IndraLab

Statements


USP4 affects HDAC2
3 1 | 32 19
USP4 binds HDAC2.
3 | 14 19
3 | 13 15

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

sparser
"Furthermore, we sought to determine whether USP4 interacts with HDAC2 in vivo ."

sparser
"These observations indicated that GATA-zinc finger domain of TRPS1 was essential for its interactions with HDAC2 and USP4."

sparser
"We further verified that TRPS1 functioned as a scaffold protein for the complex formation of TRPS1-USP4-HDAC2 and was responsible for the reduction of HDAC2 ubiquitination level by facilitating interaction between USP4 and HDAC2."

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

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
"USP4’s interaction with HDAC2 likely also emerged after WGD as a small region of USP4 (a."

No evidence text available

No evidence text available
TRPS1 binds USP4 and HDAC2. 5 / 5
| 1 4

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
"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
"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
"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 )."

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."
USP4 deubiquitinates HDAC2.
1 | 12
USP4 deubiquitinates HDAC2. 10 / 12
1 | 11

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

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
"Another DUB, USP4 deubiquitinates HDAC2 (Histone deacetylases 2) that was shown to interact with p53 thereby inhibiting the level of acetylated p53."

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

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."

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

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

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."
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 ubiquitinates HDAC2.
| 1
USP4-C311A leads to the ubiquitination of HDAC2. 1 / 1
| 1

reach
"Reconstitution with shRNA resistant USP4 restored HDAC2 ubiquitination, whereas USP4 C311A mutant can not restore HDAC2 ubiquitination (XREF_FIG)."
USP4 is modified
2 | 1 55 3
USP4 is phosphorylated.
2 | 29 3
USP4 is phosphorylated. 10 / 26
| 24 2

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

rlimsp
"Despite the proposed facultative role of this alternatively spliced exon16, the majority of conserved phosphorylation sites in USP4 are within E7, suggesting the protein isoforms may be differently regulated17."

sparser
"Importantly, AKT (also known as protein kinase B), which has been associated with poor prognosis in breast cancer, directly associates with and phosphorylates USP4."

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

sparser
"USP4 phosphorylation is an indispensable process leading to the localization of USP4 from nucleus to cytoplasm."

sparser
"According to a previous study by Iyengar [ xref ], 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-β receptor [ xref ]."

sparser
"As aforementioned, phosphorylated USP4 can relocate from nucleus to cytoplasm or cell membrane where USP4 deubiquitylates TGF-β receptor I (TβRI) and stabilizes its expression to activate TGF-β signaling pathway to induce R-Smads phosphorylation and then R-Smads are imported into the nucleus to regulate targeted genes expression [ xref ]."

sparser
"In addition, cyclin-dependent kinases (CDKs) were also involved in USP4 phosphorylation which can be hampered by purvalanol A, a CDKs inhibitor."

sparser
"Growth factors regulate Rheb ubiquitination through USP4 phosphorylation."
USP4 is phosphorylated on S445. 5 / 5
| 4 1

rlimsp
"USP4 has both nuclear importing and exporting signal motifs and can shuttle between nucleus and cytoplasm10. Subcellular localization is partially controlled by AKT-mediated phosphorylation of the serine residue at position 445, which promotes cytoplasmic retention2."

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
"Taken together, these findings indicate that EGF regulates Rheb deubiquitination by inducing USP4 phosphorylation at S445."

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
"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 )."
USP4 is phosphorylated on S680. 1 / 1
1 |

No evidence text available
USP4 is phosphorylated on T677. 1 / 1
1 |

No evidence text available
USP4 is phosphorylated on T149. 1 / 1
| 1

sparser
"Phosphorylation of USP4 at the alternate residues, Thr149 and Thr219, is mediated by cyclin-dependent kinases and exerts a negative role in pre-mRNA splicing through blocking USP4 interactions with squamous cell carcinoma antigen recognized by T cells 3 (SART3) ( xref )."
USP4 is ubiquitinated.
| 22
USP4 is ubiquitinated. 10 / 22
| 22

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

sparser
"We therefore assessed ubiquitylation of GFP-USP4 WT, GFP-USP4 CD, and GFP (assessment of endogenous USP4 ubiquitylation events could more directly address the physiological nature of such modifications but was technically not feasible; data not shown) by co-expressing these with human influenza hemagglutinin-epitope-tagged ubiquitin (HA-Ub) and immunoprecipitating ubiquitylated proteins with an HA antibody in the presence of 1 M NaCl."

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

sparser
"Our mapping of USP4 cysteine ubiquitylations and our observation that such ubiquitylations are labile under reducing conditions, highlight how cysteine ubiquitylation and deubiquitylation might occur more generally, at least within the USP-DUB ubiquitin protease family, many of which contain zinc-binding cysteine motifs ( xref )."

sparser
"To verify that USP4 was indeed ubiquitylated, we prepared GFP-immunoprecipitates from lysates of cells co-expressing HA-ubiquitin together with GFP-USP4 WT or CD."

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."

sparser
"Surprisingly, it was shown that USP4 is ubiquitylated on multiple residues including cysteine residues and that autodeubiquitylation of these residues by USP4 is required for the interaction with MRN [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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

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
"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."
USP4 is methylated.
| 2
USP4 is methylated. 2 / 2
| 2

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

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."
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."
USP4 affects RBBP8
6 | 20 32
USP4 binds RBBP8.
6 | 18 32
6 | 18 28

sparser
"To identify the regions of USP4 that are responsible for the USP4-CtIP interaction, we generated deletion mutants of USP4 ( Figure 1 C)."

sparser
"Our results revealed that USP4 interacts with CtIP and USP4-CtIP interaction is important for HR."

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

sparser
"As shown in Figure 1 B, endogenous USP4 and CtIP interact with each other in cells."

sparser
"Wijnhoven et al. revealed that the human deubiquitylase USP4 promotes homologous recombination, DNA end-resection, and CtIP recruitment and that USP4 interacts with CtIP and MRN."

reach
"In light of the above findings, we tested whether USP4 might physically interact with CtIP and/or MRN."

No evidence text available

sparser
"Because it was reported that USP4 interacts with CtIP but does not affect the latter’s ubiquitination level xref , we chose USP52 as the candidate DUB for CtIP."

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

reach
"Deletion of USP4 insert domain (residues 572-775) abolished the binding of USP4 with CtIP."
USP4 binds RBBP8 and foci. 2 / 2
| 2

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."

sparser
"As USP4 directly interacts with CtIP, we also checked CtIP foci formation in USP4-depleted cells."
| 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 phosphorylates RBBP8.
| 1
USP4 leads to the phosphorylation of RBBP8. 1 / 1
| 1

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."
USP4 increases the amount of RBBP8.
| 1
USP4 increases the amount of RBBP8. 1 / 1
| 1

reach
"USP4 knockdown, although incomplete, reduces CTIP levels (Fig. 4d), suggesting that it normally protects CTIP from degradation."
USP4 affects MAP3K7
3 1 | 28 13
USP4 binds MAP3K7.
3 | 6 11
3 | 5 11

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 )."

sparser
"It was shown that TNFα induces the association of USP4 with TAK1 and deubiquitylation of K63-linked ubiquitin chains from TAK1, leading to the inhibition of NF-κB production."

No evidence text available

reach
"Furthermore, unlike CYLD, binding of USP4 with TAK1 is induced by TNFalpha stimulation in the cells (XREF_FIG)."

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

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
"These results suggest that TNFα induces association of USP4 with TAK1."

No evidence text available

sparser
"TNFα induces association of USP4 with TAK1 to deubiquitinate TAK1 and downregulate TAK1-mediated NF-κB activation."
USP4 binds MAP3K7 and Lys63. 1 / 1
| 1

reach
"In view of the data presented here and previous reports, we propose a working model (XREF_FIG), in which that TNFalpha 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 TNFalpha induced Lys63 linked TAK1 polyubiquitination and TAK1 mediated IKK and NF-kappaB activation."
USP4 deubiquitinates MAP3K7.
1 | 17
USP4 deubiquitinates MAP3K7. 10 / 14
1 | 13

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

reach
"85 The deubiquitinating enzyme ubiquitin‐specific protease 4 (USP4) attenuates major hypertrophic signalling pathways, such as TAK1‐JNK and TAK1‐p38, by removing the K63‐linked polyubiquitination of TAK1."

"Using a functional genomic approach, we have identified ubiquitin-specific peptidase 4 (USP4) as a deubiquitinase for TAK1."

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

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
"In view of the data presented here and previous reports, we propose a working model (XREF_FIG), in which that TNFalpha 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 TNFalpha induced Lys63 linked TAK1 polyubiquitination and TAK1 mediated IKK and NF-kappaB activation."

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

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

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

reach
"USP4 deubiquitinates TAK1 in vitro and in vivo."
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. 1 / 1
| 1

reach
"USP4 deubiquitinates TAK1 with Lys63 linked polyubiquitination and inhibits Dox induced NF-kappaB activation."
USP4-C311A leads to the deubiquitination 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 inhibits MAP3K7.
| 2 2
USP4 inhibits MAP3K7. 4 / 10
| 2 2

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
"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 )."
USP4 activates MAP3K7.
| 2
USP4 activates MAP3K7. 2 / 2
| 2

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 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 USP15
3 | 13 26
USP4 binds USP15.
3 | 11 26
3 | 10 11

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
"A USP15USP4 amino acid sequence alignment in the SL region reveals the only difference to be a cysteine residue (USP15 Cys 352 ), which replaces a serine (Ser 394 ) in USP4 ( xref D and)."

sparser
"These findings suggest SART3 binds to both USP15 and USP4, and this may lead to deubiquitination of PRP31 and PRP3 simultaneously."

No evidence text available

reach
"USP4 can form stable homodimers and can also interact with USP11 and USP15."

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

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

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

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

reach
"To examine the effect of endogenous SART3, the interaction between USP4 and USP15 was examined by immunoprecipitation after depletion of SART3 using siRNA."
USP15 binds USP4 and SART3. 6 / 6
| 1 5

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
"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 )."

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

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
"Drugs interfering with the interaction between USP4 and USP15 and SART3 may selectively inhibit the DUB functions in the nucleus."
| PMC
USP11 binds USP15 and USP4. 3 / 3
| 3

sparser
"USP4 can form stable homodimers and can also interact with USP11 and USP15 ( Fig. 4 )."

sparser
"USP15 forms a subfamily with USP4 and USP11 related through a shared presence of N-terminal "domain present in ubiquitin specific proteases" (DUSP) and "ubiquitin-like" (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."
USP15 binds USP4 and BRAP. 3 / 3
| 3

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."

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
"The USP4 and USP15 DU domains interact with E3 ligases ( xref ) and the substrate recruitment factor SART3 ( xref , xref ), but no interactions have yet been reported for these domains in USP11."
USP15 binds USP4 and USP7. 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
"In the absence of USP4 and USP15 ubiquitin-bound structures, the molecular bases for these differences are difficult to rationalize at present, as multiple factors will contribute, such as the release of bound water molecules, conformational changes associated with the binding events, and differences in interacting residues."
USP15 binds USP4, USPs, and BRAP. 1 / 1
| 1

sparser
"Of these, the interaction between BRAP and two related USPs, USP4 and USP15, was of compelling physiological interest given the established role of BRAP/IMP in the regulation of the MAP kinase signaling cascade ( 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
3 | 13 26
USP15 binds USP4.
3 | 11 26
3 | 10 11

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
"A USP15USP4 amino acid sequence alignment in the SL region reveals the only difference to be a cysteine residue (USP15 Cys 352 ), which replaces a serine (Ser 394 ) in USP4 ( xref D and)."

sparser
"These findings suggest SART3 binds to both USP15 and USP4, and this may lead to deubiquitination of PRP31 and PRP3 simultaneously."

No evidence text available

reach
"USP4 can form stable homodimers and can also interact with USP11 and USP15."

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

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

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

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

reach
"To examine the effect of endogenous SART3, the interaction between USP4 and USP15 was examined by immunoprecipitation after depletion of SART3 using siRNA."
USP15 binds USP4 and SART3. 6 / 6
| 1 5

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
"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 )."

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

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
"Drugs interfering with the interaction between USP4 and USP15 and SART3 may selectively inhibit the DUB functions in the nucleus."
| PMC
USP11 binds USP15 and USP4. 3 / 3
| 3

sparser
"USP4 can form stable homodimers and can also interact with USP11 and USP15 ( Fig. 4 )."

sparser
"USP15 forms a subfamily with USP4 and USP11 related through a shared presence of N-terminal "domain present in ubiquitin specific proteases" (DUSP) and "ubiquitin-like" (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."
USP15 binds USP4 and BRAP. 3 / 3
| 3

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."

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
"The USP4 and USP15 DU domains interact with E3 ligases ( xref ) and the substrate recruitment factor SART3 ( xref , xref ), but no interactions have yet been reported for these domains in USP11."
USP15 binds USP4 and USP7. 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
"In the absence of USP4 and USP15 ubiquitin-bound structures, the molecular bases for these differences are difficult to rationalize at present, as multiple factors will contribute, such as the release of bound water molecules, conformational changes associated with the binding events, and differences in interacting residues."
USP15 binds USP4, USPs, and BRAP. 1 / 1
| 1

sparser
"Of these, the interaction between BRAP and two related USPs, USP4 and USP15, was of compelling physiological interest given the established role of BRAP/IMP in the regulation of the MAP kinase signaling cascade ( 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."
USP4 affects CTNNB1
2 1 | 27 12
USP4 binds CTNNB1.
2 | 5 10
2 | 3 9

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

No evidence text available

No evidence text available

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

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 )."

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)."

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."

reach
"XREF_BIBR - XREF_BIBR In addition, the deubiquitinating enzymes USP34 and USP7, CYLD and USP9X and USP4 can bind to Axin, Dvl and beta-catenin, respectively, thereby promoting the nuclear localization of beta-catenin and the Wnt signaling pathway by inhibiting their ubiquitination."

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]"
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 binds CTNNB1 and MYC. 1 / 1
| 1

sparser
"The wild type USP4 and USP4(261–963) were associated with Myc-β-catenin, while USP4(1–260) showed only weak interaction ( Figure 4 B)."
USP4 binds CTNNB1 and 293T. 1 / 1
| 1

reach
"The interaction of endogenous beta-catenin and USP4 was confirmed in 293T and HCT116 cells, a colon cancer cell line harboring stable beta-catenin that has a mutation at S45 phosphorylation site."
USP4 activates CTNNB1.
| 10 2
USP4 activates CTNNB1. 10 / 15
| 9 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."

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
"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
"However, USP4 had no effect on the stability of GSK3beta, a negative regulator of beta-catenin, suggesting that USP4 enhances the stability and activity of beta-catenin not by affecting beta-catenin r[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
"For instance, USP4 promote tumor progression by regulating beta-Catenin Signaling XREF_BIBR."

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]"

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]"

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

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)."
USP4-C311A activates CTNNB1. 1 / 1
| 1

reach
"However, stabilized beta-catenin was partially affected by the USP4 expression level, and the catalytically defective C311A USP4 was able to activate beta-catenin to some extent."
USP4 increases the amount of CTNNB1.
| 6
USP4 increases the amount of CTNNB1. 6 / 6
| 6

reach
"USP4 increased the level of beta-catenin by inducing its deubiquitinylation."

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
"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."
USP4 deubiquitinates CTNNB1.
1 | 4
USP4 deubiquitinates CTNNB1. 5 / 5
1 | 4

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
"We showed that USP4 deubiquitinates beta-catenin."

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

reach
"Deubiquitination of beta-catenin by USP4 reverses the ubiquitination mediated degradation of beta-catenin, upregulating Wnt signalling."

"Additionally, DUBs USP14, USP15, USP47, and Fam/USP9X have been reported to prevent β-catenin turnover by inhibiting its Ub-proteasomal degradation"
USP4 ubiquitinates CTNNB1.
| 1
Modified USP4 leads to the ubiquitination of 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."
USP4 inhibits CTNNB1.
| 1
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."
SART3 affects USP4
11 | 14 15
SART3 binds USP4.
11 | 12 15
11 | 11 9

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."

No evidence text available

sparser
"The USP4 sart3 complex helps to recruit the substrate PRP3, as well as increase the deubiquitinating activity of USP4 ( xref ; xref )."

No evidence text available

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

No evidence text available

reach
"These findings suggest SART3 binds to both USP15 and USP4, and this may lead to deubiquitination of PRP31 and PRP3 simultaneously."

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
"To have a better understanding of the interaction between ALAL-1 and SART3 and USP4, we performed coimmuno-FISH experiments coupled with confocal microscopy."
USP15 binds USP4 and SART3. 6 / 6
| 1 5

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
"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 )."

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

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

sparser
"The USP4 and USP15 DU domains interact with E3 ligases ( xref ) and the substrate recruitment factor SART3 ( xref , xref ), but no interactions have yet been reported for these domains in USP11."
SART3 inhibits USP4.
| 1
SART3 inhibits USP4. 1 / 2
| 1

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."
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."

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

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

reach
"Thus, in this study, we wished to determine whether PDCD4 is involved in the USP4 mediated inhibition of breast cancer cell proliferation."

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

reach
"USP4 inhibits breast cancer cell proliferation."

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

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
"Moreover, USP4 elevation antagonized the OGD/R-induced microglia proliferation and activation by suppressing the NO levels and the expression of the microglial marker IBA-1."

reach
"Moreover, knockdown of USP4 could significantly inhibit cell proliferation and increase cell apoptosis in U87 and T98G cells."

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
"On the other hand, SRSF1 is upregulated by high USP15 and USP4 that enhance cell proliferation and invasion (Fig. 7D)."

reach
"USP4 accelerates HCC cell proliferation, migration, and invasion in vitro."

reach
"Depletion of USP15 and USP4 decreased cell proliferation in both H157 (Fig. 1C and Supplementary Fig. 1C, D) and A549 (Supplementary Fig. 1E)."

reach
"To test this hypothesis, CCK-8 assays were used to investigate the effects of CypA on USP4 induced proliferation of HCC cell lines."

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

reach
"Inversely, overexpression of USP4 or CypA in Huh7 and PLC/PRF/5 cells significantly promoted cell proliferation; however, CypA knockdown impaired the effect in Huh7-USP4 and PLC/PRF/5-USP 4 cells."

reach
"In vitro study showed that knockdown of USP4 inhibited PC cells proliferation, migration and invasion."
USP4 affects SART3
11 | 12 15
11 | 11 9

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."

