USP4 Data Analysis

HGNC Gene Name
ubiquitin specific peptidase 4
HGNC Gene Symbol
USP4
Identifiers
hgnc:12627 NCBIGene:7375 uniprot:Q13107
Orthologs
mgi:98905 rgd:1587387
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for USP4
Number of Papers
147 retrieved on 2022-05-22

DepMap Analysis

The Dependency Map (DepMap) is a genome-wide pooled CRISPR-Cas9 knockout proliferation screen conducted in more than 700 cancer cell lines spanning many different tumor lineages. Each cell line in the DepMap contains a unique barcode, and each gene knockout is assigned a “dependency score” on a per cell-line basis which quantifies the rate of CRISPR-Cas9 guide drop. It has been found that proteins with similar DepMap scores across cell lines, a phenomenon known as co-dependent genes, have closely related biological functions. This can include activity in the same or parallel pathways or membership in the same protein complex or the same pathway.

We identified the strongest seven co-dependent genes (“Symbol”) for DUBs and ran GO enrichment analysis. We used Biogrid, IntAct, and Pathway Commons PPIDs, and the NURSA protein-protein interaction databases (PPIDs) to determine whether co-dependent genes interact with one another. The “Evidence” column contains the PPIDs in which the interaction appears as well as whether there is support for the association by an INDRA statement. As another approach to identify potential interactors, we looked at proteomics data from the Broad Institute's Cancer Cell Line Encyclopedia (CCLE) for proteins whose expression across ~375 cell lines strongly correlated with the abundance of each DUB; it has previously been observed that proteins in the same complex are frequently significantly co-expressed. The correlations and associated p-values in the CCLE proteomics dataset are provided. And, we determined whether co-dependent genes yield similar transcriptomic signatures in the Broad Institute's Connectivity Map (CMap). A CMap score greater than 90 is considered significantly similar.

DepMap Correlations

Symbol Name DepMap Correlation Evidence CCLE Correlation CCLE Z-score CCLE p-value (adj) CCLE Significant CMAP Score CMAP Type
GLT8D1 glycosyltransferase 8 domain containing 1 0.26 0.02 -0.00 8.44e-01
PPM1M protein phosphatase, Mg2+/Mn2+ dependent 1M 0.252
TMEM42 transmembrane protein 42 0.226
CCKAR cholecystokinin A receptor 0.221 Reactome (1)
BBS10 Bardet-Biedl syndrome 10 0.214
KLRK1 killer cell lectin like receptor K1 0.21
CYP8B1 cytochrome P450 family 8 subfamily B member 1 0.209

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with USP4using the terms from Gene Ontology and gene sets derived from the Gene Ontology Annotations database via MSigDB.

Using the biological processes and other Gene Ontology terms from well characterized DUBs as a positive control, several gene set enrichment analyses were considered. Threshold-less methods like GSEA had relatively poor results. Over-representation analysis with a threshold of of the top 7 highest absolute value Dependency Map correlations yielded the best results and is reported below.

GO Identifier GO Name GO Type p-value p-value (adj.) q-value

Transcriptomics

The following table shows the significantly differentially expressed genes after knocking out USP4 using CRISPR-Cas9.

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
MT-ND2 mitochondrially encoded NADH:ubiquinone oxidoreductase core subunit 2 2.93e-01 1.93e-06 4.26e-02

Gene Set Enrichment Analysis

There were too few differentially expressed genes to run a meaningful GSEA.

Literature Mining

INDRA was used to automatically assemble known mechanisms related to USP4 from literature and knowledge bases. The first section shows only DUB activity and the second shows all other results.

Deubiquitinase Activity

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USP4 deubiquitinates MAP3K7. 10 / 13
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USP4 deubiquitinates TAK1 in vitro and in vivo.

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These results indicate that USP4 mainly inhibits inducible TAK1 polyubiquitination and activation whereas CYLD mainly inhibits basal level of TAK1 polyubiquitination and activation.

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USP4 deubiquitinates TAK1 in vivo and in vitro.

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

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

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

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USP4 also deubiquitinates TAK1 in HEK293 T cells [62].

