IndraLab

Statements

"Given that JQ1 induces upregulation of DUB3 at both the mRNA and protein levels in different cell types ( Borbely et al., 2015 ) ( Figures 2 J–2M) and DUB3 binds to BRD4 and promotes its deubiquitinat[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"Given that the C-terminal region in three ubiquitously expressed BET proteins including BRD2, BRD3, and BRD4 is very much diversified and only BRD4 contains the C-terminal motif (CTM) ( xref ), we sought to investigate whether the interaction between BRD4 and DUB3 is specific."

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"CoIP assays revealed that while DUB3 bound to BRD4, it did not bind to BRD2 and BRD3 in PC-3 cells ( Figure 4 D)."

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"De-ubiquitinase DUB3 binds to BRD4, but not BRD2/3, via a specific C-terminal motif (CTM), antagonizes SPOP-mediated BRD4 ubiquitination, and promotes BRD4 de-ubiquitination and stabilization, leading to BET-BD inhibitor resistance in cancer cells (Jin et al., 2018)."

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"DUB3 binds to BRD4 and promotes its deubiquitination and stabilization."

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"Given that the C-terminal region in three ubiquitously expressed BET proteins, including BRD2, BRD3, and BRD4, is very much diversified and only BRD4 contains the C-terminal motif (CTM) ( Figure S4 A)[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"DUB3 binds to BRD4 and promotes its deubiquitination and stabilization."

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"Given that JQ1 induces upregulation of DUB3 at both mRNA and protein levels in different cell types ( xref ) ( xref ) and DUB3 binds to BRD4 and promotes its deubiquitination and protein stabilization ( xref and xref ), we sought to determine whether JQ1-induced stabilization of BRD4 is mediated through upregulation of active DUB3."

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"Interaction between endogenous BRD4 and DUB3 proteins was detected in PC-3 cells ( xref )."

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"We further demonstrated that BRD4-DUB3 interaction is mediated through the CTM motif in BRD4 ( xref )."

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BRD4 binds USP17L2, Hemagglutinins, and Flag. 1 / 1

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"To further investigate the relationship between DUB3 and BRD4, we performed reciprocal co-immunoprecipitation (co-IP) assays and demonstrated that ectopically expressed Flag-BRD4 interacted with ectopically expressed HA-DUB3 in 293T cells ( xref )."

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BRD4 binds USP17L2, Hemagglutinins, and FlaG. 1 / 1

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"To further investigate the relationship between DUB3 and BRD4, we performed reciprocal coIP assays and demonstrated that ectopically expressed FLAG-BRD4 interacted with ectopically expressed HA-DUB3 i[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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USP17L2 deubiquitinates BRD4.

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USP17L2 deubiquitinates BRD4. 10 / 10

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"Based on these genomic data and our finding that NCOR2 represses DUB3 expression in cultured cells, we hypothesized that loss of NCOR due to deletions or mutations results in DUB3 upregulation, which [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"Knockdown of DUB3 completely abolished NCOR2-depletion-induced elevation of BRD4 protein and BRD4 protein polyubiquitination but had no effect on BRD4 mRNA expression."

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"In a recent study, DUB3 was shown to promote BRD4 deubiquitination and stabilization in various cancer cell lines [XREF_BIBR]."

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"Furthermore, PD0332991 treatment also increased BRD4 polyubiquitination, shortened the BRD4 protein half-life, and reversed DUB3 mediated deubiquitination of BRD4 in DU145 cells."

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"In support of these findings, we show that inhibition of BRD4 by JQ1 blocks NCOR2 mRNA expression, which in turn dismisses NCOR2 mediated repression of DUB3 and DUB3 mediated deubiquitination of BRD4."

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"In agreement with these findings, knockdown of DUB3 shortened the BRD4 protein half-life and dramatically increased endogenous BRD4 ubiquitination in PC-3 cells."

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"DUB3 promotes BET inhibitor resistance and cancer progression by deubiquitinating BRD4."

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"DUB3 Deubiquitinates BRD4 to Promote Prostate Cancer Progression."

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"For example, BRD4 interacted with and was de-ubiquitinated by deubiquitinase DUB3."

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"Here, we demonstrate that the deubiquitinase DUB3 binds to BRD4 and promotes its deubiquitination and stabilization."

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USP17L2 activates BRD4.

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USP17L2 activates BRD4. 7 / 7

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"We demonstrated that knockdown of endogenous DUB3 by two independent shRNAs largely decreased BRD4 protein and that these effects were reversed by restored expression of DUB3-WT and the phospho mimick[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"Interestingly, a recent study shows that a proficient expression of deubiquitinase DUB3 in prostate cancer can promote BRD4 stabilization and resistance to BETi ."

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"We further showed that forced expression of DUB3 induced upregulation of BRD4 proteins in cultured cells and that elevation of DUB3 expression was correlated with a high level of BRD4 protein in a sub[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"Treatment of DU145 cells with PD0332991 decreased BRD4 protein levels in a time dependent manner, and the effect of PD0332991 was completely impeded by the proteasome inhibitor MG132, arguing that CDK[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"In contrast, knockdown of DUB3 by two independent shRNAs decreased the level of endogenous BRD4 proteins but had no overt effect on BRD4 mRNA expression in both PC-3 and DU145 cells."

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"DUB3 mediated BRD4 stabilization overcomes SPOP mediated degradation to confer BET inhibitor resistance."

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"Accordingly, overexpression of DUB3 increased the level of ectopically expressed full-length BRD4 protein in a dose dependent manner but had no effect on BRD4DeltaCTM mutant, BRD2 or BRD3 in PC-3 cell[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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USP17L2 increases the amount of BRD4.

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USP17L2 increases the amount of BRD4. 5 / 5

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"To test this hypothesis, we co-expressed DUB3 with BRD4 in 293T cells and found that DUB3 increased BRD4 protein expression in a dose dependent manner."

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"Moreover, knockdown of DUB3 largely decreased BRD4 protein levels, but little or no further reduction in BRD4 protein expression by co-treatment with PD0332991 was observed."

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"Accordingly, DUB3 knockdown decreased BRD4 protein levels in F133V expressing cells, and this effect was blocked by MG132."

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"In an array of cancer cell lines, we demonstrated that knockdown of DUB3 by shRNAs largely decreased BRD4 protein levels, but not at mRNA levels."

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"Unexpectedly, knockdown of DUB3 not only decreased BRD4 protein levels in SPOP F133V expressing DU145 cells but also sensitized SPOP-F133V cells to JQ1 treatment, suggesting the presence of a SPOP ind[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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USP17L2 ubiquitinates BRD4.

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USP17L2 leads to the ubiquitination of BRD4. 3 / 3

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"Moreover, SPOP mediated polyubiquitination of BRD4 was largely diminished by co-expression of DUB3-WT, but not the C89S mutant."

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"Downregulation of DUB3 promoted BRD4 ubiquitination."

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"Downregulation of DUB3 promoted BRD4 ubiquitination."

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USP17L2 inhibits BRD4.

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USP17L2 inhibits BRD4. 1 / 1

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"We further demonstrated that downregulation of BRD4 proteins caused by DUB3 knockdown was reversed by treating cells with the proteasome inhibitor MG132."

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USP17L2 is modified

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USP17L2 is phosphorylated.

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USP17L2 is phosphorylated on S41. 10 / 22

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"CDK4/6-mediated serine-41 phosphorylation of DUB3 has been shown to be essential for the catalytic activity of DUB3 ( xref )."

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"We next tested how CDK4/6 and S41 phosphorylation of DUB3 affects SNAIL1 ubiquitination."

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"As shown in xref , mutation at S41 abolished CDK4/6-mediated phosphorylation of DUB3 in vitro ."

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"Cell lysates were subjected to immunoprecipitation with anti-FLAG antibody and the phosphorylation of Ser41 in DUB3 was then examined."

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"We found that Ser41 is a major phosphorylation site on DUB3, which matches with a CDK consensus motif (Supplementary Fig. 6b). To test whether S41 is a CDK4/6 phosphorylation site, GST-fused WT DUB3 and S41A mutants were incubated with active CDK4 or CDK6 and an in vitro kinase assay was performed. As shown in Fig. 5d, mutation at S41 abolished CDK4/6-mediated phosphorylation of DUB3 in vitro. A phospho-Ser41-specific antibody was generated to further study the phosphorylation of Ser41 in cells."

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"Phosphorylation of Ser41 regulates DUB3 activity."

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"We next tested how CDK4/6 and S41 phosphorylation of DUB3 affects SNAIL1 ubiquitination. We transfected cells with FLAG-DUB3 and HA-SNAIL1, treated cells with vehicle or CDK4/6 inhibitor PD0332991, and SNAIL1 ubiquitination was determined. As shown in Fig. 6a, SNAIL1 ubiquitination was stronger in cells treated with PD0332991 compared to vehicle, suggesting that CDK4/6 activity is important for the catalytic activity of DUB3. We further tested whether phosphorylation of S41 on DUB3 could affect the ubiquitination of SNAIL1 in cells. As shown in Fig. 6b,c, overexpression of both WT and S41D mutant DUB3 in cells efficiently decreased the ubiquitination of SNAIL1; however, S41A mutant failed to do so. Collectively, these results suggest that phosphorylation of S41 is important for the deubiquitinase activity of DUB3 towards SNAIL1."

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"We further tested whether phosphorylation of S41 on DUB3 could affect the ubiquitination of SNAIL1 in cells."

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"We next tested how CDK4/6 and S41 phosphorylation of DUB3 affects SNAIL1 ubiquitination."

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"We further tested whether phosphorylation of S41 on DUB3 could affect the protein level of SNAIL1 in cells."

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"It was also shown that palbociclib did not directly interact with SNAIL1, but instead acted through the phosphorylation of deubiquitinating enzyme 3 (DUB3), which, in turn, downregulates SNAIL1, xref suggesting a new target for palbociclib."

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"These results establish that CDK4/6-mediated phosphorylation of DUB3 is important for DUB3 activity and SNAIL1 stability."

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"In particular, it has been demonstrated that both these CDKs can bind and phosphorylate the deubiquitinase USP51 and DUB3, to control ZEB1 [ xref ] and SNAIL1 [ xref ] expression, respectively, thereby modulating the metastatic phenotype of cancer cells."

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"Interestingly, CDK1 also phosphorylated DUB3 at Ser41 in vitro and the treatment of Roscovitine could decrease the phosphorylation of DUB3 ( xref )."

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"In agreement with the recent report that the deubiquitination activity of DUB3 relies on CDK4/6-mediated phosphorylation of DUB3 and this activity is inhibited by the CDK4/6 inhibitor ( xref ), we demonstrated that treatment of mice with the CDK4/6 inhibitor palbociclib largely sensitized DUB3-proficient prostate tumors to JQ1, but the effect of palbociclib was almost completely abolished by DUB3 knockdown."