No evidence text available

sparser
"The USP4 sart3 complex helps to recruit the substrate PRP3, as well as increase the deubiquitinating activity of USP4 ( xref ; xref )."

No evidence text available

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

No evidence text available

reach
"These findings suggest SART3 binds to both USP15 and USP4, and this may lead to deubiquitination of PRP31 and PRP3 simultaneously."

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
"To have a better understanding of the interaction between ALAL-1 and SART3 and USP4, we performed coimmuno-FISH experiments coupled with confocal microscopy."
USP15 binds USP4 and SART3. 6 / 6
| 1 5

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
"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 )."

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

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

sparser
"The USP4 and USP15 DU domains interact with E3 ligases ( xref ) and the substrate recruitment factor SART3 ( xref , xref ), but no interactions have yet been reported for these domains in USP11."
AKT affects USP4
| 21 21
AKT phosphorylates USP4.
| 12 19
AKT phosphorylates USP4. 10 / 28
| 11 17

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 )."

sparser
"In contrast, Akt can phosphorylate the deubiquitinase USP4 that promotes RHEB deubiquitination thereby releasing RHEB from TSC [ xref ]."

reach
"Importantly, AKT (also known as protein kinase B), which has been associated with poor prognosis in breast cancer, directly associates with and phosphorylates USP4."

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."

sparser
"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-β signalling."

sparser
"Although it seems complicated to determine whether a DUB cleaves with endo-or exocleavage activity, several studies have activity, have also been reported to affect the nuclear localization of DUBs. [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-(TGF-) receptor I (T R-I). [52] Furthermore, localization can also be indirectly modulated by changing the protein interactions that a DUB engages in ref. [25] ."

sparser
"Furthermore, the phosphorylation of USP4 by Akt was also required for it to associate with other DUBs to deubiquitylate the TGF-β receptors."

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

reach
"For example, phosphorylation of USP4 by AKT activates and thus stabilizes this DUB, a process required for proper regulation of TGF-beta signaling during embryonic development (further discussed below) [XREF_BIBR, XREF_BIBR]."

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
AKT phosphorylates USP4 on S445. 3 / 3
| 1 2

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."

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 ]."
AKT binds USP4.
| 5 2
| 5 2

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
"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]."

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

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

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]"

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."
AKT activates USP4.
| 3
AKT activates USP4. 3 / 3
| 3

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
"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."
AKT increases the amount of USP4.
| 1
AKT increases the amount of USP4. 1 / 1
| 1

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."
USP4 affects TRAF6
4 1 | 24 10
USP4 binds TRAF6.
4 | 7 10
4 | 7 6

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."

sparser
"The USP domain is responsible for USP4 to interact with TRAF6."

No evidence text available

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

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]."

sparser
"Moreover, USP4 associates with TRAF6 both in vitro and in vivo, independent of its deubiquitinase activity."

No evidence text available

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."

No evidence text available

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."
TRAF2 binds TRAF6 and USP4. 4 / 4
| 4

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."

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
"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 [61]."
USP4 deubiquitinates TRAF6.
1 | 7
USP4 deubiquitinates TRAF6. 8 / 8
1 | 7

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

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

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

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

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

reach
"USP4 deubiquitinates TRAF6 and thereby prevents the activation of NF-kappaB and AP-1 transcription factors and subsequent proinflammatory responses."

"The downregulation of USP4 expression may promote microglial activation and subsequent neuronal inflammation through NF-κB by attenuating the deubiquitination of TRAF6."
USP4 activates TRAF6.
| 7
USP4 activates TRAF6. 7 / 7
| 7

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."

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
"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
"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, 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 targets TRAF6 through its USP domain."
USP4 inhibits TRAF6.
| 3
USP4 inhibits TRAF6. 3 / 3
| 3

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

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."
HDAC2 affects USP4
3 | 15 19
HDAC2 binds USP4.
3 | 14 19
3 | 13 15

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

sparser
"Furthermore, we sought to determine whether USP4 interacts with HDAC2 in vivo ."

sparser
"These observations indicated that GATA-zinc finger domain of TRPS1 was essential for its interactions with HDAC2 and USP4."

sparser
"We further verified that TRPS1 functioned as a scaffold protein for the complex formation of TRPS1-USP4-HDAC2 and was responsible for the reduction of HDAC2 ubiquitination level by facilitating interaction between USP4 and HDAC2."

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

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
"USP4’s interaction with HDAC2 likely also emerged after WGD as a small region of USP4 (a."

No evidence text available

No evidence text available
TRPS1 binds USP4 and HDAC2. 5 / 5
| 1 4

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
"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
"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
"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 )."

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."
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 27 4
USP4 inhibits NFkappaB.
| 19 2
| 18 2

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

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

reach
"To further explore the role of USP4 on NF-kappaB target gene expression, we examined the effect of USP4 knockdown on the expression of other TNFalpha induced NF-kappaB target genes."

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

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
"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
"Fourth, USP4 inhibits NF-kappaB transcriptional activity through HDAC2."

reach
"USP4 negatively regulates IL-1beta-induced NF-kappaB activation [XREF_BIBR, XREF_BIBR, XREF_BIBR]."

sparser
"Recent studies have shown that USP4 serves as a critical control to downregulate NF-κB activation through deubiquitinating TAK1, TRAF2 and TRAF6. xref , xref It has also been reported that HDAC2 could inhibit NF-κB activation. xref , xref In our study we found that HDAC2 could reduce TNFα-induced acetylation of RelA in H1299 cells, but HDAC2 could not interact with RelA ( xref ), consistent with previous studies. xref Therefore, we explored the possibility that USP4 inhibits NF-κB transcriptional activity through HDAC2 using an NF-κB-dependent luciferase reporter gene assay."

reach
"Therefore, our studies reveal USP4 suppresses p53 and NF-kappaB activation by stabilizing HDAC2."
USP4 bound to RIPK1 inhibits NFkappaB. 1 / 1
| 1

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)."
USP4 activates NFkappaB.
| 1 8 2
| 1 8 2

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

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."

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

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

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."

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

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)."
USP4 affects TP53
1 | 1 1 22 3
USP4 inhibits TP53.
| 1 1 10 3
USP4 inhibits TP53. 10 / 20
| 1 1 10 3

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)."

sparser
"USP4 could inhibit p53 through deubiquitinating and stabilizing ARF-BP1 xref or HDAC2 xref and was upregulated in several cancer tissues."

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

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."

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

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

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

reach
"Therefore, USP4 suppresses p53 transcriptional activity and proapoptotic functions."

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

reach
"Increased ARF-BP1 and Mule degradation causes p53 stabilization, which is antagonized by the DUBs USP7 and USP4."
USP4 activates TP53.
| 6
USP4 activates TP53. 6 / 6
| 6

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

reach
"Notably, studies have also indicated functions for USP4 in regulating growth factor signalling by the Toll-like receptor/IL1 pathway [88] , TGFb receptor type I [89, 90] , TNFa receptor [91] , growth factoractivated kinase regulation [92] and Wnt signalling [93] , making USP4 a prime target for further evaluation as an oncology drug target with strong potential in DDR contexts.Depletion of USP5 has been reported to cause accumulation of nuclear p53 and increase p53 transcriptional activity."

reach
"Similarly, knockdown of USP4 significantly decreases cell viability in a p53 dependent manner after treating GMB cells with temozolomide."
USP4 deubiquitinates TP53.
1 | 2
USP4 deubiquitinates TP53. 3 / 3
1 | 2

reach
"USP4 is a deubiquitinating enzyme which may inhibit p53 by deubiquitinating an important p53 ubiquitin ligase ARF-BP1 [35]."

"Regulation of p53 is also subject to other DUBs, such as USP4, USP10, USP29, and USP42 [171]."

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 decreases the amount of TP53.
| 2
USP4 decreases the amount of TP53. 2 / 3
| 2

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 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]."
TRIM21 affects USP4
4 1 2 | 6 7
TRIM21 ubiquitinates USP4.
2 | 4 4
TRIM21 ubiquitinates USP4. 10 / 14
2 | 4 4

"Here, we showed that UnpEL is ubiquitinated by Ro52 in cooperation with UbcH5B in vitro"

reach
"USP4 is ubiquitinated by the ubiquitin ligase Ro52, whose deubiquitination, in turn, is facilitated by USP4."

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

No evidence text available

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 )."

reach
"UnpEL and Usp4 is ubiquitinated by Ro52 and deubiquitinated by itself."

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

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

sparser
"Conversely, USP4 can be ubiquitylated by Ro52 and subsequently degraded."
TRIM21 binds USP4.
4 1 | 2 3
4 1 | 2 3

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) ."

No evidence text available

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

No evidence text available

No evidence text available

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]."

No evidence text available

No evidence text available

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 )."
USP4 affects TGFBR1
3 1 | 1 21 1
USP4 deubiquitinates TGFBR1.
1 | 11
USP4 deubiquitinates TGFBR1. 10 / 12
1 | 11

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

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

reach
"For instance, USP4 directly interacts with and deubiquitinates TGF-beta type I receptor (TbetaRI), thereby determining the levels of TGF-beta signaling."

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 is a DUB for TGF-β 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]"

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

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 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."
USP4 binds TGFBR1.
3 | 7 1
3 | 7 1

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]"

No evidence text available

reach
"For instance, USP4 directly interacts with and deubiquitinates TGF-beta type I receptor (TbetaRI), thereby determining the levels of TGF-beta signaling."

No evidence text available

No evidence text available

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
"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
"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."

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

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."
USP4 activates TGFBR1.
| 1 3
USP4 activates TGFBR1. 4 / 4
| 1 3

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."

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
"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."
MAP3K7 affects USP4
3 | 10 11
MAP3K7 binds USP4.
3 | 6 11
3 | 5 11

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 )."

sparser
"It was shown that TNFα induces the association of USP4 with TAK1 and deubiquitylation of K63-linked ubiquitin chains from TAK1, leading to the inhibition of NF-κB production."

No evidence text available

reach
"Furthermore, unlike CYLD, binding of USP4 with TAK1 is induced by TNFalpha stimulation in the cells (XREF_FIG)."

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

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
"These results suggest that TNFα induces association of USP4 with TAK1."

No evidence text available

sparser
"TNFα induces association of USP4 with TAK1 to deubiquitinate TAK1 and downregulate TAK1-mediated NF-κB activation."
USP4 binds MAP3K7 and Lys63. 1 / 1
| 1

reach
"In view of the data presented here and previous reports, we propose a working model (XREF_FIG), in which that TNFalpha 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 TNFalpha induced Lys63 linked TAK1 polyubiquitination and TAK1 mediated IKK and NF-kappaB activation."
MAP3K7 activates USP4.
| 4
MAP3K7 activates USP4. 4 / 4
| 4

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
"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
"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 HUWE1
3 1 | 18
USP4 binds HUWE1.
3 | 7
3 | 7

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

No evidence text available

reach
"USP4 has been recently described as a key regulator of p53 stability: USP4 interacts directly and deubiquitylates the E3 HUWE1 (ARF-BP1; MULE), resulting in reduced p53 levels [86]."

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

No evidence text available

No evidence text available

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 | 10
USP4 deubiquitinates HUWE1. 10 / 11
1 | 10

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

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

reach
"USP4 has been recently described as a key regulator of p53 stability: USP4 interacts directly and deubiquitylates the E3 HUWE1 (ARF-BP1; MULE), resulting in reduced p53 levels [86]."

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

reach
"USP4 is a deubiquitinating enzyme which may inhibit p53 by deubiquitinating an important p53 ubiquitin ligase ARF-BP1 [35]."
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]."
TRAF6 affects USP4
4 | 9 10
TRAF6 binds USP4.
4 | 7 10
4 | 7 6

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."

sparser
"The USP domain is responsible for USP4 to interact with TRAF6."

No evidence text available

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

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]."

sparser
"Moreover, USP4 associates with TRAF6 both in vitro and in vivo, independent of its deubiquitinase activity."

No evidence text available

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."

No evidence text available

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."
TRAF2 binds TRAF6 and USP4. 4 / 4
| 4

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."

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
"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 [61]."
TRAF6 activates USP4.
| 2
TRAF6 activates USP4. 2 / 2
| 2

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
"USP4 targets TRAF6 through its USP domain."
| 1 22
| 1 21

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
"USP15 and USP4 promote cell proliferation and invasion in lung cancer cell lines."

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

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
"Using in vitro and in vivo assays, we demonstrated that USP4 overexpression enhanced HCC cell growth, migration, and invasion."

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
"Consistent with this correlation, USP4 knockdown in HCT116, a colon cancer cell line, reduced invasion and migration activity."

reach
"USP4 accelerates HCC cell proliferation, migration, and invasion in vitro."

reach
"Moreover, we observed that the invasion activity of HCT116 cells was suppressed by USP4 knockdown."

reach
"On the other hand, SRSF1 is upregulated by high USP15 and USP4 that enhance cell proliferation and invasion (Fig. 7D)."
| 1

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]"
USP4 affects IRF4
1 | 14 7
USP4 binds IRF4.
| 7 7
| 7 7

sparser
"Interaction between USP4 and IRF4."

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

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

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

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 | 4
USP4 deubiquitinates IRF4. 5 / 5
1 | 4

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."

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."
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."
USP4 increases the amount of IRF4.
| 1
USP4 increases the amount of IRF4. 1 / 1
| 1

reach
"USP4 knockdown not only decreased the expression level of IRF4, but also affected the expression level of Th2 related cytokines."
USP4 affects TGFB
| 1 19
USP4 activates TGFB.
| 1 13
USP4 activates TGFB. 10 / 12
| 1 11

reach
"The hypothesis that drove this study was that USP4 might also mediate the TGF-beta signal transduction pathway in hypertrophic scar fibroblasts."

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
"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 promotes invasion of breast cancer cells via Relaxin and TGF-beta 1/Smad2/MMP -9 signal."

reach
"Ubiquitin specific protease 4 (USP4) augments TGF-beta signaling through the prevention of TGF-beta RI degradation."

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
"Of the newly identified two targets of miR-148a (i.e., USP4 and S1P1), USP4 overexpression contributed to HCC progression toward more aggressive feature by facilitating TGF-beta signaling pathways, growth advantage and migrating capability."

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."
USP4 bound to TGFBR1 activates TGFB. 2 / 2
| 2

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."
USP4 deubiquitinates TGFB.
| 4
USP4 deubiquitinates TGFB. 4 / 4
| 4

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

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."

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."
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."
USP4 affects TRAF2
2 1 | 10 4
USP4 binds TRAF2.
2 | 3 4
2 | 3

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

No evidence text available

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 HEK293 T cells, and in vitro [61] ."

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]."

No evidence text available
TRAF2 binds TRAF6 and USP4. 4 / 4
| 4

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."

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
"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 [61]."
USP4 deubiquitinates TRAF2.
1 | 3
USP4 deubiquitinates TRAF2. 4 / 4
1 | 3

"Ubiquitin-specific protease 4 (USP4) targets TRAF2 and TRAF6 for deubiquitination and inhibits TNFα-induced cancer cell migration"

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
"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
"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
"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."
USP4 affects TRIM21
4 1 1 | 4 3
USP4 binds TRIM21.
4 1 | 2 3
4 1 | 2 3

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) ."

No evidence text available

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

No evidence text available

No evidence text available

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]."

No evidence text available

No evidence text available

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 )."
USP4 deubiquitinates TRIM21.
1 | 2
USP4 deubiquitinates TRIM21. 3 / 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
"Oncogenic protein UnpEL and Usp4 deubiquitinates Ro52 by its isopeptidase activity."

"Oncogenic protein UnpEL/Usp4 deubiquitinates Ro52 by its isopeptidase activity"
CTNNB1 affects USP4
2 | 5 10
2 | 3 9

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

No evidence text available

No evidence text available

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

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 )."

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)."

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."

reach
"XREF_BIBR - XREF_BIBR In addition, the deubiquitinating enzymes USP34 and USP7, CYLD and USP9X and USP4 can bind to Axin, Dvl and beta-catenin, respectively, thereby promoting the nuclear localization of beta-catenin and the Wnt signaling pathway by inhibiting their ubiquitination."

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]"
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 binds CTNNB1 and MYC. 1 / 1
| 1

sparser
"The wild type USP4 and USP4(261–963) were associated with Myc-β-catenin, while USP4(1–260) showed only weak interaction ( Figure 4 B)."
USP4 binds CTNNB1 and 293T. 1 / 1
| 1

reach
"The interaction of endogenous beta-catenin and USP4 was confirmed in 293T and HCT116 cells, a colon cancer cell line harboring stable beta-catenin that has a mutation at S45 phosphorylation site."
USP4 affects PRPF3
5 1 | 10
USP4 deubiquitinates PRPF3.
1 | 10
USP4 deubiquitinates PRPF3. 10 / 11
1 | 10

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
"Prp3 is deubiquitinated by Usp4, and is therefore unlikely to be a target for Bre5-Ubp3."

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

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

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

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."

"USP15SART3 makes a complex with USP4 and this ternary complex serves as a platform to deubiquitinate PRP31 and PRP3"
USP4 binds PRPF3.
5 |
5 |

No evidence text available

No evidence text available

No evidence text available

No evidence text available

No evidence text available
| 2 14
| 2 12

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

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

reach
"Luminescence imaging experiments indicated that knockdown of USP4 suppressed brain metastasis in vivo and promoted the overall survival and brain metastasis-free survival."

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

reach
"USP4 can promote TGF-beta-induced invasion and metastasis of breast cancer cells in a zebrafish xenograft model."

reach
"53 USP4 interacts with cyclophilin A and TGF‐β receptor type I and promotes the progression and metastasis of HCC."

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."

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

reach
"Moreover, USP4 is recently showed to enhance EMT and metastasis by stabilizing TbetaRI [XREF_BIBR]."
| 2

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."
NBN affects USP4
| 9 6
NBN binds USP4.
| 8 6
| 8 4

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."

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 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
"The above results indicated that USP4-NBS1 interaction is indeed involved in USP4 recruitment."