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

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

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In conclusion, our results provide evidence that TNFalpha induces association of USP4 with TAK1 which leads to TAK1 deubiquitination in the TNFalpha mediated NF-kappaB activation.
USP4 deubiquitinates PRPF3. 10 / 11
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In particular, non proteolytic ubiquitylation of the U4/U6 protein Prp3, promoted by the Prp19 complex, is required for stabilization of the U4/U6 * U5 tri-snRNP, while de-ubiquitylation of Prp3 by Usp4 and Sart3 is required for U4 dissociation and recycling.

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On the other hand, Usp4 and Sart3 promote de-ubiquitination and recycling of Prp3, and this modification weakens its interaction with Prp8 and allows for the dissociation of U4 during activation of the spliceosome [49].
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Moreover, we found that USP15 and USP4 deubiquitinated substrates PRP31 and PRP3 simultaneously.

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

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

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

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USP15SART3 makes a complex with USP4 and this ternary complex serves as a platform to deubiquitinate PRP31 and PRP3

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Moreover, it was reported that Sart3, Usp4 and Usp15 form a complex in order to de-ubiquitinate Prp3 and Prp31 simultaneously.
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PRP3 was deubiquitinated by USP4 consistent with a previous report but not by USP15.

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The result shows that USP4 no longer deubiquitinates Prp3 in the presence of SART3 DeltaNLS.
USP4 deubiquitinates TGFBR1. 10 / 11
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USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-beta type I receptor [XREF_BIBR].

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

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

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

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

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USP4 is a DUB for TGF-β type I receptor

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

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

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

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Taken together, our results elucidate that USP4 is highly expressed in HCC and promotes the tumor invasion and metastasis, the underlying mechanism is that USP4 directly interacts with and deubiquitinates TGFR-1 to increase TGF-beta signaling Induced EMT.
USP4 deubiquitinates HUWE1. 10 / 10
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USP2 deubiquitinates both MDM2 and MDMX [XREF_BIBR, XREF_BIBR] whereas USP4 deubiquitinates ARF-BP1 [XREF_BIBR], another ubiquitin ligase for p53, thus indirectly destabilizing p53 and inhibiting its function.

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

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

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

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

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

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USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1.

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

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

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USP4 interacts directly with and deubiquitinates ADP-ribosylatibon factor binding protein 1 (ARFBP1), which results in the stabilization of ARF-BP1 and the subsequent reduction of p53 levels.
USP4 deubiquitinates TRAF6. 8 / 8
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USP4 interacts with and deubiquitinates TRAF6, thereby preventing the activation of NF-kappaB and AP-1 transcription factors and subsequent immune responses.

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Interestingly, USP4 deubiquitinates not only TRAF2 but also TRAF6 and leads to the regulation of cell migration [12].
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USP4 deubiquitinates TRAF2 and TRAF6, but not TRAF3, and it also rescues IkappaBalpha from degradation in TNFalpha induced HEK cells [XREF_BIBR].

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

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

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

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

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However, there is no evidence of how USP4 deubiquitinates TRAF6 and TRAF2 proteins; our results prove that USP4 targets TRAF6 for K48 linked deubiquitination.
USP4 deubiquitinates HDAC2. 8 / 8
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Nonetheless, USP4 might deubiquitinate and stabilize both ARF-BP1 and its substrate HDAC2.

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

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

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

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

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USP4 suppresses HDAC2 ubiquitination.

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

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As we demonstrated that USP4 deubiquitinates HDAC2, it is possible that USP4 can stabilize HDAC2.
USP4 deubiquitinates IRF4. 5 / 5
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On the whole, our data indicate that USP4 interacts with and deubiquitinates IRF4, and also stabilizes IRF4 protein and promotes IRF4 function to facilitate IL-4 expression in Th2 cells, which may be related to the pathological process of RHD.

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USP4 deubiquitinates IRF4.

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

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To conclude, this study indicated that USP4 interacts with and deubiquitinates IRF4, and also stabilizes IRF4 protein and promotes IRF4 function to facilitate IL-4 expression in Th2 cells, which may be associated with the pathological process of RHD.
USP4 deubiquitinates PRPF31. 5 / 5
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Moreover, it was reported that Sart3, Usp4 and Usp15 form a complex in order to de-ubiquitinate Prp3 and Prp31 simultaneously.
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Moreover, we found that USP15 and USP4 deubiquitinated substrates PRP31 and PRP3 simultaneously.