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"However, S41A mutation completely abrogated the phosphorylation of DUB3 at this site, indicating the specificity of this antibody."

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"To further identify the potential phosphorylation sites in DUB3, we generated MDA-MB-231 cells stably expressing FLAG-DUB3 to perform tandem affinity purification and mass spectrometry analysis of potential phosphorylation events in DUB3."

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"We next tested CDK4/6-mediated phosphorylation of DUB3 in cells."

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"In agreement with the recent report that the deubiquitination activity of DUB3 relies on CDK4/6-mediated phosphorylation of DUB3 and that this activity is inhibited by the CDK4/6 inhibitor ( Liu et al[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"Furthermore, depletion of CDK4 or CDK6 in cells only partially decreased the phosphorylation of DUB3, while double knockdown of CDK4 and CDK6 almost completely abrogated DUB3 phosphorylation ( xref )."

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USP17L2 is ubiquitinated.

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USP17L2 is ubiquitinated. 1 / 1

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"Co-expression of wild-type (WT) Dub3 almost completely abolished ubiquitination of Slug and Twist, while co-expression of CS-Dub3 did not show this effect (lane 2 vs lane 3 in both upper panels, Figure xref )."

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USP17L2 affects SNAI1

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USP17L2 binds SNAI1.

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"The interaction of Snail with Dub3 is mediated at the N-terminal region of Snail, which holds the SNAG domain and is the most common binding site for E3[ xref ]."

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"By blocking the interaction of Dub3 and Snail, WP1130 prevents the deubiquitination of Snail, thereby blocking cancer invasion, migration, and the establishment of CSC like properties."

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"However, only Dub3 interacted with Snail1 in the co-immunoprecipitation (IP) assay ( xref )."

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"We confirmed the endogenous SNAIL1–DUB3 interaction by co-immunoprecipitation in both MDA-MB-231 and BT-549 cells ( xref ; xref )."

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"The interaction between Dub3 and Snail1 was further confirmed by immunofluorescence (IF) analysis showing that endogenous Dub3 co-localized with Snail1 in the nucleus of MDA-MB231 cells ( xref )."

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"DUB3 (official symbol USP17L2) was shown to promote breast cancer invasion and metastasis via stabilizing Snail1 in a CDK4/6 activity-dependent manner ."

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USP17L2 deubiquitinates SNAI1.

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"CDK4/6-mediated activation of DUB3 is essential to deubiquitinate and stabilize SNAIL1"

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SNAI1 affects USP17L2

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SNAI1 binds USP17L2.

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"The interaction of Snail with Dub3 is mediated at the N-terminal region of Snail, which holds the SNAG domain and is the most common binding site for E3[ xref ]."

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"By blocking the interaction of Dub3 and Snail, WP1130 prevents the deubiquitination of Snail, thereby blocking cancer invasion, migration, and the establishment of CSC like properties."

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"However, only Dub3 interacted with Snail1 in the co-immunoprecipitation (IP) assay ( xref )."

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"We confirmed the endogenous SNAIL1–DUB3 interaction by co-immunoprecipitation in both MDA-MB-231 and BT-549 cells ( xref ; xref )."

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"The interaction between Dub3 and Snail1 was further confirmed by immunofluorescence (IF) analysis showing that endogenous Dub3 co-localized with Snail1 in the nucleus of MDA-MB231 cells ( xref )."

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SNAI1 inhibits USP17L2.

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"This study found that in H1975OR, CDK4/6 inhibitor might downregulate DUB3 by inhibiting the function of CDK4, and Snail may be ubiquitinated and degraded due to the loss of DUB3 protection, thus reducing tumor invasion and metastasis."

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Cdk-4 affects USP17L2

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Cdk-4 phosphorylates USP17L2.

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"Indeed, we found that CDK4/6 could phosphorylate DUB3 in vitro ( xref )."

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"We hypothesized that CDK4/6 could phosphorylate DUB3."

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"We hypothesized that CDK4/6 could phosphorylate DUB3."

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"CDK4/6 phosphorylates and activates DUB3."

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"We next tested CDK4/6 mediated phosphorylation of DUB3 in cells."

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"As shown in XREF_FIG, mutation at S41 abolished CDK4/6 mediated phosphorylation of DUB3 in vitro."

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"Indeed, we found that CDK4/6 could phosphorylate DUB3 in vitro (XREF_SUPPLEMENTARY)."

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"These data suggest that CDK4/6 phosphorylation of DUB3 is essential for DUB3-mediated deubiquitination and stabilization of BRD4 ( Figure 6 M)."

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"These data suggest that CDK4/6 phosphorylation of DUB3 is essential for DUB3 mediated deubiquitination and stabilization of BRD4."

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"CDK4/6 phosphorylates and activates DUB3."

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Cdk-4 phosphorylates USP17L2 on S41. 7 / 7

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"We found that CDK4/6 inhibition markedly reduces the phosphorylation of DUB3 at Ser41 (XREF_FIG)."

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"CDK4/6 phosphorylates Dub3 at Ser41, a crucial site for Dub3 activity in the regulation of Snail’s stability[ xref ]."

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"CDK4/6 phosphorylates Ser41 of DUB3."

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"Liu et al. identified DUB3 as a new target of CDK4/6, and CDK4/6 phosphorylates DUB3 at serine 41."

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"We next tested how CDK4/6 and S41 phosphorylation of DUB3 affects SNAIL1 ubiquitination."

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"CDK4/6 phosphorylates Dub3 at Ser41, a crucial site for Dub3 activity in the regulation of Snail 's stability [XREF_BIBR]."

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"CDK4/6 phosphorylates Ser41 of DUB3."

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Cdk-4 activates USP17L2.

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"CDK4/6 dependent activation of DUB3 regulates cancer metastasis through SNAIL1."

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"Besides, CDK4/6 mediated activation of DUB3 has been reported to be essential to deubiquitinate and stabilize SNAIL1, a key factor promoting EMT and involved in breast cancer metastasis 34."

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"CDK4/6 phosphorylates and activates DUB3."

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"As a linker between CDK4/6 and SNAIL1, DUB3 activation by CDK4/6 is essential to deubiquitinate SNAIL1."

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"For instance, Snail1-dependent p53 repression regulates the expansion and activity of tumour-initiating cells in breast cancer [33], CDK4/6-dependent activation of DUB3 regulates cancer metastasis through Snail1 [27]."

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"CDK4/6 mediated activation of DUB3 is essential to deubiquitinate and stabilize SNAIL1, a transcription factor that promotes epithelial-mesenchymal transition (EMT) and, therefore, invasiveness."

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"CDK4/6-dependent activation of DUB3 regulates cancer metastasis through SNAIL1."

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"27 The main mechanism might be that CDK4/6‐mediated activation of DUB3 is essential to deubiquitinate and stabilize Snail."

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Cdk-4 binds USP17L2.

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"Moreover, increasing PI3K/Akt/mTOR activity, modulating apoptosis, altering Rho/Rac pathway would promote angiogenesis finally. xref , xref The CDK4/6‐DUB3 axis may act as an important regulatory mechanism of BCBM."

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"The interaction between CDK4/6 and DUB3 was also detected by endogenous co-immunoprecipitation and in vitro pull down (XREF_FIG)."

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"The interaction between CDK4/6 and DUB3 was also detected by endogenous co-immunoprecipitation and in vitro pull down ( xref )."

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Cdk-4 inhibits USP17L2.

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"These data suggest DUB3 is a critical upstream regulator of BRD4 protein stability and that inhibition of DUB3 by CDK4/6 inhibitor overcomes BET-inhibitor-induced elevation of BRD4 protein and BET inh[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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BRD4 affects USP17L2

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"CoIP assays revealed that while DUB3 bound to BRD4, it did not bind to BRD2 and BRD3 in PC-3 cells ( Figure 4 D)."

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"DUB3 binds to BRD4 and promotes its deubiquitination and stabilization."

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"DUB3 binds to BRD4 and promotes its deubiquitination and stabilization."

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"Interaction between endogenous BRD4 and DUB3 proteins was detected in PC-3 cells ( xref )."

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"We further demonstrated that BRD4-DUB3 interaction is mediated through the CTM motif in BRD4 ( xref )."

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BRD4 inhibits USP17L2.

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"Using a gain-of-function approach, we demonstrated that overexpression of BRD4 elevated NCOR2 expression but repressed DUB3 at both the mRNA and protein levels in C4-2 cells."

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"Particularly, it has been found that USP17L2 interacts with and stabilizes Slug and Twist through de-ubiquitination (28)."

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"Our current results demonstrated that Dub3 interacts with Slug and Twist and prevents Slug and Twist from degradation mediated by these E3 ligases."

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"Dub3 interacts with Slug and Twist."

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"Taken together, our results demonstrated that Slug and Twist associate with Dub3 and are subject to Dub3 mediated de-ubiquitination, which contributes to their protein stabilization."

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"We found that Dub3 interacted with and stabilized Slug and Twist through de-ubiquitination."

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"However, we found that only Dub3, but not USP28, interacted with Slug (top panel, Figure xref )."

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"Of importance, Dub3 interacted with Slug and Twist and prevented them from degradation, thereby promoting migration, invasion, and cancer stem cell (CSC)-like properties of breast cancer cells."

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"Taken together, our results demonstrated that Slug and Twist associate with Dub3 and are subject to Dub3-mediated de-ubiquitination, which contributes to their protein stabilization."

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"Our current results demonstrated that Dub3 interacts with Slug and Twist and prevents Slug and Twist from degradation mediated by these E3 ligases."

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"Dub3 interacts with Slug and Twist."

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"In addition, DUB3 also interacts with SLUG and TWIST and prevents their degradation, thereby promoting migration, invasion, and cancer stem cell-like properties in breast cancer cells [ xref ]."

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"Concurrently, we also performed endogenous Co-IP and confirmed the association of Dub3 with Slug and Twist in MDA-MB157 and SUM159 cells (Figure xref )."

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"Of importance, Dub3 interacted with Slug and Twist and prevented them from degradation, thereby promoting migration, invasion, and cancer stem cell (CSC)-like properties of breast cancer cells."

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USP17L2 increases the amount of SNAI2.

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Modified USP17L2 increases the amount of SNAI2. 2 / 2

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"Expression of Dub3 in these two cell lines dramatically increased the levels of Slug and Twist and reduced E-cadherin and ER expression."

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"We further found that Dub3 overexpression increased Slug and Twist protein levels in a dose dependent manner, whereas Dub3-knockdown decreased their protein levels."