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
"Mechanistically, USP4 interacts with CtIP and MRN via a specific, conserved region and the catalytic domain of USP4, respectively, and regulates CtIP recruitment to sites of DNA damage."

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

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

reach
"In light of the above findings, we tested whether USP4 might physically interact with CtIP and/or MRN."
| 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."
NBN activates USP4.
| 1
NBN activates USP4. 1 / 1
| 1

reach
"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]"
USP4 affects DDX58
2 1 | 1 9 1
USP4 binds DDX58.
2 | 2 1
2 | 1 1

No evidence text available

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."

No evidence text available
USP4 binds DDX58 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 deubiquitinates DDX58.
1 | 4
USP4 deubiquitinates DDX58. 4 / 4
1 | 3

reach
"Conversely, USP15 and USP4 deubiquitinate TRIM25 and RIG-I, respectively, to stabilize the proteins."

reach
"RIG-I can be ubiquitinated and degraded by RNF125 (Ring Finger Protein 125) and deubiquitinated and stabilized by USP4."

"Furthermore, USP4 was found to interact with RIG-I and remove K48-linked polyubiquitination chains from RIG-I."

reach
"USP4 deubiquitinates and stabilizes RIG-I to promote type I IFN induction after viral infection [83]."
USP4 deubiquitinates DDX58 on K48. 1 / 1
| 1

reach
"USP4, it positively regulates the RIG-I-mediated antiviral response by deubiquitinating K48-linked ubiquitin chains and stabilizing RIG-I (77)."
USP4 activates DDX58.
| 1 2
USP4 activates DDX58. 3 / 3
| 1 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
"USP4 remove the K48-linked ubiquitination of RIG-I and promotes RIG-I signaling."

eidos
"USP4 remove the K48-linked ubiquitination of RIG-I and promotes RIG-I signaling ."
USP4 increases the amount of DDX58.
| 1
USP4 increases the amount of DDX58. 1 / 1
| 1

reach
"Additionally, overexpression of USP4 dramatically enhanced the RIG-I protein level, while knockdown of USP4 had an opposite effect."
| 1 13
USP4 activates cell migration.
| 1 8
| 1 7

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

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

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

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

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."

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 ] ."
USP4 bound to CTTN activates cell migration. 1 / 1
| 1

reach
"Binding of USP4 to cortactin enhances cell migration in HCT116 human colon cancer cells."
USP4 inhibits cell migration.
| 5

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

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

reach
"AKT induced breast cancer cell migration could be inhibited by depletion of USP4 (Zhang et al., 2012)."
| 13
USP4 activates apoptotic process.
| 8

reach
"Moreover, knockdown of USP4 could significantly inhibit cell proliferation and increase cell apoptosis in U87 and T98G cells."

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 knockout mice exhibited exacerbated hepatic I/R injury, as evidenced by enhanced liver inflammation via the NF-kappaB signalling pathway and increased hepatocyte apoptosis."

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

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

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."
| 5

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

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

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

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
"It was found that over-expression of USP4 enhanced the ability of RD cells to fight against invading EV71, and also reduced cell apoptosis."
USP4 affects PPIA
1 1 | 8 4
USP4 binds PPIA.
1 | 7 4
1 | 7 4

sparser
"Collectively, these data indicated that both endogenous and exogenous USP4 and CypA proteins can interact."

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."

No evidence text available

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

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

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

reach
"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."

sparser
"The results revealed that USP4 forms a complex with CypA, both endogenously and exogenously, and is responsible for CypA stabilization via deubiquitination."
USP4 increases the amount of PPIA.
| 1
USP4 increases the amount of PPIA. 1 / 1
| 1

reach
"Inhibition of USP4 by shRNA in MHCC97H cells significantly decreased CypA protein levels."
USP4 deubiquitinates PPIA.
1 |
USP4 deubiquitinates PPIA. 1 / 1
1 |

"Mechanistically, cyclophilin A (CypA) was identified as an important molecule for USP4-mediated oncogenic activity in HCC."
IRF4 affects USP4
| 7 7
| 7 7

sparser
"Interaction between USP4 and IRF4."

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

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

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

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."
3 | 3 5
USP4 translocates.
| 3 5
USP4 translocates to the membrane. 4 / 4
| 2 2

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."

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
"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
"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."

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 )."
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 binds.
3 |
3 |

No evidence text available

No evidence text available

No evidence text available
USP4 affects Wnt
| 5 6
USP4 activates Wnt.
| 3 3
USP4 activates Wnt. 6 / 7
| 3 3

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
"( D ) Wnt signaling : USP4 enhances Wnt signaling through deubiquitinating and stabilizing P-catenin ."

reach
"However, later studies demonstrated that USP4 enhanced Wnt signaling through stabilizing and facilitating nuclear localization of beta-catenin, especially in cancer."

reach
"However, in contrast to the previous work RNAi depletion of USP4 caused an up-regulation of Wnt signalling."

eidos
"According to a study , USP4 activates Wnt signaling by deubiquitinating and stabilizing beta-catenin ( Yun et al ., 2015 ) ."
USP4 inhibits Wnt.
| 2 2
USP4 inhibits Wnt. 4 / 4
| 2 2

eidos
"Conversely , USP4 inhibits Wnt signaling by deubiquitinating Dvl ."

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
"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
"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]."
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 Ubiquitin
| 8 2
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 promotes the activation of Rheb by removing ubiquitin from it."

reach
"Like other USPs, USP4 also mediates the removal and processing of ubiquitin."

reach
"USP4 DUSP-Ubl promotes ubiquitin release."

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.
| 2

sparser
"The ubiquitin peptidase inactive form of USP4 (USP4-C311A) abolished its ability to stabilize HDAC2 ( xref and xref )."
| 1

sparser
"In the absence of USP4 and USP15 ubiquitin-bound structures, the molecular bases for these differences are difficult to rationalize at present, as multiple factors will contribute, such as the release of bound water molecules, conformational changes associated with the binding events, and differences in interacting residues."
USP4 phosphorylates Ubiquitin.
| 1
USP4 leads to the phosphorylation of Ubiquitin. 1 / 1
| 1

reach
"One possibility is that Src may regulate this pathway through activation of AKT since Src can directly induce AKT phosphorylation and AKT can induce phosphorylation of ubiquitin specific protease 4 (USP4), a deubiquitinating enzyme that prevents TGF-beta receptor I degradation [XREF_BIBR]."
PPIA affects USP4
1 | 7 4
1 | 7 4

sparser
"Collectively, these data indicated that both endogenous and exogenous USP4 and CypA proteins can interact."

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."

No evidence text available

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

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

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

reach
"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."

sparser
"The results revealed that USP4 forms a complex with CypA, both endogenously and exogenously, and is responsible for CypA stabilization via deubiquitination."
HUWE1 affects USP4
3 | 7
3 | 7

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

No evidence text available

reach
"USP4 has been recently described as a key regulator of p53 stability: USP4 interacts directly and deubiquitylates the E3 HUWE1 (ARF-BP1; MULE), resulting in reduced p53 levels [86]."

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

No evidence text available

No evidence text available

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 RB1
5 2 | 1 2
5 2 | 1 2

No evidence text available

No evidence text available

No evidence text available

No evidence text available

No evidence text available

reach
"The de-ubiquitinating enzyme Unp interacts with the retinoblastoma protein."

No evidence text available

No evidence text available

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."
USP4 affects BRAP
3 | 5
3 |

No evidence text available

No evidence text available

No evidence text available
USP15 binds USP4 and BRAP. 3 / 3
| 3

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."

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 )."
USP4 binds MYC and BRAP. 1 / 1
| 1

sparser
"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 A , compare lanes 2 and 4 with 9 and 11 )."
USP15 binds USP4, USPs, and BRAP. 1 / 1
| 1

sparser
"Of these, the interaction between BRAP and two related USPs, USP4 and USP15, was of compelling physiological interest given the established role of BRAP/IMP in the regulation of the MAP kinase signaling cascade ( xref )."
TGFBR1 affects USP4
3 | 7 1
3 | 7 1

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]"

No evidence text available

reach
"For instance, USP4 directly interacts with and deubiquitinates TGF-beta type I receptor (TbetaRI), thereby determining the levels of TGF-beta signaling."

No evidence text available

No evidence text available

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
"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
"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."

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

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."
RB1 affects USP4
5 2 | 1 2
5 2 | 1 2

No evidence text available

No evidence text available

No evidence text available

No evidence text available

No evidence text available

reach
"The de-ubiquitinating enzyme Unp interacts with the retinoblastoma protein."

No evidence text available

No evidence text available

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."
BRAP affects USP4
3 | 5
3 |

No evidence text available

No evidence text available

No evidence text available
USP15 binds USP4 and BRAP. 3 / 3
| 3

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."

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 )."
USP4 binds MYC and BRAP. 1 / 1
| 1

sparser
"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 A , compare lanes 2 and 4 with 9 and 11 )."
USP15 binds USP4, USPs, and BRAP. 1 / 1
| 1

sparser
"Of these, the interaction between BRAP and two related USPs, USP4 and USP15, was of compelling physiological interest given the established role of BRAP/IMP in the regulation of the MAP kinase signaling cascade ( xref )."
USP4 affects USP11
3 | 2 5
3 | 2

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."

reach
"USP4 can form stable homodimers and can also interact with USP11 and USP15."

No evidence text available

No evidence text available

No evidence text available
USP11 binds USP15 and USP4. 3 / 3
| 3

sparser
"USP4 can form stable homodimers and can also interact with USP11 and USP15 ( Fig. 4 )."

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."
| 2

sparser
"cDNAs encoding Myc-tagged forms of USP4, USP11, Ataxin-3 and A20 were gifts from Dr P.J. Lehner (17, 26, 54) ."

sparser
"cDNAs encoding Myc-tagged forms of USP4, USP11, Ataxin-3 and A20 were gifts from Dr P.J. Lehner (University of Cambridge, UK) (51), Dr J. Yang (Baylor College of Medicine, Houston, USA) (52), Dr E.A. Fon (Montreal Neurological Institute, Canada) (23) and Dr K. Li (University of Texas Medical Branch, Galveston, USA) (53), respectively."
USP4 affects RIPK1
1 3 | 4 1
USP4 binds RIPK1.
3 | 3 1
3 | 3 1

No evidence text available

reach
"USP4 directly interacts with receptor interacting protein 1 (RIP1) and deubiquitinates K63 linked ubiquitination from RIP1."

sparser
"USP4 directly interacts with receptor-interacting protein 1 (RIP1) and deubiquitinates K63-linked ubiquitination from RIP1."

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

No evidence text available

No evidence text available

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)."
USP4 inhibits RIPK1.
| 1
USP4 inhibits RIPK1. 1 / 1
| 1

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."
USP4 deubiquitinates RIPK1.
1 |
USP4 deubiquitinates RIPK1 on K377. 1 / 1
1 |

No evidence text available
USP4 affects RHEB
| 2 8
USP4 binds RHEB.
| 8
| 8

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

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

sparser
"Moreover, our data suggest that the DUSP domain of USP4 accounts for the interaction between Rheb and USP4 (Supplementary information, Fig.  xref )."
USP4 phosphorylates RHEB.
| 1
USP4 phosphorylates RHEB. 1 / 1
| 1

reach
"Moreover, in LPS treated AML12 cells, LPS induced USP4, inflammatory and fibrotic cytokines, phosphorylated mTOR and Rheb."
USP4 deubiquitinates RHEB.
| 1
USP4 leads to the deubiquitination of RHEB. 1 / 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 affects PTP4A3
2 1 | 2 4
USP4 binds PTP4A3.
2 | 1 2
2 | 1 2

trips
"Mechanistically, we observed that USP4 interacted with and stabilized PRL-3 via deubiquitination."

No evidence text available

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."

No evidence text available
USP4 deubiquitinates PTP4A3.
1 | 1 2
USP4 deubiquitinates PTP4A3. 4 / 4
1 | 1 2

trips
"Mechanistically, we observed that USP4 interacted with and stabilized PRL-3 via deubiquitination."

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."

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."
USP4 affects AQP2
| 1 9
USP4 binds AQP2.
| 9
| 9

sparser
"The Deubiquitylase USP4 Interacts with the Water Channel AQP2 to Modulate Its Apical Membrane Accumulation and Cellular Abundance."

sparser
"To investigate if USP4 interacts with AQP2, co-immunoprecipitation studies were initially performed on lysates from cultured cells."

sparser
"USP4 Interacts with AQP2 in Cultured Kidney Epithelial Cells and In Vivo."

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
"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
"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
"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
"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)."
USP4 activates AQP2.
| 1
USP4 activates AQP2. 1 / 1
| 1

reach
"In mpkCCD14 cells, shRNA mediated knockdown of USP4 decreased AQP2 protein abundance, whereas no changes in AQP2 mRNA levels or VP induced cAMP production were detected."
USP4 affects AKT
| 8 2
USP4 binds AKT.
| 5 2
| 5 2

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
"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]."

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

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

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]"

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."
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
"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."

reach
"The deubiquitinating enzyme USP4 modulates AKT regulation of mesothelial-to-mesenchymal transition in peritoneal dialysis (Xiao et al., 2015)."
USP11 affects USP4
3 | 2 5
3 | 2

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."

reach
"USP4 can form stable homodimers and can also interact with USP11 and USP15."

No evidence text available

No evidence text available

No evidence text available
USP11 binds USP15 and USP4. 3 / 3
| 3

sparser
"USP4 can form stable homodimers and can also interact with USP11 and USP15 ( Fig. 4 )."

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."
| 2

sparser
"cDNAs encoding Myc-tagged forms of USP4, USP11, Ataxin-3 and A20 were gifts from Dr P.J. Lehner (17, 26, 54) ."

sparser
"cDNAs encoding Myc-tagged forms of USP4, USP11, Ataxin-3 and A20 were gifts from Dr P.J. Lehner (University of Cambridge, UK) (51), Dr J. Yang (Baylor College of Medicine, Houston, USA) (52), Dr E.A. Fon (Montreal Neurological Institute, Canada) (23) and Dr K. Li (University of Texas Medical Branch, Galveston, USA) (53), respectively."
TRAF2 affects USP4
2 | 3 4
2 | 3

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

No evidence text available

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 HEK293 T cells, and in vitro [61] ."

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]."

No evidence text available
TRAF2 binds TRAF6 and USP4. 4 / 4
| 4

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."

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
"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 [61]."
USP4 affects USP4
| 7
USP4 activates USP4.
| 4
USP4 activates USP4. 4 / 6
| 4

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

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

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."

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 increases the amount of USP4.
| 2
USP4 increases the amount of USP4. 2 / 2
| 2

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."
USP4 phosphorylates USP4.
| 1
USP4 phosphorylates USP4. 1 / 1
| 1

reach
"They further showed that USP4 could interact with Akt at endogenous level, and phosphorylate USP4 in vitro and in vivo."
USP4 affects TNF
| 6
USP4 inhibits TNF.
| 5
USP4 inhibits TNF. 5 / 7
| 5

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

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
"Additionally, the overexpression of USP4 suppressed the release of microglia activation-induced pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α."

reach
"USP4 was identified by studies to negatively regulate both TNF-αand IL-1β-induced NF-κB activation [60] [61] [62] ."

reach
"USP4 negatively regulates TNFalpha induced, K63 linked TAK1 polyubiquitination and TAK1 mediated IKK and NF-kappaB activation [XREF_BIBR]."
USP4 activates TNF.
| 1
USP4 activates TNF. 1 / 2
| 1

reach
"Ubiquitin specific protease 4 (USP4) targets TRAF2 and TRAF6 for deubiquitination and inhibits TNFalpha induced cancer cell migration."
USP4 affects HAS2
1 | 4 4
USP4 binds HAS2.
| 1 4
| 3

sparser
"Thus, both co-immunoprecipitation and PLA analyses supported the notion that HAS2 forms complexes 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
"HAS2 interacts with USP17 and USP4."
| 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. 3 / 3
1 | 2

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

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."

"USP17 efficiently removed polyubiquitination, whereas USP4 preferentially removed monoubiquitination of 6myc-HAS2.;The deubiquitinating enzymes USP4 and USP17 target hyaluronan synthase 2 and differentially affect its function;USP17 and USP4 differently affect HAS2 ubiquitination, and the stability and function of HAS2"
USP4 increases the amount of HAS2.
| 1
USP4 increases the amount of HAS2. 1 / 1
| 1

reach
"These results suggest that USP4 and Lys190 of HAS2 are important for HAS2 protein expression, but not for stability, and that USP17 and USP4 differentially modulate HAS2 protein levels."
AQP2 affects USP4
| 9
| 9

sparser
"The Deubiquitylase USP4 Interacts with the Water Channel AQP2 to Modulate Its Apical Membrane Accumulation and Cellular Abundance."

sparser
"To investigate if USP4 interacts with AQP2, co-immunoprecipitation studies were initially performed on lysates from cultured cells."

sparser
"USP4 Interacts with AQP2 in Cultured Kidney Epithelial Cells and In Vivo."

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
"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
"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
"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
"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)."
USP4 affects TRPS1
| 3 5
TRPS1 binds USP4 and HDAC2. 5 / 5
| 1 4

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
"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
"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
"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 )."

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."
| 2 1

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)."

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)."
RIPK1 affects USP4
3 | 3 1
3 | 3 1

No evidence text available

reach
"USP4 directly interacts with receptor interacting protein 1 (RIP1) and deubiquitinates K63 linked ubiquitination from RIP1."

sparser
"USP4 directly interacts with receptor-interacting protein 1 (RIP1) and deubiquitinates K63-linked ubiquitination from RIP1."

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

No evidence text available

No evidence text available

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)."
RHEB affects USP4
| 8
| 8

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

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

sparser
"Moreover, our data suggest that the DUSP domain of USP4 accounts for the interaction between Rheb and USP4 (Supplementary information, Fig.  xref )."
USP4 affects cell growth
| 5 2
USP4 activates cell growth.
| 4
| 4

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."

reach
"Using in vitro and in vivo assays, we demonstrated that USP4 overexpression enhanced HCC cell growth, migration, and invasion."
USP4 inhibits cell growth.
| 1 2
| 1 2

sparser
"Studies have reported that USP4 could inhibit breast cancer cell growth by upregulating PDCD4 [ xref ]."

