP15, SART3, and USP4."

sparser
"Consistent with our prediction, SART3 interacted with endogenous USP4 and USP15 (Figure xref )."
RNPS1 affects USP4
4 | 1
4 | 1

reach
"USP4 binds to a variety of effectors, including RNA-binding protein with serine-rich domain 1 (RNPS1) [6], the A2a adenosine receptor [7] and diverse components of the spliceosome assembly [8,9]."
P-Inter affects USP4
| 6
USP4 binds P-Inter. 6 / 6
| 6

sparser
"In Experiment 2, comparing responding to X in Group F-Block-Unp ABB with Group P-Inter-Unp ABB could assess overshadowing as a result of Phase 2 containing training of YX compound and X alone, respectively."

sparser
"An outlier analysis, as in Experiment 1, eliminated one subject from Group P-Inter-P ABB, two from Group P-Inter-Unp ABC, and two from Group F-Block-Unp ABB."

sparser
"Data from seven subjects were lost due to malfunctioning of the equipment (two subjects from each from Groups F-Block-Unp ABB and F-Block-Unp ABC, and one subject from each from Groups P-Inter-Unp ABB, F-Block-P ABC, and F-Block-Unp ABC)."

sparser
"Four additional subjects were eliminated for failing to complete an initial 5 cumulative seconds of drinking by the end of the first minute (i.e., before CS onset) (one from each Groups P-Inter-Unp ABB, P-Inter-P ABC, F-Block-Unp ABC, and F-Block-P ABC)."

sparser
"Contrasts revealed no differences in suppression between Group P-Inter-Unp ABB and Group P-Inter-P ABB, F (1, 72) = 1.51, p = ."

sparser
"Lastly, a comparison of F-Block-Unp ABB (effectively an overshadowing treatment) with P-Inter-Unp ABB (effectively an overshadowing control condition) detected no appreciable difference, which indicates that with the present parameters no appreciable overshadowing of X by Y occurred when testing occurred in Context B, F (1, 72) = 1.72, p = ."
HAS2 affects USP4
1 | 1 4
| 3

sparser
"HAS2 interacts with USP17 and USP4."

sparser
"To confirm complex formation of endogenous components, proximity ligation assay (PLA) was performed using the breast cancer cell line MDA-231-BM, known to produce high levels of hyaluronan. xref Using antibodies against HAS2 and USP4 or USP17, reactive signals in the form of red dots indicating interactions between endogenous HAS2 and USP17, and HAS2 and USP4, were observed; only a low background level of dots was seen when each antibody was used alone, or in the fixation control without antibody ( xref )."

sparser
"Thus, both co-immunoprecipitation and PLA analyses supported the notion that HAS2 forms complexes with USP17 and USP4."
1 | 1 1

sparser
"The analysis revealed bands of 113 and 55 kDa, i.e., the expected sizes of USP4 and USP17 ( xref ), and of ~70 kDa ( xref ), which is the expected size of 6myc-HAS2, suggesting the formation of complexes between HAS2 and USP4, as well as between HAS2 and USP17."

reach
"HAS2 interacts with USP17 and USP4."
CTTN affects USP4
4 | 1 1
4 | 1 1

reach
"Binding of USP4 to cortactin enhances cell migration in HCT116 human colon cancer cells."

sparser
"Binding of USP4 to cortactin enhances cell migration in HCT116 human colon cancer cells."
Vialinin A affects USP4
| 5
Vialinin A inhibits USP4. 5 / 5
| 5

reach
"As shown in Figure 4 , treatment with vialinin A reduced the activity of USP4 (IC 50 = 1.5 μM) and UCH-L1 (IC 50 = 22.3 μM), but no significant inhibition was observed in terms of the UCH-L3, USP2, an[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Although USP4 and UCH-L1 were inhibited by vialinin A, the binding affinities to the biotin-DMT probe were different from that of USP5, where USP4 bound the probe more weakly and UCH-L1 did not bind t[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"17–20,29 In the present study, we demonstrated that vialinin A, whose structure is different from those of compounds previously reported, strongly inhibited the enzymatic activities of USP5 and USP4."

reach
"Notably, vialinin A is an inhibitor of ubiquitin-specific peptidase 4 (USP4) that shows anti-inflammatory and antioxidative properties."

reach
"Mechanistically, vialinin A inhibited the deubiquitinating enzymatic activity of USP4, leading to enhanced ubiquitination of Keap1 and subsequently promoting its degradation."
USP4 affects p38
| 5
USP4 inhibits p38.
| 3
USP4 inhibits p38. 3 / 3
| 3

reach
"Considering current results and previous known mechanism of USP, it can be hypothesized that USP4 is likely to regulate the function of key signaling proteins in myogenesis via protein-protein interac[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"These results showed that USP4 suppresses myoblast differentiation by inhibiting the p38 signaling pathway.The ubiquitin proteasome system plays a critical role in muscle differentiation by controllin[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"We also found that the effect of USP4 knockdown enhances the AKT and p38 signaling that are known to be involved in myogenesis by activating transcription-regulatory activity of MyoD through a direct [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 dephosphorylates p38.
| 2
USP4-C311A leads to the dephosphorylation of p38. 2 / 2
| 2

reach
"USP4 (C311A) mutation did not inhibit the TAK1 polyubiquitination, and phosphorylation of TAK1, = JNK1/2, and p38 in angiotensin treated myocytes."

reach
"In the same context, the overexpression of mutant USP4 C311A decreased the phosphorylation of AKT and p38 (Supplementary Figs."
USP4 affects TCF4
1 | 3 1
USP4 deubiquitinates TCF4.
1 | 2
USP4 deubiquitinates TCF4. 2 / 3
1 | 2

reach
"USP4 deubiquitinated a subpopulation of TCF4."

reach
"For example, USP4 interacts with and deubiquitinates TCF4, which inhibits beta-catenin-dependent transcription [XREF_BIBR]."
USP4 binds TCF4.
| 1 1
| 1 1

sparser
"For example, USP4 interacts with TCF4 and further deubiquitinates it, thus restraining β-catenin dependent process of transcription xref ; USP47 xref , USP2a xref , USP5 xref , USP20 xref are identified to deubiquitinating and stabilizing β-catenin directly."

reach
"For example, USP4 interacts with and deubiquitinates TCF4, which inhibits beta-catenin-dependent transcription [XREF_BIBR]."
USP4 affects RAD50
1 | 1 2
1 | 1

reach
"During the course of our studies, we observed that mutating theUSP4 catalytic cysteine to alanine (C311A) to render USP4 enzymatically inactive (" catalytic-dead " [CD]), almost totally abrogated its interactions with CtIP and MRN (XREF_FIG A; note that binding of USP4 to CtIP and RAD50 was not abrogated by the DNA intercalating agent ethidium bromide (EtBr), suggesting that interaction was not mediated by DNA bridging."
| 2

sparser
"We and others report that USP4 interacts with CtIP and the MRE11RAD50NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites and DNA end resection ( xref , xref )."

sparser
"We also report that USP4 interacts with CtIP and the MRE11-RAD50-NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites."
USP4 affects ODC1
| 1 4
USP4 activates ODC1. 5 / 5
| 1 4

sparser
"It is worth noting that the activation of ODC by GNP or UNP decreases as the number of the phosphates, from triphos- phates to monophosphates, decrease."

sparser
"Another interesting observation is that, whereas the native E. coli ODC is activated by many nucleotides [4], the recombinant, over- produced E. coli ODC is activated only by GNP or UNP."

sparser
"Another interesting observation is that, whereas the native E. coli ODC is activated by many nucleotides [4], the recombinant, over- produced E. coli ODC is activated only by GNP or UNP."

reach
"Another interesting observation is that, whereas the native E. coli ODC is activated by many nucleotides [4], the recombinant, over- produced E. coli ODC is activated only by GNP or UNP."

sparser
"It is worth noting that the activation of ODC by GNP or UNP decreases as the number of the phosphates, from triphos- phates to monophosphates, decrease."
USP4 affects HNRNPD
| 2 3
| 2 3

sparser
"In this study, we examined that METTL3 knockdown significantly decreased the binding of HNRNPD to USP4 pre-mRNA(Figure xref N and xref B); however, the interaction between ELAVL1 and USP4 pre-mRNA were not significantly changed(Figure xref O and xref C)."

sparser
"Taken together, these results suggested m 6 A methylation reduces USP4 mRNA stability by promoting the binding of HNRNPD to USP4 mRNA."

reach
"In this study, we examined that METTL3 knockdown significantly decreased the binding of HNRNPD to USP4 pre-mRNA; however, the interaction between ELAVL1 and USP4 pre-mRNA were not significantly changed."

reach
"Taken together, these results suggested m 6 A methylation reduces USP4 mRNA stability by promoting the binding of HNRNPD to USP4 mRNA."

sparser
"The mRNA of USP4 can bind to the RNA-binding protein HNRNPD, with its mRNA A2696 checkpoint modified by m6A via METTL3 and YTHDF2, resulting in mRNA degradation ( xref )."
USP4 affects CS
| 5
CS binds USP4. 5 / 5
| 5

sparser
"Our data showed that overexpression of USP4-WT, but not USP4-CS, promoted the EGF-dependent mTORC1 activation (Fig.  xref )."

sparser
"Meanwhile, reintroducing USP4 WT, but not the enzymatic dead mutant (USP4-CS), in USP4-deficient cells rescued the mTORC1 activation (Supplementary information, Fig. S xref )."

sparser
"In addition, the ectopical expression of USP4, but not the deubiquitinase enzyme dead mutant USP4-CS, blocked the interaction between Rheb and TSC2 (Supplementary information, Fig. S xref )."

sparser
"Additionally, ectopically expressed USP4-WT not mutant USP4-CS eliminated endogenous SMAD4 mononucleotide ( xref M)."

sparser
"Our data showed that ectopical expression of wild-type USP4 (USP4-WT), but not the enzyme-dead mutant USP4-CS, in which cysteine 311 was replaced with arginine xref , abrogated TSC2/RNF152-mediated ubiquitination of Rheb (Fig.  xref and Supplementary information, Fig.  xref )."

reach
"USP4 can promote the migration and invasion of lung adenocarcinoma cells."

reach
"USP4 promotes proliferation and metastasis in human lung adenocarcinoma."

reach
"Our study showed that after interfering with USP4 expression, lung adenocarcinoma cells changed from a long spindle shape to round, the migration and invasion abilities of cells decreased, N-cadherin expression decreased, and E-cadherin expression increased, indicating that USP4 promoted the invasion and migration of lung adenocarcinoma cells by promoting the EMT of cancer cells."

reach
"SPSS statistical analysis showed that silencing USP4 expression inhibited the proliferation of lung adenocarcinoma cells, and the difference was statistically significant P < 0.05(Fig. 3C)."

reach
"USP4 promotes the migration and invasion of lung adenocarcinoma cells by regulating cellular EMT processes."
TRPS1 affects HDAC2
| 1 4
HDAC2 binds USP4 and TRPS1. 5 / 5
| 1 4

reach
"Similarly, trichorhinophalangeal syndrome type I (TRPS1) functions as a scaffold protein involved in the USP4 induced stabilization of HDAC2 through bringing them together to form the TRPS1, USP4, and HDAC2 complex."

sparser
"We hypothesized that TRPS1, USP4, and HDAC2 formed a complex, used Co-IP to test this notion, and found that TRPS1 co-immunoprecipitated with USP4 and HDAC2 (Fig. xref )."

sparser
"To further confirm the interaction between TRPS1, USP4, and HDAC2, we generated serial TRPS1 truncates based on the domain structure of TRPS1 consisting of an N-terminal domain and GATA and C-terminal domains (Fig. xref )."

sparser
"The results indicated that N-terminal or C-terminal domains of TRPS1 together with the GATA domain were sufficient to interact with HDAC2 and USP4 while neither TRPS1 N-terminal or C-terminal domain alone interacted with HDAC2 and USP4 (Fig. xref )."

sparser
"Similarly, trichorhinophalangeal syndrome type I (TRPS1) functions as a scaffold protein involved in the USP4-induced stabilization of HDAC2 through bringing them together to form the TRPS1-USP4-HDAC2 complex ( xref )."
RAD50 affects USP4
1 | 1 2
1 | 1

reach
"During the course of our studies, we observed that mutating theUSP4 catalytic cysteine to alanine (C311A) to render USP4 enzymatically inactive (" catalytic-dead " [CD]), almost totally abrogated its interactions with CtIP and MRN (XREF_FIG A; note that binding of USP4 to CtIP and RAD50 was not abrogated by the DNA intercalating agent ethidium bromide (EtBr), suggesting that interaction was not mediated by DNA bridging."
| 2

sparser
"We and others report that USP4 interacts with CtIP and the MRE11RAD50NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites and DNA end resection ( xref , xref )."

sparser
"We also report that USP4 interacts with CtIP and the MRE11-RAD50-NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites."
RAB7A affects USP4
| 2 3
| 2 3

sparser
"In conclusion, these findings highlight the interaction between USP4 and RAB7A as a promising target for therapeutic intervention in managing periodontal diseases."

sparser
"Through co-immunoprecipitation (co-IP) and rigid protein-protein docking, we observed an interaction between USP4 and RAB7A in THP-1 cells (Figure S5A; xref )."

sparser
"These findings highlight the RAB7A-USP4 interaction as a promising target for potential therapeutic interventions in periodontal disease."

reach
"In conclusion, these findings highlight the interaction between USP4 and RAB7A as a promising target for therapeutic intervention in managing periodontal diseases.Abbreviation: 3-MA: 3-methyladenine; Baf A1:bafilomycin A 1 ; BECN1: beclin 1, autophagy related; CEJ-ABC: cementoenamel junctionto alveolar bone crest; IL1B/IL-1beta: interleukin 1 beta; KD:knockdown; LPS: lipopolysaccharide; MOI: multiplicity of infection;OE: overexpression; P.g."