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USP17L2 increases the amount of SNAI2. 1 / 1

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"When Dub3 was co-expressed with Slug in HEK293 cells, we found that Dub3 significantly increased protein levels of Slug, an effect comparable to treatment with proteasome inhibitor MG132 (top panel, Figure XREF_FIG)."

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USP17L2 deubiquitinates SNAI2.

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"In this study, we identified Dub3 as a novel DUB for both Slug and Twist. We further found that Dub3 overexpression increased Slug and Twist protein levels in a dose-dependent manner, whereas Dub3-knockdown decreased their protein levels."

29088851

➶

reach

"Dub3 deubiquitinates Slug and Twist."

USP17L2 affects TWIST1

2 1 | 11 8

USP17L2 binds TWIST1.

2 | 6 7

TWIST1 binds USP17L2. 9 / 9

2 | 6 1

➶

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"Particularly, it has been found that USP17L2 interacts with and stabilizes Slug and Twist through de-ubiquitination (28)."

30628680

➶

biogrid

No evidence text available

29088851

➶

reach

"We found that Dub3 interacted with and stabilized Slug and Twist through de-ubiquitination."

29088851

➶

reach

"Taken together, our results demonstrated that Slug and Twist associate with Dub3 and are subject to Dub3 mediated de-ubiquitination, which contributes to their protein stabilization."

29088851

➶

biogrid

No evidence text available

29088851

➶

reach

"Of importance, Dub3 interacted with Slug and Twist and prevented them from degradation, thereby promoting migration, invasion, and cancer stem cell (CSC)-like properties of breast cancer cells."

29088851

➶

reach

"Dub3 interacts with Slug and Twist."

29088851

➶

reach

"Our current results demonstrated that Dub3 interacts with Slug and Twist and prevents Slug and Twist from degradation mediated by these E3 ligases."

29088851

➶

sparser

"Similar to Slug, Twist also interacted with Dub3 but not USP28 (bottom panel, Figure xref )."

29088851

SNAI2 binds TWIST1 and USP17L2. 6 / 6

| 6

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sparser

"Taken together, our results demonstrated that Slug and Twist associate with Dub3 and are subject to Dub3-mediated de-ubiquitination, which contributes to their protein stabilization."

29088851

➶

sparser

"Our current results demonstrated that Dub3 interacts with Slug and Twist and prevents Slug and Twist from degradation mediated by these E3 ligases."

29088851

➶

sparser

"Dub3 interacts with Slug and Twist."

29088851

➶

sparser

"In addition, DUB3 also interacts with SLUG and TWIST and prevents their degradation, thereby promoting migration, invasion, and cancer stem cell-like properties in breast cancer cells [ xref ]."

32268558

➶

sparser

"Concurrently, we also performed endogenous Co-IP and confirmed the association of Dub3 with Slug and Twist in MDA-MB157 and SUM159 cells (Figure xref )."

29088851

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sparser

"Of importance, Dub3 interacted with Slug and Twist and prevented them from degradation, thereby promoting migration, invasion, and cancer stem cell (CSC)-like properties of breast cancer cells."

29088851

USP17L2 deubiquitinates TWIST1.

1 | 2

USP17L2 deubiquitinates TWIST1. 2 / 2

1 | 1

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ubibrowser

29088851

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"Dub3 deubiquitinates Slug and Twist."

29088851

Modified USP17L2 leads to the deubiquitination of TWIST1. 1 / 1

| 1

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29088851

USP17L2 increases the amount of TWIST1.

| 2

Modified USP17L2 increases the amount of TWIST1. 2 / 2

| 2

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reach

"We further found that Dub3 overexpression increased Slug and Twist protein levels in a dose dependent manner, whereas Dub3-knockdown decreased their protein levels."

29088851

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reach

"Expression of Dub3 in these two cell lines dramatically increased the levels of Slug and Twist and reduced E-cadherin and ER expression."

29088851

USP17L2 ubiquitinates TWIST1.

| 1

USP17L2 ubiquitinates TWIST1. 1 / 1

| 1

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sparser

29088851

USP17L2 activates TWIST1.

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USP17L2 activates TWIST1. 1 / 1

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"Surprisingly, Dub3 also significantly increased Twist protein (bottom panel, Figure XREF_FIG)."

29088851

USP17L2 affects cell population proliferation

| 2 16

USP17L2 inhibits cell population proliferation.

| 10

USP17L2 inhibits cell population proliferation. 10 / 10

| 10

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reach

"Dub-3, which is known as Usp17, is responsible for the regulation of cell growth and survival, and the constitutive expression of Dub-3 can block cell proliferation XREF_BIBR - XREF_BIBR."

22984479

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reach

"DUB3 inhibited HCC cell proliferation in vitro and tumor growth in vivo while enhancing the chemosensitivity of HCC cells in a KLF4-dependent manner."

35383144

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reach

"More recently, we have also reported that constitutive expression of DUB-3 can block cell proliferation [XREF_BIBR, XREF_BIBR] and subsequently we have demonstrated that this is due to its regulation of the ubiquitination and activity of the ' CAAX ' box protease Ras converting enzyme 1 (RCE1) [XREF_BIBR]."

20403174

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reach

"The constitutive expression of DUB-3 can block cell proliferation and initiate apoptosis [25]."

23773437

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reach

"Knockdown of Dub3 could inhibit the proliferation of ovarian cancer cells and increase cell apoptosis."

25776484

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reach

"DUB-3, a cytokine inducible deubiquitinating enzyme that blocks proliferation."

14699124

➶

reach

"We originally showed that constitutive expression of DUB-3 can block cell proliferation and more recently we have demonstrated that this is due to its regulation of the ubiquitination and activity of the ' CAAX ' box protease RCE1."

20403174

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reach

"In particular, DUB-1 expression results in cell cycle arrest prior to S-phase [XREF_BIBR], DUB-2 expression markedly inhibits apoptosis induced by cytokine withdrawal [XREF_BIBR] and we have previously reported that constitutive expression of DUB-3 blocks cell proliferation [XREF_BIBR, XREF_BIBR, XREF_BIBR] through its regulation of the ubiquitination and activity of the ' CAAX ' box protease RCE1 [XREF_BIBR, XREF_BIBR]."

20403174

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reach

"Finally, we have demonstrated that constitutive expression of DUB-3 blocks proliferation and can initiate apoptosis in both IL-3-dependent Ba/F3 cells and NIH3T3 fibroblasts."

14699124

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reach

"USP17 subfamily members have been previously identified [XREF_BIBR] and one of them, DUB-3, has shown that the constitutive expression of DUB-3 blocks proliferation and can lead to apoptosis [XREF_BIBR]."

17109758

USP17L2 activates cell population proliferation.

| 2 6

USP17L2 activates cell population proliferation. 8 / 8

| 2 6

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reach

"DUB3 promoted OSCC cells proliferation, while suppressing apoptosis via facilitating EZH2 production."

32110043

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eidos

"The knockdown of USP17 also suppressed cell proliferation and glycolysis ."

35076962

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reach

"In summary, we found that DUB3 enhanced OSCC cells proliferation and xenograft tumor growth, while inhibited their apoptosis via promoting BRD4 mediated upregulation of EZH2."

32110043

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reach

"Similar to our observations, previous shRNA studies have also indicated that Dub3 knockdown reduces proliferation by inhibiting the G1-S phase cell cycle progression and inhibits chemotaxis [14,15,26][MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

25776484

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reach

"In vitro, Dub3 knockdown could inhibit the proliferation of ovarian cancer cells and increase cell apoptosis."

25776484

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eidos

"McFarlane et al. identify that USP17 is highly expressed in several tumor biopsies , and USP17 depletion significantly impairs G1-S phase transition and blocks cell proliferation ( 56 ) ."

33194625

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reach

"Functionally, we found that the effect of DUB3 on cyclin A mediates proliferation of NSCLC cells."

30935108

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reach

"DUB3 may also promote the proliferation of NSCLC by inhibiting Cyclin A degradation."

33943009

USP17L2 affects Snail1

| 17

USP17L2 activates Snail1.

| 5

USP17L2 activates Snail1. 5 / 5

| 5

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"However, knockdown of Dub3 blocked the Snail1 stabilization effect mediated by the knockdown of either beta-TRCP1 or FBXL14 (lanes 4 and 5, XREF_FIG), indicating that Dub3 is a critical factor controlling Snail1 stability."

28198361

➶

reach

"Together, these data indicate that Dub3 can induce EMT (luminal to basal like phenotype conversion) by stabilizing Snail1 in breast cancer cells."

28198361

➶

reach

"Dub3 expression induced Snail1 stabilization as well as downregulation of E-cadherin and oestrogen receptor alpha (ERalpha) in these cells (XREF_FIG)."

28198361

➶

reach

"Expression of the WT-Dub3, but not CS-Dub3, blocked Snail1 degradation mediated by these two ligases."

28198361

➶

reach

"DUB3 mediated Snail1 stabilization is induced and activated by cytokine IL-6 [XREF_BIBR] in a CDK4/6 dependent manner [XREF_BIBR]."

33466790

USP17L2 binds Snail1.

| 4

USP17L2 binds Snail1. 4 / 4

| 4

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reach

"Taken together, our results indicate that Dub3 interacts with Snail1 and that this interaction is mediated through the N-terminal regions of Dub3 and N-terminal region of Snail1."

28198361

➶

reach

"Dub3 interacts with Snail1."

28198361

➶

reach

"However, only Dub3 interacted with Snail1 in the co-immunoprecipitation (IP) assay (XREF_SUPPLEMENTARY)."

28198361

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reach

"The interaction between Dub3 and Snail1 was further confirmed by immunofluorescence (IF) analysis showing that endogenous Dub3 co-localized with Snail1 in the nucleus of MDA-MB231 cells (XREF_FIG)."

28198361

USP17L2 increases the amount of Snail1.

| 3

USP17L2 increases the amount of Snail1. 2 / 2

| 2

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reach

"In contrast, Dub3 knockdown in MDA-MB231 and MDA-MB157 cells not only reduced the endogenous level of Snail1 but also blocked IL-6-induced Snail1 stabilization (XREF_FIG)."

28198361

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reach

"When these DUBs were co-expressed with Snail1 in HEK293 cells, we found that USP12, Dub3 and USP28 significantly increased Snail1 levels, similar to results obtained when cells were treated with the proteasome inhibitor MG132 (XREF_SUPPLEMENTARY)."

28198361

Modified USP17L2 increases the amount of Snail1. 1 / 1

| 1

➶

reach

"A steady-state level of Snail1 was enhanced by increasing Dub3 expression in a dose dependent manner (XREF_FIG)."