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 affects activation
| 7
USP4 inhibits activation. 7 / 7
| 7

sparser
"In addition, USP4 inhibits TNF-α-induced activation of NF-κB through USP4 deubiquitination of TAK1 xref ."

sparser
"USP4 inhibits TNFα-induced NF-κB activation by acting as a TAK1 deubiquitinase [ xref ]."

sparser
"USP4 acts as a TAK1 Lys63-specific deubiquitinase to deubiquitinate TAK1 and inhibit Dox-induced NF-κB activation."

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
"Taken together, these results suggest that USP4 inhibits TNFα-induced IKK/NF-κB activation through suppressing TAK1 polyubiquitination."

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

sparser
"USP4 inhibits TAK1/TAB1 co-overexpression-mediated NF-κB activation."
USP4 affects PDCD4
| 6 1
USP4 activates PDCD4.
| 3
USP4 activates PDCD4. 3 / 3
| 3

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."

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."
USP4 increases the amount of PDCD4.
| 2
USP4 increases the amount of PDCD4. 2 / 2
| 2

reach
"Furthermore, the knockdown of USP4 significantly decreased the endogenous PDCD4 protein expression level (XREF_FIG)."

reach
"USP4 upregulates PDCD4 expression in breast cancer cells."
USP4 binds PDCD4.
| 1 1
| 1 1

sparser
"The physical interaction between USP4 and PDCD4 indicated that USP4 targets PDCD4 for deubiquitination and subsequent inhibition of its degradation."

reach
"The physical interaction between USP4 and PDCD4 indicated that USP4 targets PDCD4 for deubiquitination and subsequent inhibition of its degradation."
USP4 affects E3_Ub_ligase
| 5 2
| 2 2

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

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

sparser
"The USP4 and USP15 DU domains interact with E3 ligases ( xref ) and the substrate recruitment factor SART3 ( xref , xref ), but no interactions have yet been reported for these domains in USP11."
USP4 deubiquitinates E3_Ub_ligase.
| 3
USP4 deubiquitinates E3_Ub_ligase. 3 / 3
| 3

reach
"In contrast to USP2a, USP4 deubiquitinates and stabilizes a different E3 that ubiquitinates p53 called ARF-BP1, thereby destabilizing p53 [XREF_BIBR]."

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 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."
USP4 affects CDH1
| 6 1
USP4 decreases the amount of CDH1.
| 4
USP4 decreases the amount of CDH1. 4 / 4
| 4

reach
"Surprisingly, USP4 knockdown also reduces the levels of SKP2 and CDH1 pointing to distortions in the dynamic equilibrium between APC/C and SCF ."

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
"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
"Importantly, depressed expression of USP4 inhibited TβRI expression and partially reversed EMT stimulated by TGF-β1.In the meantime, blunted phosphorylation of Akt promoted the E-cadherin expression, and inhibited α-SMA and Vimentin expression in response to TGF-β1."
USP4 inhibits CDH1.
| 2 1
USP4 inhibits CDH1. 3 / 3
| 2 1

sparser
"Neither transient nor stable overexpression of USP4 inhibited E-cadherin in Huh7 cells (Figure xref )."

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
"Neither transient nor stable overexpression of USP4 inhibited E-cadherin in Huh7 cells."
USP15 affects SART3
| 1 6
USP15 binds USP4 and SART3. 6 / 6
| 1 5

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
"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 )."

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

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

sparser
"The USP4 and USP15 DU domains interact with E3 ligases ( xref ) and the substrate recruitment factor SART3 ( xref , xref ), but no interactions have yet been reported for these domains in USP11."
TNF affects USP4
| 6
TNF activates USP4. 6 / 7
| 6

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."

reach
"Consistently, we also found that TNFalpha induced co-immunoprecipitation of endogenous USP4 and TAK1 as well as IKKbeta and RIPK1 (XREF_FIG)."

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
"These results suggest that TNFalpha induces association of USP4 with TAK1."

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
"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."
SART3 affects USP15
| 1 6
USP15 binds USP4 and SART3. 6 / 6
| 1 5

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
"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 )."

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

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

sparser
"The USP4 and USP15 DU domains interact with E3 ligases ( xref ) and the substrate recruitment factor SART3 ( xref , xref ), but no interactions have yet been reported for these domains in USP11."
DDX58 affects USP4
2 | 3 1
DDX58 binds USP4.
2 | 2 1
2 | 1 1

No evidence text available

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."

No evidence text available
USP4 binds DDX58 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."
DDX58 activates USP4.
| 1
DDX58 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."
| 1 3

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 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]"
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."
| 4

reach
"Ubiquitin specific protease 4 (USP4) suppresses myoblast differentiation by down regulating MyoD activity in a catalytic independent manner."

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
"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
"We observed that the activity and protein levels of both HDAC1 and HDAC4 are decreased when myoblast differentiation is promoted by the USP4 knockdown."
| 2

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."
USP4 affects TWIST1
| 6
| 6

sparser
"Co-Immunoprecipitation assay showed that USP4 interacted with Twist1 ( xref D)."

sparser
"Thus, targeting the USP4Twist1 axis may represent a novel therapeutic approach for lung cancer treatment."

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
"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
"Together, these results indicate that the USP4Twist1 axis plays a critical role in lung cancer stemness and clinical prognoses ( xref E)."

sparser
"To this end, we first asked whether USP4 can form a stable protein complex with Twist1."
USP4 affects SRSF1
| 6
USP4 activates SRSF1.
| 3
USP4 activates SRSF1. 3 / 3
| 3

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
"Overexpression of USP15 and USP4 upregulated SRSF1 (Fig. 3A), while the knockdown caused its downregulation (Fig. 3B)."

reach
"On the other hand, SRSF1 is upregulated by high USP15 and USP4 that enhance cell proliferation and invasion (Fig. 7D)."
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 deubiquitinates SRSF1.
| 1
USP4 deubiquitinates SRSF1. 1 / 1
| 1

reach
"As shown in Supplementary Fig. 3A, B, SRSF1 was not deubiquitinated by USP15 or USP4, respectively."
USP4 affects SMAD4
1 | 3 2
USP4 deubiquitinates SMAD4.
1 | 2
USP4 leads to the deubiquitination of SMAD4. 3 / 3
1 | 2

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) ."

"We demonstrated that ubiquitin-specific protease (USP) 4 strongly induces activin/BMP signaling by removing the inhibitory monoubiquitination from SMAD4."

reach
"USP4 inhibits SMAD4 monoubiquitination and promotes activin and BMP signaling."
USP4 binds SMAD4.
| 1 2
| 1 2

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."

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
"GST pull-down in vitro exhibited that USP4 interacted with SMAD4 ( xref E)."
USP4 affects PRPF31
1 1 | 4
USP4 deubiquitinates PRPF31.
1 | 4
USP4 deubiquitinates PRPF31. 5 / 5
1 | 4

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

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
"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."

"USP15SART3 makes a complex with USP4 and this ternary complex serves as a platform to deubiquitinate PRP31 and PRP3"
USP4 binds PRPF31.
1 |
1 |

No evidence text available
USP4 affects IRF8
2 | 4
USP4 binds IRF8.
2 | 1
2 | 1

No evidence text available

No evidence text available

reach
"Taken together, our results suggest that USP4 interacts with and stabilizes IRF8 to promote the suppressive function of Treg cells."
USP4 activates IRF8.
| 2
USP4 activates IRF8. 2 / 2
| 2

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."

reach
"USP4 interacts and positively regulates IRF8 function via K48 linked deubiquitination in regulatory T cells."
USP4 ubiquitinates IRF8.
| 1
USP4 leads to the ubiquitination of IRF8. 1 / 1
| 1

reach
"Depletion of USP4 promoted the polyubiquitination of IRF8 and the upregulation of type 2 inflammatory cytokine gene expression in Treg cells."
USP4 affects ELAVL1
| 1 3 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)."

reach
"The results showed that METL3 knockdown markedly enhanced the interaction between USP4 and ELAVL1."

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)."
USP4 activates ELAVL1.
| 1 1
USP4 activates ELAVL1. 2 / 2
| 1 1

reach
"Consistently, USP4 knockdown markedly reduced protein stability of ELAVL1."

eidos
"Taken together , our results demonstrated that USP4 upregulates ELAVL1 expression by removing the ubiquitin group from ELAVL1 protein ."
USP4 decreases the amount of ELAVL1.
| 1
USP4 decreases the amount of ELAVL1. 1 / 1
| 1

reach
"Additionally, the overexpression of USP4 effectively decreased the ubiquitination levels of ELAVL1."
TWIST1 affects USP4
| 6
| 6

sparser
"Co-Immunoprecipitation assay showed that USP4 interacted with Twist1 ( xref D)."

sparser
"Thus, targeting the USP4Twist1 axis may represent a novel therapeutic approach for lung cancer treatment."

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
"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
"Together, these results indicate that the USP4Twist1 axis plays a critical role in lung cancer stemness and clinical prognoses ( xref E)."

sparser
"To this end, we first asked whether USP4 can form a stable protein complex with Twist1."
SART3 affects USP15, and USP4
| 1 5
USP15 binds USP4 and SART3. 6 / 6
| 1 5

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
"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 )."

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

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
"Drugs interfering with the interaction between USP4 and USP15 and SART3 may selectively inhibit the DUB functions in the nucleus."
| PMC
PTP4A3 affects USP4
2 | 1 2
2 | 1 2

trips
"Mechanistically, we observed that USP4 interacted with and stabilized PRL-3 via deubiquitination."

No evidence text available

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."

No evidence text available
METTL3 affects USP4
| 6
METTL3 decreases the amount of USP4.
| 5
METTL3 decreases the amount of USP4. 5 / 5
| 5

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."

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
"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
"We next found that METTL3 knockdown significantly upregulated USP4 mRNA levels in PCa cells."
METTL3 methylates USP4.
| 1
METTL3 leads to the methylation of USP4. 1 / 1
| 1

reach
"Metformin attenuates multiple myeloma cell proliferation and encourages apoptosis by suppressing METTL3-mediated m6A methylation of THRAP3, RBM25, and USP4."
DUSP affects USP4
| 1 5
DUSP binds USP4.
| 5
DUSP binds USP4 and UBL. 4 / 4
| 4

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."

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
"Indeed, surface plasmon resonance (SPR) shows an interaction of DUSPUbl with immobilized USP4 CD ( 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 ."
| 1

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 )."
DUSP activates USP4.
| 1
DUSP activates USP4. 1 / 1
| 1

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."
AKT1 affects USP4
1 3 | 1
AKT1 phosphorylates USP4.
1 | 1
AKT1 phosphorylates USP4. 1 / 2
| 1

reach
"[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)."
AKT1 phosphorylates USP4 on S445. 1 / 1
1 |

No evidence text available
AKT1 binds USP4.
3 |
3 |

No evidence text available

No evidence text available

No evidence text available
| 1 4
| 1 2

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

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."

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 ."
| 2

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."
USP4 affects UBL
| 5
DUSP binds USP4 and UBL. 4 / 4
| 4

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."

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
"Indeed, surface plasmon resonance (SPR) shows an interaction of DUSPUbl with immobilized USP4 CD ( 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 ."
USP4 binds UBL. 1 / 1
| 1

sparser
"Even a subunit not known for ubiquitin binding, Rpn6, seems to be bound by Usp4’s UBL domain [ xref ]."
USP4 affects RNPS1
4 |
4 |

No evidence text available

No evidence text available

No evidence text available

No evidence text available
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."

No evidence text available
| 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."

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
"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."

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."
USP4 affects MRE11
2 | 2
2 |

No evidence text available

No evidence text available
| 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 INS
| 5
USP4 deubiquitinates INS.
| 2
USP4 deubiquitinates INS. 2 / 2
| 2

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
"Upregulation of USP4 reduces the ubiquitination and degradation of insulin receptors, upregulates the level of insulin receptors, and ultimately improves insulin resistance."
USP4 decreases the amount of INS.
| 1
USP4 decreases the amount of INS. 1 / 1
| 1

reach
"Upregulation of USP4 reduces the ubiquitination and degradation of insulin receptors, upregulates the level of insulin receptors, and ultimately improves insulin resistance."
USP4 binds INS.
| 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."
USP4 activates INS.
| 1
USP4 activates INS. 1 / 1
| 1

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 DUSP
| 5
DUSP binds USP4 and UBL. 4 / 4
| 4

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."

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
"Indeed, surface plasmon resonance (SPR) shows an interaction of DUSPUbl with immobilized USP4 CD ( 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 ."
| 1

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 affects DNA repair
| 3
| 3

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)."

reach
"Here, we establish that the deubiquitylating enzyme USP4 promotes DNA-end resection and DNA repair by homologous recombination."
USP4 affects CS
| 5
USP4 binds CS. 4 / 4
| 4

sparser
"Our data showed that overexpression of USP4-WT, but not USP4-CS, promoted the EGF-dependent mTORC1 activation (Fig.  xref )."

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 )."

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
"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 )."
USP4 binds CS. 1 / 1
| 1

sparser
"Additionally, ectopically expressed USP4-WT not mutant USP4-CS eliminated endogenous SMAD4 mononucleotide ( xref M)."
UBL affects USP4
| 5
DUSP binds USP4 and UBL. 4 / 4
| 4

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."

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
"Indeed, surface plasmon resonance (SPR) shows an interaction of DUSPUbl with immobilized USP4 CD ( 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 ."
USP4 binds UBL. 1 / 1
| 1

sparser
"Even a subunit not known for ubiquitin binding, Rpn6, seems to be bound by Usp4’s UBL domain [ xref ]."
TRPS1 affects HDAC2
| 1 4
TRPS1 binds USP4 and HDAC2. 5 / 5
| 1 4

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
"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
"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
"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 )."

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."
RNPS1 affects USP4
4 |
4 |

No evidence text available

No evidence text available

No evidence text available

No evidence text available
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."

No evidence text available
| 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."
PRPF3 affects USP4
5 |
5 |

No evidence text available

No evidence text available

No evidence text available

No evidence text available

No evidence text available
MRE11 affects USP4
2 | 2
2 |

No evidence text available

No evidence text available
| 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."
HDAC2 affects TRPS1, and USP4
| 1 4
TRPS1 binds USP4 and HDAC2. 5 / 5
| 1 4

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
"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
"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
"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 )."

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."
HAS2 affects USP4
| 1 4
| 3

sparser
"Thus, both co-immunoprecipitation and PLA analyses supported the notion that HAS2 forms complexes 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
"HAS2 interacts with USP17 and USP4."
| 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."
CS affects USP4
| 5
USP4 binds CS. 4 / 4
| 4

sparser
"Our data showed that overexpression of USP4-WT, but not USP4-CS, promoted the EGF-dependent mTORC1 activation (Fig.  xref )."

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 )."

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
"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 )."
USP4 binds CS. 1 / 1
| 1

sparser
"Additionally, ectopically expressed USP4-WT not mutant USP4-CS eliminated endogenous SMAD4 mononucleotide ( xref M)."
Ubiquitin affects USP4
| 2 2
Ubiquitin binds USP4.
| 2

sparser
"The ubiquitin peptidase inactive form of USP4 (USP4-C311A) abolished its ability to stabilize HDAC2 ( xref and xref )."
| 1

sparser
"In the absence of USP4 and USP15 ubiquitin-bound structures, the molecular bases for these differences are difficult to rationalize at present, as multiple factors will contribute, such as the release of bound water molecules, conformational changes associated with the binding events, and differences in interacting residues."
Ubiquitin activates USP4.
| 2
| 2

reach
"Pre-steady-state kinetics measurements reveal that USP4 catalytic domain activity is strongly inhibited by slow dissociation of ubiquitin after substrate hydrolysis."

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."
USP4 affects insulin receptors
| 4
USP4 deubiquitinates insulin receptors.
| 2
USP4 deubiquitinates insulin receptors. 2 / 2
| 2

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."
USP4 decreases the amount of insulin receptors.
| 1
USP4 decreases the amount of insulin receptors. 1 / 1
| 1

reach
"Upregulation of USP4 reduces the ubiquitination and degradation of insulin receptors, upregulates the level of insulin receptors, and ultimately improves insulin resistance."
USP4 binds insulin receptors.
| 1
USP4 binds insulin receptors. 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."

reach
"LOXL3-promoted hepatocellular carcinoma progression via promotion of Snail1/USP4-mediated epithelial-mesenchymal transition."

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
"Collectively, these data demonstrated that USP4 promotes melanoma cell migration and invasion by promoting EMT."
USP4 affects activity
| 4
USP4 inhibits activity. 4 / 4
| 4

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
"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
"In this screen, USP4 significantly inhibited the TAK1-induced NF-κB luciferase reporter activity whereas other USPs had no or less effects ( xref )."

sparser
"USP4 inhibits NF-κB transcriptional activity through HDAC2."
USP4 affects UBC
4 |
4 |

No evidence text available

No evidence text available

No evidence text available

No evidence text available
USP4 affects TGFB1
| 3
USP4 activates TGFB1. 3 / 4
| 3

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
"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
"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 TCF4
1 | 3
USP4 deubiquitinates TCF4.
1 | 2
USP4 deubiquitinates TCF4. 3 / 3
1 | 2

"DUBs regulate canonical Wnt signaling, by modulating?β-catenin activity. USP4 deubiquitinases TCF4, to suppress?β-catenin dependent transcription"

reach
"For example, USP4 interacts with and deubiquitinates TCF4, which inhibits beta-catenin-dependent transcription [XREF_BIBR]."

reach
"USP4 deubiquitinated a subpopulation of TCF4."
USP4 binds TCF4.
| 1
| 1

reach
"For example, USP4 interacts with and deubiquitinates TCF4, which inhibits beta-catenin-dependent transcription [XREF_BIBR]."
USP4 affects Proteasome
| 2

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]"

reach
"USP4-Myc was also readily detected in the blots confirming that USP4 interacts with the assembled proteasome."
USP4 affects PDPK1
1 | 3
USP4 deubiquitinates PDPK1.
1 | 2
USP4 deubiquitinates PDPK1. 3 / 3
1 | 2

reach
"USP4 deubiquitinates PDK1 and co-localizes at the plasma membrane."

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."