reach
"Through co-immunoprecipitation (co-IP) and rigid protein-protein docking, we observed an interaction between USP4 and RAB7A in THP-1 cells (Figure S5A; Figure 5B,C)."
HNRNPD affects USP4
| 2 3
| 2 3

sparser
"In this study, we examined that METTL3 knockdown significantly decreased the binding of HNRNPD to USP4 pre-mRNA(Figure xref N and xref B); however, the interaction between ELAVL1 and USP4 pre-mRNA were not significantly changed(Figure xref O and xref C)."

sparser
"Taken together, these results suggested m 6 A methylation reduces USP4 mRNA stability by promoting the binding of HNRNPD to USP4 mRNA."

reach
"In this study, we examined that METTL3 knockdown significantly decreased the binding of HNRNPD to USP4 pre-mRNA; however, the interaction between ELAVL1 and USP4 pre-mRNA were not significantly changed."

reach
"Taken together, these results suggested m 6 A methylation reduces USP4 mRNA stability by promoting the binding of HNRNPD to USP4 mRNA."

sparser
"The mRNA of USP4 can bind to the RNA-binding protein HNRNPD, with its mRNA A2696 checkpoint modified by m6A via METTL3 and YTHDF2, resulting in mRNA degradation ( xref )."
HDAC2 affects TRPS1, and USP4
| 1 4
HDAC2 binds USP4 and TRPS1. 5 / 5
| 1 4

reach
"Similarly, trichorhinophalangeal syndrome type I (TRPS1) functions as a scaffold protein involved in the USP4 induced stabilization of HDAC2 through bringing them together to form the TRPS1, USP4, and HDAC2 complex."

sparser
"We hypothesized that TRPS1, USP4, and HDAC2 formed a complex, used Co-IP to test this notion, and found that TRPS1 co-immunoprecipitated with USP4 and HDAC2 (Fig. xref )."

sparser
"To further confirm the interaction between TRPS1, USP4, and HDAC2, we generated serial TRPS1 truncates based on the domain structure of TRPS1 consisting of an N-terminal domain and GATA and C-terminal domains (Fig. xref )."

sparser
"The results indicated that N-terminal or C-terminal domains of TRPS1 together with the GATA domain were sufficient to interact with HDAC2 and USP4 while neither TRPS1 N-terminal or C-terminal domain alone interacted with HDAC2 and USP4 (Fig. xref )."

sparser
"Similarly, trichorhinophalangeal syndrome type I (TRPS1) functions as a scaffold protein involved in the USP4-induced stabilization of HDAC2 through bringing them together to form the TRPS1-USP4-HDAC2 complex ( xref )."
CS affects USP4
| 5
CS binds USP4. 5 / 5
| 5

sparser
"Our data showed that overexpression of USP4-WT, but not USP4-CS, promoted the EGF-dependent mTORC1 activation (Fig.  xref )."

sparser
"Meanwhile, reintroducing USP4 WT, but not the enzymatic dead mutant (USP4-CS), in USP4-deficient cells rescued the mTORC1 activation (Supplementary information, Fig. S xref )."

sparser
"In addition, the ectopical expression of USP4, but not the deubiquitinase enzyme dead mutant USP4-CS, blocked the interaction between Rheb and TSC2 (Supplementary information, Fig. S xref )."

sparser
"Additionally, ectopically expressed USP4-WT not mutant USP4-CS eliminated endogenous SMAD4 mononucleotide ( xref M)."

sparser
"Our data showed that ectopical expression of wild-type USP4 (USP4-WT), but not the enzyme-dead mutant USP4-CS, in which cysteine 311 was replaced with arginine xref , abrogated TSC2/RNF152-mediated ubiquitination of Rheb (Fig.  xref and Supplementary information, Fig.  xref )."
CNR2 affects USP4
| 4 1
CNR2 inhibits USP4. 5 / 5
| 4 1

reach
"Additionally, it has been reported that CB2 inhibited USP4, leading to the stabilization of TGF-β1R, and subsequently ameliorating hepatic autoimmune hepatitis (74)."

reach
"Liver X Receptor alpha-Induced Cannabinoid Receptor 2 Inhibits Ubiquitin-Specific Peptidase 4 Through miR-27b, Protecting Hepatocytes From TGF-beta."

reach
"Conclusion: LXRalpha exerts a cytoprotective effect against TGF-beta by transcriptionally regulating the CB2 gene in hepatocytes, and CB2 then inhibits USP4-stabilizing TbetaRI through miR-27b."

sparser
"Additionally, it has been reported that CB2 inhibited USP4, leading to the stabilization of TGF-β1R, and subsequently ameliorating hepatic autoimmune hepatitis ( xref )."

reach
"Thus, LXRalpha could exert a protective effect against TGF-beta by transcriptional regulation of the CB2R gene in hepatocytes, and then CB2 might inhibit USP4 stabilizing TbetaRI via miR-27b."
Ubiquitin affects USP4
| 3 1
Ubiquitin activates USP4.
| 3
| 3

reach
"The DUSP domain plays a crucial role in enhancing the activity of USP4 by Ub removal from its catalytic site [91]."

reach
"The Effects of the Transforming Growth Factor-beta1 (TGF-beta1) Signaling Pathway on Cell Proliferation and Cell Migration are Mediated by Ubiquitin Specific Protease 4 (USP4) in Hypertrophic Scar Tissue and Primary Fibroblast Cultures."

reach
"Pre-steady-state kinetics measurements reveal that USP4 catalytic domain activity is strongly inhibited by slow dissociation of ubiquitin after substrate hydrolysis."
Ubiquitin binds USP4.
| 1

sparser
"The ubiquitin peptidase inactive form of USP4 (USP4-C311A) abolished its ability to stabilize HDAC2 ( xref and xref )."

reach
"These results supported the negative association of USP4 with myoblast differentiation.From these analyses, we found that USP4 negatively regulates myogenesis in contrast to our original hypothesis."

reach
"Although the mechanisms behind the USP4-driven inhibition of myogenesis or its correlation to AKT and p38 signaling have yet to be explored in detail, our findings clearly suggest that USP4 works as a[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Then we observed that co-treatment of HDAC inhibitors (MC1568 and SAHA) with USP4 overexpression further decreased protein levels of myogenesis markers ( Fig. 5 A)."

reach
"If p values were < 0.05, the differences were considered statistically significant and labeled in the following ways: * p < 0.05, ** p < 0.01, and *** p < 0.001, in the corresponding graph.Because USP[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"To test this hypothesis, we evaluated the effect of USP4 on myoblast differentiation in C2C12 cells, a mouse myoblast cell line, and confirmed that a USP4 knockdown promotes myoblast differentiation."

reach
"These results showed that USP4 suppresses myoblast differentiation by inhibiting the p38 signaling pathway.The ubiquitin proteasome system plays a critical role in muscle differentiation by controllin[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Thus the effect of USP4 on myogenesis is independent of the catalytic activity of USP4.It is known that HDAC1 directly binds to MyoD for the inhibition of myogenic differentiation and that the inhibit[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Considering current results and previous known mechanism of USP, it can be hypothesized that USP4 is likely to regulate the function of key signaling proteins in myogenesis via protein-protein interac[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 affects insulin receptors
| 4
USP4 deubiquitinates insulin receptors. 4 / 4
| 4

reach
"USP4 further reduces the ubiquitination of insulin receptors and increases their expression."

reach
"Additionally, USP4 decreases the ubiquitination and degradation of insulin receptors, consequently leading to reduced insulin resistance (118)."

reach
"Upregulation of USP4 reduces the ubiquitination and degradation of insulin receptors, upregulates the level of insulin receptors, and ultimately improves insulin resistance."

reach
"USP4 is a deubiquitinating enzyme and may deubiquitinate insulin receptors to inhibit their degradation, which maintains the expression level of insulin receptors on the membrane surface and improves insulin resistance."

reach
"The inhibition of USP4 promotes the activation of the innate immune response, resulting in an increase in production of interferon-stimulated genes (ISGs) and expression of MHC-I molecules."

reach
"USP4 also negatively regulates the TLR signaling-mediated innate immune response by removing the K63-linked ubiquitin chain on TAK1 [ 60 ]."
| 2

reach
"We found that PBLD deubiquitinates and stabilizes MAVS through ubiquitin-specific protease 4 (USP4) to promote antiviral innate immunity."

reach
"USP4 also negatively regulates the TLR signaling-mediated innate immune response by removing the K63-linked ubiquitin chain on TAK1 [ 60 ]."
USP4 affects activity
| 4
USP4 inhibits activity. 4 / 4
| 4

sparser
"As a consequence, USP4 inhibited p53-mediated luciferase activity in wild-type but not HDAC2 knockdown H1299 cells that were transfected with p53 ( xref )."

sparser
"Furthermore, we demonstrated that USP4 inhibited p53-mediated transcriptional activity in wild-type but not HDAC2 knockdown U2OS cells in response to DNA damage or not ( xref )."

sparser
"USP4 inhibits NF-κB transcriptional activity through HDAC2."

sparser
"In this screen, USP4 significantly inhibited the TAK1-induced NF-κB luciferase reporter activity whereas other USPs had no or less effects ( xref )."
USP4 affects UBL
| 4
USP4 binds UBL and DUSP. 4 / 4
| 4

sparser
"The crystal structure of USP4 DUSP-UBL shows a dimer formation where the subunits are packed against each other in an antiparallel orientation ( xref ) ( xref )."

sparser
"The binding of USP4 N-terminal DUSP-Ubl domain promotes a change of a switching loop near the active site, and hence enhances ubiquitin dissociation and makes it achieve full catalytic activity xref ."

sparser
"Indeed, surface plasmon resonance (SPR) shows an interaction of DUSPUbl with immobilized USP4 CD ( xref )."

sparser
"By binding to the linker between the DUSP and UBL domain of USP4, SART3 can shuttle USP4 to the nucleus from the cytosol through its NLS."
USP4 affects TGFB1
| 3
USP4 activates TGFB1. 3 / 4
| 3

reach
"Further studies demonstrated that USP4 mediated TGF-beta1 activation not only enhances the phosphorylation of Smad2 through TGF-beta, but also directly upregulate matrix metalloproteinase (MMP)-9-mediated cell migration and invasion of breast cancer cells."

reach
"Western blot analyses showed that the TbetaR-1 expression was significantly increased in HPMCs treated with TGF-beta1 and Flag-Akt, whereas no change was seen in cells treated with Smurf2 siRNA or USP4 siRNA."

reach
"Three examples of deubiquitinating enzymes for TbetaR-I are ubiquitin specific peptidase-4 (USP4), -11 (USP11) and -15 (USP15), all of which antagonize the effect of SMAD7 and strongly induce TGF-beta1 signalling [XREF_BIBR]."
USP4 affects SMAD2
| 3 1
USP4 leads to the phosphorylation of SMAD2. 4 / 4
| 3 1

reach
"Further studies demonstrated that USP4 mediated TGF-beta1 activation not only enhances the phosphorylation of Smad2 through TGF-beta, but also directly upregulate matrix metalloproteinase (MMP)-9-mediated cell migration and invasion of breast cancer cells."

reach
"Furthermore, USP4 promotes the phosphorylation of SMAD2, thereby activating the TGF-β signaling pathway by upregulating Relaxin [62]."

reach
"USP4 directly deubiquitylates TGF-β receptor I to induce the phosphorylation of Smad2 and up-regulate matrix metalloproteinase (MMP)-9, thereby facilitating cell migration and invasion of breast cancer cells [28,29]."

sparser
"Furthermore, USP4 promotes the phosphorylation of SMAD2, thereby activating the TGF-β signaling pathway by upregulating Relaxin [ xref ]."
USP4 affects Proteasome
| 2

reach
"USP4-Myc was also readily detected in the blots confirming that USP4 interacts with the assembled proteasome."

reach
"As illustrated by the representative experiment shown in Fig. 1 C, purified His (6x)-USP4 exclusively co-precipitated with GST-S9, confirming that the interaction is specific and direct.We next tested[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 affects PDPK1
1 | 3
USP4 deubiquitinates PDPK1.
1 | 2
USP4 deubiquitinates PDPK1. 2 / 3
1 | 2

reach
"In addition, the closely related USP15, which shares 61% amino acid sequence identity with USP4 XREF_BIBR, had no effect on Ub-PDK1 levels, further suggesting that the ability of USP4 to deubiquitinate PDK1 is specific."

reach
"USP4 deubiquitinates PDK1 and co-localizes at the plasma membrane."
USP4 ubiquitinates PDPK1.
| 1
USP4 leads to the ubiquitination of PDPK1. 1 / 1
| 1

reach
"A catalytically inactive USP4 mutant (C311S), in which the active site cysteine 311 residue is mutated to serine, failed to modulate PDK1 ubiquitination, indicating that the effect of USP4 on PDK1 is dependent on its deubiquitinase activity (XREF_FIG)."
USP4 affects MYOD1
| 4
USP4 inhibits MYOD1. 4 / 4
| 4

reach
"When MyoD activity was monitored by means of a luciferase reporter, it was revealed that the USP4 knockdown increased the MyoD activity, as compared to the control (MyoD + siUSP4 vs. MyoD; Fig. 2 A )."