28198361

USP17L2 ubiquitinates Snail1.

| 2

Modified USP17L2 leads to the ubiquitination of Snail1. 2 / 2

| 2

➶

2 | 6 1

➶

reach

"Particularly, it has been found that USP17L2 interacts with and stabilizes Slug and Twist through de-ubiquitination (28)."

30628680

➶

biogrid

No evidence text available

29088851

➶

reach

"We found that Dub3 interacted with and stabilized Slug and Twist through de-ubiquitination."

29088851

➶

reach

"Taken together, our results demonstrated that Slug and Twist associate with Dub3 and are subject to Dub3 mediated de-ubiquitination, which contributes to their protein stabilization."

29088851

➶

biogrid

No evidence text available

29088851

➶

reach

"Of importance, Dub3 interacted with Slug and Twist and prevented them from degradation, thereby promoting migration, invasion, and cancer stem cell (CSC)-like properties of breast cancer cells."

29088851

➶

reach

"Dub3 interacts with Slug and Twist."

29088851

➶

reach

"Our current results demonstrated that Dub3 interacts with Slug and Twist and prevents Slug and Twist from degradation mediated by these E3 ligases."

29088851

➶

sparser

"Similar to Slug, Twist also interacted with Dub3 but not USP28 (bottom panel, Figure xref )."

29088851

SNAI2 binds TWIST1 and USP17L2. 6 / 6

| 6

➶

sparser

"Taken together, our results demonstrated that Slug and Twist associate with Dub3 and are subject to Dub3-mediated de-ubiquitination, which contributes to their protein stabilization."

29088851

➶

sparser

"Our current results demonstrated that Dub3 interacts with Slug and Twist and prevents Slug and Twist from degradation mediated by these E3 ligases."

29088851

➶

sparser

"Dub3 interacts with Slug and Twist."

29088851

➶

sparser

"In addition, DUB3 also interacts with SLUG and TWIST and prevents their degradation, thereby promoting migration, invasion, and cancer stem cell-like properties in breast cancer cells [ xref ]."

32268558

➶

sparser

"Concurrently, we also performed endogenous Co-IP and confirmed the association of Dub3 with Slug and Twist in MDA-MB157 and SUM159 cells (Figure xref )."

29088851

➶

sparser

"Of importance, Dub3 interacted with Slug and Twist and prevented them from degradation, thereby promoting migration, invasion, and cancer stem cell (CSC)-like properties of breast cancer cells."

29088851

SNAI2 affects USP17L2

2 | 6 7

SNAI2 binds USP17L2. 9 / 9

2 | 6 1

➶

biogrid

No evidence text available

29088851

➶

reach

"Particularly, it has been found that USP17L2 interacts with and stabilizes Slug and Twist through de-ubiquitination (28)."

30628680

➶

reach

"Our current results demonstrated that Dub3 interacts with Slug and Twist and prevents Slug and Twist from degradation mediated by these E3 ligases."

29088851

➶

reach

"Dub3 interacts with Slug and Twist."

29088851

➶

reach

"Taken together, our results demonstrated that Slug and Twist associate with Dub3 and are subject to Dub3 mediated de-ubiquitination, which contributes to their protein stabilization."

29088851

➶

biogrid

No evidence text available

29088851

➶

reach

"We found that Dub3 interacted with and stabilized Slug and Twist through de-ubiquitination."

29088851

➶

sparser

"However, we found that only Dub3, but not USP28, interacted with Slug (top panel, Figure xref )."

29088851

➶

reach

"Of importance, Dub3 interacted with Slug and Twist and prevented them from degradation, thereby promoting migration, invasion, and cancer stem cell (CSC)-like properties of breast cancer cells."

29088851

SNAI2 binds TWIST1 and USP17L2. 6 / 6

| 6

➶

sparser

"Taken together, our results demonstrated that Slug and Twist associate with Dub3 and are subject to Dub3-mediated de-ubiquitination, which contributes to their protein stabilization."

29088851

➶

sparser

"Our current results demonstrated that Dub3 interacts with Slug and Twist and prevents Slug and Twist from degradation mediated by these E3 ligases."

29088851

➶

sparser

"Dub3 interacts with Slug and Twist."

29088851

➶

sparser

"In addition, DUB3 also interacts with SLUG and TWIST and prevents their degradation, thereby promoting migration, invasion, and cancer stem cell-like properties in breast cancer cells [ xref ]."

32268558

➶

sparser

"Concurrently, we also performed endogenous Co-IP and confirmed the association of Dub3 with Slug and Twist in MDA-MB157 and SUM159 cells (Figure xref )."

29088851

➶

sparser

"Of importance, Dub3 interacted with Slug and Twist and prevented them from degradation, thereby promoting migration, invasion, and cancer stem cell (CSC)-like properties of breast cancer cells."

29088851

USP17L2 affects Neoplasm Metastasis

| 3 10

USP17L2 activates Neoplasm Metastasis.

| 3 8

USP17L2 activates Neoplasm Metastasis. 10 / 11

| 3 8

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reach

"To directly assess whether Dub3 promotes metastasis in vivo, we intravenously injected Dub3-knockdown MDA-MB231 cells into female SCID mice and subjected these mice to bioluminescent imaging (BLI)."

28198361

➶

reach

"Dub3 inhibition suppresses breast cancer invasion and metastasis by promoting Snail1 degradation."

31147601

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eidos

"It has been reported that Snail1 pathway is involved in the progression of many diseases , for instance , Dub3 inhibition suppresses breast cancer invasion and metastasis by promoting Snail1 degradation.25 CLDN6 promotes tumor progression through the YAP1-snail1 axis in gastric cancer.26 Moreover , it has been reported that Snail1 has involved the progression of DN.27 Consistent with our research , mRNA and protein expression of Snail1 was decreased in PVT1-KD MCs , which was reversed by treating with miR-325-3p inhibitor ."

33907435

➶

reach

"DUB3 (official symbol USP17L2) was shown to promote breast cancer invasion and metastasis via stabilizing Snail1 in a CDK4/6 activity-dependent manner ."

32968046

➶

eidos

"Inhibition of USP17 promotes SNAI1 degradation , thereby suppressing breast cancer invasion and metastasis ( 49 , 53 ) ."

33194625

➶

reach

"Dub3 knockdown after DOX treatment significantly decreased lung metastasis and lung weight, but these parameters showed no difference in control mice with or without DOX treatment (middle and right panels, XREF_FIG)."

28198361

➶

eidos

"USP17 Knockdown Impairs Tumor Proliferation and Metastasis Through Targeting MMPs Because degradation of the basement membrane by MMPs is required for tumor cell migration and invasion ( 16,17 ) , we sought to determine whether MMPs were responsible for USP17-dependent growth and invasion ."

27656837

➶

reach

"Dub3 inhibition suppresses breast cancer invasion and metastasis by promoting Snail1 degradation."

28198361

➶

reach

"Dub3 is overexpressed in breast cancer; knockdown of Dub3 resulted in Snail1 destabilization, suppressed EMT and decreased tumour cell migration, invasion, and metastasis."

28198361

➶

reach

"Our results (shown in XREF_FIG and XREF_SUPPLEMENTARY) demonstrate DUB3 's ability to increase breast cancer cell migration and metastasis by targeting SNAIL1, thereby supporting our hypothesis that DUB3 promotes breast carcinoma metastasis in patients."

28067227

USP17L2 inhibits Neoplasm Metastasis.

| 2

USP17L2 inhibits Neoplasm Metastasis. 2 / 2

| 2

➶

reach

"Knockdown of Dub3 blocks breast cancer metastasis."

28198361

➶

reach

"DUB3 (official symbol USP17L2) was shown to promote breast cancer invasion and metastasis via stabilizing Snail1 in a CDK4/6 activity-dependent manner ."

32968046

CDK6 affects USP17L2

3 | 1 9

CDK6 phosphorylates USP17L2.

| 1 9

CDK6 leads to the phosphorylation of USP17L2. 7 / 7

| 1 6

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rlimsp

"(h) The working model to illustrate that CDK4/6 phosphorylation-dependent activation of DUB3 regulates epithelial–mesenchymal transition and metastasis through SNAIL1."

28067227

➶

rlimsp

"As shown in Fig. 5d, mutation at S41 abolished CDK4/6-mediated phosphorylation of DUB3 in vitro."

28067227

➶

rlimsp

"We hypothesized that CDK4/6 could phosphorylate DUB3."

28067227

➶

rlimsp

"We next tested CDK4/6-mediated phosphorylation of DUB3 in cells."

28067227

➶

reach

28067227

➶

rlimsp

"(d) CDK4/6 phosphorylates DUB3 in vitro."

28067227

➶

rlimsp

"CDK4/6 phosphorylates and activates DUB3."

28067227

CDK6 phosphorylates USP17L2 on S41. 3 / 3

| 3

➶

rlimsp

"These findings provide evidence that Ser41 is the major CDK4/6-mediated phosphorylation site on DUB3, which in turn regulates SNAIL1 protein level."

28067227

➶

rlimsp

"CDK4/6 phosphorylates Ser41 of DUB3."

28067227

➶

rlimsp

"CDK4/6 phosphorylates DUB3 at Ser 41."

28067227

CDK6 binds USP17L2.

3 |

CDK6 binds USP17L2. 3 / 3

3 |

➶

biogrid

No evidence text available

28067227

➶

biogrid

No evidence text available

28067227

➶

biogrid

No evidence text available

28067227

USP17L2 affects Neoplasm Invasiveness

| 3 9

USP17L2 activates Neoplasm Invasiveness.

| 3 7

USP17L2 activates Neoplasm Invasiveness. 9 / 9

| 3 6

➶

eidos

"USP17 promotes proliferation and invasion through PI3K / AKT activation in NSCLC Consistent with the findings from the USP17-OE cells , knock-down ( KD ) of USP17 decreased the protein expression levels of p-AKT and p-PI3K in NSCLC cells ( NC vs. KD , P < 0.0001 ; Fig. 6A-F ) ."

32565935

➶

eidos

"Suppression of Ubiquitin-Specific Peptidase 17 ( USP17 ) Inhibits Tumorigenesis and Invasion in Non-Small Cell Lung Cancer Cells USP17 PROMOTES TUMORIGENESIS AND METASTASIS IN NSCLC ZHANG , YUAN , AND ZHENG Recently , deubiquitinating enzymes ( DUBs ) are emerging as new regulators in cancer progression ."

27656837

➶

reach

"DUB3 (official symbol USP17L2) was shown to promote breast cancer invasion and metastasis via stabilizing Snail1 in a CDK4/6 activity-dependent manner ."

32968046

➶

reach

"Dub3 mediates migration, invasion and CSC like properties of breast cancer cells."

29088851

➶

reach

"Dub3 is overexpressed in breast cancer; knockdown of Dub3 resulted in Snail1 destabilization, suppressed EMT and decreased tumour cell migration, invasion, and metastasis."