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USP15SART3 makes a complex with USP4 and this ternary complex serves as a platform to deubiquitinate PRP31 and PRP3

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

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When PRP31 was ubiquitinated by PRP19, PRP31 was deubiquitinated by USP4.
USP4 deubiquitinates PTP4A3. 4 / 4
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Specifically, up-regulated USP4 potentiated the growth and invasion of colorectal cancer though deubiquitination and stabilization of PRL-3.19 In addition, USP4 transduced Akt activation to TGF-beta signalling by deubiquitinating and stabilizing TGF-beta type I receptor, thus augmented breast cancer cell invasion and migration.33 These studies demonstrate USP4 as a powerful tumour promoter and an important determinant for canonical oncogenic signalling.

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

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Deubiquitinating PRL-3 by USP4 leads to AKT activation and E-cadherin reduction in colorectal cancer, where an elevated level of USP4 is associated with tumor size, differentiation, distant metastasis, and poor survival.
USP4 deubiquitinates CTNNB1. 4 / 4
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In a colon cancer cell line, USP4 deubiquitinates beta-catenin and mediates its nuclear transportation, thus promoting Wnt and beta-catenin signaling and cancer cells growth, migration, and invasion.

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We showed that USP4 deubiquitinates beta-catenin.

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

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Additionally, DUBs USP14, USP15, USP47, and Fam/USP9X have been reported to prevent β-catenin turnover by inhibiting its Ub-proteasomal degradation
USP4 deubiquitinates TRAF2. 4 / 4
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Ubiquitin-specific protease 4 (USP4) targets TRAF2 and TRAF6 for deubiquitination and inhibits TNFα-induced cancer cell migration

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

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

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Interestingly, USP4 deubiquitinates not only TRAF2 but also TRAF6 and leads to the regulation of cell migration [12].
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USP4 deubiquitinates DDX58. 4 / 4
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Furthermore, USP4 was found to interact with RIG-I and remove K48-linked polyubiquitination chains from RIG-I.

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

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

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RIG-I can be ubiquitinated and degraded by RNF125 (Ring Finger Protein 125) and deubiquitinated and stabilized by USP4.
USP4 deubiquitinates PDPK1. 3 / 3
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In addition, the closely related USP15, which shares 61% amino acid sequence identity with USP4 XREF_BIBR, had no effect on Ub-PDK1 levels, further suggesting that the ability of USP4 to deubiquitinate PDK1 is specific.

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

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USP4 deubiquitinates PDK1 and co-localizes at the plasma membrane.
USP4 deubiquitinates TCF4. 3 / 3
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For example, USP4 interacts with and deubiquitinates TCF4, which inhibits beta-catenin-dependent transcription [XREF_BIBR].

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

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USP4 deubiquitinated a subpopulation of TCF4.
USP4 deubiquitinates HAS2. 3 / 3
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For example, USP4 targets and deubiquitinates hyaluronan synthase 2 (HAS2), but USP4 does not maintain the stability of HAS, and, rather, loss of USP4 increases hyaluronan synthesis [33].
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The de-ubiquitinase USP17 preferentially deconjugated polyubiquitin chains from HAS2, whereas USP4 significantly reduced the monoubiquitination of HAS2; thus, the two DUBs were found to selectively affect the activity and stability of HAS2.

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USP17 efficiently removed polyubiquitination, whereas USP4 preferentially removed monoubiquitination of 6myc-HAS2.;The deubiquitinating enzymes USP4 and USP17 target hyaluronan synthase 2 and differentially affect its function;USP17 and USP4 differently affect HAS2 ubiquitination, and the stability and function of HAS2
USP4 deubiquitinates TGFB. 3 / 3
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Mechanistically, hepatocyte USP4 directly bound to and deubiquitinated transforming growth factor-beta activated kinase 1 (TAK1), leading to a suppression of the activation of downstream NF-kappaB and JNK cascades, which in turn reversed the disruption of the IRS-AKT-GSK3beta signaling.