reach
"Conversely, USP4 overexpression decreased the MyoD activity as compared to the control (MyoD + USP4 vs. MyoD; Fig. 2 B), and accordingly the effect of SAHA and MC1568 on MyoD activity was attenuated b[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"The role of USP4 in many pathological and physiological processes has been reported; USP4 promotes breast cancer invasive migration through the relaxin2-mediated TGF-β1/Smad2/MMP-9 pathway [31]; USP4 inhibits myogenic cell differentiation by catalyzing MyoD activity [32]; The H19/miR-148a/USP4 axis promotes hepatic stellate cells by enhancing and TGF-β signaling in hepatocytes to promote liver fibrosis [33]."

reach
"For instance, the deubiquitinase ubiquitin‐specific protease 4 (USP4) has been shown to suppress MyoD activity in a catalytic activity independent manner."
USP4 affects IKK_complex
| 4
Modified USP4 leads to the dephosphorylation of IKK_complex. 2 / 2
| 2

reach
"Furthermore, we found that overexpression of USP4 wild-type inhibited TAK1 and TAB1 co-overexpression-induced TAK1, IKK and MAPK phosphorylation in HEK293T cells whereas TAK1 C311A mutant and CYLD had no any inhibitory effect (XREF_SUPPLEMENTARY)."

reach
"Furthermore, it was found that overexpression of USP4 can inhibit interleukin-1 beta (IL-1beta), lipopolysaccharide (LPS), and TGF-beta-induced NF-kappaB-dependent luciferase reporter activity and Ika[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 leads to the dephosphorylation of IKK_complex. 2 / 2
| 2

reach
"Also USP4WT-R rescued the effect of USP4 knockdown on TNFalpha induced IKK phosphorylation and IkappaBalpha phosphorylation (XREF_FIG)."

reach
"Therefore, we further analyzed the effect of USP4 knockdown on the TNFalpha induced IKK phosphorylation, IkappaBalpha phosphorylation, ubiquitination and degradation."
USP4 affects HMGA2
| 4
USP4 increases the amount of HMGA2. 4 / 4
| 4

reach
"Furthermore, we point out, for the first time, that KLF2 modulates cell growth, apoptosis, and sensitivity to BTZ through HMGA2.Our study further elucidates the intricate regulatory network in BTZ-resistant MM cells by revealing that USP4 modulates HMGA2 expression via KLF2, establishing a previously uncharacterized USP4/KLF2/HMGA2 cascade in MM resistance to BTZ."

reach
"Future work will be warranted to uncover the downstream effectors underlying the activity of HMGA2.In summary, our study demonstrates a novel regulatory network where USP4 stabilizes KLF2 protein via deubiquitination and thus enhances HMGA2 expression, with the ability to modulate BTZ sensitivity, growth, and apoptosis of BTZ-resistant MM cells (Fig. 7C)."

reach
"Additionally, USP4 modulated HMGA2 expression via KLF2 in the two BTZ-resistant cell lines."

reach
"USP4 modulates HMGA2 expression via KLF2."
USP4 affects GST
| 4
| 4

sparser
"As expected, interaction of GST-S9 with USP4(1–318) was readily detected."

sparser
"To confirm the interaction between USP4 and BRCA1, we performed binding assay using recombinant USP4 fused with GST (GST-USP4)."

sparser
"To validate whether USP4 is a direct deubiquitinase for Rheb, we performed an in vitro deubiquitination assay using purified GST-USP4 protein."

sparser
"The results showed that the purified GST-USP4 but not the GST control was able to pull-down BRCA1 in vitro (Fig. xref ), suggesting that a direct interaction might exist between USP4 and BRCA1."
USP4 affects DNA repair
| 2
| 2

reach
"USP4 depletion also sensitized cells to ionizing radiation (IR) (XREF_FIG E; see XREF_SUPPLEMENTARY D for depletion of the NHEJ protein XRCC4), providing additional evidence that USP4 promotes DNA repair."

reach
"Next, we examined how USP4 promotes DNA repair using well established reporter assays for HR and NHEJ (Bennardo et al., 2008; Fattah et al., 2010; Moynahan et al., 2001)."
UBL affects USP4
| 4
USP4 binds UBL and DUSP. 4 / 4
| 4

sparser
"The crystal structure of USP4 DUSP-UBL shows a dimer formation where the subunits are packed against each other in an antiparallel orientation ( xref ) ( xref )."

sparser
"The binding of USP4 N-terminal DUSP-Ubl domain promotes a change of a switching loop near the active site, and hence enhances ubiquitin dissociation and makes it achieve full catalytic activity xref ."

sparser
"Indeed, surface plasmon resonance (SPR) shows an interaction of DUSPUbl with immobilized USP4 CD ( xref )."

sparser
"By binding to the linker between the DUSP and UBL domain of USP4, SART3 can shuttle USP4 to the nucleus from the cytosol through its NLS."
SOX9 affects USP4
| 4
| 4

sparser
"These data indicate that USP4 interacts with SOX9 and stabilizes its function via proteasome pathway."

sparser
"EVO inhibites CRC stemness via affecting USP4-SOX9 axis."

sparser
"These findings suggest that EVO decreases SOX9 level by inducing USP4 degradation, thus further inhibits CRC cell stemness by impairing USP4-SOX9 axis."

sparser
"Next, we observed physical interactions between USP4 and SOX9 by immunoprecipitation assay (Fig.  xref D)."
Proteasome affects USP4
| 2

reach
"USP4-Myc was also readily detected in the blots confirming that USP4 interacts with the assembled proteasome."

reach
"As illustrated by the representative experiment shown in Fig. 1 C, purified His (6x)-USP4 exclusively co-precipitated with GST-S9, confirming that the interaction is specific and direct.We next tested[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
PDCD4 affects USP4
| 3 1
PDCD4 binds USP4.
| 1 1
| 1 1

reach
"The physical interaction between USP4 and PDCD4 indicated that USP4 targets PDCD4 for deubiquitination and subsequent inhibition of its degradation."

sparser
"The physical interaction between USP4 and PDCD4 indicated that USP4 targets PDCD4 for deubiquitination and subsequent inhibition of its degradation."
PDCD4 activates USP4.
| 2
PDCD4 activates USP4. 2 / 2
| 2

reach
"The physical interaction between USP4 and PDCD4 indicated that USP4 targets PDCD4 for deubiquitination and subsequent inhibition of its degradation."

reach
"To examine this hypothesis, we first determined whether PDCD4 is a downstream target of USP4 in breast cancer cells."
IRF8 affects USP4
2 | 2
2 | 2

reach
"We found that USP4 promoted the suppressive function of Treg cells by stabilizing interferon regulatory factor (IRF)8. USP4 interacts with and stabilizes IRF8 by deubiquitination of K48-linked polyubi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Taken together, our results suggest that USP4 interacts with and stabilizes IRF8 to promote the suppressive function of Treg cells."
GST affects USP4
| 4
| 4

sparser
"As expected, interaction of GST-S9 with USP4(1–318) was readily detected."

sparser
"To confirm the interaction between USP4 and BRCA1, we performed binding assay using recombinant USP4 fused with GST (GST-USP4)."

sparser
"To validate whether USP4 is a direct deubiquitinase for Rheb, we performed an in vitro deubiquitination assay using purified GST-USP4 protein."

sparser
"The results showed that the purified GST-USP4 but not the GST control was able to pull-down BRCA1 in vitro (Fig. xref ), suggesting that a direct interaction might exist between USP4 and BRCA1."
DUSP affects UBL, and USP4
| 4
USP4 binds UBL and DUSP. 4 / 4
| 4

sparser
"The crystal structure of USP4 DUSP-UBL shows a dimer formation where the subunits are packed against each other in an antiparallel orientation ( xref ) ( xref )."

sparser
"The binding of USP4 N-terminal DUSP-Ubl domain promotes a change of a switching loop near the active site, and hence enhances ubiquitin dissociation and makes it achieve full catalytic activity xref ."

sparser
"Indeed, surface plasmon resonance (SPR) shows an interaction of DUSPUbl with immobilized USP4 CD ( xref )."

sparser
"By binding to the linker between the DUSP and UBL domain of USP4, SART3 can shuttle USP4 to the nucleus from the cytosol through its NLS."
CK2 affects USP4
| 4
CK2 phosphorylates USP4. 4 / 4
| 4

sparser
"Mechanistically, CK2-induced phosphorylation of USP4 is important for stabilization of SIRT1 by suppressing ubiquitin-dependent proteasomal degradation."

sparser
"The phosphorylation of USP4 by Ck2 can also inhibit the transcription of Sost by inhibiting ubiquitination degradation of SIRT1."

sparser
"Osteocytes are the main cells in mature bone tissue, accounting for about 95% of the total bone cells. xref Osteocytes can secrete paracrine factors, such as OPG, RANKL and sclerostin (Sost), which can participate in the regulation of osteoblast and osteoclast differentiation and activity and play a key role in bone remodelling. xref , xref Sost binds to LPR5/6 on osteoblast cell membranes to interfere with WNT binding to WNT receptor Frizzled, which acts as an antagonist of WNT/β‐catenin signalling to inhibit osteogenesis and bone formation. xref Sirtuin 1 (SIRT1) inhibits the expression of Sost by modifying the acetylation of H3K9 at the Sost promoter. xref , xref The phosphorylation of USP4 by casein kinase 2 (Ck2) inhibits the ubiquitination degradation of SIRT1, thus inhibiting the transcription of Sost and reducing the RANKL/OPG ratio in osteocytes, thereby reducing osteoclastogenesis and increasing osteoblastogenesis. xref Overall, Sost expression regulated by CK2–USP4–SIRT1 pathway is essential for osteocytes to maintain bone homeostasis."

sparser
"A study showed that casein kinase 2-induced phosphorylation of USP4 stabilizes sirtuin1 by inhibiting ubiquitin-dependent proteasomal degradation."
Curcumin affects USP4
| 1 2
| 1 2

eidos
"Curcumin downregulated USP4 to impeded the progression of colorectal cancer via repressing LAMP3 expression ."

reach
"Curcumin downregulated USP4 to impeded the progression of colorectal cancer via repressing LAMP3 expression."

reach
"A recent study reported that curcumin downregulated ubiquitin-specific peptidase 4 to modulate lysosome-associated membrane protein 3, and thus inhibited the malignant progression of colorectal cancer cells (24)."
Vialinin A affects USP4
| 1 2
Vialinin A inhibits USP4. 3 / 3
| 1 2

eidos
"It clearly indicates that Vialinin A can reduce USP4 level in the liver of autoimmune hepatitis , which contributes to reduction of inflammation and fibrosis in the liver ."

reach
"Since WP1130 showed inhibitory effects on USP5 and other 3 DUBs, we used another small compound, Vialinin A, that is able to inhibit the enzyme activities of USP5 and USP4 in further tests [41]."

reach
"Vialinin A, a natural substance extracted from edible mushrooms, effectively inhibits USP4 activity."
Vi-A affects USP4
| 3
Vi-A binds USP4. 3 / 3
| 3

reach
"We took advantage of the crystal structure of USP4 to establish a model of the USP4/Vi-A complex, with the binding site identified."

reach
"An in silico model of the Vi-A-USP4 complex was elaborated and five potential binding sites were identified using the CASTp 3.0 software."

reach
"This site overlaps with A102.A detailed model of Vi-A bound to USP4 is presented in Figure 2."
| 3

reach
"These results indicated that USP4 inhibits antitumor immunity and that inhibition of USP4 may reshape the TME into an immunostimulatory microenvironment.Given the data indicating that USP4 inhibits th[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Moreover, USP4 depletion stimulated the antitumor immune response and improved the sensitivity to anti-PD-1 therapy in CRC [ 53 ]."

reach
"For example, USP3, USP25, and USP18 played a positive regulation of the antiviral immune response [ 5–8 ], while USP5, USP4, USP13, USP15, USP14, USP2b, and USP19 negatively regulated antiviral immune[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
| 3
| 3

reach
"USP4 promotes glucose uptake and lactate production in gastric cancer cells."

reach
"The higher level of USP4 caused higher glucose uptake in cells."

reach
"Overexpression of USP4 promotes cell proliferation, glucose uptake, and lactate production in gastric cancer cells."
USP4 affects degradation
| 3
USP4 inhibits degradation. 3 / 3
| 3

sparser
"In addition, proteasome inhibition by the addition of MG132 induced a significant increase in the PDCD4 expression level ( xref ), suggesting that USP4 inhibits PDCD4 degradation."

sparser
"Because USP4 inhibits ubiquitination-mediated HDAC2 degradation, we hypothesized that USP4 inhibits p53 functions through HDAC2."

sparser
"USP4, a member of the USP family, inhibits the degradation of target proteins that depend on the ubiquitin proteasome pathway."

reach
"In addition, USP4 suppressed IFN response and antigen presentation process, thus impeding the antitumor immune response in CRC cells and a syngeneic mouse model."

reach
"In the current study, we demonstrated that USP4 suppresses the IFN response and antigen presentation process in CRC cells, suggesting that USP4 negatively regulates cytosolic PRR-mediated signaling an[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"In addition, knockdown of USP4 significantly elevated the gene expression levels of the MHC-I-dependent antigen processing and presentation pathway in CRC cells ( Fig. 3 C–D)."
USP4 affects adenosine
| 3
USP4 deubiquitinates adenosine.
| 2
USP4 deubiquitinates adenosine on A2. 2 / 2
| 2

reach
"In contrast to these observations, the deubiquitination of the adenosine A 2A receptor (A 2A R) by USP4 is necessary for the cell surface delivery of a functionally active receptor (XREF_FIG, pathway 4) [XREF_BIBR]."