28198361

➶

reach

"Dub3 inhibition suppresses breast cancer invasion and metastasis by promoting Snail1 degradation."

28198361

➶

reach

"Dub3 inhibition suppresses breast cancer invasion and metastasis by promoting Snail1 degradation."

31147601

➶

eidos

"Taken together , our study showed that USP17 promotes tumorigenesis and invasion through regulation of MMPs ( MMP3 and MMP9 ) in NSCLC cells and provides a promising approach for NSCLC treatment and prevention ."

27656837

➶

reach

"Furthermore, we demonstrated that Dub3 promoted migration, invasion and CSC like properties of breast cancer cells."

29088851

USP17L2 bound to SNAI1 activates Neoplasm Invasiveness. 1 / 1

| 1

➶

reach

"By blocking the interaction of Dub3 and Snail, WP1130 prevents the deubiquitination of Snail, thereby blocking cancer invasion, migration, and the establishment of CSC like properties."

29147673

USP17L2 inhibits Neoplasm Invasiveness.

| 2

USP17L2 inhibits Neoplasm Invasiveness. 2 / 2

| 2

➶

reach

"Depletion of DUB3 significantly inhibited the migratory ability and invasiveness of MDA-MB-231 cells (XREF_FIG), although it did not affect cell proliferation (XREF_SUPPLEMENTARY)."

28067227

➶

reach

"DUB3 (official symbol USP17L2) was shown to promote breast cancer invasion and metastasis via stabilizing Snail1 in a CDK4/6 activity-dependent manner ."

32968046

USP17L2 affects ITCH

| 8 3

USP17L2 binds ITCH.

| 3 3

ITCH binds USP17L2. 6 / 6

| 3 3

➶

sparser

"DUB3 binds effectively to ITCH, but its association with LATS or AMOT appeared to be less stable in co-IP experiments."

28061504

➶

reach

"These findings present an apparent conundrum : DUB3 interacts with ITCH and affects ITCH ubiquitylation and stability, and higher ITCH expression should increase turnover of LATS and AMOT."

28061504

➶

sparser

"These data suggest that DUB3 physically interacts with ITCH."

28061504

➶

reach

"These data suggest that DUB3 physically interacts with ITCH."

28061504

➶

reach

"DUB3 binds effectively to ITCH, but its association with LATS or AMOT appeared to be less stable in co-IP experiments."

28061504

➶

sparser

"These findings present an apparent conundrum: DUB3 interacts with ITCH and affects ITCH ubiquitylation and stability, and higher ITCH expression should increase turnover of LATS and AMOT."

28061504

USP17L2 deubiquitinates ITCH.

| 2

Modified USP17L2 leads to the deubiquitination of ITCH. 1 / 1

| 1

➶

reach

"Expression of DUB3 strongly reduced the amount of poly-ubiquitylated ITCH (XREF_FIG)."

| 9 2

USP17L2 binds AMOT.

| 4 2

AMOT binds USP17L2. 5 / 5

| 4 1

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reach

"These data provide evidence that DUB3 interacts with AMOT and LATS2 proteins and regulates their turnover."

28061504

➶

reach

"The purpose of the seemingly contradictory function of DUB3 with respect to ITCH in this setting remains elusive but it is feasible that DUB3 binding to the AMOT and LATS complex may be regulated by p[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

28923280

➶

reach

"Interestingly DUB3 also interacts with and deubiquitinates AMOT, AMOTL1, and the kinases LATS1 and LATS2 to promote their stability and in so doing decrease YAP activity [124]."

28923280

➶

sparser

"Although DUB3 also stabilizes the E3 ligase ITCH, interaction of DUB3 with LATS1/2 and AMOT in this complex is hypothesized to offset the effects of increased ITCH activity toward these substrates."

28061504

➶

reach

"Although DUB3 also stabilizes the E3 ligase ITCH, interaction of DUB3 with LATS1/2 and AMOT in this complex is hypothesized to offset the effects of increased ITCH activity toward these substrates."

28061504

AMOT binds USP17L2 and LATS2. 1 / 1

| 1

➶

sparser

"These data provide evidence that DUB3 interacts with AMOT and LATS2 proteins and regulates their turnover."

28061504

USP17L2 deubiquitinates AMOT.

| 2

USP17L2 deubiquitinates AMOT. 1 / 1

| 1

➶

reach

"Interestingly DUB3 also interacts with and deubiquitinates AMOT, AMOTL1, and the kinases LATS1 and LATS2 to promote their stability and in so doing decrease YAP activity [124]."

28923280

Modified USP17L2 leads to the deubiquitination of AMOT. 1 / 1

| 1

➶

reach

"Reciprocally, overexpression of DUB3 reduced the ubiquitylation of AMOT, while the inactive C89S DUB3 mutant had no effect (XREF_SUPPLEMENTARY)."

28061504

USP17L2 activates AMOT.

| 2

USP17L2 activates AMOT. 2 / 2

| 2

➶

reach

"We therefore considered the possibility that DUB3 might directly regulate the turnover of AMOT and LATS proteins."

28061504

➶

reach

"Thus DUB3 activity can promote the stability of LATS1/2 and AMOT, which act to reduce YAP activity and increase YAP turnover, while also increasing expression of ITCH, which can promote YAP turnover."

28061504

USP17L2 increases the amount of AMOT.

| 1

Modified USP17L2 increases the amount of AMOT. 1 / 1

| 1

➶

reach

"Interestingly, DUB3 expression increased the levels of AMOT, AMOTL1, LATS1 and LATS2 and a decrease in YAP level."

28061504

NCOR2 affects USP17L2

| 11

NCOR2 decreases the amount of USP17L2.

| 7

NCOR2 decreases the amount of USP17L2. 5 / 5

| 5

➶

reach

"These data suggest that NCOR2 and HDAC10 work in concert in the same complex to repress expression of DUB3 in prostate cancer cells."

30057199

➶

reach

"Our current findings show that NCOR2, functioning as a transcriptional repressor, represses DUB3 expression."

30057199

➶

reach

30057199

➶

reach

"We found that knockdown of NCOR2 by two independent shRNAs increased expression of DUB3 and BRD4 proteins, but not BRD2 and BRD3 proteins, while NCOR2 knockdown increased mRNA expression of DUB3, but [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

30057199

➶

reach

"We demonstrated that NCOR2 represses DUB3 expression by specifically interacting with HDAC10."

30057199

NCOR2 bound to HDAC10 decreases the amount of USP17L2. 2 / 2

| 2

➶

reach

"Expression of DUB3 is transcriptionally repressed by the NCOR2 and HDAC10 complex."

30057199

➶

reach

"We also show that expression of DUB3 is negatively regulated by the NCOR2 and HDAC10 complex."

30057199

NCOR2 inhibits USP17L2.

| 2

NCOR2 inhibits USP17L2. 2 / 2

| 2

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"The NCOR2 gene is frequently deleted in castration resistant prostate cancer patient specimens, and loss of NCOR2 induces elevation of DUB3 and BRD4 proteins in cancer cells."

30057199

➶

2 1 | 1 5 1

USP17L2 deubiquitinates H2AX.

1 | 1 3

USP17L2 deubiquitinates H2AX. 5 / 5

1 | 1 3

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"Dub3 controls DNA damage signalling by direct deubiquitination of H2AX"

28762656

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"Overexpression of DUB3 decreased monoubiquitination of γH2AX in the absence of an exogenous DNA damage source as well as post-IR [33]."

32708614

➶

reach

"Moreover, Dub3 and H2AX interact and Dub3 deubiquitinates H2AX in vitro."

24704006

➶

trips

"Moreover, Dub3 and H2AX interact and Dub3 deubiquitinates H2AX in vitro."

24704006

➶

reach

"DUB3 (also known as USP17L2) directly interacts with and deubiquitylates H2AX [73]."

28764946

USP17L2 binds H2AX.

2 | 2 1

USP17L2 binds H2AX. 5 / 5

2 | 2 1

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biogrid

No evidence text available

24704006

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biogrid

No evidence text available

24704006

➶

sparser

"Moreover, Dub3 and H2AX interact and Dub3 deubiquitinates H2AX in vitro."

24704006

➶

reach

"DUB3 (also known as USP17L2) directly interacts with and deubiquitylates H2AX [73]."

28764946

➶

reach

"Moreover, Dub3 and H2AX interact and Dub3 deubiquitinates H2AX in vitro."

24704006

USP17L2 affects CDC25A

1 | 6 2

USP17L2 deubiquitinates CDC25A.

1 | 3

USP17L2 deubiquitinates CDC25A. 4 / 4

1 | 3

➶

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"We also assessed the level of ubiquitin hydrolase DUB3 that is known to deubiquitylate and stabilize CDC25A 46."

29416040

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"DUB3 and USP17 mediates deubiquitination of CDC25A, preventing CDC25A degradation by the proteasome during the G1/S and G2/M phases promoting cell-cycle progression [XREF_BIBR]."

28031783

➶

reach

"Dub3 knockdown in cells increased Cdc25A ubiquitylation and degradation, resulting in reduced Cdk and Cyclin activity and arrest at G1/S and G2/M phases of the cell cycle."

20228808

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ubibrowser

No evidence text available

USP17L2 binds CDC25A.

| 1 2

CDC25A binds USP17L2. 3 / 3

| 1 2

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sparser

"To verify the association of Dub3 and Cdc25A, we examined the expression of Cdc25A in our ovarian carcinomas by IHC."

25776484

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"Recently, Pereg et al. reported that Dub3 can specifically bind Cdc25A and removes the polyubiquitin modifications that mark Cdc25A for proteasomal degradation [15]."

| 8

➶

reach

"Here our studies indicate that DUB3 is crucial to induce EMT through the stabilization of SNAIL1 protein in breast cancer."

28067227

➶

reach

"Dub3 is overexpressed in breast cancer; knockdown of Dub3 resulted in Snail1 destabilization, suppressed EMT and decreased tumour cell migration, invasion, and metastasis."

28198361

➶

reach

"Consistently, Dub3 expression induced a morphologic change indicative of EMT (XREF_FIG), including downregulation of epithelial markers (E-cadherin, Claudin-7 and Occludin) and the upregulation of mesenchymal molecules (N-cadherin and Vimentin) (XREF_FIG, XREF_SUPPLEMENTARY)."

28198361

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reach

"DUB3 binds, deubiquitylates and increases cellular levels of the EMT transcription factor SNAIL1 (REF."

31511663

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reach

"In fact, DUBs involved in Snail regulation so far are shown to be induced differently, while USP27x is induced by TGF-β; DUB3/USP17L2 seems to play a role in CDK4/6-mediated activation of EMT, whereas OTUB1 is under the transcriptional regulation of oestrogen-related receptor alpha, and USP37 regulation is induced during EMT via the stimulation of the hedgehog signalling pathway."