"By screening a library of ubiquitin proteases, we further identify the Ubiquitin-Specific Protease 4 (USP4) as an enzyme that removes ubiquitin from PDK1 in vivo and in vitro and co-localizes with PDK1 at the plasma membrane when the two proteins are overexpressed, indicating direct deubiquitination."
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 Neoplasms
| 1 3
USP4 inhibits Neoplasms.
| 2
| 2

reach
"In contrast, knockdown of USP4 markedly inhibited gastric cancer cell growth, and suppressed the tumor growth of gastric cancer."

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."
USP4 activates Neoplasms.
| 1 1
| 1 1

reach
"Studies of USP4 knockout mice revealed that USP4 upregulates tumor growth in an mTORC1-dependent manner."

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 ) ."
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 HNRNPD
| 2 2
| 2 2

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."

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
"Taken together, these results suggested m 6 A methylation reduces USP4 mRNA stability by promoting the binding of HNRNPD to USP4 mRNA."

sparser
"Taken together, these results suggested m 6 A methylation reduces USP4 mRNA stability by promoting the binding of HNRNPD to USP4 mRNA."
USP4 affects EV71
| 4
USP4 inhibits 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
"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."

reach
"Overexpression of USP4 inhibits EV71 replication by stabilizing TRAF6 to activate NF-kappaB inflammatory signaling."
USP4 decreases the amount of EV71.
| 1
Modified USP4 decreases the amount of EV71. 1 / 1
| 1

reach
"In order to confirm the relationship between USP4 and EV71 infection, USP4 was transfected into EV71 infected RD cells and it was found that the overexpression of USP4 decreased the mRNA and protein expression of EV71 and VP1, inhibiting the replication of EV71, while also reducing RD cell apoptosis."
USP4 affects ERK
| 4
USP4 increases the amount of ERK.
| 2
USP4 increases the amount of phosphorylated ERK. 2 / 2
| 2

reach
"TGF-betaR inhibition reduced level of TGF-betaR1, p-smad2 and p-ERK1/2 which can partially be rescued by USP4 overexpression."

reach
"Inhibition of USP4 downregulated the expression of PCNA, Bcl-2 and p-ERK1/2, but upregulated the expression of Bax both in vitro and in vivo."
USP4 activates ERK.
| 2
USP4 activates ERK. 2 / 2
| 2

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]."
USP15 affects BRAP
| 4
USP15 binds USP4 and BRAP. 3 / 3
| 3

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."

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 )."
USP15 binds USP4, USPs, and BRAP. 1 / 1
| 1

sparser
"Of these, the interaction between BRAP and two related USPs, USP4 and USP15, was of compelling physiological interest given the established role of BRAP/IMP in the regulation of the MAP kinase signaling cascade ( xref )."
UBL affects DUSP
| 4
DUSP binds USP4 and UBL. 4 / 4
| 4

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."

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
"Indeed, surface plasmon resonance (SPR) shows an interaction of DUSPUbl with immobilized USP4 CD ( 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 ."
UBC affects USP4
4 |
4 |

No evidence text available

No evidence text available

No evidence text available

No evidence text available
TRAF6 affects TRAF2
| 4
TRAF2 binds TRAF6 and USP4. 4 / 4
| 4

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."

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
"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 [61]."
SMAD4 affects USP4
| 2 2
SMAD4 binds USP4.
| 1 2
| 1 2

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."

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
"GST pull-down in vitro exhibited that USP4 interacted with SMAD4 ( xref E)."
SMAD4 increases the amount of USP4.
| 1
Ubiquitinated SMAD4 increases the amount of USP4. 1 / 1
| 1

reach
"Studies have shown that SOX2 increases the expression of the microRNA (miRNA) miR-30e, which decreases the expression of ubiquitin carboxyl-terminal hydrolase 4 (USP4), increasing ubiquitination and proteasomal degradation of mothers against decapentaplegic homolog 4 (SMAD4)."
| PMC
Proteasome affects USP4
| 2

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]"

reach
"USP4-Myc was also readily detected in the blots confirming that USP4 interacts with the assembled proteasome."
PDCD4 affects USP4
| 3 1
PDCD4 binds USP4.
| 1 1
| 1 1

sparser
"The physical interaction between USP4 and PDCD4 indicated that USP4 targets PDCD4 for deubiquitination and subsequent inhibition of its degradation."

reach
"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
"To examine this hypothesis, we first determined whether PDCD4 is a downstream target of USP4 in breast cancer cells."

reach
"The physical interaction between USP4 and PDCD4 indicated that USP4 targets PDCD4 for deubiquitination and subsequent inhibition of its degradation."
HNRNPD affects USP4
| 2 2
| 2 2

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."

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
"Taken together, these results suggested m 6 A methylation reduces USP4 mRNA stability by promoting the binding of HNRNPD to USP4 mRNA."

sparser
"Taken together, these results suggested m 6 A methylation reduces USP4 mRNA stability by promoting the binding of HNRNPD to USP4 mRNA."
Gastrodin affects USP4
| 4
Gastrodin increases the amount of USP4. 4 / 4
| 4

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
"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
"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."
E3_Ub_ligase affects USP4
| 2 2

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

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

sparser
"The USP4 and USP15 DU domains interact with E3 ligases ( xref ) and the substrate recruitment factor SART3 ( xref , xref ), but no interactions have yet been reported for these domains in USP11."
DUSP affects UBL, and USP4
| 4
DUSP binds USP4 and UBL. 4 / 4
| 4

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."

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
"Indeed, surface plasmon resonance (SPR) shows an interaction of DUSPUbl with immobilized USP4 CD ( 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 ."
BRAP affects USP15
| 4
USP15 binds USP4 and BRAP. 3 / 3
| 3

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."

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 )."
USP15 binds USP4, USPs, and BRAP. 1 / 1
| 1

sparser
"Of these, the interaction between BRAP and two related USPs, USP4 and USP15, was of compelling physiological interest given the established role of BRAP/IMP in the regulation of the MAP kinase signaling cascade ( xref )."

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
"The hypothesis that drove this study was that USP4 might also mediate the TGF-beta signal transduction pathway in hypertrophic scar fibroblasts."

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."
USP4 affects degradation
| 3
USP4 inhibits degradation. 3 / 3
| 3

sparser
"USP4, a member of the USP family, inhibits the degradation of target proteins that depend on the ubiquitin proteasome pathway."

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

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."
USP4 affects VIM
| 3
USP4 increases the amount of VIM.
| 2
USP4 increases the amount of VIM. 2 / 2
| 2

reach
"Importantly, depressed expression of USP4 inhibited TβRI expression and partially reversed EMT stimulated by TGF-β1.In the meantime, blunted phosphorylation of Akt promoted the E-cadherin expression, and inhibited α-SMA and Vimentin expression in response to TGF-β1."

reach
"Results showed that inhibition of USP4 and Smurf2 expression significantly reverses the altered expression of ZO-1, Vimentin and TbetaRI induced by TGF-beta1, while overexpression of Akt augments these effects."
USP4 decreases the amount of 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."
| 3

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
"17 However , USP4 as an deubiquitinating enzymes reverses the ubiquitination ."

eidos
"When substrate is not present RHO52 may auto-ubiquitinate itself and USP4 reverses this ubiquitination ."
USP4 affects USP17L24
| 3
| 3

sparser
"Thus, both co-immunoprecipitation and PLA analyses supported the notion that HAS2 forms complexes 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
"HAS2 interacts with USP17 and USP4."
USP4 affects SMAD7
| 3
USP4 decreases the amount of SMAD7.
| 2
USP4 decreases the amount of SMAD7. 2 / 2
| 2

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
"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."
USP4 increases the amount of SMAD7.
| 1
USP4 increases the amount of SMAD7. 1 / 1
| 1

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."
USP4 affects RORC
1 1 | 1
USP4 binds RORC.
1 | 1
1 | 1

No evidence text available

sparser
"Co-immunoprecipitation experiments using human CD4 + T cell lysates demonstrated that USP4 associates with RORγt."
USP4 deubiquitinates RORC.
1 |
USP4 deubiquitinates RORC. 1 / 1
1 |

"Ubiquitin-specific protease 4 promotes Th17 cell function under inflammation by deubiquitinating and stabilizing RORγt"
USP4 affects RBL1
1 1 | 1
1 1 | 1

No evidence text available

reach
"We conclude that within cells UNP does physically associate with pRb, and can also associate with p107 and p130."

No evidence text available
USP4 affects PSMD11
3 |
3 |

No evidence text available

No evidence text available

No evidence text available
USP4 affects PSMC5
3 |
3 |

No evidence text available

No evidence text available

No evidence text available
USP4 affects IL1B
| 1 2
USP4 inhibits IL1B. 3 / 3
| 1 2

sparser
"Similarly, USP4 inhibited IL-1β-, LPS- and TGFβ-induced NF-κB production xref ."

sparser
"USP4 inhibits IL-1β-, LPS-and TGFβ-induced NF-κB activation."

reach
"Additionally, the overexpression of USP4 suppressed the release of microglia activation-induced pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α."
USP4 affects IGKV2D-29
3 |

No evidence text available

No evidence text available

No evidence text available
USP4 affects C6orf89
| 3
USP4 binds C6orf89.
| 2
| 2

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."

reach
"In summary, our data show that USP4 and -15 can both interact with BRAP and thereby attenuate its autoubiquitylation."
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 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 AKT1
3 |
3 |

No evidence text available

No evidence text available

No evidence text available
USP17L24 affects USP4
| 3
| 3

sparser
"Thus, both co-immunoprecipitation and PLA analyses supported the notion that HAS2 forms complexes 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
"HAS2 interacts with USP17 and USP4."
USP15 affects USP11
| 3
USP11 binds USP15 and USP4. 3 / 3
| 3

sparser
"USP4 can form stable homodimers and can also interact with USP11 and USP15 ( Fig. 4 )."

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."
RBL1 affects USP4
1 1 | 1
1 1 | 1

No evidence text available

reach
"We conclude that within cells UNP does physically associate with pRb, and can also associate with p107 and p130."

No evidence text available
PSMD11 affects USP4
3 |
3 |

No evidence text available

No evidence text available

No evidence text available
PSMC5 affects USP4
3 |
3 |

No evidence text available

No evidence text available

No evidence text available
IRF8 affects USP4
2 | 1
2 | 1

No evidence text available

No evidence text available

reach
"Taken together, our results suggest that USP4 interacts with and stabilizes IRF8 to promote the suppressive function of Treg cells."
IGKV2D-29 affects USP4
3 |

No evidence text available

No evidence text available

No evidence text available
HAS2 affects USP17L24, and USP4
| 3
| 3

sparser
"Thus, both co-immunoprecipitation and PLA analyses supported the notion that HAS2 forms complexes 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
"HAS2 interacts with USP17 and USP4."
EV71 affects USP4
| 3
EV71 decreases the amount of USP4. 3 / 3
| 3

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."

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."
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)."

reach
"The results showed that METL3 knockdown markedly enhanced the interaction between USP4 and ELAVL1."

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)."
BRAP affects USP15, and USP4
| 3
USP15 binds USP4 and BRAP. 3 / 3
| 3

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."

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 )."
Torcetrapib affects USP4
2 |
Torcetrapib increases the amount of USP4. 2 / 2
2 |

No evidence text available

No evidence text available
2 |
Sodium arsenite increases the amount of USP4. 2 / 2
2 |

No evidence text available

No evidence text available
| 2

sparser
"Inhibition of USP4 by shRNA in MHCC97H cells significantly decreased CypA protein levels."

sparser
"In contrast, inhibition of USP4 by shRNA in MHCC97H cells reduced p-ERK1/2 and increased p-CrkII levels."
Methyl methanesulfonate increases the amount of USP4. 2 / 2
2 |

No evidence text available

No evidence text available
Foci affects USP4
| 2
USP4 binds RBBP8 and foci. 2 / 2
| 2

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."

sparser
"As USP4 directly interacts with CtIP, we also checked CtIP foci formation in USP4-depleted cells."
2 |
Benzo[a]pyrene increases the amount of USP4. 2 / 2
2 |

No evidence text available

No evidence text available
Vialinin A affects USP4
| 1 1
Vialinin A inhibits USP4. 2 / 2
| 1 1

reach
"Vialinin A inhibited the peptidase activity of USP5 and IsoT and also inhibited the enzymatic activities of USP4 among deubiquitinating enzymes tested."

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 ."
USP7 affects USP4
| 2
USP15 binds USP4 and USP7. 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 localization
| 2
USP4 bound to TP53 activates localization. 1 / 1
| 1

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]."
| 1

reach
"The AKT-mediated phosphorylation of USP4, on the other hand, triggers its subcellular localization predominantly in the membrane and cytoplasm, whereas the non-phosphorylated form is mostly condensed into the nucleus [54]."
USP4 affects hyaluronan
| 2
| 2

reach
"The silencing of USP17 led to decreased hyaluronan production, whereas the suppression of USP4 increased hyaluronan synthesis."

reach
"Knockdown of USP17 decreases, whereas knockdown of USP4 increases hyaluronan production."
USP4 affects foci
| 2
USP4 binds RBBP8 and foci. 2 / 2
| 2

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."

sparser
"As USP4 directly interacts with CtIP, we also checked CtIP foci formation in USP4-depleted cells."
USP4 affects 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 affects ZEB1
| 2
USP4 increases the amount of ZEB1. 2 / 2
| 2

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 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."
USP4 affects USP7
| 2
USP15 binds USP4 and USP7. 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 UBL domain
| 2
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 binds USP39 and UBL domain. 1 / 1
| 1

reach
"USP39 binds with USP4 via its UBL domain and correspondingly enhances the stability of USP4 in T cells [XREF_BIBR, XREF_BIBR], implying that USP39 might be deubiquitylating USP4."
USP4 affects TP53BP2
1 1 |
1 1 |

No evidence text available

No evidence text available
USP4 affects TNFAIP3
| 2
| 2

sparser
"cDNAs encoding Myc-tagged forms of USP4, USP11, Ataxin-3 and A20 were gifts from Dr P.J. Lehner (17, 26, 54) ."

sparser
"cDNAs encoding Myc-tagged forms of USP4, USP11, Ataxin-3 and A20 were gifts from Dr P.J. Lehner (University of Cambridge, UK) (51), Dr J. Yang (Baylor College of Medicine, Houston, USA) (52), Dr E.A. Fon (Montreal Neurological Institute, Canada) (23) and Dr K. Li (University of Texas Medical Branch, Galveston, USA) (53), respectively."
USP4 affects TJP1
| 2
USP4 increases the amount of TJP1.
| 1
USP4 increases the amount of TJP1. 1 / 1
| 1

reach
"Results showed that inhibition of USP4 and Smurf2 expression significantly reverses the altered expression of ZO-1, Vimentin and TbetaRI induced by TGF-beta1, while overexpression of Akt augments these effects."
USP4 decreases the amount of TJP1.
| 1
USP4 decreases the amount of TJP1. 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."
USP4 affects TGFBR
| 2
USP4 inhibits TGFBR.
| 1
USP4 inhibits TGFBR. 1 / 1
| 1

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)."
USP4 activates TGFBR.
| 1
USP4 activates TGFBR. 1 / 1
| 1

reach
"Both USP15 and USP4 stimulate TGF-beta signaling by deubiquitylating and stabilizing two key signaling molecules in this pathway, TGF-beta receptor I (TbetaRI) and R-SMADs, suggesting that these two closely related DUBs act in concert to modulate central signaling processes that are involved in oncogenesis and innate immunity."
USP4 affects TCF7L2
2 |
2 |

No evidence text available

No evidence text available
USP4 affects TCEAL1
2 |
2 |

No evidence text available

No evidence text available
USP4 affects TAB1
| 2
USP4 ubiquitinates TAB1.
| 1
Modified USP4 leads to the ubiquitination of TAB1. 1 / 1
| 1

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 inhibits TAB1.
| 1
USP4 inhibits TAB1. 1 / 1
| 1

reach
"USP4 inhibits TAK1 and TAB1 co-overexpression-mediated NF-kappaB activation."
USP4 affects TA
| 2
USP4 binds TA. 2 / 2
| 2

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
"Ten genes viz., TaAPX7, TaCam1-1, TaSST, TaSOD2, TaPEX11-1, TaGly-I, TaMIOX, Ta-UnP, TaNIP and TaERF4 were upregulated, whereas the expression of two genes (viz., TaCRT1 and TaTZF1 ) were both down-regulated in shoot tissues during the tillering stage under salt stress (Fig.  xref )."
| PMC
USP4 affects Survival
| 2
USP4 activates Survival. 2 / 2
| 2

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

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 ) ."
USP4 affects STN1
2 |
2 |

No evidence text available

No evidence text available
USP4 affects SNAI1
| 1 1
| 1 1

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."

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."
USP4 affects RPS4X
| 2
USP4 inhibits RPS4X. 2 / 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."
USP4 affects PDK1
2 |
2 |

No evidence text available

No evidence text available
USP4 affects PCNA
1 | 1
USP4 increases the amount of PCNA.
| 1
USP4 increases the amount of PCNA. 1 / 1
| 1

reach
"Inhibition of USP4 downregulated the expression of PCNA, Bcl-2 and p-ERK1/2, but upregulated the expression of Bax both in vitro and in vivo."
USP4 binds PCNA.
1 |
1 |

No evidence text available
USP4 affects NLK
2 |
2 |

No evidence text available

No evidence text available
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 MYOD1
| 2
USP4 inhibits MYOD1. 2 / 2
| 2

reach
"Ubiquitin specific protease 4 (USP4) suppresses myoblast differentiation by down regulating MyoD activity in a catalytic independent manner."

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 MYC
| 2
USP4 binds MYC and BRAP. 1 / 1
| 1

sparser
"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 A , compare lanes 2 and 4 with 9 and 11 )."
USP4 binds CTNNB1 and MYC. 1 / 1
| 1

sparser
"The wild type USP4 and USP4(261–963) were associated with Myc-β-catenin, while USP4(1–260) showed only weak interaction ( Figure 4 B)."
USP4 affects METTL3
| 2
USP4 inhibits METTL3. 2 / 2
| 2

eidos
"Moreover , we observed that USP4 knockdown effectively alleviated METTL3 knockdown-induced inhibited xenograft tumor growth ( Figure 7A-C ) ."

eidos
"Moreover , we also found that the knockdown of USP4 effectively alleviated METTL3 decifiency-induced suppressed xenograft tumor formation ."
USP4 affects IL1
| 2
USP4 inhibits IL1. 2 / 2
| 2

reach
"USP4 negatively regulates IL-1β-induced NF-κB activation [60] [61] [62] ."

reach
"USP4 was identified by studies to negatively regulate both TNF-αand IL-1β-induced NF-κB activation [60] [61] [62] ."
USP4 affects IFNB1
| 1 1
USP4 activates IFNB1. 2 / 2
| 1 1

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."