reach
"The Adenosine A2 receptor is deubiquitinated by USP4; the ubiquitination status and trafficking of the EGFR growth factor receptor is regulated by the USP8 and STAM complex; the beta2-AR undergoes increased agonist stimulated ubiquitination, lysosomal trafficking, and degradation after knockdown of USPs 20 and 33."
USP4 binds adenosine.
| 1
USP4 binds adenosine-A2A. 1 / 1
| 1

reach
"USP4 binds to and deubiquitinates adenosine A2A receptor and enhances cell surface level of the receptor [14] ."
USP4 affects Vi-A
| 3
Vi-A binds USP4. 3 / 3
| 3

reach
"We took advantage of the crystal structure of USP4 to establish a model of the USP4/Vi-A complex, with the binding site identified."

reach
"An in silico model of the Vi-A-USP4 complex was elaborated and five potential binding sites were identified using the CASTp 3.0 software."

reach
"This site overlaps with A102.A detailed model of Vi-A bound to USP4 is presented in Figure 2."
| 3

eidos
"17 However , USP4 as an deubiquitinating enzymes reverses the ubiquitination ."

eidos
"Inhibition of USP4 significantly produced ubiquitination level of Rheb in immunoprecipitated solution , although same amount of Rheb and USP4 proteins were loaded to immunoprecipitation solution ( Figure 6C ) ."

eidos
"When substrate is not present RHO52 may auto-ubiquitinate itself and USP4 reverses this ubiquitination ."
USP4 affects USP17L24
| 3
| 3

sparser
"HAS2 interacts with USP17 and USP4."

sparser
"To confirm complex formation of endogenous components, proximity ligation assay (PLA) was performed using the breast cancer cell line MDA-231-BM, known to produce high levels of hyaluronan. xref Using antibodies against HAS2 and USP4 or USP17, reactive signals in the form of red dots indicating interactions between endogenous HAS2 and USP17, and HAS2 and USP4, were observed; only a low background level of dots was seen when each antibody was used alone, or in the fixation control without antibody ( xref )."

sparser
"Thus, both co-immunoprecipitation and PLA analyses supported the notion that HAS2 forms complexes with USP17 and USP4."
USP4 affects Th17
| 3
USP4 activates Th17. 3 / 3
| 3

reach
"By isolating T cells from patients with RHD as well as healthy volunteers and detecting the mRNA level of USP4 in CD4 T cells, the researchers found that the mRNA level of USP4 was related to the mRNA level of IL-17 and the function of Th17, indicating that USP4 may mediate the function of Th17 under inflammatory stimulation."

reach
"Inhibition of the catalytic activity of USP4 with vialinin A, an inhibitor of USP4 isolated from the Chinese mushroom, impairs Th17 differentiation, suggesting that USP4 promotes Th17 differentiation."

reach
"Conversely, deubiquitination of the K48 linked polyubiquitination of RORgammat by the deubiquitinase ubiquitinspecific protease USP4 stabilizes RORgammat and promotes its activation of Th17 associated genes, whereas inhibition of USP4 activity diminishes Th17 differentiation."
USP4 affects TGFBR
| 3
USP4 deubiquitinates TGFBR. 3 / 3
| 3

reach
"MicroRNA 27b (miR-27b) was identified as an inhibitor of ubiquitin-specific peptidase 4 (USP4), deubiquitylating TGF-beta receptor 1 (TbetaRI), downstream from CB2."

reach
"The authors further go on to show that USP4 was able to deubiquitylate the TGF-beta receptor I (TbetaRI) directly and rescue it from proteasome mediated degradation."

reach
"It has been known that the TGF-β receptors can be deubiquitinated and stabilized by USP4, USP15 and USP11 [[18], [19], [20]]."
USP4 affects SNAI1
1 | 1 1
1 | 1 1

reach
"Mechanistically, LOXL3 interacted with snail family transcriptional repressor 1 (Snail1) through STRING database and RIP assay, and Snail1 bound to ubiquitin-specific peptidase 4 (USP4) promoter by JASPAR database, luciferase reporter gene and Co-IP assays."

sparser
"To investigate if Snail1 can indeed bind and regulate the USP4 promoter, luciferase reporter constructs were generated in which luciferase expression was controlled by the wild type USP4 promoter or promoters with the E-box sequence mutations shown in xref and co-transfected with Snail1 into HEK293 cells."
USP4 affects RYBP
| 2 1
USP4 binds RYBP.
| 1 1
| 1 1

reach
"After ubibrowser database analysis, the interaction between USP4 and RYBP was verified using Co-immunoprecipitation (CoIP) assay."

sparser
"After ubibrowser database analysis, the interaction between USP4 and RYBP was verified using Co-immunoprecipitation (CoIP) assay."
USP4 inhibits RYBP.
| 1
USP4 inhibits RYBP. 1 / 1
| 1

reach
"In addition, USP4 repressed the PI3K/AKT signaling pathway by regulating RYBP."
USP4 affects RORC
1 | 2
1 | 2

sparser
"Importantly, USP4 interacts with RORγt and deubiquitinates its K48-linked polyubiquitination, thereby stabilizing RORγt and facilitating its function."

sparser
"Co-immunoprecipitation experiments using human CD4 + T cell lysates demonstrated that USP4 associates with RORγt."
USP4 affects RGR
| 3
USP4 binds RGR. 3 / 3
| 3

sparser
"The corridors between LPGR-UNP and RGR-UNP exhibited the lowest CWD:EucD ratios, suggesting that the costs for elephants to move between these PAs were lower than for other pairs of PAs throughout the study period ( xref )."

sparser
"The lowest CWD:LCP ratio was estimated for the corridors between LPGR-UNP and RGR-UNP, indicating low resistance for elephant movement along these corridors ( xref )."

sparser
"Among the active corridors, interview partners reported the highest relative numbers of elephants in areas located near corridors linking LGR-KFR, RGR-UNP, and KNP-UNP ( xref )."
USP4 affects RBL1
1 1 | 1
1 1 | 1

reach
"We conclude that within cells UNP does physically associate with pRb, and can also associate with p107 and p130."
USP4 affects MAPK
| 3
USP4 activates MAPK. 3 / 3
| 3

reach
"We demonstrated that USP4 drives HCC progression by stabilizing CypA through direct interaction and deubiquitination and thus constitutively activates the MAPK and CrkII signaling pathways."

reach
"Notably, this study demonstrated that USP4 promotes PTC proliferation by modulating the MAPK and AKT signaling pathways."

reach
"USP4 promotes PTC progression by stabilizing LDHA and activating the MAPK and AKT signaling pathway."
USP4 affects EV71
| 3
USP4 inhibits EV71. 3 / 3
| 3

reach
"More recently, Xu et al. demonstrated that upon enterovirus 71 (EV71) infections, USP4 expression was repressed, whereas the overexpression of USP4 suppressed EV71 replication."

reach
"Overexpression of USP4 inhibits EV71 replication by stabilizing TRAF6 to activate NF-kappaB inflammatory signaling."

reach
"In this study, we found that enterovirus 71 (EV71) infection attenuated the expression of Ubiquitin specific protease 4 (USP4) in vitro and in vivo, while overexpression of USP4 significantly suppressed EV71 replication."
USP4 affects ERK
| 3
USP4 activates ERK. 3 / 3
| 3

reach
"XREF_BIBR also demonstrated that inhibiting USP4 expression in GBM cells both inhibited their proliferation and induced apoptosis via antagonizing USP4 mediated stimulation of the ERK signaling pathway."

reach
"Zhou et al. found that USP4, as a potential novel oncogene, promotes Glioblastoma multiforme (GBM) by activating the ERK pathway through TGF-beta regulation [XREF_BIBR]."

reach
"Our results showed that USP4 positively regulates the MER/ERK signaling pathway via a TAK1-dependent process."

reach
"For example, USP4 drives breast cancer cell invasion via Relaxin/TGF-β1/Smad2/MMP-9 (matrix metallopeptidase 9) signalling [93] and promotes hepatocellular carcinoma metastasis by enhancing TGF-β sign[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"The USPs family is the largest and most important DUB family, and many of these elements are involved in the occurrence and development of multiple cancers, such as USP1, USP4, USP7, USP22, and USP28, which promote or inhibit the development and progression of colorectal, breast, and hepatocellular carcinomas via deubiquitining the hub genes of cancer-related signaling pathways [10, 11]."

reach
"For example, Li et al. found that USP4 can promote hepatocellular carcinoma progression via cyclophilin A stabilization and de-ubiquitination [23] ."
| 1 1
| 1 1

eidos
"Vialinin A , an inhibitor of USP4 , inhibited the tumorigenesis ( Figs ."

reach
"For example, USP4 promotes tumorigenesis when overexpressed in mice [19] ."
USP4 affects C6orf89
| 3
USP4 binds C6orf89.
| 2
| 2

reach
"In summary, our data show that USP4 and -15 can both interact with BRAP and thereby attenuate its autoubiquitylation."

reach
"This reinforces the notion that although both USP4 and USP15 can interact with BRAP under certain experimental conditions, the USP15 : BRAP rather than USP4 : BRAP interaction may be of most relevance within a physiological setting."
USP4 activates C6orf89.
| 1
USP4 activates C6orf89. 1 / 1
| 1

reach
"As expected, the FLAG antibody detects bands coinciding with the higher molecular weight forms of myc-BRAP induced by the expression of catalytically inactive USP4 and 15, which are absent in the case of mutant myc-BRAP-WA (XREF_FIG A, compare lanes 2 and 4 with 9 and 11)."
USP4 affects BRAP
| 3
USP4 binds USP15 and BRAP. 3 / 3
| 3

sparser
"This reinforces the notion that although both USP4 and USP15 can interact with BRAP under certain experimental conditions, the USP15:BRAP rather than USP4:BRAP interaction may be of most relevance within a physiological setting."

sparser
"In summary, USP4 and USP15 interact with the coiled-coil domain of BRAP through their N-terminal regions, requiring a combination of DUSP and UBL domains ( xref C )."

sparser
"We turned to expression of epitope-tagged proteins to confirm the interactions of USP4 and USP15 with BRAP in the context of a mammalian cell system."
USP4 affects BMP
| 2 1
USP4 activates BMP. 3 / 3
| 2 1

eidos
"( B ) BMP signaling : USP4 can deubiquitinate TI3RI and Smad4 , and enhance BMP signaling ."

eidos
"Moreover , USP4 stabilizes Smad4 and activates BMP signaling by inhibiting Smad4 monoubiquitination ( Zhou et al ., 2017 ) ."

reach
"Furthermore, USP4 stabilizes Smad4 through inhibiting its monoubiquitination and enhances activin as well as BMP signaling [86]."
USP4 affects ARHGDIA
| 3
USP4 increases the amount of ARHGDIA. 3 / 3
| 3

reach
"The reduction in USP4 expression decreases the level of ELAVL1 protein deubiquitination, leading to decreased ELAVL1 protein expression and increased ARHGDIA expression, promoting bladder cancer cell migration and invasion [98]."

reach
"And downregulated USP4 promotes ARHGDIA expression by reducing ELAVL1 protein, thus accelerating invasion and metastasis of PCa."

reach
"The decreased USP4 mRNA could enhance Rho GDP dissociation inhibitor α (ARHGDIA) expression via the METTL3-USP4-ELAVL1 axis, which finally promotes the progression of PCa cells."
USP17L24 affects USP4
| 3
| 3

sparser
"HAS2 interacts with USP17 and USP4."

sparser
"To confirm complex formation of endogenous components, proximity ligation assay (PLA) was performed using the breast cancer cell line MDA-231-BM, known to produce high levels of hyaluronan. xref Using antibodies against HAS2 and USP4 or USP17, reactive signals in the form of red dots indicating interactions between endogenous HAS2 and USP17, and HAS2 and USP4, were observed; only a low background level of dots was seen when each antibody was used alone, or in the fixation control without antibody ( xref )."

sparser
"Thus, both co-immunoprecipitation and PLA analyses supported the notion that HAS2 forms complexes with USP17 and USP4."
USP15 affects USP11
| 3
USP4 binds USP11 and USP15. 3 / 3
| 3

sparser
"USP15 forms a subfamily with USP4 and USP11 related through a shared presence of N-terminal &quot;domain present in ubiquitin specific proteases&quot; (DUSP) and &quot;ubiquitin-like&quot; (UBL) domains (DU subfamily)."

sparser
"Human deubiquitinase Usp15 forms a small subfamily with its close relatives Usp11 and Usp4, which all share a common domain architecture."

sparser
"USP4 can form stable homodimers and can also interact with USP11 and USP15 ( Fig. 4 )."
USP15 affects BRAP
| 3
USP4 binds USP15 and BRAP. 3 / 3
| 3

sparser
"This reinforces the notion that although both USP4 and USP15 can interact with BRAP under certain experimental conditions, the USP15:BRAP rather than USP4:BRAP interaction may be of most relevance within a physiological setting."

sparser
"In summary, USP4 and USP15 interact with the coiled-coil domain of BRAP through their N-terminal regions, requiring a combination of DUSP and UBL domains ( xref C )."

sparser
"We turned to expression of epitope-tagged proteins to confirm the interactions of USP4 and USP15 with BRAP in the context of a mammalian cell system."
USP11 affects USP15, and USP4
| 3
USP4 binds USP11 and USP15. 3 / 3
| 3

sparser
"USP15 forms a subfamily with USP4 and USP11 related through a shared presence of N-terminal &quot;domain present in ubiquitin specific proteases&quot; (DUSP) and &quot;ubiquitin-like&quot; (UBL) domains (DU subfamily)."

sparser
"Human deubiquitinase Usp15 forms a small subfamily with its close relatives Usp11 and Usp4, which all share a common domain architecture."