32636467

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"Together, these data indicate that Dub3 can induce EMT (luminal to basal like phenotype conversion) by stabilizing Snail1 in breast cancer cells."

28198361

➶

reach

"Dub3 expression induces EMT."

28198361

➶

reach

"By contrast, ectopic expression of Dub3 induces EMT through an upregulation of Snail."

29147673

USP17L2 affects apoptotic process

| 8

USP17L2 activates apoptotic process.

| 5

USP17L2 activates apoptotic process. 5 / 5

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"Several studies have examined the mechanism by which DUB-3 and USP17 induces apoptosis."

23773437

➶

reach

"The constitutive expression of DUB-3 can block cell proliferation and initiate apoptosis [25]."

23773437

➶

reach

"Finally, we have demonstrated that constitutive expression of DUB-3 blocks proliferation and can initiate apoptosis in both IL-3-dependent Ba/F3 cells and NIH3T3 fibroblasts."

14699124

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reach

"DUB3 and USP17 was reported to induce apoptosis through caspase-3 activation."

28279784

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reach

"In vitro, Dub3 knockdown could inhibit the proliferation of ovarian cancer cells and increase cell apoptosis."

25776484

USP17L2 inhibits apoptotic process.

| 3

USP17L2 inhibits apoptotic process. 3 / 3

| 3

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"Knockdown of Dub3 could inhibit the proliferation of ovarian cancer cells and increase cell apoptosis."

25776484

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reach

"DUB3 Facilitates Growth and Inhibits Apoptosis Through Enhancing Expression of EZH2 in Oral Squamous Cell Carcinoma."

32110043

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reach

"Furthermore, overexpression of Mcl-1 or DUB3 inhibited apoptosis by PTC596."

34576269

AMOT affects USP17L2

| 6 2

AMOT binds USP17L2.

| 4 2

AMOT binds USP17L2. 5 / 5

| 4 1

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"These data provide evidence that DUB3 interacts with AMOT and LATS2 proteins and regulates their turnover."

28061504

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reach

28923280

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"Interestingly DUB3 also interacts with and deubiquitinates AMOT, AMOTL1, and the kinases LATS1 and LATS2 to promote their stability and in so doing decrease YAP activity [124]."

28923280

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"Although DUB3 also stabilizes the E3 ligase ITCH, interaction of DUB3 with LATS1/2 and AMOT in this complex is hypothesized to offset the effects of increased ITCH activity toward these substrates."

28061504

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"Although DUB3 also stabilizes the E3 ligase ITCH, interaction of DUB3 with LATS1/2 and AMOT in this complex is hypothesized to offset the effects of increased ITCH activity toward these substrates."

28061504

AMOT binds USP17L2 and LATS2. 1 / 1

| 1

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"These data provide evidence that DUB3 interacts with AMOT and LATS2 proteins and regulates their turnover."

28061504

AMOT activates USP17L2.

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AMOT activates USP17L2. 2 / 2

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"In light of this, we asked if AMOT and the related AMOTL1 and AMOTL2 proteins are required to mediate the effect of DUB3 on LATS kinase and YAP levels."

28061504

➶

reach

"Similarly, any of the three AMOT proteins appears to support the activity of DUB3 on YAP activity."

28061504

USP17L2 affects SNAIL1

| 7

USP17L2 deubiquitinates SNAIL1.

| 3

USP17L2 deubiquitinates SNAIL1. 3 / 3

| 3

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"In addition, WT DUB3, but not the C89S mutant, markedly decreased SNAIL1 ubiquitination in vitro (XREF_FIG)."

28067227

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reach

"DUB3 deubiquitinates and stabilizes SNAIL1."

28067227

➶

reach

"Since DUB3 deubiquitinates and stabilizes SNAIL1 and consequently decreases E-cadherin expression, we hypothesized that DUB3 is critical for breast cancer cell migration and invasion in vitro."

28067227

USP17L2 binds SNAIL1.

| 2

USP17L2 binds SNAIL1. 2 / 2

| 2

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"The interaction of DUB3 and SNAIL1 prompted us to examine a potential role for DUB3 in the regulation of SNAIL1 stability and function."

| 4

USP17L2 activates NFE2L2. 4 / 4

| 4

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"Importantly, ectopic expression of DUB3 caused NRF2 dependent chemotherapy resistance in colon cancer cell lines."

30778200

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reach

"Further experiments demonstrated that DUB3 promoted NRF2 stability and transcriptional activity by decreasing the K48 linked ubiquitination of NRF2."

30778200

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reach

"DUB3 promotes Nrf2 stability and transcriptional activity by decreasing the K48 linked ubiquitination of Nrf2."

33805928

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reach

"Moreover, these authors demonstrated that ectopic expression of DUB3 caused Nrf2 dependent chemotherapy resistance in colon cancer cell lines [XREF_BIBR]."

33805928

USP17L2 binds NFE2L2.

| 2

KEAP1 binds USP17L2 and NFE2L2. 1 / 1

| 1

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"Coimmunoprecipitation studies revealed interactions between NRF2 and DUB3, as well as between KEAP1 and DUB3, indicating that NRF2, DUB3, and KEAP1 formed a large functional complex."

30778200

USP17L2 binds NFE2L2. 1 / 1

| 1

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"Coimmunoprecipitation studies revealed interactions between NRF2 and DUB3, as well as between KEAP1 and DUB3, indicating that NRF2, DUB3, and KEAP1 formed a large functional complex."

30778200

USP17L2 deubiquitinates NFE2L2.

| 1

USP17L2 deubiquitinates NFE2L2. 1 / 1

| 1

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"DUB3 deubiquitinates and stabilizes NRF2 in chemotherapy resistance of colorectal cancer."

30778200

ITCH affects USP17L2

| 4 3

ITCH binds USP17L2.

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ITCH binds USP17L2. 6 / 6

| 3 3

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"DUB3 binds effectively to ITCH, but its association with LATS or AMOT appeared to be less stable in co-IP experiments."

28061504

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"These findings present an apparent conundrum : DUB3 interacts with ITCH and affects ITCH ubiquitylation and stability, and higher ITCH expression should increase turnover of LATS and AMOT."

28061504

➶

sparser

"These data suggest that DUB3 physically interacts with ITCH."

28061504

➶

reach

"These data suggest that DUB3 physically interacts with ITCH."

28061504

➶

reach

"DUB3 binds effectively to ITCH, but its association with LATS or AMOT appeared to be less stable in co-IP experiments."

28061504

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sparser

"These findings present an apparent conundrum: DUB3 interacts with ITCH and affects ITCH ubiquitylation and stability, and higher ITCH expression should increase turnover of LATS and AMOT."

28061504

ITCH inhibits USP17L2.

| 1

ITCH inhibits USP17L2. 1 / 1

| 1

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reach

"Depletion of ITCH from this complex reduces the effects of DUB3 on YAP, and this effect was stronger when NEDD4, another E3 ligase was also removed (XREF_FIG)."

28061504

IL6 affects USP17L2

| 7

IL6 activates USP17L2.

| 6

IL6 activates USP17L2. 6 / 6

| 6

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"Interestingly, Dub3 activity and expression, at both the mRNA and protein levels, can be induced by IL-6 through the JAK and STAT3 signaling pathway [XREF_BIBR, XREF_BIBR, XREF_BIBR]."

29147673

➶

reach

"In addition, the DUB-3 protein, induced by IL-4 and IL-6, is also involved in the regulation of cell growth and survival where its constitutive expression leads to growth suppression and apoptosis [25[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

23773437

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reach

"Specifically, Dub3 is rapidly induced by IL-4 and IL-6."

28198361

➶

reach

"Mechanistically, IL-6 induces the deubiquitinase (DUB3), which removes ubiquitin from SNAIL to prevent its proteasomal degradation."

31036052

➶

reach

"In addition, Dub3 can be rapidly induced by inflammatory cytokine IL-6 [XREF_BIBR, XREF_BIBR]."

29088851

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reach

"Curiously, the DUB3 gene, a part of the highly polymorphic RS447 megasatellite sequence, is induced by cytokines interleukin (IL-) 4 and IL-6 in certain mammalian cells XREF_BIBR XREF_BIBR."

28067227

IL6 increases the amount of USP17L2.

| 1

IL6 increases the amount of USP17L2. 1 / 1

| 1

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"Consistent with this, we also found that IL-6 rapidly induces Dub3 expression, exerting a maximum effect at 2hr [XREF_BIBR]."

29147673

USP17L2 affects SUDS3

4 1 | 1

USP17L2 binds SUDS3.

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SUDS3 binds USP17L2. 4 / 4

4 |

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No evidence text available

21239494

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No evidence text available

21239494

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"These data provide evidence that DUB3 interacts with AMOT and LATS2 proteins and regulates their turnover."

28061504

USP17L2 deubiquitinates LATS2.

| 2

USP17L2 deubiquitinates LATS2. 1 / 1

| 1

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reach

"Interestingly DUB3 also interacts with and deubiquitinates AMOT, AMOTL1, and the kinases LATS1 and LATS2 to promote their stability and in so doing decrease YAP activity [124]."

sparser

"Our current results demonstrated that Dub3 interacts with Slug and Twist and prevents Slug and Twist from degradation mediated by these E3 ligases."

29088851

➶

sparser

"Dub3 interacts with Slug and Twist."

29088851

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sparser

"In addition, DUB3 also interacts with SLUG and TWIST and prevents their degradation, thereby promoting migration, invasion, and cancer stem cell-like properties in breast cancer cells [ xref ]."

32268558

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sparser

"Concurrently, we also performed endogenous Co-IP and confirmed the association of Dub3 with Slug and Twist in MDA-MB157 and SUM159 cells (Figure xref )."

29088851

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sparser

"Of importance, Dub3 interacted with Slug and Twist and prevented them from degradation, thereby promoting migration, invasion, and cancer stem cell (CSC)-like properties of breast cancer cells."

29088851

WP1130 affects USP17L2

| 1 4

WP1130 binds USP17L2.

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USP17L2 binds WP1130. 3 / 3

| 3

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No evidence text available

24704006

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No evidence text available

24704006

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"Moreover, Dub3 and H2AX interact and Dub3 deubiquitinates H2AX in vitro."

24704006

➶

reach

"DUB3 (also known as USP17L2) directly interacts with and deubiquitylates H2AX [73]."

28764946

➶

reach

"Moreover, Dub3 and H2AX interact and Dub3 deubiquitinates H2AX in vitro."