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 ) ."
USP4 affects GST
| 2
| 2

sparser
"To validate whether USP4 is a direct deubiquitinase for Rheb, we performed an in vitro deubiquitination assay using purified GST-USP4 protein."

sparser
"As expected, interaction of GST-S9 with USP4(1–318) was readily detected."
USP4 affects Flag
| 2
| 2

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
"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 )."
USP4 affects FN1
| 2
USP4 decreases the amount of FN1.
| 1
USP4 decreases the amount of FN1. 1 / 1
| 1

reach
"In addition, Smurf2 siRNA and USP4 siRNA reduced the up-regulated expression of FN in HPMCs induced by TGF-beta1plus Flag-Akt."
USP4 activates FN1.
| 1
USP4 activates FN1. 1 / 1
| 1

reach
"No change in the FN expression was observed in cells treated with Smurf2 siRNA or USP4 siRNA alone compared to basal levels."
USP4 affects ERK1/2-MAPK
| 2
USP4 activates ERK1/2-MAPK. 2 / 2
| 2

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."

reach
"These data indicate that USP4 positively regulates the ERK1/2-MAPK and CrkII signaling pathways via a CypA dependent process."
USP4 affects ELMO1
2 |
2 |

No evidence text available

No evidence text available
USP4 affects DSB repair
| 2
USP4 activates DSB repair. 2 / 2
| 2

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)."

reach
"We have established that USP4 promotes DSB repair by HR and cellular resistance to IR and the topoisomerase I inhibitor camptothecin."

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
"These data indicate that USP4 positively regulates the ERK1/2-MAPK and CrkII signaling pathways via a CypA dependent process."

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."
| 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 ) ."
| 1
| 1

eidos
"Vialinin A , an inhibitor of USP4 , inhibited the tumorigenesis ( Figs ."
USP4 affects CTTN
| 1 1
| 1 1

sparser
"Binding of USP4 to cortactin enhances cell migration in HCT116 human colon cancer cells."

reach
"Binding of USP4 to cortactin enhances cell migration in HCT116 human colon cancer cells."
USP4 affects CT55
2 |
2 |

No evidence text available

No evidence text available
USP4 affects CRLF3
| 2
| 2

sparser
"cDNAs encoding Myc-tagged forms of USP4, USP11, Ataxin-3 and A20 were gifts from Dr P.J. Lehner (17, 26, 54) ."

sparser
"cDNAs encoding Myc-tagged forms of USP4, USP11, Ataxin-3 and A20 were gifts from Dr P.J. Lehner (University of Cambridge, UK) (51), Dr J. Yang (Baylor College of Medicine, Houston, USA) (52), Dr E.A. Fon (Montreal Neurological Institute, Canada) (23) and Dr K. Li (University of Texas Medical Branch, Galveston, USA) (53), respectively."
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 BCL2
| 2
USP4 increases the amount of BCL2. 2 / 2
| 2

reach
"Inhibition of USP4 downregulated the expression of PCNA, Bcl-2 and p-ERK1/2, but upregulated the expression of Bax both in vitro and in vivo."

reach
"Additionally, qRT-PCR analysis showed that USP4 knockdown significantly downregulated the expressions of cyclin D2 (CCND2) and B cell leukemia/lymphoma 2 (BCL2)."
| 2
| 2

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."

reach
"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."
USP4 affects Activin
| 1 1
USP4 activates Activin. 2 / 2
| 1 1

reach
"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 ATXN3
| 2
| 2

sparser
"cDNAs encoding Myc-tagged forms of USP4, USP11, Ataxin-3 and A20 were gifts from Dr P.J. Lehner (17, 26, 54) ."

sparser
"cDNAs encoding Myc-tagged forms of USP4, USP11, Ataxin-3 and A20 were gifts from Dr P.J. Lehner (University of Cambridge, UK) (51), Dr J. Yang (Baylor College of Medicine, Houston, USA) (52), Dr E.A. Fon (Montreal Neurological Institute, Canada) (23) and Dr K. Li (University of Texas Medical Branch, Galveston, USA) (53), respectively."
UBL domain affects USP4
| 2
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 binds USP39 and UBL domain. 1 / 1
| 1

reach
"USP39 binds with USP4 via its UBL domain and correspondingly enhances the stability of USP4 in T cells [XREF_BIBR, XREF_BIBR], implying that USP39 might be deubiquitylating USP4."
TP53BP2 affects USP4
1 1 |
1 1 |

No evidence text available

No evidence text available
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]."
TNFAIP3 affects USP4
| 2
| 2

sparser
"cDNAs encoding Myc-tagged forms of USP4, USP11, Ataxin-3 and A20 were gifts from Dr P.J. Lehner (17, 26, 54) ."

sparser
"cDNAs encoding Myc-tagged forms of USP4, USP11, Ataxin-3 and A20 were gifts from Dr P.J. Lehner (University of Cambridge, UK) (51), Dr J. Yang (Baylor College of Medicine, Houston, USA) (52), Dr E.A. Fon (Montreal Neurological Institute, Canada) (23) and Dr K. Li (University of Texas Medical Branch, Galveston, USA) (53), respectively."
TCF7L2 affects USP4
2 |
2 |

No evidence text available

No evidence text available
TCEAL1 affects USP4
2 |
2 |

No evidence text available

No evidence text available
TA affects USP4
| 2
USP4 binds TA. 2 / 2
| 2

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
"Ten genes viz., TaAPX7, TaCam1-1, TaSST, TaSOD2, TaPEX11-1, TaGly-I, TaMIOX, Ta-UnP, TaNIP and TaERF4 were upregulated, whereas the expression of two genes (viz., TaCRT1 and TaTZF1 ) were both down-regulated in shoot tissues during the tillering stage under salt stress (Fig.  xref )."
| PMC
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."
STN1 affects USP4
2 |
2 |

No evidence text available

No evidence text available
SNAI1 affects USP4
| 1 1
| 1 1

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."

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."
Rho52 affects USP4
| 2
Rho52 ubiquitinates USP4. 2 / 2
| 2

reach
"Rho52 in turn can ubiquitinate USP4."

reach
"However, if Rho52 ubiquitinates USP4 the DUB may be degraded."
RORC affects USP4
1 | 1
1 | 1

No evidence text available

sparser
"Co-immunoprecipitation experiments using human CD4 + T cell lysates demonstrated that USP4 associates with RORγt."
RBBP8 affects foci
| 2
USP4 binds RBBP8 and foci. 2 / 2
| 2

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."

sparser
"As USP4 directly interacts with CtIP, we also checked CtIP foci formation in USP4-depleted cells."
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."
PDK1 affects USP4
2 |
2 |

No evidence text available

No evidence text available
NLK affects USP4
2 |
2 |

No evidence text available

No evidence text available
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
USP4 binds MYC and BRAP. 1 / 1
| 1

sparser
"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 A , compare lanes 2 and 4 with 9 and 11 )."
USP4 binds CTNNB1 and MYC. 1 / 1
| 1

sparser
"The wild type USP4 and USP4(261–963) were associated with Myc-β-catenin, while USP4(1–260) showed only weak interaction ( Figure 4 B)."
MRE11 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."
KITLG affects USP4
| 1 1
KITLG activates USP4. 2 / 2
| 1 1

reach
"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 ."
GST affects USP4
| 2
| 2

sparser
"To validate whether USP4 is a direct deubiquitinase for Rheb, we performed an in vitro deubiquitination assay using purified GST-USP4 protein."

sparser
"As expected, interaction of GST-S9 with USP4(1–318) was readily detected."
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."
GC affects USP4
| 2
GC increases the amount of USP4. 2 / 2
| 2

reach
"Examination of DNA sequence 5 ' of the presumed transcriptional start site (based on alignment with the longest cDNA clones) suggested that expression of Unp is driven by a TATA-less promoter of the G[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Expression of Unp is driven by a GC rich, ' housekeeping ' type promoter."
Flag affects USP4
| 2
| 2

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
"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 )."
ELMO1 affects USP4
2 |
2 |

No evidence text available

No evidence text available
CTTN affects USP4
| 1 1
| 1 1

sparser
"Binding of USP4 to cortactin enhances cell migration in HCT116 human colon cancer cells."

reach
"Binding of USP4 to cortactin enhances cell migration in HCT116 human colon cancer cells."
CT55 affects USP4
2 |
2 |

No evidence text available

No evidence text available
CRLF3 affects USP4
| 2
| 2

sparser
"cDNAs encoding Myc-tagged forms of USP4, USP11, Ataxin-3 and A20 were gifts from Dr P.J. Lehner (17, 26, 54) ."

sparser
"cDNAs encoding Myc-tagged forms of USP4, USP11, Ataxin-3 and A20 were gifts from Dr P.J. Lehner (University of Cambridge, UK) (51), Dr J. Yang (Baylor College of Medicine, Houston, USA) (52), Dr E.A. Fon (Montreal Neurological Institute, Canada) (23) and Dr K. Li (University of Texas Medical Branch, Galveston, USA) (53), respectively."
CNR2 affects USP4
| 2
CNR2 inhibits USP4. 2 / 2
| 2

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."

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."
CK2 affects USP4
| 2
CK2 phosphorylates USP4. 2 / 2
| 2

sparser
"Mechanistically, CK2-induced phosphorylation of USP4 is important for stabilization of SIRT1 by suppressing ubiquitin-dependent proteasomal degradation."

sparser
"A study showed that casein kinase 2-induced phosphorylation of USP4 stabilizes sirtuin1 by inhibiting ubiquitin-dependent proteasomal degradation."
C6orf89 affects USP4
| 2
| 2

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."

reach
"In summary, our data show that USP4 and -15 can both interact with BRAP and thereby attenuate its autoubiquitylation."
ATXN3 affects USP4
| 2
| 2

sparser
"cDNAs encoding Myc-tagged forms of USP4, USP11, Ataxin-3 and A20 were gifts from Dr P.J. Lehner (17, 26, 54) ."

sparser
"cDNAs encoding Myc-tagged forms of USP4, USP11, Ataxin-3 and A20 were gifts from Dr P.J. Lehner (University of Cambridge, UK) (51), Dr J. Yang (Baylor College of Medicine, Houston, USA) (52), Dr E.A. Fon (Montreal Neurological Institute, Canada) (23) and Dr K. Li (University of Texas Medical Branch, Galveston, USA) (53), respectively."
Vinclozolin affects USP4
1 |
Vinclozolin decreases the amount of USP4. 1 / 1
1 |

No evidence text available
1 |
Valproic acid decreases the amount of USP4. 1 / 1
1 |

No evidence text available
Type I receptor affects USP4
| 1
USP4 binds type I receptor. 1 / 1
| 1

sparser
"Molecular mechanism studies have shown that USP4 is strongly associated with the transforming growth factor-β (TGF-β) type I receptor (TβRI) and deubiquitinates and stabilizes TβRI at the plasma membrane."
| PMC
Temozolomide affects USP4
| 1
| 1

reach
"In addition, the results revealed that cleaved poly (ADP-ribose) polymerase level increased when USP4 was knocked down in glioblastoma cells treated with TMZ."
ShRNA lentiviral transduction particles affects USP4
| 1
ShRNA lentiviral transduction particles activates USP4. 1 / 1
| 1

reach
"The human shRNA lentiviral transduction particles targeting USP4 and the control particles were purchased from GenePharma (Shanghai, China)."
1 |
Selenium atom decreases the amount of USP4. 1 / 1
1 |

No evidence text available
Resveratrol affects USP4
1 |
Resveratrol increases the amount of USP4. 1 / 1
1 |

No evidence text available
Quercetin affects USP4
1 |
Quercetin decreases the amount of USP4. 1 / 1
1 |

No evidence text available
1 |
Pirinixic acid increases the amount of USP4. 1 / 1
1 |

No evidence text available
Phlorizin affects USP4
1 |
Phlorizin increases the amount of USP4. 1 / 1
1 |

No evidence text available

sparser
"The ubiquitin peptidase inactive form of USP4 (USP4-C311A) abolished its ability to stabilize HDAC2 ( xref and xref )."
1 |
Pentachlorophenol decreases the amount of USP4. 1 / 1
1 |

No evidence text available
Paracetamol affects USP4
1 |
Paracetamol decreases the amount of USP4. 1 / 1
1 |

No evidence text available
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."
MiR-148a affects USP4
| 1
MiR-148a decreases the amount of USP4. 1 / 1
| 1

reach
"Specifically, in liver fibrosis, lower levels of miR-148a and miR-27b lead to the overexpression of USP4 in hepatic stellate cells and hepatocytes."
Metformin affects USP4
| 1
Metformin decreases the amount of USP4. 1 / 1
| 1

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."
Luteolin affects USP4
| 1
Luteolin increases the amount of USP4. 1 / 1
| 1

reach
"(4) Luteolin promoted the expression of USP4 but inhibited miR-136-5p expression."
| 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."

sparser
"Distinct specificities of these enzymes were detected; notably, in addition to UCH-D, isopeptidase activity [ubiquitin-(epsilonN)-lysine cleavage] was only associated with Yuh1p, Unp, Ubp1p, and Ubp2p."
Insulin receptors affects USP4
| 1
USP4 binds insulin receptors. 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."
Importin affects USP4
| 1
USP4 binds importin. 1 / 1
| 1

sparser
"A model involving shuttling of USP4 to the nucleus was also supported by mass spectrometric analysis which revealed associations of USP4 with importin as well as with exportin ( Supplementary Table 1 [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
Hsa_circ_0001326 affects USP4
| 1
Hsa_circ_0001326 decreases the amount of USP4. 1 / 1
| 1

reach
"In addition, hsa_circ_0001326 attenuated the inhibition effect of luteolin on hsa-miR-136-5p expression, and the promotion effect on USP4 expression."
Gene product affects USP4
| 1
USP4 binds gene product. 1 / 1
| 1

reach
"Here, we show that cellular Unp specifically interacts with the retinoblastoma gene product (pRb)."
Endonuclease CtIP affects USP4
| 1
USP4 binds endonuclease CtIP. 1 / 1
| 1

reach
"Of note, the interaction between USP4 and the DNA endonuclease CtIP (RDDP8), critical to DSB end resection in XREF_BIBR; XREF_BIBR), represents a postWGD neofunctionalization."
Coumestrol affects USP4
1 |
Coumestrol decreases the amount of USP4. 1 / 1
1 |

No evidence text available
CooH affects adenosine receptor
| 1
USP4 binds cooH and adenosine receptor. 1 / 1
| 1

sparser
"USP4 associates with the cytosolic COOH terminus of the A 2a -adenosine receptor, a Gs-coupled receptor ( xref )."
CircBMPR2 affects USP4
| 1
CircBMPR2 activates USP4. 1 / 1
| 1

reach
"Our findings demonstratedthat circBMPR2 might function as a miR-553 sponge and then relieve the suppression of USP4 to inhibit the progression and tamoxifen resistance of breast cancer."
Catalytic affects USP4
| 1
Catalytic activates USP4. 1 / 1
| 1

eidos
"USP4 is involved in the regulation of many crucial signaling pathways due to its catalytic activity ."
Catalytic domain turnover affects USP4
| 1
Catalytic domain turnover activates USP4. 1 / 1
| 1

eidos
"The primary function of the DUSP-UBL domain is to activate USP4 by promoting catalytic domain turnover ."
BznB affects USP4
| 1

sparser
"The USP4 and USP15 DU domains interact with E3 ligases ( xref ) and the substrate recruitment factor SART3 ( xref , xref ), but no interactions have yet been reported for these domains in USP11."
Bisphenol A affects USP4
1 |
Bisphenol A decreases the amount of USP4. 1 / 1
1 |

No evidence text available
Adenosine receptor affects cooH
| 1
USP4 binds cooH and adenosine receptor. 1 / 1
| 1

sparser
"USP4 associates with the cytosolic COOH terminus of the A 2a -adenosine receptor, a Gs-coupled receptor ( xref )."
YWHAH affects USP4
1 |
1 |

No evidence text available
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]."
UnpDelta1-168H880A affects USP4
| 1
UnpDelta1-168H880A inhibits USP4. 1 / 1
| 1

reach
"The other single His mutation (UnpDelta1-168H880A, Fig. 2, lane 9) abolished the deubiquitinating activity of Unp in a manner similar to the effect of the Cys and double His mutants (lane 10)."
Ubx affects USP4
| 1
Ubx decreases the amount of USP4. 1 / 1
| 1

reach
"Expression of unp in the founder cells for the cerebral branch within the first tracheal metamere is repressed in posterior segments by Ubx and other bithorax complex genes."
Ubl domain affects USP4
| 1
Ubl domain inhibits USP4. 1 / 1
| 1

reach
"We therefore conclude that the Ubl domain is sufficient to inhibit the DUB activity of USP4, through competitive inhibition of Ub binding."

sparser
"The ubiquitin peptidase inactive form of USP4 (USP4-C311A) abolished its ability to stabilize HDAC2 ( xref and xref )."
Ubiquitin affects USP15
| 1
| 1

sparser
"In the absence of USP4 and USP15 ubiquitin-bound structures, the molecular bases for these differences are difficult to rationalize at present, as multiple factors will contribute, such as the release of bound water molecules, conformational changes associated with the binding events, and differences in interacting residues."
USPs affects USP4
| 1
USP15 binds USP4, USPs, and BRAP. 1 / 1
| 1

sparser
"Of these, the interaction between BRAP and two related USPs, USP4 and USP15, was of compelling physiological interest given the established role of BRAP/IMP in the regulation of the MAP kinase signaling cascade ( xref )."
USP7 affects USP15
| 1
USP15 binds USP4 and USP7. 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 verify above results
| 1
USP4 activates verify above results. 1 / 1
| 1

eidos
"SOX2 Increased Tumor Growth of EC in Nude Mice by Mediating the USP4 / SMAD4 / CK2 Axis via miR-30e To verify the above results in vivo , we subcutaneously injected TE-1 cells transfected with different lentiviral plasmids into nude mice ."
USP4 affects type I receptor
| 1
USP4 binds type I receptor. 1 / 1
| 1

sparser
"Molecular mechanism studies have shown that USP4 is strongly associated with the transforming growth factor-β (TGF-β) type I receptor (TβRI) and deubiquitinates and stabilizes TβRI at the plasma membrane."
| PMC
USP4 affects type 2 inflammatory cytokine gene
| 1
USP4 increases the amount of type 2 inflammatory cytokine gene. 1 / 1
| 1

reach
"Depletion of USP4 promoted the polyubiquitination of IRF8 and the upregulation of type 2 inflammatory cytokine gene expression in Treg cells."
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 subsequent immune responses
| 1
USP4 inhibits subsequent immune responses. 1 / 1
| 1