sparser
"USP4 can form stable homodimers and can also interact with USP11 and USP15 ( Fig. 4 )."
TRAF6 affects TRAF2
| 3
USP4 binds TRAF2 and TRAF6. 3 / 3
| 3

sparser
"Xiao et al.’s study added on to this by demonstrating USP4’s interaction and deubiquitination of TRAF2 and TRAF6, but not TRAF3, both in vivo, in HEK293 T cells, and in vitro [ xref ]."

sparser
"We found that USP4 specifically interacts with TRAF2 and TRAF6, but not TRAF3."

sparser
"It was confirmed that USP4 associates with TRAF2 and TRAF6, consistent with our results."
SNAI1 affects USP4
1 | 1 1
1 | 1 1

reach
"Mechanistically, LOXL3 interacted with snail family transcriptional repressor 1 (Snail1) through STRING database and RIP assay, and Snail1 bound to ubiquitin-specific peptidase 4 (USP4) promoter by JASPAR database, luciferase reporter gene and Co-IP assays."

sparser
"To investigate if Snail1 can indeed bind and regulate the USP4 promoter, luciferase reporter constructs were generated in which luciferase expression was controlled by the wild type USP4 promoter or promoters with the E-box sequence mutations shown in xref and co-transfected with Snail1 into HEK293 cells."
RORC affects USP4
1 | 2
1 | 2

sparser
"Importantly, USP4 interacts with RORγt and deubiquitinates its K48-linked polyubiquitination, thereby stabilizing RORγt and facilitating its function."

sparser
"Co-immunoprecipitation experiments using human CD4 + T cell lysates demonstrated that USP4 associates with RORγt."
RGR affects USP4
| 3
USP4 binds RGR. 3 / 3
| 3

sparser
"The corridors between LPGR-UNP and RGR-UNP exhibited the lowest CWD:EucD ratios, suggesting that the costs for elephants to move between these PAs were lower than for other pairs of PAs throughout the study period ( xref )."

sparser
"The lowest CWD:LCP ratio was estimated for the corridors between LPGR-UNP and RGR-UNP, indicating low resistance for elephant movement along these corridors ( xref )."

sparser
"Among the active corridors, interview partners reported the highest relative numbers of elephants in areas located near corridors linking LGR-KFR, RGR-UNP, and KNP-UNP ( xref )."
RBL1 affects USP4
1 1 | 1
1 1 | 1

reach
"We conclude that within cells UNP does physically associate with pRb, and can also associate with p107 and p130."
IRF3 affects USP4
| 2 1
| 2 1

reach
"Coimmunoprecipitation (Co-IP) experiments confirmed the interaction between USP4 and IRF3 in CRC cells ( Fig. 5 F)."

sparser
"Therefore, it is hypothesized that USP4 may interact with IRF3 to modulate its ubiquitination status."

reach
"In addition, USP4 binds and deubiquitinates K63-linked polyubiquitination of IRF3."
HAS2 affects USP17L24, and USP4
| 3
| 3

sparser
"HAS2 interacts with USP17 and USP4."

sparser
"To confirm complex formation of endogenous components, proximity ligation assay (PLA) was performed using the breast cancer cell line MDA-231-BM, known to produce high levels of hyaluronan. xref Using antibodies against HAS2 and USP4 or USP17, reactive signals in the form of red dots indicating interactions between endogenous HAS2 and USP17, and HAS2 and USP4, were observed; only a low background level of dots was seen when each antibody was used alone, or in the fixation control without antibody ( xref )."

sparser
"Thus, both co-immunoprecipitation and PLA analyses supported the notion that HAS2 forms complexes with USP17 and USP4."
EV71 affects USP4
| 3
EV71 decreases the amount of USP4. 3 / 3
| 3

reach
"However, we found that EV71 infection inhibit the expression of USP4 to attenuate the activation of the NF-kappaB pathway, an example of an evolved mechanism through which EV71 antagonizes host defences."

reach
"From this study it can be speculated that EV71 infection inhibits USP4 expression and promotes TRAF6 polyubiquitination of K48-linkage as a way to regulate the proteasomal degradation of TRAF6."

reach
"These results suggest that EV71 infection inhibit the expression of USP4 in vitro and in vivo."
ELAVL1 affects USP4
| 1 2
| 1 2

sparser
"The results showed that METL3 knockdown markedly enhanced the interaction between USP4 and ELAVL1(Figure xref S and xref N)."

sparser
"In this study, we examined that METTL3 knockdown significantly decreased the binding of HNRNPD to USP4 pre-mRNA(Figure xref N and xref B); however, the interaction between ELAVL1 and USP4 pre-mRNA were not significantly changed(Figure xref O and xref C)."

reach
"The results showed that METL3 knockdown markedly enhanced the interaction between USP4 and ELAVL1."
E3_Ub_ligase affects USP4
| 2 1

sparser
"ARF-BP1 is a p53-specific E3 ligase that binds to USP4."
| PMC

reach
"ARF-BP1 is a p53-specific E3 ligase that binds to USP4."
| PMC

reach
"USP4 interacts with and deubiquitylates another E3 ubiquitin ligase for p53, ARF-BP1/Mule/HUWE, leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels."
BRAP affects USP4
| 3
USP4 binds USP15 and BRAP. 3 / 3
| 3

sparser
"This reinforces the notion that although both USP4 and USP15 can interact with BRAP under certain experimental conditions, the USP15:BRAP rather than USP4:BRAP interaction may be of most relevance within a physiological setting."

sparser
"In summary, USP4 and USP15 interact with the coiled-coil domain of BRAP through their N-terminal regions, requiring a combination of DUSP and UBL domains ( xref C )."

sparser
"We turned to expression of epitope-tagged proteins to confirm the interactions of USP4 and USP15 with BRAP in the context of a mammalian cell system."
| 2

sparser
"In contrast, inhibition of USP4 by shRNA in MHCC97H cells reduced p-ERK1/2 and increased p-CrkII levels."

sparser
"Inhibition of USP4 by shRNA in MHCC97H cells significantly decreased CypA protein levels."
Luteolin affects USP4
| 2
Luteolin increases the amount of USP4. 2 / 2
| 2

reach
"(4) Luteolin promoted the expression of USP4 but inhibited miR-136-5p expression."

reach
"Luteolin also mediated the expression of hsa-miR-136-5p and USP4."
Foci affects USP4
| 2
USP4 binds RBBP8 and foci. 2 / 2
| 2

sparser
"As USP4 directly interacts with CtIP, we also checked CtIP foci formation in USP4-depleted cells."

sparser
"Because USP4 interacts with the N-terminal of CtIP through its insert domain, CtIP N-terminal is essential for its foci formation and depletion of USP4 decreased CtIP foci formation."
AflR affects USP4
| 2
| 2

sparser
"Each plasmid DNA, pUNP-aflR Ao, M1, M2 and M3, was used to transform aflJ -transformants via the protoplast-PEG method."

sparser
"After identifying their aflR sequence, each aflR gene was transferred into the destination vector, pUNPgate, as pUNP-aflR Ao (including original aflR ), pUNP-aflR M1 (aflR-M1), pUNP-aflR M2 (aflR-M2) [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP7 affects USP4
| 2
USP4 binds USP7 and USP15. 1 / 1
| 1

sparser
"For example, USP11 has been found to interact with USP4, USP7 and USP15; and PSMD7 interacts with USP15 and PSMD14 [ xref ]."
| 1

sparser
"As substrates may compete for USP4 binding occurring with USP7, this must also be factored into this analysis."

reach
"USP20 and USP4 induce drug resistance in breast cancer and colorectal cancer cells by stabilizing β-catenin, the key modulator of the Wnt pathway [249, 250]."

reach
"USP20 and USP4 promote the stability of β-catenin, thus continuously activating the Wnt-β-catenin signaling pathway and mediating drug resistance in breast cancer and CRC ( Fig. 3 )."
USP4 affects ptc
| 2
USP4 activates ptc. 2 / 2
| 2

reach
"USP4 promotes PTC progression by stabilizing LDHA and activating the MAPK and AKT signaling pathway."

reach
"Notably, this study demonstrated that USP4 promotes PTC proliferation by modulating the MAPK and AKT signaling pathways."

reach
"Notably, this study demonstrated that USP4 promotes PTC proliferation by modulating the MAPK and AKT signaling pathways."

reach
"USP4 promotes PTC progression by stabilizing LDHA and activating the MAPK and AKT signaling pathway."

reach
"USP4 which together with USP1 belongs to the USP family, negatively regulates osteoblast differentiation and bone formation induced by WNT [38]."

reach
"For example, USP4 was reported to antagonise osteoblast differentiation through inhibition of Wnt signalling [ 26 ]."
USP4 affects lactate
| 2
USP4 activates lactate. 2 / 2
| 2

reach
"Overexpression of USP4 promotes cell proliferation, glucose uptake, and lactate production in gastric cancer cells."

reach
"USP4 promotes glucose uptake and lactate production in gastric cancer cells."
| 2

reach
"Knockdown of USP17 decreases, whereas knockdown of USP4 increases hyaluronan production."

reach
"The silencing of USP17 led to decreased hyaluronan production, whereas the suppression of USP4 increased hyaluronan synthesis."
USP4 affects foci
| 2
USP4 binds RBBP8 and foci. 2 / 2
| 2

sparser
"As USP4 directly interacts with CtIP, we also checked CtIP foci formation in USP4-depleted cells."

sparser
"Because USP4 interacts with the N-terminal of CtIP through its insert domain, CtIP N-terminal is essential for its foci formation and depletion of USP4 decreased CtIP foci formation."

reach
"Loss of USP4 enhances cytokine production mediated by LPS and IL-1β."

reach
"56 Loss of USP4 enhances cytokine production mediated by LPS and IL-1beta."
USP4 affects aflR
| 2
| 2

sparser
"Each plasmid DNA, pUNP-aflR Ao, M1, M2 and M3, was used to transform aflJ -transformants via the protoplast-PEG method."

sparser
"After identifying their aflR sequence, each aflR gene was transferred into the destination vector, pUNPgate, as pUNP-aflR Ao (including original aflR ), pUNP-aflR M1 (aflR-M1), pUNP-aflR M2 (aflR-M2) [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 affects ZEB1
| 2
USP4 increases the amount of ZEB1. 2 / 2
| 2

reach
"In the present study, we found that the USP4 and beta-catenin axis was involved in metastatic potential through USP4 mediated stabilization of beta-catenin and that knockdown of USP4 and beta-catenin suppressed the metastatic potential including clonogenicity, migration, and invasion, and induced MET by downregulating ZEB1 expression."

reach
"We found that knockdown of both USP4 and beta-catenin downregulated the expression of ZEB1 and thereby increased the level of E-cadherin, indicating that the USP4 and beta-catenin axis is required for the EMT process and involves the regulation of ZEB1."
USP4 affects USP7
| 2
USP4 binds USP7 and USP15. 1 / 1
| 1

sparser
"For example, USP11 has been found to interact with USP4, USP7 and USP15; and PSMD7 interacts with USP15 and PSMD14 [ xref ]."
| 1

sparser
"As substrates may compete for USP4 binding occurring with USP7, this must also be factored into this analysis."
USP4 affects U4 snRNP
| 2
USP4 deubiquitinates U4 snRNP. 2 / 2
| 2

reach
"It is possible that localization of USP15 and USP4 may be regulated by phosphorylation or a nuclear signal such as NLS and NES depending on the cellular conditions.USP15 and USP4 are required for the [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"In addition, the other study reports that USP4, the USP15 homolog, binds to Tip110 and deubiquitinates Prp3, component of the U4 snRNP, during the spilceosome cycle ( Song et al., 2010 )."
USP4 affects TRIM25
| 2
USP4 activates TRIM25. 2 / 2
| 2

reach
"On the other hand, USP4 and USP15 enhance the stability of RIG-I and TRIM25, respectively, by proteolytically cleaving K48 linked ubiquitylation from these molecules XREF_BIBR, XREF_BIBR."

reach
"Deubiquitinase USP4 and USP15 can increase the stability of RIG-I and TRIM25 by decreasing their K48-linked ubiquitination (Wang et al., 2013; Pauli et al., 2014)."
USP4 affects TRAF3
| 2
USP4 deubiquitinates TRAF3. 2 / 2
| 2

reach
"USP4 deubiquitinates TRAF2 and TRAF6, but not TRAF3, and it also rescues IkappaBalpha from degradation in TNFalpha induced HEK cells [XREF_BIBR]."

reach
"For example, TNFAIP3, CYLD, USP3, USP4, USP15, USP25, and OTUD5 deubiquitinate key components of the IFN production pathway, including RIG-I, TRAF2, TRAF3, TRAF6, RIP1, and TRIF (reviewed in [93,94])."
USP4 affects Survival
| 2
USP4 activates Survival. 2 / 2
| 2

eidos
"The high expression levels of some genes like USP4 , DTNBP1 may contribute to better survival rates ( these genes were termed as favourable ones ) , while some of the others ( termed as un-favourable ones ) such as AHSA1 and MESDC2 may lead to worse survivals ( Fig. 2a and b ) ."

eidos
"In addition , USP4 reportedly mediates cell proliferation , survival and metastasis ( 32 , 33 ) ."
USP4 affects SMAD7
| 2
USP4 decreases the amount of SMAD7. 2 / 2
| 2

reach
"In addition, inhibition of Ubiquitin carboxyl-terminal hydrolase 4 (USP4) decreased TGF- beta1 induced expression of TbetaR-I and reversed the altered expression of Smad7, Smurf2, ZO-1 and Vimentin."

reach
"Also, detection of the expression levels of TGF-betaR1and Smad7 proteins showed that the down-regulation of USP4 inhibited the expression of TGF-betaR1 and promoted the expression of Smad7."