24704006

ESRRB affects USP17L2

| 5

ESRRB activates USP17L2.

| 4

ESRRB activates USP17L2. 4 / 4

| 4

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"As expected, only wild type Esrrb and not the C-terminally truncated receptor increased Dub3 transcriptional activity (XREF_FIG), indicating that coactivator recruitment through the C-terminus that contains the AF2 domain is essential to the Esrrb mediated transcriptional response on the Dub3 promoter."

24695638

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reach

"ERRbeta knockdown in and DY131 stimulation of mouse ESCs reduces or enhances Dub3 and Cdc25A, respectively, and RNAi mediated inhibition of Dub3 or Cdc25A led these cells to differentiate."

27507929

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"To address the specific role of the two splice variants NCoA and SRC1A and NCoA and SRC1E on Esrrb mediated Dub3 transcription, we individually cotransfected each coactivators with Esrrb and measured the activity of a luciferase reporter gene."

24695638

➶

reach

"Surprisingly, we also found an interaction through the Q rich domain, which seemed to convey inhibitory signals since deletion of this region resulted in increased Esrrb mediated Dub3 transcription (XREF_FIG)."

24695638

ESRRB decreases the amount of USP17L2.

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ESRRB decreases the amount of USP17L2. 1 / 1

| 1

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"These findings further highlight the complexity of the regulatory network of transcription factors in pluripotent mESCs and may explain why downregulation of Esrrb does not completely abolish Dub3 gene expression in mESCs XREF_BIBR."

24695638

CPOX affects USP17L2

| 5

CPOX increases the amount of USP17L2.

| 3

CPOX increases the amount of USP17L2. 3 / 3

| 3

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"Currently, we have no clue why and how CPX downregulated CK1alpha and upregulated DUB3 expression."

29725502

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reach

"On the contrary, CPX slightly increased the expression of DUB3 in a concentration dependent manner."

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CDK4 binds USP17L2. 3 / 3

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No evidence text available

28067227

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No evidence text available

28067227

| 1 3

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eidos

"Moreover , Matrigel-Transwell analysis showed that suppression of USP17 decreased cell migration and invasion capacity ."

27656837

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reach

"Dub3 is overexpressed in breast cancer; knockdown of Dub3 resulted in Snail1 destabilization, suppressed EMT and decreased tumour cell migration, invasion, and metastasis."

28198361

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reach

"Dub3 expression markedly increased the cell migration and invasive capacity (XREF_FIG, XREF_SUPPLEMENTARY)."

28198361

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reach

"Individual cell tracking also revealed Dub3 knockdown reduced the velocity and directionality of cell migration, and strongly inhibited the net distance of cell migration in MDA-MB231 and MDA-MB157 cells (XREF_FIG, XREF_SUPPLEMENTARY)."

28198361

USP17L2 affects SNAIL1 protein

| 4

USP17L2 increases the amount of SNAIL1 protein.

| 3

USP17L2 increases the amount of SNAIL1 protein. 2 / 2

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"WT DUB3 and the S41D mutant could rescue SNAIL1 protein level, while the S41A mutant failed to do so."

28067227

➶

reach

"As shown in XREF_FIG, DUB3 knockdown efficiently decreased SNAIL1 protein level."

28067227

Modified USP17L2 increases the amount of SNAIL1 protein. 1 / 1

reach

"By blocking the interaction of Dub3 and Snail, WP1130 prevents the deubiquitination of Snail, thereby blocking cancer invasion, migration, and the establishment of CSC like properties."

29147673

USP17L2 inhibits Neoplastic Stem Cells.

| 1

USP17L2 inhibits Neoplastic Stem Cells. 1 / 1

| 1

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"Knockdown of Dub3 inhibits migration, invasion and cancer stem cell (CSC)-like characteristics in cells by downregulating of Snail."

29147673

USP17L2 affects LGMN

3 1 |

USP17L2 binds LGMN.

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USP17L2 binds LGMN. 3 / 3

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No evidence text available

24610907

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No evidence text available

24610907

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No evidence text available

24610907

USP17L2 deubiquitinates LGMN.

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USP17L2 deubiquitinates LGMN. 1 / 1

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"We demonstrate that TRAF6 ubiquitinates the proform of AEP through K63-linked polyubiquitin, reversible by USP17, and forms a complex with HSP90伪 to subsequently promote pro-AEP intracellular stability as well as secretion.?"

24610907

USP17L2 affects Cyclin_A

| 1 3

USP17L2 binds Cyclin_A.

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Cyclin_A binds USP17L2. 3 / 3

| 3

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"These results suggest that the DUB3–cyclin A axis plays a key role in G1/S transition during cell cycle progression and at least partially explain the mechanism of DUB3 which promotes the proliferation of NSCLC cells, providing a promising target for NSCLC treatment [ xref ]."

34072267

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sparser

"Mechanistically, DUB3 interacts with cyclin A, which removes the polyubiquitin chains conjugated onto cyclin A and stabilizes the cyclin A protein."

30935108

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sparser

"Similar to USP37, DUB3 binds cyclin A, leading to its deubiquitination and stabilization, and regulates the G1/S transition."

32201366

USP17L2 inhibits Cyclin_A.

| 1

USP17L2 inhibits Cyclin_A. 1 / 1

| 1

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"DUB3 may also promote the proliferation of NSCLC by inhibiting Cyclin A degradation."

33943009

USP17L2 affects Carcinogenesis

| 4

USP17L2 activates Carcinogenesis. 4 / 4

| 4

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"Moreover , the in vivo animal models revealed that USP17 suppression reduced tumorigenesis and growth ."

27656837

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eidos

"Suppression of USP17 reduced tumorigenesis and progression of NSCLC in vivo ."

27656837

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eidos

27656837

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27656837

Snail1 affects USP17L2

| 4

USP17L2 binds Snail1. 4 / 4

| 4

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"Taken together, our results indicate that Dub3 interacts with Snail1 and that this interaction is mediated through the N-terminal regions of Dub3 and N-terminal region of Snail1."

28198361

➶

reach

"Dub3 interacts with Snail1."

28198361

➶

reach

"However, only Dub3 interacted with Snail1 in the co-immunoprecipitation (IP) assay (XREF_SUPPLEMENTARY)."

28198361

➶

reach

"The interaction between Dub3 and Snail1 was further confirmed by immunofluorescence (IF) analysis showing that endogenous Dub3 co-localized with Snail1 in the nucleus of MDA-MB231 cells (XREF_FIG)."

28198361

SUDS3 affects USP17L2

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SUDS3 binds USP17L2. 4 / 4

4 |

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No evidence text available

21239494

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No evidence text available

21239494

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biogrid

No evidence text available

21239494

➶

biogrid

No evidence text available

21239494

CDK affects USP17L2

| 4

CDK phosphorylates USP17L2.

| 3

CDK phosphorylates USP17L2. 3 / 3

| 3

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"Importantly, it has been shown recently in breast cancer cells that DUB3 can be phosphorylated by CYCLIN-dependent kinases 4 and 6 (CDK4/6), and this phosphorylation is essential for the deubiquitinas[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

30057199

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sparser

"Importantly, it has been shown recently in breast cancer cells that DUB3 can be phosphorylated by CYCLIN-dependent kinases 4 and 6 (CDK4/6) and this phosphorylation is essential for the deubiquitinase activity of DUB3 ( xref ), highlighting that DUB3 is a druggable target for cancer therapy."

30057199

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CDK binds USP17L2.

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CDK binds USP51 and USP17L2. 1 / 1

| 1

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34204543

USP17L2 affects cell differentiation

| 3

USP17L2 inhibits cell differentiation.

| 2

USP17L2 inhibits cell differentiation. 2 / 2

| 2

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"Finally, knockdown of either Dub3 or Cdc25A induced spontaneous differentiation of ESCs."

24207026

➶

reach

"This transcriptional control appears to be very complex and gene specific and remains to be further clarified.We observed that while forced Dub3 expression could not inhibit differentiation upon LIF w[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

24207026

USP17L2 activates cell differentiation.

| 1

USP17L2 activates cell differentiation. 1 / 1

| 1

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reach

"Gene Expression Analysis of PTEN Positive Glioblastoma Stem Cells Identifies DUB3 and Wee1 Modulation in a Cell Differentiation Model."

24349068

USP17L2 affects cdk-4

| 1 2

USP17L2 binds cdk-4. 3 / 3

| 1 2

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29992751

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"The interaction between CDK4/6 and DUB3 was also detected by endogenous co-immunoprecipitation and in vitro pull down (XREF_FIG)."

28067227

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sparser

"The interaction between CDK4/6 and DUB3 was also detected by endogenous co-immunoprecipitation and in vitro pull down ( xref )."

28067227

USP17L2 affects breast cancer invasion

| 3

USP17L2 activates breast cancer invasion. 3 / 3

| 3

➶

eidos

"Pristimerin Down-Regulated DUB3 in Breast Cancer In previous study , DUB3 inhibition was confirmed to suppresses breast cancer invasion and metastasis.25 Bioinformatic analysis by TIMER was used to evaluate DUB3 level in various cancer and normal tissues , as shown in Figure 3A ."

32753899

➶

eidos

"Inhibition of USP17 promotes SNAI1 degradation , thereby suppressing breast cancer invasion and metastasis ( 49 , 53 ) ."

33194625

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eidos

33907435

USP17L2 affects WP1130

| 3

USP17L2 binds WP1130. 3 / 3

| 3

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28198361

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| 2

USP17L2 inhibits Neoplasms. 2 / 2

| 2

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"In conclusion, this study revealed a positive DUB3/KLF4 feedback loop that inhibits tumor growth and chemoresistance in HCC."

35383144

➶

reach

"DUB3 inhibited HCC cell proliferation in vitro and tumor growth in vivo while enhancing the chemosensitivity of HCC cells in a KLF4-dependent manner."

35383144

USP17L2 activates Neoplasms.

| 1

USP17L2 activates Neoplasms. 1 / 1

| 1

| 3

USP17L2 inhibits FAM126A.

| 2

USP17L2 inhibits FAM126A. 2 / 2

| 2

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"DUB3 inhibited HCC cell proliferation in vitro and tumor growth in vivo while enhancing the chemosensitivity of HCC cells in a KLF4-dependent manner."

35383144

➶

reach

"In conclusion, this study revealed a positive DUB3/KLF4 feedback loop that inhibits tumor growth and chemoresistance in HCC."

35383144

USP17L2 deubiquitinates FAM126A.

| 3

USP17L2 decreases the amount of CDH1.

| 2

USP17L2 decreases the amount of CDH1. 1 / 1

| 1

➶

reach

"Since DUB3 deubiquitinates and stabilizes SNAIL1 and consequently decreases E-cadherin expression, we hypothesized that DUB3 is critical for breast cancer cell migration and invasion in vitro."