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

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USP4 has been reported to enhance TGFbeta signalling by directly interacting with and deubiquitylating type I TGFbeta receptor, ALK5 XREF_BIBR.
USP4 leads to the deubiquitination of SMAD4. 2 / 2
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USP4 inhibits SMAD4 monoubiquitination and promotes activin and BMP signaling.

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We demonstrated that ubiquitin-specific protease (USP) 4 strongly induces activin/BMP signaling by removing the inhibitory monoubiquitination from SMAD4.
USP4 deubiquitinates E3_Ub_ligase. 2 / 2
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In contrast to USP2a, USP4 deubiquitinates and stabilizes a different E3 that ubiquitinates p53 called ARF-BP1, thereby destabilizing p53 [XREF_BIBR].

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USP4 interacts with and deubiquitylates another E3 ubiquitin ligase for p53, ARF-BP1/Mule/HUWE, leading to the stabilization of ARF-BP1 and subsequent reduction of p53 levels.
Modified USP4 leads to the deubiquitination of MAP3K7. 2 / 2
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Overexpression of USP4 wild-type, but not deuibiquitinase deficient C311A mutant, inhibits both TNFalpha- and TAK1 and TAB1 co-overexpression-induced TAK1 polyubiquitination and NF-kappaB activation.

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As shown in XREF_FIG, overexpression of USP4 wild-type but not deubiquitinase deficient C311A mutant abrogated TAK1 and TAB1 co-overexpression-induced TAK1 polyubiquitination.
USP4 deubiquitinates TRIM21. 2 / 2
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Oncogenic protein UnpEL/Usp4 deubiquitinates Ro52 by its isopeptidase activity

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Oncogenic protein UnpEL and Usp4 deubiquitinates Ro52 by its isopeptidase activity.
USP4 deubiquitinates adenosine on A2. 2 / 2
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In contrast to these observations, the deubiquitination of the adenosine A 2A receptor (A 2A R) by USP4 is necessary for the cell surface delivery of a functionally active receptor (XREF_FIG, pathway 4) [XREF_BIBR].