reach
"This evidence indicated USP4 can stabilize TRAF6 protein expression in PC cells.To further confirm the role of TRAF6 in USP4 mediated PC cell proliferation, migration and invasion, we performed rescue[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"In summary, these data indicated that USP4 promoting malignant biological behaviors of PC cells may depend on TRAF6/NF-κBp65 signaling pathway.To determine how USP4 influences TRAF6 to activate NF-κB [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 affects PROM1
| 2
USP4 increases the amount of PROM1. 2 / 2
| 2

reach
"Ectopic expression of USP4 in CRC cells induced SOX9, OCT4 and CD133 expression significantly."

reach
"Conversely, silencing of USP4 dramatically reduced SOX9, OCT4 and CD133 levels in SW480 cells and HCT116 cells."
USP4 affects POU5F1
| 2
USP4 increases the amount of POU5F1. 2 / 2
| 2

reach
"Conversely, silencing of USP4 dramatically reduced SOX9, OCT4 and CD133 levels in SW480 cells and HCT116 cells."

reach
"Ectopic expression of USP4 in CRC cells induced SOX9, OCT4 and CD133 expression significantly."
USP4 affects PDGFR
| 2
USP4 deubiquitinates PDGFR. 2 / 2
| 2

reach
"In our previous research, we found that USP17 and USP4 deubiquitinated PDGFRβ and increased the level of activated STAT3 [40]."

reach
"By overexpressing a panel of deubiquitinating enzymes (DUBs), we found that USP17 and USP4 efficiently deubiquitinate PDGF receptor β (PDGFRβ) and are able to remove both Lys63 and Lys48-linked polyubiquitin chains from the receptor."
USP4 affects NPR1
| 1 1
| 1 1

sparser
"UNP binds to the NPR-A, -B and –C receptors with binding curves superimposable with ANP [ xref ][ xref ]."

reach
"UNP binds to the NPR-A, -B and –C receptors with binding curves superimposable with ANP [51][Fig. S1]."
USP4 affects NFKBIA
| 2
USP4 leads to the dephosphorylation of NFKBIA. 2 / 2
| 2

reach
"Also USP4WT-R rescued the effect of USP4 knockdown on TNFalpha induced IKK phosphorylation and IkappaBalpha phosphorylation (XREF_FIG)."

reach
"Therefore, we further analyzed the effect of USP4 knockdown on the TNFalpha induced IKK phosphorylation, IkappaBalpha phosphorylation, ubiquitination and degradation."
USP4 affects NF-kappaB luciferase
| 2
USP4 activates NF-kappaB luciferase. 2 / 2
| 2

reach
"It was found that USP4 significantly promoted the activities of NF-kappaB luciferase reporter gene."

reach
"Remarkably, knockdown of USP4 inhibited the activities of the NF-kappaB luciferase reporter gene that were induced by HMW poly (I : C)."
USP4 affects MYOG
| 2
USP4 decreases the amount of MYOG. 2 / 2
| 2

reach
"In line with this finding, the USP4 knockdown increased the mRNA expression of both MyoD and myogenin ( Fig. 1 C)."

reach
"Accordingly, SB203580 attenuated the expression of MHC and myogenin that had been stimulated by the USP4 knockdown ( Fig. 7 C)."
USP4 affects MYC
| 2
| 2

sparser
"To whether USP4 can indeed deubiquitinate CENPF, HCT116 cells were transfected with CENPF-HA, Flag-UB, USP4-Myc or USP4 C311S-Myc, and then anti-HA immunoprecipitates were probed for the level of ubiquitination using Flag-antibody."

sparser
"Immunoprecipitation with anti-Myc antibody demonstrated that Myc-USP4 interacted with overexpressed CENPF-HA (Fig. xref )."
USP4 affects MRE11
| 2
| 2

sparser
"We and others report that USP4 interacts with CtIP and the MRE11RAD50NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites and DNA end resection ( xref , xref )."

sparser
"We also report that USP4 interacts with CtIP and the MRE11-RAD50-NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites."
USP4 affects METTL3
| 2
USP4 inhibits METTL3. 2 / 2
| 2

eidos
"Moreover , we also found that the knockdown of USP4 effectively alleviated METTL3 decifiency-induced suppressed xenograft tumor formation ."

eidos
"Moreover , we observed that USP4 knockdown effectively alleviated METTL3 knockdown-induced inhibited xenograft tumor growth ( Figure 7A-C ) ."
USP4 affects LDHA
| 2
| 2

sparser
"Furthermore, our investigation revealed a specific interaction between USP4 and lactate dehydrogenase A (LDHA), wherein USP4 played a crucial role in stabilizing LDHA protein levels via deubiquitination in PTC cells."

sparser
"Immunoprecipitation (IP) with antibodies against USP4 or LDHA demonstrated that USP4 and LDHA interact with each other ( xref , xref )."
USP4 affects LAMP3
| 2
| 2

sparser
"Co-IP was also conducted to determine the interaction between USP4 and LAMP3."

sparser
"USP4 interacted with LAMP3, and positively regulated LAMP3 expression in colorectal cancer cells."
USP4 affects KLF2
| 2
USP4 deubiquitinates KLF2. 2 / 2
| 2

reach
"By contrast, si-USP4-driven USP4 depletion led to a distinct increase in ubiquitinated KLF2 levels in MM1.S/BTZ cells (Fig. 3H), indicating that USP4 inhibition can promote KLF2 protein ubiquitination and degradation."

reach
"Taken together, these findings demonstrate that USP4 deubiquitinates and stabilizes KLF2 protein."
USP4 affects INSR
1 | 1
1 | 1

sparser
"Furthermore, gastrodin significantly upregulated the expression of USP4 and increased the binding of USP4 to the insulin receptor."
USP4 affects IL6
| 2
USP4 inhibits IL6. 2 / 2
| 2

reach
"Notably, USP4 overexpression antagonized OGD/R-induced IL-1β, IL-6, and TNF-α transcriptional levels (Fig. 3A–C)."

reach
"Additionally, the overexpression of USP4 suppressed the release of microglia activation-induced pro-inflammatory cytokines, including IL-1beta, IL-6, and TNF-alpha."
USP4 affects IL17A
| 1
USP4 increases the amount of IL17A. 1 / 2
| 1

reach
"For example, USP4 has been shown to interact with and deubiquitinate RORγt, promoting its function and IL-17A transcription in rheumatic heart disease (Yang et al. 2015); similarly, USP7 has been found to promote lupus nephritis by regulating NF-κB p65 signaling via JMJD3 stabilization (Zhang et al. 2021)."
USP4 affects IFNB1
| 1 1
USP4 activates IFNB1. 2 / 2
| 1 1

eidos
"Similarly , in vesicular stomatitis virus ( VSV ) infection , removing K48-linked polyubiquitin chains from RIG-I allows USP4 to enhance RIG-I-triggered IFN-beta signaling , thereby inducing an antiviral immune response ( Wang et al ., 2013 ) ."

reach
"Thus, USP4 positively regulates IFN-beta signaling by interacting with the N-terminal domain of RIG-I, subsequently leading to the inhibition of RIG-I degradation."
USP4 affects Hypertrophy
| 2
| 2

reach
"Thus, the increased expression of USP4 can suppress pathological cardiac hypertrophy."

reach
"They also demonstrated that deficiency of endogenous USP4 promotes myocyte hypertrophy induced by Ang II in vitro."
USP4 affects HDAC1
| 2
USP4 decreases the amount of HDAC1. 2 / 2
| 2

reach
"The USP4 knockdown decreased the protein levels of both HDAC1 and HDAC4 ( Fig. 4 A), but not their mRNA levels (Supplementary Fig. 3A)."

reach
"The western blotting assay revealed that the expression of the HDAC1 protein was markedly suppressed by USP4, USP7, and USP5, with USP5 exerting the most pronounced inhibitory effect."

reach
"In addition, USP4 promotes the proliferation, migration, and invasion of esophageal squamous cell carcinoma by targeting TAK1."

reach
"USP4 promotes the proliferation, migration, and invasion of esophageal squamous cell carcinoma by targeting TAK1."
USP4 affects ERK1/2-MAPK
| 2
USP4 activates ERK1/2-MAPK. 2 / 2
| 2

reach
"These data indicate that USP4 positively regulates the ERK1/2-MAPK and CrkII signaling pathways via a CypA dependent process."

reach
"In our study, results showed that USP4 positively regulates the ERK1/2-MAPK signaling pathway and inhibits p-CrkII via a CypA dependent process."
USP4 affects DSB repair
| 2
USP4 activates DSB repair. 2 / 2
| 2

reach
"We have established that USP4 promotes DSB repair by HR and cellular resistance to IR and the topoisomerase I inhibitor camptothecin."

reach
"Importantly, in line with our other studies implying that USP4 promotes DSB repair via mechanisms distinct from its spliceosomal functions in concert with SART3, HR was not significantly altered by SART3 depletion (XREF_SUPPLEMENTARY D; see XREF_SUPPLEMENTARY C for siSART3 depletion)."
USP4 affects DNA Damage
| 2
| 2

reach
"In contrast, silencing USP4 by shRNA remarkably increased the p53 activity in response to DNA damage or not (XREF_FIG)."

reach
"Notably, only PARP1 and TP53 expression levels were downregulated following USP4 knockdown (Fig. 5L), suggesting that USP4 may promote drug resistance by inducing the activation of the DNA damage repair pathway."

reach
"So far, however, we only have a relatively limited understanding of the DDR roles for deubiquitylation enzymes (DUBs), which mediate the processing of DNA end resection.In this study, we show that the[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"These results suggest that USP4 promotes DSB repair by HR.HR is initiated by DNA end resection, which generates 3 ' ssDNA tails that are coated by RPA (Chen et al., 2013)."
USP4 affects CrkII
| 2
USP4 activates CrkII. 2 / 2
| 2

reach
"We demonstrated that USP4 drives HCC progression by stabilizing CypA through direct interaction and deubiquitination and thus constitutively activates the MAPK and CrkII signaling pathways."

reach
"These data indicate that USP4 positively regulates the ERK1/2-MAPK and CrkII signaling pathways via a CypA dependent process."
USP4 affects Cicatrix
| 2
| 2

reach
"The findings showed that the expression of TGF-betaR1 and USP4 were increased in hypertrophic scar tissues and fibroblasts, and that down-regulating USP4 inhibited hypertrophic scar fibroblast proliferation and migration and induced cell apoptosis in vitro."

reach
"The Cell Counting Kit-8 (CCK-8) assay results showed that the proliferation of hypertrophic scar fibroblasts transfected with siUSP4 was significantly inhibited on the fifth and seventh day, indicating that down-regulation of USP4 could suppress the proliferation of hypertrophic scar fibroblasts."
| 1 1
| 1 1

reach
"Similarly, knockdown of USP4 significantly decreases cell viability in a p53 dependent manner after treating GMB cells with temozolomide."

eidos
"Similarly , knockdown of USP4 significantly decreases cell viability in a p53-dependent manner after treating GMB cells with temozolomide ( Qin et al ., 2019 ) ."
USP4 affects CHEK1
| 2
USP4 leads to the phosphorylation of CHEK1. 2 / 2
| 2

reach
"As shown in Figures 6 A-6G, WT USP4, but not the CA mutant, restored HR efficiency, CtIP, RAD51, RPA foci, and CHK1 phosphorylation in USP4 depleted cells after IR."

reach
"We also found that WT USP4, but not the insert domain deletion mutant, restored the HR efficiency and CHK1 phosphorylation to their level in the wild-type cells."
USP4 affects CDH2
| 2
USP4 increases the amount of CDH2. 2 / 2
| 2

reach
"In line with previous studies, we also showed that USP4 promoted melanoma metastasis by suppressing E-cadherin expression and increasing N-cadherin expression, indicating the ubiquitous existence of the crosstalk between USP4 and EMT in different kinds of cancer."

reach
"Moreover, we performed RT-PCR experiment, and it also showed that the knockdown of USP4 could significantly decrease N-cadherin and increase E-cadherin expression at the transcriptional level."
USP4 affects CCR6
| 2
USP4 activates CCR6. 2 / 2
| 2

reach
"Here we illustrate that in the context of murine allergic inflammation, Usp4 −/− mice displayed enhanced CCR6 expression in Treg cells compared with WT mice, while there was no difference of CCR4 expr[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Therefore, USP4-mediated CCR6 regulation is different from Foxp3 regulation, and the underlying mechanisms of CCR6 modulation require further investigation.Another limitation of our research is the of[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
| 2
| 2

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"Overexpression of USP4 can prevent angiotensin II induced cardiac hypertrophy and fibrosis in vitro and ameliorate cardiac dysfunction in vivo through downregulation of the TAK1/JNK1/2/p38 signaling pathway."

reach
"Adenovirus mediated gain- and loss-of-function approaches indicated that deficiency of endogenous USP4 promoted myocyte hypertrophy induced by angiotensin II in vitro, whereas restoration of USP4 significantly attenuated the prohypertrophic effect of angiotensin II."
USP4 affects Activin
| 1 1
USP4 activates Activin. 2 / 2
| 1 1

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"Furthermore, USP4 stabilizes Smad4 through inhibiting its monoubiquitination and enhances activin as well as BMP signaling [86]."

eidos
"Furthermore , USP4 stabilizes Smad4 through inhibiting its monoubiquitination and enhances activin as well as BMP signaling [ 86 ] ."
USP4 affects ANXA2
1 | 1
1 | 1

sparser
"Specifically, USP4 interacts with ANXA2, stabilizing its protein by deubiquitinating ANXA2, which mediates its proteasomal degradation and Y24 phosphorylation."
USP4 affects ADP-ribosylatibon factor-binding protein 1
| 2
USP4 deubiquitinates ADP-ribosylatibon factor-binding protein 1. 2 / 2
| 2