28067227

Modified USP17L2 decreases the amount of CDH1. 1 / 1

| 1

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reach

"Expression of Dub3 in these two cell lines dramatically increased the levels of Slug and Twist and reduced E-cadherin and ER expression."

29088851

USP17L2 activates CDH1.

| 1

USP17L2 activates CDH1. 1 / 1

| 1

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| 1 2

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"We find that the deubiquitinase USP17L2 interacts with and deubiquitinates SIRT7, thereby increasing SIRT7 protein stability."

36040642

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sparser

"USP17L2-SIRT7 axis regulates DNA damage repair and chemoresistance in breast cancer cells."

36040642

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36040642

NCOA1 affects USP17L2

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NCOA1 activates USP17L2.

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NCOA1 activates USP17L2. 2 / 2

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"In addition we present evidence that NCoA1 splice variants directly interact with Esrrb and potentiate Dub3 promoter activity."

24695638

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"In support to this possibility, expression of the individual NCoA1 splice variants (NCoA and SRC1A or NCoA and SRC1E) in mESCs, both led to an increase of endogenous Dub3 mRNA without affecting Esrrb gene expression (XREF_SUPPLEMENTARY)."

24695638

NCOA1 increases the amount of USP17L2.

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"Likewise, we examined the interaction between DUB3 and LATS2."

28061504

AMOT binds USP17L2 and LATS2. 1 / 1

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"These data provide evidence that DUB3 interacts with AMOT and LATS2 proteins and regulates their turnover."

28061504

IL4 affects USP17L2

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IL4 activates USP17L2. 3 / 3

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23773437

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"In mRNA level, DUB-3 expression increased in Raji cells when treated with IL-4 and in U937 cells when treated with IL-6 [XREF_BIBR]."

31208841

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"Specifically, Dub3 is rapidly induced by IL-4 and IL-6."

28198361

Cyclin_A affects USP17L2

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Cyclin_A binds USP17L2. 3 / 3

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34072267

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"Mechanistically, DUB3 interacts with cyclin A, which removes the polyubiquitin chains conjugated onto cyclin A and stabilizes the cyclin A protein."

30935108

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"Similar to USP37, DUB3 binds cyclin A, leading to its deubiquitination and stabilization, and regulates the G1/S transition."

32201366

CDK1 affects USP17L2

| 2 1

CDK1 phosphorylates USP17L2.

| 1 1

CDK1 leads to the phosphorylation of USP17L2 on S41. 2 / 2

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"Interestingly, CDK1 also phosphorylated DUB3 at Ser41 in vitro and the treatment of Roscovitine could decrease the phosphorylation of DUB3 (XREF_SUPPLEMENTARY)."

28067227

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"Interestingly, CDK1 also phosphorylated DUB3 at Ser41 in vitro and the treatment of Roscovitine could decrease the phosphorylation of DUB3 ( xref )."

28067227

CDK1 dephosphorylates USP17L2.

| 2 1

BABAM2 binds USP17L2.

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BABAM2 binds USP17L2 and fbxw1. 1 / 1

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"We also failed to detect any physical interaction between BRE and DUB3 (Supplementary Fig. xref ) or β-TRCP (Supplementary Fig. xref ), indicating that BRE overexpression-mediated CDC25A deregulation is independent of β-TRCP and DUB3."

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"In addition, human DUB enzyme DUB-3, highly homologous to USP17 and induced by cytokines interleukin (IL) -4 and IL-6, has been recently isolated and showed that it has significant homology to the known murine DUB subfamily members."

16611142

Fbxw1 affects USP17L2

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BABAM2 binds USP17L2 and fbxw1. 1 / 1

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"Instead, DUB3 depletion increased YAP protein levels."

28061504

USP17L2 decreases the amount of protein.

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USP17L2 binds fbxw1. 1 / 1

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"DUB3 inhibits cell growth through regulating Hippo pathway activity."

28061504

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"DUB3 inhibits cell growth through regulating Hippo pathway activity."

28061504

USP17L2 affects cell cycle

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USP17L2 inhibits cell cycle.

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USP17L2 inhibits cell cycle. 1 / 1

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25776484

USP17L2 activates cell cycle.

| 1

USP17L2 activates cell cycle. 1 / 1

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20403174

USP17L2 deubiquitinates RAS.

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USP17L2 deubiquitinates RAS. 1 / 1

31998374

BRD4 binds USP17L2, Hemagglutinins, and Flag. 1 / 1

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"We found that knockdown of DUB3 decreases cyclin A levels, whereas overexpression of DUB3 strongly increases cyclin A levels."

30935108

USP17L2 affects CDC25C

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CDC25C binds USP17L2. 2 / 2

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biogrid

No evidence text available

20228808

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No evidence text available

20228808

USP17L2 affects BABAM2

| 1 1

BABAM2 binds USP17L2 and fbxw1. 1 / 1

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SNAI1 binds NXN and USP17L2. 1 / 1

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26101254

Histone deacetylase inhibitors affects USP17L2

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Histone deacetylase inhibitors decreases the amount of USP17L2. 1 / 1

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"Most interestingly, we found that histone deacetylase inhibitors (HDACis) could significantly activate MGMT and DUB3 expression; the combined administration of HDACis and PaTrin-2 led to the ideal therapeutic effect."

30718431

Fbxw1 affects BABAM2

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34204543

USP17L2 affects CBX1

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CBX1 binds USP17L2. 1 / 1

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biogrid

No evidence text available

19615732

USP17L2 affects BRD4DeltaCTM mutant

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USP17L2 activates BRD4DeltaCTM mutant. 1 / 1

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30057199

USP17L2 affects BRD4 deubiquitination stabilization various cancer cell lines

| 1

USP17L2 activates BRD4 deubiquitination stabilization various cancer cell lines. 1 / 1

| 1

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"In a recent study , DUB3 was shown to promote BRD4 deubiquitination and stabilization in various cancer cell lines [ 135 ] ."

33327527

USP17L2 affects BRD3

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USP17L2 activates BRD3. 1 / 1

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30057199

USP17L2 affects BRD2

| 1

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35927236

NFE2L2 affects KEAP1

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KEAP1 binds USP17L2 and NFE2L2. 1 / 1

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"Coimmunoprecipitation studies revealed interactions between NRF2 and DUB3, as well as between KEAP1 and DUB3, indicating that NRF2, DUB3, and KEAP1 formed a large functional complex."

30778200

NCOR2-HDAC10 affects USP17L2

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30057199

Hemagglutinins affects FlaG

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30057199

FlaG affects USP17L2

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"PTC596 and BMI-1 siRNA induced downregulation of DUB3 deubiquitinase, which was strongly linked to Mcl-1 destabilization."

34576269

BABAM2 affects fbxw1

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ctd

No evidence text available

19561079

IndraLab

Statements

USP17L2 affects BRD4

USP17L2 binds BRD4.

BRD4 binds USP17L2. 10 / 22

BRD4 binds USP17L2, Hemagglutinins, and Flag. 1 / 1

BRD4 binds USP17L2, Hemagglutinins, and FlaG. 1 / 1

USP17L2 deubiquitinates BRD4.

USP17L2 deubiquitinates BRD4. 10 / 10

USP17L2 activates BRD4.

USP17L2 activates BRD4. 7 / 7

USP17L2 increases the amount of BRD4.

USP17L2 increases the amount of BRD4. 5 / 5

USP17L2 ubiquitinates BRD4.

USP17L2 leads to the ubiquitination of BRD4. 3 / 3

USP17L2 inhibits BRD4.

USP17L2 inhibits BRD4. 1 / 1

USP17L2 is modified

USP17L2 is phosphorylated.

USP17L2 is phosphorylated on S41. 10 / 22

USP17L2 is phosphorylated. 10 / 15

USP17L2 is ubiquitinated.

USP17L2 is ubiquitinated. 1 / 1

USP17L2 affects SNAI1

USP17L2 binds SNAI1.

SNAI1 binds USP17L2. 10 / 29

SNAI1 binds NXN and USP17L2. 1 / 1

USP17L2 activates SNAI1.

USP17L2 activates SNAI1. 3 / 3

USP17L2 inhibits SNAI1.

USP17L2 inhibits SNAI1. 2 / 2

USP17L2 deubiquitinates SNAI1.

USP17L2 deubiquitinates SNAI1. 1 / 1

SNAI1 affects USP17L2

SNAI1 binds USP17L2.

SNAI1 binds USP17L2. 10 / 29

SNAI1 binds NXN and USP17L2. 1 / 1

SNAI1 inhibits USP17L2.

SNAI1 inhibits USP17L2. 1 / 1

Cdk-4 affects USP17L2

Cdk-4 phosphorylates USP17L2.

Cdk-4 phosphorylates USP17L2. 10 / 11

Cdk-4 phosphorylates USP17L2 on S41. 7 / 7

Cdk-4 activates USP17L2.

Cdk-4 activates USP17L2. 8 / 8

Cdk-4 binds USP17L2.

USP17L2 binds cdk-4. 3 / 3

Cdk-4 inhibits USP17L2.

Cdk-4 inhibits USP17L2. 1 / 1

BRD4 affects USP17L2

BRD4 binds USP17L2.

BRD4 binds USP17L2. 10 / 22

BRD4 binds USP17L2, Hemagglutinins, and Flag. 1 / 1

BRD4 binds USP17L2, Hemagglutinins, and FlaG. 1 / 1

BRD4 inhibits USP17L2.

BRD4 inhibits USP17L2. 2 / 2

BRD4 increases the amount of USP17L2.

BRD4 increases the amount of USP17L2. 1 / 1

BRD4 activates USP17L2.

BRD4 activates USP17L2. 1 / 1

USP17L2 affects SNAI2

USP17L2 binds SNAI2.

SNAI2 binds USP17L2. 9 / 9

SNAI2 binds TWIST1 and USP17L2. 6 / 6

USP17L2 increases the amount of SNAI2.

Modified USP17L2 increases the amount of SNAI2. 2 / 2

USP17L2 increases the amount of SNAI2. 1 / 1

USP17L2 deubiquitinates SNAI2.

USP17L2 deubiquitinates SNAI2. 2 / 2

Modified USP17L2 leads to the deubiquitination of SNAI2. 1 / 1

USP17L2 ubiquitinates SNAI2.

USP17L2 ubiquitinates SNAI2. 1 / 1

USP17L2 activates SNAI2.

USP17L2 activates SNAI2. 1 / 1

USP17L2 affects TWIST1

USP17L2 binds TWIST1.

TWIST1 binds USP17L2. 9 / 9

SNAI2 binds TWIST1 and USP17L2. 6 / 6

USP17L2 deubiquitinates TWIST1.

USP17L2 deubiquitinates TWIST1. 2 / 2