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

reach
"In contrast to these observations with ANPs, although UNP and CNP triggered increased ROS, notably in AT2 and MAC, this did not impact on mitochondrial integrity or cell viability, indicating the significance of surface chemistry in cellular bioreactivity."
USP4 affects protein stability ELAVL1
| 1
USP4 activates protein stability ELAVL1. 1 / 1
| 1

eidos
"Consistently , USP4 knockdown markedly reduced protein stability of ELAVL1 ( Figure 5Q-R and Figure S7L-M ) ."
USP4 affects polyubiquitin chain
| 1
USP4 ubiquitinates polyubiquitin chain. 1 / 1
| 1

reach
"A study demonstrates that USP4 inhibits this pathway by deubiquitinating the polyubiquitin chain from Dvl, resulting in inhibiting of Wnt signal and decreased osteoblast differentiation and mineralization [70]."
USP4 affects phosphorylation p-S6
| 1
USP4 activates phosphorylation p-S6. 1 / 1
| 1

eidos
"In addition , USP4 inhibitor , Vialinin A , inhibited tumor growth and reduced the phosphorylation level of p-S6 ( Fig. 7g-i ; Supplementary information , Fig. S7c ) ."
| 1

sparser
"The ubiquitin peptidase inactive form of USP4 (USP4-C311A) abolished its ability to stabilize HDAC2 ( xref and xref )."
USP4 affects pathway
| 1
USP4 inhibits pathway. 1 / 1
| 1

sparser
"A study demonstrates that USP4 inhibits this pathway by deubiquitinating the polyubiquitin chain from Dvl, resulting in inhibiting of Wnt signal and decreased osteoblast differentiation and mineralization [ 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 p53 transcriptional
| 1
USP4 inhibits p53 transcriptional. 1 / 1
| 1

eidos
"USP4 inhibits p53 transcriptional activation via stabilizing HDAC2 and ARF-BP1 , which acts as a deacetylase and E3 ubiquitin ligase of p53 , respectively ( Zhang et al ., 2011 ; Li Z. et al ., 2016 ) ."
USP4 affects p38
| 1
USP4-C311A leads to the deubiquitination of p38. 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 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."

eidos
"19 A recent study has demonstrated that USP4 could promote osteoblast differentiation via Activation of Wnt / beta-catenin signalling by inducing Runx2 ."
USP4 affects oncogene-induced primary cell transformation
| 1
USP4 activates oncogene-induced primary cell transformation. 1 / 1
| 1

eidos
"Indeed , it has been suggested that Usp4 is a potential oncogene because it inhibits p53 activity , p53-associated apoptosis and cell-cycle checkpoints ; depletion of USP4 promotes cell senescence ; loss of USP4 inhibits oncogene-induced primary cell transformation , and finally USP4 is over-expressed in a subset of human cancers [ 86 ] ."
USP4 affects nuclear factor-kappaB
| 1
USP4 activates nuclear factor-kappaB. 1 / 1
| 1

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."
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."

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

reach
"We confirmed that interacting of USP4 with CTTN increased cell movement."
USP4 affects migration
| 1
USP4 activates migration. 1 / 1
| 1

eidos
"By promoting activation of the relaxin / TGF-beta1 / 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 ( Cao et al ., 2016 ; Wang et al ., 2018 ) ."
USP4 affects mTORC1
| 1
USP4 activates mTORC1. 1 / 1
| 1

reach
"Studies of USP4 knockout mice revealed that USP4 upregulates tumor growth in an mTORC1-dependent manner."
USP4 affects j different USP4 mutants USP4-WT S445A S445D mTPRC1 activation Considering Rheb ubiquitination
| 1
USP4 inhibits j different USP4 mutants USP4-WT S445A S445D mTPRC1 activation Considering Rheb ubiquitination. 1 / 1
| 1

eidos
"j The effects of different USP4 mutants ( USP4-WT , S445A , S445D ) on mTPRC1 activation Considering Rheb ubiquitination could be reversed by USP4 , we examined whether USP4 has any effect on EGF-induced mTORC1 activation ."

sparser
"Distinct specificities of these enzymes were detected; notably, in addition to UCH-D, isopeptidase activity [ubiquitin-(epsilonN)-lysine cleavage] was only associated with Yuh1p, Unp, Ubp1p, and Ubp2p."

eidos
"In the study of rheumatic heart disease , Guo et al. revealed that USP4 positively modulated IL-4 secretion by T helper type 2 cells through deubiquitinating and stabilizing IRF4 which is usually the reason of allergic immune responses diseases , such as rheumatic heart disease [ 62 ] ."
USP4 affects inflammatory responses
| 1
USP4 inhibits inflammatory responses. 1 / 1
| 1

eidos
"The connection between USP4 and NF-kappaB is identified in lung cancers where stable knockdown of USP4 augments inflammatory responses , stemness properties , chemoresistance , the expression of programmed death ligand 1 , and tumor growth ( Lai et al ., 2020 ) ."
USP4 affects inflammation liver R injury
| 1
USP4 inhibits inflammation liver R injury. 1 / 1
| 1

eidos
"As some reported , USP4 deficiency intensifies the inflammation in the liver of hepatic I / R injury 8 and NAFLD ."
USP4 affects importin
| 1
USP4 binds importin. 1 / 1
| 1

sparser
"A model involving shuttling of USP4 to the nucleus was also supported by mass spectrometric analysis which revealed associations of USP4 with importin as well as with exportin ( Supplementary Table 1 [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
USP4 affects gene product
| 1
USP4 binds gene product. 1 / 1
| 1

reach
"Here, we show that cellular Unp specifically interacts with the retinoblastoma gene product (pRb)."
USP4 affects formation
| 1
USP4 inhibits formation. 1 / 1
| 1

sparser
"If INA and UNP inhibited the formation of heme O, it is possible that they also interfered with the mitochondrial potential."
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 endonuclease CtIP
| 1
USP4 binds endonuclease CtIP. 1 / 1
| 1

reach
"Of note, the interaction between USP4 and the DNA endonuclease CtIP (RDDP8), critical to DSB end resection in XREF_BIBR; XREF_BIBR), represents a postWGD neofunctionalization."
USP4 affects dissociation TSC
| 1
USP4 activates dissociation TSC. 1 / 1
| 1

eidos
"In parallel , USP4 removes ubiquitin from Rheb and promotes the dissociation of TSC from Rheb , which ultimately activates Rheb upon the growth factor treatment ( Supplementary information , Fig. S4g ) ."
USP4 affects deubiquitination translocation SMAD4
| 1
USP4 activates deubiquitination translocation SMAD4. 1 / 1
| 1

eidos
"The above experimental results showed that USP4 promoted the deubiquitination and translocation of SMAD4 into nuclei in EC cells ."

reach
"USP4 positively regulates the RIG-I-mediated antiviral response through the deubiquitination of Lys48-linked polyubiquitin from RIG-I43."
USP4 affects de-ubiquitination recycling Prp3
| 1
USP4 activates de-ubiquitination recycling Prp3. 1 / 1
| 1

eidos
"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
USP4 affects cooH
| 1
USP4 binds cooH and adenosine receptor. 1 / 1
| 1

sparser
"USP4 associates with the cytosolic COOH terminus of the A 2a -adenosine receptor, a Gs-coupled receptor ( xref )."
USP4 affects content PRL-3
| 1
USP4 activates content PRL-3. 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 cleaved-PARP
| 1
USP4 decreases the amount of cleaved-PARP. 1 / 1
| 1

reach
"Similarly, USP4 knockdown resulted in an increase in the apoptosis rate of MHCC97H and LM3 cells and upregulated the protein expression of cleaved-caspase3 and cleaved-PARP, which are indicators of cell apoptosis."
USP4 affects cell migration invasion breast cancer
| 1
USP4 activates cell migration invasion breast cancer. 1 / 1
| 1

eidos
"USP4 and USP20 can promote the cell migration and invasion activities in breast cancer by inhibiting NFkappaB activation via deubiquitination of TRAF2 and TRAF6 [ 74 ] ."
USP4 affects cell death
| 1
| 1

reach
"Although UNP and CNP did not induce significant cell death, both these particles induced a high ROS response in AT2, similar to that observed following ANP exposure, but less so in TT1 cells, illustrating that induction of ROS varies according to the target cell."
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 bznB
| 1

sparser
"The USP4 and USP15 DU domains interact with E3 ligases ( xref ) and the substrate recruitment factor SART3 ( xref , xref ), but no interactions have yet been reported for these domains in USP11."
USP4 affects breast cell invasion
| 1
USP4 activates breast cell invasion. 1 / 1
| 1

eidos
"By promoting activation of the relaxin / TGF-beta1 / 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 ( Cao et al ., 2016 ; Wang et al ., 2018 ) ."
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
USP4 affects beta-catenin signalling inducing Runx2
| 1
USP4 activates beta-catenin signalling inducing Runx2. 1 / 1
| 1

eidos
"19 A recent study has demonstrated that USP4 could promote osteoblast differentiation via Activation of Wnt / beta-catenin signalling by inducing Runx2 ."
USP4 affects antiviral immune response
| 1
USP4 activates antiviral immune response. 1 / 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 ) ."
USP4 affects adenosine receptor, and cooH
| 1
USP4 binds cooH and adenosine receptor. 1 / 1
| 1

sparser
"USP4 associates with the cytosolic COOH terminus of the A 2a -adenosine receptor, a Gs-coupled receptor ( xref )."
USP4 affects activation polyubiquitinated TAK1
| 1
USP4 inhibits activation polyubiquitinated TAK1. 1 / 1
| 1

eidos
"USP4 expression can deubiquitinate and inhibit the activation of polyubiquitinated TAK1 which hinder the activation of TAK1 / c-Jun N-terminal kinase 1/2 ( JNK1 / 2 ) / p38 signaling pathway [ 84 ] ."
USP4 affects activation NF-kappaB
| 1
USP4 inhibits activation NF-kappaB. 1 / 1
| 1

eidos
"Liang et al. ( 2013 ) 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 ."
USP4 affects activation NF-kappaB AP-1 transcription
| 1
USP4 inhibits activation NF-kappaB AP-1 transcription. 1 / 1
| 1

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

No evidence text available
| 1

sparser
"The ubiquitin peptidase inactive form of USP4 (USP4-C311A) abolished its ability to stabilize HDAC2 ( xref and xref )."
USP4 affects USPs
| 1
USP15 binds USP4, USPs, and BRAP. 1 / 1
| 1

sparser
"Of these, the interaction between BRAP and two related USPs, USP4 and USP15, was of compelling physiological interest given the established role of BRAP/IMP in the regulation of the MAP kinase signaling cascade ( xref )."
USP4 affects USP39
| 1
USP4 binds USP39 and UBL domain. 1 / 1
| 1

reach
"USP39 binds with USP4 via its UBL domain and correspondingly enhances the stability of USP4 in T cells [XREF_BIBR, XREF_BIBR], implying that USP39 might be deubiquitylating USP4."
USP4 affects USP32
1 |
1 |

No evidence text available
USP4 affects USP28
1 |
1 |

No evidence text available
USP4 affects USP21
1 |
1 |

No evidence text available
USP4 affects UL83
| 1
USP4 decreases the amount of UL83. 1 / 1
| 1

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 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 Transferase
| 1

reach
"Interestingly, both USP4 and USP15 associated with Terminal Uridylyl Transferase (TUT1) previously implicated in 3 ' uridylation of U6 snRNA, but not known to associate with the U5/U6 and snRNP complex."
USP4 affects Th17
| 1
USP4 activates Th17. 1 / 1
| 1

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 TUT1
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1 |

No evidence text available
USP4 affects TRMT1
1 |
1 |

No evidence text available
USP4 affects TRIM55
1 |
1 |

No evidence text available
USP4 affects TRIM25
| 1
USP4 deubiquitinates TRIM25. 1 / 1
| 1

reach
"Conversely, USP15 and USP4 deubiquitinate TRIM25 and RIG-I, respectively, to stabilize the proteins."
USP4 affects TNF-alpha-induced IkappaB-alpha
| 1
USP4 activates TNF-alpha-induced IkappaB-alpha. 1 / 1
| 1

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."
USP4 affects TLE5
| 1
USP4 inhibits TLE5. 1 / 1
| 1

reach
"Considering the function of the regulatory axis of TRPS1, USP4, and HDAC2 on transcriptional regulation, we further confirmed that silencing USP4 led to consistent up-regulation of AES, CASP7, IFT27, PERP, SHISA2, TPM4, and ZW10, and additional overexpression of HDAC2 restored the expression levels of these genes (Fig. 5e, f)."
USP4 affects TK1
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1 |

No evidence text available
USP4 affects TH2-related cytokines
| 1
USP4 activates TH2-related cytokines. 1 / 1
| 1

eidos
"USP4 also promotes the development of TH2 cells and upregulation of TH2-related cytokines through physically interacting with and deubiquitinating interferon regulatory factor 4 ( IRF4 ) ( Guo et al ., 2017 ) ."
USP4 affects TGFbetaRI
| 1
USP4 binds TGFbetaRI. 1 / 1
| 1

reach
"At the receptor level, USP4 interacts directly with TGFbetaRI to maintain its stability."
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 TGF-betaR1
| 1
USP4 decreases the amount of TGF-betaR1. 1 / 1
| 1

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."
USP4 affects TGF-beta-induced EMT
| 1
USP4 activates TGF-beta-induced EMT. 1 / 1
| 1

eidos
"Depletion of USP4 blocks TGF-beta-induced EMT ."
USP4 affects TENT5A
1 |
1 |

No evidence text available
USP4 affects SRP9
1 |
1 |

No evidence text available
USP4 affects SRC
| 1
USP4 activates SRC. 1 / 1
| 1

reach
"Additionally, we observed that USP4 overexpression led to a significant increase in CTTN phosphorylation, which is a requisite mechanism for cell migration, by regulating Src/focal adhesion kinase (FAK) binding to CTTN and its activation."
USP4 affects SLX1A
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1 |

No evidence text available
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 ."
USP4 affects RORgammat
| 1
USP4 deubiquitinates RORgammat. 1 / 1
| 1

reach
"Interestingly, TGF-beta plus IL-6 enhanced USP4 mediated deubiquitination of RORgammat."
USP4 affects RNF19B
1 |
1 |

No evidence text available
USP4 affects RL6
1 |
1 |

No evidence text available
USP4 affects RIPPLY2
1 |
1 |

No evidence text available
USP4 affects RCC1
1 |
1 |

No evidence text available
USP4 affects RBL2
1 |
USP4 deubiquitinates RBL2. 1 / 1
1 |

"USP4, reported as an oncogenic protein, is known to interact with the pocket proteins (Rb, p107, and p130) although no deubiquitinating activity has been reported"
USP4 affects Phosphatase
| 1
USP4 increases the amount of Phosphatase. 1 / 1
| 1

reach
"We also found that USP4 knockdown decreased the expressions of phosphatase of regenerating liver-3 (PRL-3), in contrast, overexpression of PRL-3 attenuated the inhibitory effects of USP4 knockdown on NF-κB signaling and cell viability in gastric cancer cells."
USP4 affects PTEN
1 |
1 |

No evidence text available
USP4 affects PRPF4
1 |
1 |

No evidence text available
USP4 affects PPIH
1 |
1 |

No evidence text available
USP4 affects PLOD1
1 |
1 |

No evidence text available
USP4 affects PI3K Akt
| 1
USP4 activates PI3K Akt. 1 / 1
| 1

eidos
"Xiao et al. ( 42 ) revealed that USP4 could activate PI3K / Akt to regulate the progression of peritoneal dialysis ."
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 PGM1
1 |
1 |

No evidence text available
USP4 affects PDGF
| 1
USP4 deubiquitinates PDGF. 1 / 1
| 1

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 PC
| 1
USP4 activates PC. 1 / 1
| 1

reach
"In vitro study showed that knockdown of USP4 inhibited PC cells proliferation, migration and invasion."
USP4 affects P12
| 1
USP4 bound to SMAD4 activates P12. 1 / 1
| 1

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."
USP4 affects NPC2
1 |
1 |

No evidence text available
USP4 affects NOLC1
1 |
1 |

No evidence text available
USP4 affects NFAT-mediated Il4 promoter activity
| 1
USP4 activates NFAT-mediated Il4 promoter activity. 1 / 1
| 1

eidos
"Ubiquitin-specific peptidase 4 ( USP4 ) interacts with IRF4 and NFAT1 to enhance NFAT-mediated Il4 promoter activity ( 63 ) ."
USP4 affects N-end rule substrate Tyr-beta-galactosidase
| 1
USP4 activates N-end rule substrate Tyr-beta-galactosidase. 1 / 1
| 1

reach
"We have demonstrated here that the high-level expression of Unp in yeast does not disrupt the degradation of the N-end rule substrate Tyr-beta-galactosidase (betagal), the non-N-end rule substrate ubiquitin-Pro-betagal, or the degradation of abnormal, canavanine containing proteins."
USP4 affects MTOR
| 1
USP4 phosphorylates MTOR. 1 / 1
| 1

isi
"Moreover, in LPS-treated AML12 cells, LPS-induced USP4, inflammatory and fibrotic cytokines, phosphorylated mTOR and Rheb."
USP4 affects MEPCE
1 |
1 |

No evidence text available
USP4 affects MDM2
| 1
USP4 inhibits MDM2. 1 / 1
| 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]."
USP4 affects MAPK
| 1
Modified USP4 leads to the dephosphorylation of MAPK. 1 / 1
| 1