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"USP4 interacts directly with and deubiquitinates ADP-ribosylatibon factor-binding protein 1 (ARF-BP1), leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels [12] ."

reach
"USP4 interacts directly with and deubiquitinates ADP-ribosylatibon factor binding protein 1 (ARFBP1), which results in the stabilization of ARF-BP1 and the subsequent reduction of p53 levels."
USP4 affects ACE2
| 2
USP4 increases the amount of ACE2. 2 / 2
| 2

reach
"The authors proposed that USP4 overexpression enhances ACE2 protein levels [134]; nevertheless, the supporting data are lacking."

reach
"To verify whether USP4 may regulate ACE2 expression through deubiquitination, we performed Co-IP experiments, which showed that USP4 could interact with ACE2 and that overexpression of USP4 upregulated ACE2 expression (Fig. 5V)."
TP53 affects USP4
| 2
| 2

reach
"ARF-BP1 is a p53-specific E3 ligase that binds to USP4."
| PMC

reach
"USP4, for example, interacts directly with end resection factors CtIP and MRN [172], USP21 deubiquitinates and stabilizes BRCA2 to promote RAD51 binding and successful HR [173], and USP10 deubiquitinates and stabilizes p53 to promote its nuclear localization and apoptosis in response to DSBs [174]."
TCF4 affects USP4
| 1 1
| 1 1

sparser
"For example, USP4 interacts with TCF4 and further deubiquitinates it, thus restraining β-catenin dependent process of transcription xref ; USP47 xref , USP2a xref , USP5 xref , USP20 xref are identified to deubiquitinating and stabilizing β-catenin directly."

reach
"For example, USP4 interacts with and deubiquitinates TCF4, which inhibits beta-catenin-dependent transcription [XREF_BIBR]."
Ser-Leu affects USP4
| 2
Ser-Leu activates USP4. 2 / 2
| 2

reach
"Mutations in the SL modulate USP4 activity."

reach
"On the side of the catalytic domain, we found that mutation F386G in the SL region, near the catalytic site (XREF_FIG), substantially increases USP4 CD activity (XREF_FIG), in the absence of the DUSP-Ubl."
Rho52 affects USP4
| 2
Rho52 ubiquitinates USP4. 2 / 2
| 2

reach
"However, if Rho52 ubiquitinates USP4 the DUB may be degraded."

reach
"Rho52 in turn can ubiquitinate USP4."
RYBP affects USP4
| 1 1
| 1 1

reach
"After ubibrowser database analysis, the interaction between USP4 and RYBP was verified using Co-immunoprecipitation (CoIP) assay."

sparser
"After ubibrowser database analysis, the interaction between USP4 and RYBP was verified using Co-immunoprecipitation (CoIP) assay."
RBBP8 affects foci
| 2
USP4 binds RBBP8 and foci. 2 / 2
| 2

sparser
"As USP4 directly interacts with CtIP, we also checked CtIP foci formation in USP4-depleted cells."

sparser
"Because USP4 interacts with the N-terminal of CtIP through its insert domain, CtIP N-terminal is essential for its foci formation and depletion of USP4 decreased CtIP foci formation."
RBBP8 affects RAD50
| 2
| 2

sparser
"We and others report that USP4 interacts with CtIP and the MRE11RAD50NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites and DNA end resection ( xref , xref )."

sparser
"We also report that USP4 interacts with CtIP and the MRE11-RAD50-NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites."
PI3K_p110 affects USP4
| 2
| 2

reach
"As shown in Figs 6A and 6B and S5A and S5B, silencing FBXO3 significantly rescued the p110α -induced up-regulation of Twist1, USP4, and β-catenin as well as revised the p110α -mediated increase of cell migration."

reach
"In addition, p110α drastically promoted FBXO3 and USP4 in both nucleus and cytoplasm (S4D Fig)."
PI3K affects USP4
| 2
PI3K increases the amount of USP4. 2 / 2
| 2

reach
"Mechanistically, gastrodin activates the PI3K/AKT signaling pathway, which promotes the phosphorylation of GATA binding protein 1 (GATA1) and increases the transcription of USP4."

reach
"Therefore, these results suggest that gastrodin stimulates the PI3K/AKT pathway and that activation of the PI3K/AKT pathway promotes USP4 expression by enhancing the phosphorylation of GATA1 in HepG2 cells."
NPR1 affects USP4
| 1 1
| 1 1

sparser
"UNP binds to the NPR-A, -B and –C receptors with binding curves superimposable with ANP [ xref ][ xref ]."

reach
"UNP binds to the NPR-A, -B and –C receptors with binding curves superimposable with ANP [51][Fig. S1]."
NBN affects RBBP8
| 2
| 2

sparser
"We and others report that USP4 interacts with CtIP and the MRE11RAD50NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites and DNA end resection ( xref , xref )."

sparser
"We also report that USP4 interacts with CtIP and the MRE11-RAD50-NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites."
MYC affects USP4
| 2
| 2

sparser
"To whether USP4 can indeed deubiquitinate CENPF, HCT116 cells were transfected with CENPF-HA, Flag-UB, USP4-Myc or USP4 C311S-Myc, and then anti-HA immunoprecipitates were probed for the level of ubiquitination using Flag-antibody."

sparser
"Immunoprecipitation with anti-Myc antibody demonstrated that Myc-USP4 interacted with overexpressed CENPF-HA (Fig. xref )."
MRE11 affects USP4
| 2
| 2

sparser
"We and others report that USP4 interacts with CtIP and the MRE11RAD50NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites and DNA end resection ( xref , xref )."

sparser
"We also report that USP4 interacts with CtIP and the MRE11-RAD50-NBS1 (MRN) complex and is required for CtIP recruitment to DNA damage sites."
LncRNA affects USP4
| 2
LncRNA increases the amount of USP4. 2 / 2
| 2

reach
"LncRNA H19 targets miR-148a, increases deubiquitinating enzyme USP4 expression, activates the TGF-β signaling pathway in hepatic stellate cells and hepatocytes, and exacerbates hepatic fibrosis 180."

reach
"LncRNA H19 180 acts as a ceRNA to downregulate the expression of miR-148a and upregulate the expression of USP4, which stabilizes the TGFβRⅠ and activates the TGF-β/smad signaling pathway and promotes the development of liver fibrosis."
LDHA affects USP4
| 2
| 2

sparser
"Furthermore, our investigation revealed a specific interaction between USP4 and lactate dehydrogenase A (LDHA), wherein USP4 played a crucial role in stabilizing LDHA protein levels via deubiquitination in PTC cells."

sparser
"Immunoprecipitation (IP) with antibodies against USP4 or LDHA demonstrated that USP4 and LDHA interact with each other ( xref , xref )."
LAMP3 affects USP4
| 2
| 2

sparser
"Co-IP was also conducted to determine the interaction between USP4 and LAMP3."

sparser
"USP4 interacted with LAMP3, and positively regulated LAMP3 expression in colorectal cancer cells."
KITLG affects USP4
| 1 1
KITLG activates USP4. 2 / 2
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"CtIP-rescue may involve a direct dampening of APC/C activity, or a SCF -dependent activation of USP4, similar to Claspin stabilization by USP28 ."

sparser
"CtIP-rescue may involve a direct dampening of APC/C CDH1 activity, or a SCF SKP2 -dependent activation of USP4, similar to Claspin stabilization by USP28 xref , xref ."
INSR affects USP4
1 | 1
1 | 1

sparser
"Furthermore, gastrodin significantly upregulated the expression of USP4 and increased the binding of USP4 to the insulin receptor."
INS affects USP4
| 1 1
| 1 1

reach
"Dexamethasone did not affect the binding of USP4 to insulin receptors compared with the control group, but the expression of USP4 and the binding of USP4 to insulin receptors increased after the addition of gastrodin."

sparser
"Furthermore, Gastrodin has been shown to upregulate the expression of USP4 and enhance the interaction between USP4 and insulin receptors to treat diabetes ( xref )."
GPI affects USP4
| 2
GPI activates USP4. 2 / 2
| 2

reach
"Interestingly, NLK promoted nuclear accumulation USP4."

reach
"Overexpression of a catalytically active Nlk promotes nuclear accumulation of USP4 whereas a subpopulation of TCF4 is a substrate of USP4 dependent deubiquitination."
EVO affects USP4
| 2
EVO decreases the amount of USP4. 2 / 2
| 2

reach
"As shown in Fig. 4A, EVO significantly reduced USP4, SOX9, OCT4 and CD133 expression in a dose-dependent manner, indicating EVO could regulate CRC cell stemness."

reach
"Importantly, EVO inhibited USP4 expression and reduced the levels of SOX9, OCT4, and CD133.These results suggest that EVO may relieve the regulation of CRC stemness by inhibiting USP4 deubiquitination and stabilizing SOX9."
DIPK2A affects USP4
| 2
DIPK2A phosphorylates USP4. 2 / 2
| 2

sparser
"AKT-induced phosphorylation of USP4 promotes its subcellular distribution mostly in the membrane and cytoplasm, while the non-phosphorylated form is predominantly condensed into the nucleus [14] ."

sparser
"Additionally, AKT-induced phosphorylation of USP4 is required for maintaining the stability of USP4, thereby enhancing TGF-β-induced pro-tumorigenic responses in breast cancer cells."
CDK affects USP4
| 1 1
CDK phosphorylates USP4. 2 / 2
| 1 1

reach
"Therefore, these results suggest that phosphorylation of USP15 and USP4 by CDKs may regulate the interaction with SART3, thereby controlling the deubiquitinating activity toward PRP31 and PRP3 in the [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"Therefore, these results suggest that phosphorylation of USP15 and USP4 by CDKs may regulate the interaction with SART3, thereby controlling the deubiquitinating activity toward PRP31 and PRP3 in the [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
C6orf89 affects USP4
| 2
| 2

reach
"In summary, our data show that USP4 and -15 can both interact with BRAP and thereby attenuate its autoubiquitylation."

reach
"This reinforces the notion that although both USP4 and USP15 can interact with BRAP under certain experimental conditions, the USP15 : BRAP rather than USP4 : BRAP interaction may be of most relevance within a physiological setting."
ARHGDIA affects USP4
| 2
ARHGDIA inhibits USP4. 2 / 2
| 2

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"As predicted, we found that METTL3 overexpression induced ARHGDIA expression, but downregulated ELAVL1 and USP4 (XREF_SUPPLEMENTARY)."

reach
"Degraded USP4 inhibits ELAVL1 ubiquitination, decreasing the expression of Rho GDP-dissociation inhibitor 1, a risk factor for PCa metastasis and progression."
ANXA2 affects USP4
1 | 1
1 | 1

sparser
"Specifically, USP4 interacts with ANXA2, stabilizing its protein by deubiquitinating ANXA2, which mediates its proteasomal degradation and Y24 phosphorylation."
AKT1 affects USP4
| 1
AKT1 phosphorylates USP4. 1 / 2
| 1

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"[49, 50, 51, 52, 53] To illustrate, phosphorylation of USP4 by protein kinase B (PKB, also known as AKT) results in its redistribution from the nucleus to the cytoplasm, which enables USP4 to reach the cell membrane and deubiquitinate the transforming growth factor-beta (TGF-beta) receptor I (TbetaR-I)."

sparser
"The ubiquitin peptidase inactive form of USP4 (USP4-C311A) abolished its ability to stabilize HDAC2 ( xref and xref )."
Natural small molecule product U4-I05 affects USP4
| 1
Natural small molecule product U4-I05 inhibits USP4. 1 / 1
| 1

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"A natural small molecule product U4-I05 diminished the stem-like features of CSCs and enhanced their sensitivity to oxaliplatin and 5-fluorouracil by targeting inhibition of its deubiquitinating enzyme activity through binding the catalytic domain of USP4 (311 cysteine site) at nanomolar concentrations, triggering proteasome-mediated degradation of beta-catenin and Twist1."
MiR-553 affects USP4
| 1
MiR-553 inhibits USP4. 1 / 1
| 1

reach
"USP4 is also negatively regulated by miR-553 in breast cancer, and this inhibition could be reversed by circBMPR2, which acts as a sponge to prevent miR-553 associating with USP4 mRNA."
| 1
Lipopolysaccharide decreases the amount of USP4. 1 / 1
| 1

reach
"In vitro LPS induced activation of microglia showed decreased expression of USP4 and increased expression of p-p65 and TRAF6."
Catalytic affects USP4
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Catalytic activates USP4. 1 / 1
| 1

eidos
"USP4 is involved in the regulation of many crucial signaling pathways due to its catalytic activity ."
Adenosine affects USP4
| 1
USP4 binds adenosine-A2A. 1 / 1
| 1

reach
"USP4 binds to and deubiquitinates adenosine A2A receptor and enhances cell surface level of the receptor [14] ."
| 1

reach
"USP4 binds to a variety of effectors, including RNA-binding protein with serine-rich domain 1 (RNPS1) [6], the A2a adenosine receptor [7] and diverse components of the spliceosome assembly [8,9]."
VLX1570 affects USP4
| 1
VLX1570 inhibits USP4. 1 / 1
| 1

reach
"VLX1570 is known to induce apoptosis of myeloma by targeting USP4 and UCHL5 [XREF_BIBR]."