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The Adenosine A2 receptor is deubiquitinated by USP4; the ubiquitination status and trafficking of the EGFR growth factor receptor is regulated by the USP8 and STAM complex; the beta2-AR undergoes increased agonist stimulated ubiquitination, lysosomal trafficking, and degradation after knockdown of USPs 20 and 33.
USP4 deubiquitinates INS. 2 / 2
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USP4 is a deubiquitinating enzyme and may deubiquitinate insulin receptors to inhibit their degradation, which maintains the expression level of insulin receptors on the membrane surface and improves insulin resistance.
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Upregulation of USP4 reduces the ubiquitination and degradation of insulin receptors, upregulates the level of insulin receptors, and ultimately improves insulin resistance.
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USP4 deubiquitinates ADORA2A. 1 / 1
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No evidence text available
USP4 deubiquitinates TRAF6 on lysine. 1 / 1
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No evidence text available
Modified USP4 leads to the deubiquitination of NFkappaB. 1 / 1
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Overexpression of USP4 wild-type, but not deuibiquitinase deficient C311A mutant, inhibits both TNFalpha- and TAK1 and TAB1 co-overexpression-induced TAK1 polyubiquitination and NF-kappaB activation.
USP4 leads to the deubiquitination of DVL. 1 / 1
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USP4 was initially identified as a repressor of the Wnt and beta-catenin signaling pathway, given that USP4 can mediate deubiquitination and stabilization of Dvl, a key molecule involved in the turnover of cytosolic beta-catenin.
Modified USP4 leads to the deubiquitination of AQP2. 1 / 1
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Taken together, the data suggest that USP4 is a key regulator of AQP2 deubiquitylation and that loss of USP4 leads to increased AQP2 ubiquitylation, decreased AQP2 levels, and decreased cell surface AQP2 accumulation upon VP treatment.
USP4 deubiquitinates RB1. 1 / 1
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USP4, reported as an oncogenic protein, is known to interact with the pocket proteins (Rb, p107, and p130) although no deubiquitinating activity has been reported
USP4 deubiquitinates IRF8. 1 / 1
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In the present study, we demonstrate that ubiquitin-specific protease (USP)4 physically interacted with interferon regulatory factor 8 (IRF8) function via a K48-linked deubiquitinase, which stabilized IRF8 protein levels in Treg cells.
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USP4 has been shown to deubiquitinate A 2a receptor, a G S -coupled receptor at the cell surface, and deubiquitination of A 2a receptor by USP4 enhanced cell surface expression of the receptor in cult[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
USP4-C311A leads to the deubiquitination of JNK. 1 / 1
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USP4 (C311A) mutation did not inhibit the TAK1 polyubiquitination, and phosphorylation of TAK1, = JNK1/2, and p38 in angiotensin treated myocytes.
USP4 deubiquitinates RNPS1. 1 / 1
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Although RNPS1 is polyubiquitinated by both K48- and K63-linkages, USP4 exclusively deubiquitinates K63-linked polyubiquitin chains of RNPS1.
USP4 deubiquitinates NR2C2. 1 / 1
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Mechanistically, hepatocyte USP4 directly bound to and deubiquitinated transforming growth factor-β activated kinase 1 (TAK1)
USP4 leads to the deubiquitination of NFKBIA. 1 / 1
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Therefore, we further analyzed the effect of USP4 knockdown on the TNFalpha induced IKK phosphorylation, IkappaBalpha phosphorylation, ubiquitination and degradation.
USP4 deubiquitinates RBBP8. 1 / 1
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Although USP4 does not directly deubiquitinate CtIP, its interaction with CtIP is essential for HR as blocking their binding reduces HR efficiency.
USP4 deubiquitinates RBL1. 1 / 1
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USP4, reported as an oncogenic protein, is known to interact with the pocket proteins (Rb, p107, and p130) although no deubiquitinating activity has been reported
USP4 deubiquitinates TRAF3. 1 / 1
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USP4 deubiquitinates TRAF2 and TRAF6, but not TRAF3, and it also rescues IkappaBalpha from degradation in TNFalpha induced HEK cells [XREF_BIBR].
USP4 deubiquitinates USP4. 1 / 1
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UnpEL/Usp4 is ubiquitinated by Ro52 and deubiquitinated by itself
USP4 deubiquitinates AQP2. 1 / 1
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AQP2 and USP4 co-immunoprecipitated from mpkCCD14 cells and mouse kidney, and in vitro, USP4 can deubiquitylate AQP2.
USP4 deubiquitinates TRAF2 on lysine. 1 / 1
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No evidence text available
USP4 deubiquitinates BIRC2. 1 / 1
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In contrast, USP4 wild-type failed to deubiquitinate cIAP1 (XREF_SUPPLEMENTARY).
USP4 deubiquitinates TGFBR. 1 / 1
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The authors further go on to show that USP4 was able to deubiquitylate the TGF-beta receptor I (TbetaRI) directly and rescue it from proteasome mediated degradation.
USP4 deubiquitinates RIPK1. 1 / 1
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USP4 directly interacts with receptor-interacting protein 1 (RIP1) and deubiquitinates K63-linked ubiquitination from RIP1.
USP4 deubiquitinates PPIA. 1 / 1
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Mechanistically, cyclophilin A (CypA) was identified as an important molecule for USP4-mediated oncogenic activity in HCC.
USP4 deubiquitinates TP53. 1 / 1
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Regulation of p53 is also subject to other DUBs, such as USP4, USP10, USP29, and USP42 [171].
USP4 deubiquitinates DDX58 on K48. 1 / 1
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USP4, it positively regulates the RIG-I-mediated antiviral response by deubiquitinating K48-linked ubiquitin chains and stabilizing RIG-I (77).
USP4 deubiquitinates RIPK1 on K377. 1 / 1
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No evidence text available
USP4 deubiquitinates RBL2. 1 / 1
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USP4, reported as an oncogenic protein, is known to interact with the pocket proteins (Rb, p107, and p130) although no deubiquitinating activity has been reported
Modified USP4 leads to the deubiquitination of HDAC2. 1 / 1
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As shown in XREF_FIG, overexpression of USP4-WT but not C311A mutant abrogated HDAC2 polyubiquitination.
USP4 deubiquitinates Histone. 1 / 1
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Another DUB, USP4 deubiquitinates HDAC2 (Histone deacetylases 2) that was shown to interact with p53 thereby inhibiting the level of acetylated p53.
USP4 deubiquitinates RORC. 1 / 1
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Ubiquitin-specific protease 4 promotes Th17 cell function under inflammation by deubiquitinating and stabilizing RORγt
USP4 leads to the deubiquitination of IKK_complex. 1 / 1
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Therefore, we further analyzed the effect of USP4 knockdown on the TNFalpha induced IKK phosphorylation, IkappaBalpha phosphorylation, ubiquitination and degradation.
USP4-C311A leads to the deubiquitination of p38. 1 / 1
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USP4 (C311A) mutation did not inhibit the TAK1 polyubiquitination, and phosphorylation of TAK1, = JNK1/2, and p38 in angiotensin treated myocytes.
USP4 leads to the deubiquitination of RHEB. 1 / 1
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Thus, we propose a mechanistic model whereby Rheb mediated mTORC1 activation is dictated by a dynamic opposing act between Rheb ubiquitination and deubiquitination that are catalyzed by RNF152 and USP4 respectively.
USP4 deubiquitinates MAP3K7 on K63. 1 / 1
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USP4 deubiquitinates TAK1 with Lys63 linked polyubiquitination and inhibits Dox induced NF-kappaB activation.
USP4-C311A leads to the deubiquitination of MAP3K7. 1 / 1
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USP4 (C311A) mutation did not inhibit the TAK1 polyubiquitination, and phosphorylation of TAK1, = JNK1/2, and p38 in angiotensin treated myocytes.
USP4 deubiquitinates Interferon. 1 / 1
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We speculated that ubiquitin specific peptidase4 (USP4) may deubiquitinate interferon regulatory factor4 (IRF4) and affect Thelper type2 (Th2) cell function.
USP4 deubiquitinates TRIM25. 1 / 1
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Conversely, USP15 and USP4 deubiquitinate TRIM25 and RIG-I, respectively, to stabilize the proteins.