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)."
USP4 affects MAP4K1
| 1
USP4 decreases the amount of MAP4K1. 1 / 1
| 1

reach
"As shown in XREF_FIG, the upregulation of USP4 significantly inhibited the expression of u-PAR, MAP4K1 and c-Jun, and the knockdown of USP4 significantly upregulated the expression of u-PAR, MAP4K1 and c-Jun (XREF_FIG)."
USP4 affects MAP3K6
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1 |

No evidence text available
USP4 affects Lys63
| 1
USP4 binds MAP3K7 and Lys63. 1 / 1
| 1

reach
"In view of the data presented here and previous reports, we propose a working model (XREF_FIG), in which that TNFalpha 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 TNFalpha induced Lys63 linked TAK1 polyubiquitination and TAK1 mediated IKK and NF-kappaB activation."
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 LSM8
1 |
1 |

No evidence text available
USP4 affects LSM6
1 |
1 |

No evidence text available
USP4 affects LGALS7
1 |
1 |

No evidence text available
USP4 affects LC3II
| 1
USP4 inhibits LC3II. 1 / 1
| 1

eidos
"We found that knockdown or knockout of USP4 led to a sharp increase of LC3II level ( Fig. 6d and Supplementary information , Fig. S6b ) ."
USP4 affects KSPRK
| 1
USP4 leads to the phosphorylation of KSPRK. 1 / 1
| 1

reach
"The phosphorylation of histone H1, KSPRY, and KSPRK by [unP] Cdk2-Speedy and Ringo A2 increased linearly up to the maximum concentration of each substrate."
USP4 affects K48-linked ubiquitination RIG-I
| 1
USP4 inhibits K48-linked ubiquitination RIG-I. 1 / 1
| 1

eidos
"The K48-linked ubiquitination of RIG-I is reversed by USP4 [ 76 ] ."
USP4 affects JUNB
1 |
1 |

No evidence text available
| 1

eidos
"These findings suggest that USP4 may alleviate ischemic stroke by restraining microglia-mediated neuro-inflammation and neurotoxicity via the TRAF6-NF-kappaB pathway , due to which it is a promising therapeutic agent against strokes ."
USP4 affects INSYN2A
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1 |

No evidence text available
USP4 affects IL13
| 1
USP4 inhibits IL13. 1 / 1
| 1

reach
"Compared to the lung cells isolated from WT mice, Usp4 -/- lung cells decreased secretion of IL-4, IL-13 and IL-17A upon stimulation in vitro."
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 Hypertrophy
| 1
| 1

reach
"Thus, the increased expression of USP4 can suppress pathological cardiac hypertrophy."
USP4 affects Histone_H1
| 1
USP4 leads to the phosphorylation of Histone_H1. 1 / 1
| 1

reach
"The phosphorylation of histone H1, KSPRY, and KSPRK by [unP] Cdk2-Speedy and Ringo A2 increased linearly up to the maximum concentration of each substrate."
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 Glioblastoma multiforme GBM
| 1
USP4 activates Glioblastoma multiforme GBM. 1 / 1
| 1

eidos
"Zhou et al. found that USP4 , as a potential novel oncogene , promotes Glioblastoma multiforme ( GBM ) by activating the ERK pathway through TGF-beta regulation [ 11 ] ."
USP4 affects Fibrosis
| 1
| 1

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 ."
USP4 affects FAM126A
| 1
USP4 activates FAM126A. 1 / 1
| 1

reach
"53 USP4 interacts with cyclophilin A and TGF‐β receptor type I and promotes the progression and metastasis of HCC."
USP4 affects ENSA
1 |
1 |

No evidence text available
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 DDX58 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 affects DSB Repair
| 1
USP4 activates DSB Repair. 1 / 1
| 1

reach
"USP4 Promotes DSB Repair."
USP4 affects Cyclin
| 1
USP4 increases the amount of Cyclin. 1 / 1
| 1

reach
"Additionally, qRT-PCR analysis showed that USP4 knockdown significantly downregulated the expressions of cyclin D2 (CCND2) and B cell leukemia/lymphoma 2 (BCL2)."
USP4 affects CDKN1A
1 |
1 |

No evidence text available
USP4 affects CD44s protein
| 1
USP4 activates CD44s protein. 1 / 1
| 1

reach
"To determine the upstream regulators mediating CD44s protein stabilization by ATG7, USP4, USP8, USP28, ITCH, and XIAP were evaluated and compared with T24T (shATG7) vs. T24T (Nonsense) cells."
USP4 affects CCCP-induced clustering ubiquitin mitochondria
| 1
USP4 inhibits CCCP-induced clustering ubiquitin mitochondria. 1 / 1
| 1

eidos
"Importantly , overexpression of USP15 , but not the catalytically inactive C269A USP15 mutant or USP4 , strongly reduced CCCP-induced clustering of ubiquitin on mitochondria , indicating that USP15 opposed Parkin-mediated mitochondrial ubiquitination ( Fig. 6A and D ) ."
USP4 affects C6orf141
1 |
1 |

No evidence text available
USP4 affects BSPRY
1 |
1 |

No evidence text available
USP4 affects BCAR1
| 1
| 1

reach
"We conclude that within cells UNP does physically associate with pRb, and can also associate with p107 and p130."
USP4 affects Aging
| 1
USP4 inhibits Aging. 1 / 1
| 1

reach
"Indeed, it has been suggested that Usp4 is a potential oncogene because it inhibits p53 activity, p53-associated apoptosis and cell-cycle checkpoints; depletion of USP4 promotes cell senescence; loss of USP4 inhibits oncogene-induced primary cell transformation, and finally USP4 is over-expressed in a subset of human cancers [86]."
USP4 affects ATPase
| 1
USP4 inhibits ATPase. 1 / 1
| 1

reach
"Effect of ATP on menadione inhibition of UNP stimulated ATPase."
USP4 affects ATP6V0D1
1 |
1 |

No evidence text available
USP4 affects ATP1B1
1 |
1 |

No evidence text available
USP4 affects ANXA7
1 |
1 |

No evidence text available
USP4 affects AKAP7
1 |
1 |

No evidence text available
USP4 affects 293T
| 1
USP4 binds CTNNB1 and 293T. 1 / 1
| 1

reach
"The interaction of endogenous beta-catenin and USP4 was confirmed in 293T and HCT116 cells, a colon cancer cell line harboring stable beta-catenin that has a mutation at S45 phosphorylation site."
USP39 affects USP4
| 1
USP4 binds USP39 and UBL domain. 1 / 1
| 1

reach
"USP39 binds with USP4 via its UBL domain and correspondingly enhances the stability of USP4 in T cells [XREF_BIBR, XREF_BIBR], implying that USP39 might be deubiquitylating USP4."
USP32 affects USP4
1 |
1 |

No evidence text available
USP28 affects USP4
1 |
1 |

No evidence text available
USP21 affects USP4
1 |
1 |

No evidence text available
USP15 affects bznB
| 1

sparser
"The USP4 and USP15 DU domains interact with E3 ligases ( xref ) and the substrate recruitment factor SART3 ( xref , xref ), but no interactions have yet been reported for these domains in USP11."
USP15 affects Ubiquitin
| 1
| 1

sparser
"In the absence of USP4 and USP15 ubiquitin-bound structures, the molecular bases for these differences are difficult to rationalize at present, as multiple factors will contribute, such as the release of bound water molecules, conformational changes associated with the binding events, and differences in interacting residues."
USP15 affects USPs
| 1
USP15 binds USP4, USPs, and BRAP. 1 / 1
| 1

sparser
"Of these, the interaction between BRAP and two related USPs, USP4 and USP15, was of compelling physiological interest given the established role of BRAP/IMP in the regulation of the MAP kinase signaling cascade ( xref )."
USP15 affects USP7
| 1
USP15 binds USP4 and USP7. 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 affects USP4, and Ubiquitin
| 1
| 1

sparser
"In the absence of USP4 and USP15 ubiquitin-bound structures, the molecular bases for these differences are difficult to rationalize at present, as multiple factors will contribute, such as the release of bound water molecules, conformational changes associated with the binding events, and differences in interacting residues."
USP15 affects USP4, and USP7
| 1
USP15 binds USP4 and USP7. 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
"The USP4 and USP15 DU domains interact with E3 ligases ( xref ) and the substrate recruitment factor SART3 ( xref , xref ), but no interactions have yet been reported for these domains in USP11."
UBL domain affects USP39, and USP4
| 1
USP4 binds USP39 and UBL domain. 1 / 1
| 1

reach
"USP39 binds with USP4 via its UBL domain and correspondingly enhances the stability of USP4 in T cells [XREF_BIBR, XREF_BIBR], implying that USP39 might be deubiquitylating USP4."
UBL domain affects CTNNB1
| 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."
Transferase affects USP4
| 1

reach
"Interestingly, both USP4 and USP15 associated with Terminal Uridylyl Transferase (TUT1) previously implicated in 3 ' uridylation of U6 snRNA, but not known to associate with the U5/U6 and snRNP complex."
TUT1 affects USP4
1 |
1 |

No evidence text available
TRMT1 affects USP4
1 |
1 |

No evidence text available
TRIM55 affects USP4
1 |
1 |

No evidence text available
TK1 affects USP4
1 |
1 |

No evidence text available
TGFbetaRI affects USP4
| 1
USP4 binds TGFbetaRI. 1 / 1
| 1

reach
"At the receptor level, USP4 interacts directly with TGFbetaRI to maintain its stability."
TGFB1 affects USP4
| 1
TGFB1 activates USP4. 1 / 1
| 1

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."
TENT5A affects USP4
1 |
1 |

No evidence text available
TCF4 affects USP4
| 1
| 1

reach
"For example, USP4 interacts with and deubiquitinates TCF4, which inhibits beta-catenin-dependent transcription [XREF_BIBR]."
Snail1 affects USP4
| 1
Snail1 decreases the amount of USP4. 1 / 1
| 1

reach
"Snail1 was induced in lung cancer cells by interaction with macrophages, and epigenetically suppressed USP4 expression by promoter methylation."
SRP9 affects USP4
1 |
1 |

No evidence text available
SLX1A affects USP4
1 |
1 |

No evidence text available
SART3 affects bznB
| 1

sparser
"The USP4 and USP15 DU domains interact with E3 ligases ( xref ) and the substrate recruitment factor SART3 ( xref , xref ), but no interactions have yet been reported for these domains in USP11."
RNF19B affects USP4
1 |
1 |

No evidence text available
RL6 affects USP4
1 |
1 |

No evidence text available
RIPPLY2 affects USP4
1 |
1 |

No evidence text available
RCC1 affects USP4
1 |
1 |

No evidence text available
1 |
Plant Extracts increases the amount of USP4. 1 / 1
1 |

No evidence text available
1 |
1 |

No evidence text available
PTEN affects USP4
1 |
1 |

No evidence text available
PRPF4 affects USP4
1 |
1 |

No evidence text available
PRPF31 affects USP4
1 |
1 |

No evidence text available
PR-619 affects USP4
| 1
PR-619 inhibits USP4. 1 / 1
| 1

reach
"Finally, PR-619, which has been proven to inhibit the activities of USP4 and other deubiquitinases, could inhibit cell viability and NF-κB signaling in gastric cancer cells."
PPIH affects USP4
1 |
1 |

No evidence text available
PLOD1 affects USP4
1 |
1 |

No evidence text available
PITX2 affects USP4
1 |
PITX2 decreases the amount of USP4. 1 / 1
1 |

No evidence text available
PI3K affects USP4
| 1
PI3K increases the amount of USP4. 1 / 1
| 1

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."
PGM1 affects USP4
1 |
1 |

No evidence text available
PCNA affects USP4
1 |
1 |

No evidence text available
NPC2 affects USP4
1 |
1 |

No evidence text available
NOLC1 affects USP4
1 |
1 |

No evidence text available
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]."
MYC affects CTNNB1
| 1
USP4 binds CTNNB1 and MYC. 1 / 1
| 1

sparser
"The wild type USP4 and USP4(261–963) were associated with Myc-β-catenin, while USP4(1–260) showed only weak interaction ( Figure 4 B)."
MYC affects BRAP
| 1
USP4 binds MYC and BRAP. 1 / 1
| 1

sparser
"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 A , compare lanes 2 and 4 with 9 and 11 )."
METTL3 overexpression affects USP4
| 1
METTL3 overexpression inhibits USP4. 1 / 1
| 1

eidos
"As predicted , we found that METTL3 overexpression induced ARHGDIA expression , but downregulated ELAVL1 and USP4 ( Figure S9 ) ."
MEPCE affects USP4
1 |
1 |

No evidence text available
MAP3K7 affects Lys63
| 1
USP4 binds MAP3K7 and Lys63. 1 / 1
| 1

reach
"In view of the data presented here and previous reports, we propose a working model (XREF_FIG), in which that TNFalpha 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 TNFalpha induced Lys63 linked TAK1 polyubiquitination and TAK1 mediated IKK and NF-kappaB activation."
MAP3K6 affects USP4
1 |
1 |

No evidence text available
Lys63 affects USP4
| 1
USP4 binds MAP3K7 and Lys63. 1 / 1
| 1

reach
"In view of the data presented here and previous reports, we propose a working model (XREF_FIG), in which that TNFalpha 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 TNFalpha induced Lys63 linked TAK1 polyubiquitination and TAK1 mediated IKK and NF-kappaB activation."
LSM8 affects USP4
1 |
1 |

No evidence text available
LSM6 affects USP4
1 |
1 |

No evidence text available
LGALS7 affects USP4
1 |
1 |

No evidence text available
JUNB affects USP4
1 |
1 |

No evidence text available
INSYN2A affects USP4
1 |
1 |

No evidence text available
INS affects USP4
| 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."
GLI3 affects USP4
| 1
GLI3 inhibits USP4. 1 / 1
| 1

reach
"PHS damage elevated endoprotease activity and consequently increased the degradation of polymeric UNP and free asparagine concentration in wheat samples."
FOLH1 affects USP4
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FOLH1 inhibits USP4. 1 / 1
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reach
"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."
ENSA affects USP4
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No evidence text available
EGR3 affects USP4
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EGR3 decreases the amount of USP4. 1 / 1
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No evidence text available
EGR2 affects USP4
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EGR2 decreases the amount of USP4. 1 / 1
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No evidence text available
E3_Ub_ligase affects bznB
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sparser
"The USP4 and USP15 DU domains interact with E3 ligases ( xref ) and the substrate recruitment factor SART3 ( xref , xref ), but no interactions have yet been reported for these domains in USP11."
DUSP-Ubl domain affects USP4
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DUSP-Ubl domain activates USP4. 1 / 1
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reach
"Whereas ubiquitin release by USP4 FL is completed in < 1min, USP4 CD requires nearly 1h for full dissociation (XREF_FIG), confirming that the DUSP-Ubl domain activates USP4 by promoting ubiquitin release."
DUSP domain affects USP4
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USP4 binds DDX58 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."
DIPK2A affects USP4
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DIPK2A phosphorylates USP4. 1 / 1
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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."
DDX58 affects DUSP domain, and USP4
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USP4 binds DDX58 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."
CYLD affects OTUB1, SMAD, UCHL5, USP11, USP15, and USP4
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sparser
"Numerous studies have implicated the potential of DUBs to regulate the TGF-β signaling pathway including USP4, USP11, USP15, CYLD, OTUB1, and UCHL5, which interact with Smads to regulate TGF-β signaling [ xref , xref – xref ]."
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."
CTNNB1 affects MYC, and USP4
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USP4 binds CTNNB1 and MYC. 1 / 1
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sparser
"The wild type USP4 and USP4(261–963) were associated with Myc-β-catenin, while USP4(1–260) showed only weak interaction ( Figure 4 B)."
CTNNB1 affects 293T
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USP4 binds CTNNB1 and 293T. 1 / 1
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"The interaction of endogenous beta-catenin and USP4 was confirmed in 293T and HCT116 cells, a colon cancer cell line harboring stable beta-catenin that has a mutation at S45 phosphorylation site."
CPSF3 affects USP4
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CPSF3 inhibits USP4. 1 / 1
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"Interestingly, depletion of CPSF73 substantially reduced Pol II unph, S2P, and S5P pausing over the TES (XREF_FIG A)."
CDKN1A affects USP4
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No evidence text available
C6orf141 affects USP4
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No evidence text available
Brodifacoum affects USP4
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Brodifacoum increases the amount of USP4. 1 / 1
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No evidence text available
BSPRY affects USP4
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No evidence text available
BRAP affects USPs
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USP15 binds USP4, USPs, and BRAP. 1 / 1
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sparser
"Of these, the interaction between BRAP and two related USPs, USP4 and USP15, was of compelling physiological interest given the established role of BRAP/IMP in the regulation of the MAP kinase signaling cascade ( xref )."
BRAP affects MYC, and USP4
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USP4 binds MYC and BRAP. 1 / 1
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sparser
"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 A , compare lanes 2 and 4 with 9 and 11 )."
BCAR1 affects USP4
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reach
"We conclude that within cells UNP does physically associate with pRb, and can also associate with p107 and p130."
Antirheumatic Agents decreases the amount of USP4. 1 / 1
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No evidence text available
ATP6V0D1 affects USP4
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No evidence text available
ATP1B1 affects USP4
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No evidence text available
ARHGDIA affects USP4
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ARHGDIA inhibits USP4. 1 / 1
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reach
"As predicted, we found that METTL3 overexpression induced ARHGDIA expression, but downregulated ELAVL1 and USP4 (XREF_SUPPLEMENTARY)."
ANXA7 affects USP4
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No evidence text available
AKAP7 affects USP4
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No evidence text available
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No evidence text available
293T affects USP4
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USP4 binds CTNNB1 and 293T. 1 / 1
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reach
"The interaction of endogenous beta-catenin and USP4 was confirmed in 293T and HCT116 cells, a colon cancer cell line harboring stable beta-catenin that has a mutation at S45 phosphorylation site."
17alpha-ethynylestradiol increases the amount of USP4. 1 / 1
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No evidence text available
4,4'-diaminodiphenylmethane decreases the amount of USP4. 1 / 1
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No evidence text available
3,4,3',4'-tetrachlorobiphenyl increases the amount of USP4. 1 / 1
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No evidence text available
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No evidence text available