sparser
"The ubiquitin peptidase inactive form of USP4 (USP4-C311A) abolished its ability to stabilize HDAC2 ( xref and xref )."
USP7 affects USP15
| 1
USP4 binds USP7 and USP15. 1 / 1
| 1

sparser
"For example, USP11 has been found to interact with USP4, USP7 and USP15; and PSMD7 interacts with USP15 and PSMD14 [ xref ]."
USP4 affects transport
| 1
| 1

reach
"The assay results revealed that transcriptional activity increases in proportion to the amount of USP4 in the nucleus, which suggests that USP4 enhances beta-catenin activity by facilitating its trans[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 affects siUSP4-2
| 1
USP4 activates siUSP4-2. 1 / 1
| 1

reach
"These results indicate that beta-catenin level is not transcriptionally regulated by USP4, but its stability is controlled in protein level by the catalytic activity of USP4.To corroborate its stabili[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 affects several inflammatory cytokines T cells
| 1
USP4 activates several inflammatory cytokines T cells. 1 / 1
| 1

eidos
"USP4 deficiency protected mice from OVA-induced AHR and decreased the production of several inflammatory cytokines in T cells in vivo ."
| 1

sparser
"The ubiquitin peptidase inactive form of USP4 (USP4-C311A) abolished its ability to stabilize HDAC2 ( xref and xref )."
USP4 affects pathological cardiac hypertrophy
| 1
USP4 inhibits pathological cardiac hypertrophy. 1 / 1
| 1

eidos
"Thus , the increased expression of USP4 can suppress pathological cardiac hypertrophy ."
USP4 affects p-CrkII
| 1
USP4 decreases the amount of p-CrkII. 1 / 1
| 1

reach
"In contrast, inhibition of USP4 by shRNA in MHCC97H cells reduced p-ERK1/2 and increased p-CrkII levels."
USP4 affects nitric oxide
| 1
USP4 decreases the amount of nitric oxide. 1 / 1
| 1

reach
"Interestingly, the unloaded HEP-HSA NPs (UNP) also dramatically reduced NO expression compared to the PC (4.7 vs. 18.3 μM) (Figure 2f), supporting additive effects of HEP coating on the suppression of inflammation."
USP4 affects fibrosis progress autoimmune hepatitis
| 1
USP4 inhibits fibrosis progress autoimmune hepatitis. 1 / 1
| 1

eidos
"9 , 21 , 22 Our present study clearly demonstrated that inhibiting USP4 expression alleviates the fibrosis progress in autoimmune hepatitis ."
USP4 affects catalytic activity
| 1
USP4 inhibits catalytic activity. 1 / 1
| 1

sparser
"This is in contrast to the internal Ubl domain in USP4, which competitively inhibits catalytic activity ( Luna-Vargas et al., 2011 )."
USP4 affects breast cancer cell migration
| 1
USP4 activates breast cancer cell migration. 1 / 1
| 1

eidos
"In addition , USP4 depletion inhibits breast cancer cell migration , which is induced by AKT [ 13 ] ."
| PMC
| 1

reach
"USP4 binds to a variety of effectors, including RNA-binding protein with serine-rich domain 1 (RNPS1) [6], the A2a adenosine receptor [7] and diverse components of the spliceosome assembly [8,9]."
USP4 affects VIM
| 1
USP4 decreases the amount of VIM. 1 / 1
| 1

reach
"In addition, inhibition of Ubiquitin carboxyl-terminal hydrolase 4 (USP4) decreased TGF- beta1 induced expression of TbetaR-I and reversed the altered expression of Smad7, Smurf2, ZO-1 and Vimentin."
| 1

sparser
"The ubiquitin peptidase inactive form of USP4 (USP4-C311A) abolished its ability to stabilize HDAC2 ( xref and xref )."
USP4 affects UBL domain
| 1
USP4 binds CTNNB1 and UBL domain. 1 / 1
| 1

reach
"We observed that both USP4 (140-572) and USP4 (261-963) bind to beta-catenin, thus the second UBL domain (483-571) seems to have a major role in interaction with beta-catenin."
USP4 affects U6-snRNA
| 1
USP4 increases the amount of U6-snRNA. 1 / 1
| 1

reach
"We also reveal that USP4 alters TUT1 subnuclear localization, shifting it from the nucleolus to the nucleoplasm, and modulates the level of U6-snRNA."
USP4 affects Tumor Growth
| 1
USP4 activates Tumor Growth. 1 / 1
| 1

eidos
"SOX2 Modulates the USP4 / SMAD4 / CK2 Axis via miR-30e Upregulation to Induce the Tumor Growth of EC in Nude Mice After overexpression of SOX2 , the expression of miR-30e and CK2 was increased and that of USP4 and SMAD4 was decreased ."
USP4 affects TH2
| 1
USP4 activates TH2. 1 / 1
| 1

reach
"USP4 deficiency led to decreased Th2 and Th17 infiltration in the lungs.We identified decreased IL-4, IL-5, IL-13 and IL-17A expression in OVA-induced Usp4 −/− mice."
USP4 affects TGFbeta receptor
| 1
USP4 leads to the deubiquitination of TGFbeta receptor. 1 / 1
| 1

reach
"USP4 has been reported to enhance TGFbeta signalling by directly interacting with and deubiquitylating type I TGFbeta receptor, ALK5 XREF_BIBR."
USP4 affects Smad433
| 1
USP4 deubiquitinates Smad433. 1 / 1
| 1

reach
"However, USP4 was also identified to regulate the deubiquitination of Smad433, which was excluded in the current study due to the content of USP4 in fibroblasts being much lower than USP10."
USP4 affects SMAD2/3/4 reporter
| 1
USP4 activates SMAD2/3/4 reporter. 1 / 1
| 1

reach
"Two DUBs, USP4 and USP15, that have been reported to stabilize TGFBR1 also potentiated TGF-β-induced activation of the SMAD2/3/4 reporter in our system ( Eichhorn et al., 2012; Zhang et al., 2012 ) ( [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 affects SKP2
| 1
USP4 decreases the amount of SKP2. 1 / 1
| 1

reach
"Surprisingly, USP4 knockdown also reduces the levels of SKP2 and CDH1 pointing to distortions in the dynamic equilibrium between APC/C and SCF ."
| 1

reach
"It was found that over-expression of USP4 enhanced the ability of RD cells to fight against invading EV71, and also reduced cell apoptosis."
| 1
| 1

reach
"Last, by proteomics analysis, we revealed that the ubiquitination of RAB7A was mediated by USP4 and validated that upregulation of USP4 could attenuate periodontitis in vivo."
USP4 affects PI3K Akt pathway
| 1
USP4 activates PI3K Akt pathway. 1 / 1
| 1

eidos
"The increased expression of USP4 will reduce the ubiquitination process of downstream PRL-3 and increase the content of PRL-3 , thereby activating the PI3K / Akt pathway ."
USP4 affects NPs
| 1
NPs binds USP4. 1 / 1
| 1

reach
"We have used these models in the following studies of the interaction of 50 and 100nm polystyrene latex NPs, unmodified (UNP) and also surface modified with amine (ANP) and carboxyl groups (CNP)."
USP4 affects MMP2
| 1
USP4 decreases the amount of MMP2. 1 / 1
| 1

reach
"In addition, USP4 expression interference in lung adenocarcinoma cells caused a decrease in MMP2 and VEGF expression, indicating that USP4 induced lymphangiogenesis and promoted lymph node metastasis of lung adenocarcinoma by upregulating VEGF and MMP2 expression ."
USP4 affects LvBr4
| 1
USP4 inhibits LvBr4. 1 / 1
| 1

reach
"Knockdown of USP4 significantly inhibited the invasive activity of PC14PE6 and LvBr4 cells (XREF_FIG)."
USP4 affects IGF-I-Myr-AKT-induced migration MDA-MB-231 breast cancer cells
| 1
USP4 activates IGF-I-Myr-AKT-induced migration MDA-MB-231 breast cancer cells. 1 / 1
| 1

eidos
"However , USP4 is phosphorylated upon IGF-I and TGF-beta induction , and depletion of USP4 reduces IGF-I-Myr-AKT-induced migration in MDA-MB-231 breast cancer cells [ 31 ] ."
USP4 affects Histone
| 1
USP4 deubiquitinates Histone. 1 / 1
| 1

reach
"Another DUB, USP4 deubiquitinates HDAC2 (Histone deacetylases 2) that was shown to interact with p53 thereby inhibiting the level of acetylated p53."
USP4 affects HLA-B
| 1
USP4-C311A decreases the amount of HLA-B. 1 / 1
| 1

reach
"Furthermore, immunofluorescence analysis revealed that knockdown of USP4 resulted in an upregulation of HLA-A, HLA-B, and HLA-C molecules on the cell surface, whereas overexpression of wild-type USP4 [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 affects GW3965
| 1
USP4 inhibits GW3965. 1 / 1
| 1

reach
"Consistently, USP4 overexpression diminished the cytoprotective effect of GW3965 against TGF‐β1 (Fig. 6B, right)."
USP4 affects EMT process liver cancer
| 1
USP4 activates EMT process liver cancer. 1 / 1
| 1

eidos
"Together with these reports , we suggested that USP4 may promote EMT process in liver cancer through activation of PI3K / Akt ."
USP4 affects DUSP domain
| 1
USP4 binds RIGI and DUSP domain. 1 / 1
| 1

reach
"Moreover, whereas USP4 binds through its N-terminal DUSP domain to RIG-I, our study showed that the C-terminal His Box of USP15 interacted with the B-boxes of TRIM25."

reach
"Thus, it is likely that USP4 and USP11 would have a similar function on YY1 stability and inhibit HIV-1 transcription."
USP4 affects CD274
| 1
USP4 increases the amount of CD274. 1 / 1
| 1

reach
"TAM-secreted inflammatory cytokines (e.g., IL-1β and TNF-α) induce Snail expression in lung cancer cells, epigenetically downregulating USP4 to promote drug resistance, stemness and PD-L1 expression [56]."

reach
"For the first time, a molecular modeling analysis has been performed to locate the interaction site for the p-terphenyl fungal product vialinin A bound to the ubiquitin-specific protease USP4."
USP15 affects USP7
| 1
USP4 binds USP7 and USP15. 1 / 1
| 1

sparser
"For example, USP11 has been found to interact with USP4, USP7 and USP15; and PSMD7 interacts with USP15 and PSMD14 [ xref ]."
UBL domain affects USP4
| 1
USP4 binds CTNNB1 and UBL domain. 1 / 1
| 1

reach
"We observed that both USP4 (140-572) and USP4 (261-963) bind to beta-catenin, thus the second UBL domain (483-571) seems to have a major role in interaction with beta-catenin."
U0126 affects USP4
| 1
U0126 increases the amount of USP4. 1 / 1
| 1

reach
"U0126, a specific inhibitor of MEK/ERK, counteracted the promoting effects of USP4 overexpression on cell proliferation, metastasis, and tumor growth."
RIGI affects DUSP domain
| 1
USP4 binds RIGI and DUSP domain. 1 / 1
| 1

reach
"Moreover, whereas USP4 binds through its N-terminal DUSP domain to RIG-I, our study showed that the C-terminal His Box of USP15 interacted with the B-boxes of TRIM25."
OTUD1 affects USP4
| 1
OTUD1 inhibits USP4. 1 / 1
| 1

reach
"This suggests that Ang II, in addition to increasing OTUD1, may supress USP4."
NPs affects USP4
| 1
NPs binds USP4. 1 / 1
| 1

reach
"We have used these models in the following studies of the interaction of 50 and 100nm polystyrene latex NPs, unmodified (UNP) and also surface modified with amine (ANP) and carboxyl groups (CNP)."
NES affects USP4
| 1
NES activates USP4. 1 / 1
| 1

reach
"The function of the DUSP and UBL domains are unknown while the NES works in concert with a C-terminal nuclear localization (NLS), enabling the nuclear cytoplasmic shuttling of USP4 [23]."
Mice affects USP4
| 1
Mice increases the amount of USP4. 1 / 1
| 1

reach
"By employing these approaches to respectively enhance mouse USP4 expression and suppress RAB7A activity, we investigated their impact on periodontitis development in mice."
FOLH1 affects USP4
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FOLH1 inhibits USP4. 1 / 1
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"For the second step, a copper assisted click reaction was undertaken between the azide functionalized version of the nanoparticles, either PSMA targeted TNP or untargeted UNP, and alkyne-function-alized 111 In-DOTA-PEG-alkyne from step 1."
Evodiamine affects USP4
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Evodiamine decreases the amount of USP4. 1 / 1
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"At the same time, evodiamine can significantly inhibit the expression of USP4, SOX9, OCT4, and CD133 in CRC cells."
EDX pattern affects USP4
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EDX pattern activates USP4. 1 / 1
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"As can be seen in Figure 1c, the EDX pattern clearly supports the good dispersion of the UNP sample."
DUSP domain affects USP4
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USP4 binds RIGI and DUSP domain. 1 / 1
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"Moreover, whereas USP4 binds through its N-terminal DUSP domain to RIG-I, our study showed that the C-terminal His Box of USP15 interacted with the B-boxes of TRIM25."
CTNNB1 affects UBL domain, and USP4
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USP4 binds CTNNB1 and UBL domain. 1 / 1
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"We observed that both USP4 (140-572) and USP4 (261-963) bind to beta-catenin, thus the second UBL domain (483-571) seems to have a major role in interaction with beta-catenin."
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"This suggests that Ang II, in addition to increasing OTUD1, may supress USP4."
ATF4 affects USP4
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ATF4 increases the amount of USP4. 1 / 1
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"Atf4 siRNA significantly downregulated the expression of Usp4, 7, 8, 11, 12, 19, 20, 21, 22, 27, 28, 30 31, 32, 36, 42, 44, 46, 50, 53, and 54; however, the expression of Usp7, also called herpesvirus-associated ubiquitin-specific protease (HAUSP), was the most significantly repressed [45]."

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"For the first time, a molecular modeling analysis has been performed to locate the interaction site for the p-terphenyl fungal product vialinin A bound to the ubiquitin-specific protease USP4."