Other Statements

psp cbn pc bel_lc signor biogrid lincs_drug tas hprd trrust ctd vhn pe drugbank omnipath conib crog dgi | rlimsp isi tees geneways eidos trips medscan sparser reach

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

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

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

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To determine whether PDCD4 is involved in the anti-proliferative function of USP4, we further examined the role of PDCD4 in the USP4 induced inhibition of proliferation by knocking down PDCD4 using siRNA.

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The Cell Counting Kit-8 (CCK-8) assay results showed that the proliferation of hypertrophic scar fibroblasts transfected with siUSP4 was significantly inhibited on the fifth and seventh day, indicating that down-regulation of USP4 could suppress the proliferation of hypertrophic scar fibroblasts.

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

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

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

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USP4 inhibits breast cancer cell proliferation through the upregulation of PDCD4.

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

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In vitro study showed that knockdown of USP4 inhibited PC cells proliferation, migration and invasion.

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

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Taken together, CypA is indispensable for USP4 mediated cell proliferation in HCC.

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

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

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

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

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

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

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To test this hypothesis, CCK-8 assays were used to investigate the effects of CypA on USP4 induced proliferation of HCC cell lines.
USP4 affects NFkappaB
| 1 3 28
USP4 inhibits NFkappaB.
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| 1 18

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

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USP4 inhibits NF-kappaB transcriptional activity through HDAC2.

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

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

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

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

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Also, USP4 de-ubiquitinated and then inhibited the activation of p53 and NF-kappaB [XREF_BIBR].

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It was also found that USP4 inhibited NF-kappaB activation, but in this study we confirmed that USP4 positively regulates the NF-kappaB signalling pathway during EV71 infection.

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

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USP4 acts as a TAK1 Lys63 specific deubiquitinase to deubiquitinate TAK1 and inhibit Dox induced NF-kappaB activation.
Modified USP4 inhibits NFkappaB. 1 / 1
| 1

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Ectopic expression of USP4 inhibits the TRAF2- and TRAF6 stimulated NF-kappaB reporter gene and negatively regulates the TNFalpha induced IkappaBalpha (inhibitor of NF-kappaBalpha) degradation and NF-kappaB activation.
USP4 bound to RIPK1 inhibits NFkappaB. 1 / 1
| 1

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An association between USP4 and RIP1 was reported to impair NF-kappaB activation and exacerbate TNF-alpha-induced apoptosis in head and neck squamous cell carcinoma (HNSCC).
USP4 activates NFkappaB.
| 1 2 8
| 1 2 8

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

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

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

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

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

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

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USP4 positively regulates the antiviral NF-kappaB pathway.

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

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It was also found that USP4 inhibited NF-kappaB activation, but in this study we confirmed that USP4 positively regulates the NF-kappaB signalling pathway during EV71 infection.

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Therefore, to further confirm USP4 induced NF-kappaB activation, we designed and synthesized two siRNAs to knock down the intrinsic expression of USP4.
USP4 affects TP53
| 1 3 19
USP4 inhibits TP53.
| 1 3 10
USP4 inhibits TP53. 10 / 19
| 1 3 10

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

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Increased ARF-BP1 and Mule degradation causes p53 stabilization, which is antagonized by the DUBs USP7 and USP4.

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

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

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

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Also, USP4 de-ubiquitinated and then inhibited the activation of p53 and NF-kappaB [XREF_BIBR].

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

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

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

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USP4 inhibits p53 through deubiquitinating and stabilizing ARF-BP1.
USP4 activates TP53.
| 6
USP4 activates TP53. 6 / 6
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However, in response to cisplatin treatment, USP4 deficiency significantly augmented melanoma cells apoptosis by activating p53 signalling.

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

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

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

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

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Similarly, knockdown of USP4 significantly decreases cell viability in a p53 dependent manner after treating GMB cells with temozolomide.
USP4 decreases the amount of TP53.
| 2
USP4 decreases the amount of TP53. 2 / 3
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In fact, our data show that USP4 inhibited the levels of acetylation but not protein expression of p53 (XREF_FIG).

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For instance, USP4 was shown to reduce p53 levels via deubiquitination of ARF-BP1 XREF_BIBR.
USP4 increases the amount of TP53.
| 1
USP4 increases the amount of TP53. 1 / 1
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More importantly, in response to cisplatin treatment, USP4 deficiency resulted in up-regulation of p53 expression both at transcriptional level and translational level.
USP4 affects CTNNB1
| 2 17
USP4 activates CTNNB1.
| 2 9
USP4 activates CTNNB1. 10 / 14
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In addition to these newly identified nuclear functions, both USP4 and USP15 are well known to function in the cytosol, i.e. USP4 modulates the Wnt and beta-catenin, NF-kappaB, p53 and TGF-beta signaling pathways while USP15 performs functions in the TGF-beta receptor and NF-kappaB signaling pathways.

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For instance, USP4 promote tumor progression by regulating beta-Catenin Signaling XREF_BIBR.

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The assay results revealed that transcriptional activity increases in proportion to the amount of USP4 in the nucleus, which suggests that USP4 enhances beta-catenin activity by facilitating its trans[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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

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

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In the present study, we found that the USP4 and beta-catenin axis was involved in metastatic potential through USP4 mediated stabilization of beta-catenin and that knockdown of USP4 and beta-catenin suppressed the metastatic potential including clonogenicity, migration, and invasion, and induced MET by downregulating ZEB1 expression.

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

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This observation raised the possibility that USP4-dependent activation of β-catenin is not only caused by the catalytic activity of USP4 but also mediated by another mechanism such as a nuclear transp[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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

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However, USP4 had no effect on the stability of GSK3beta, a negative regulator of beta-catenin, suggesting that USP4 enhances the stability and activity of beta-catenin not by affecting beta-catenin r[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
USP4-C311A activates CTNNB1. 1 / 1
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However, stabilized beta-catenin was partially affected by the USP4 expression level, and the catalytically defective C311A USP4 was able to activate beta-catenin to some extent.
USP4 increases the amount of CTNNB1.
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USP4 increases the amount of CTNNB1. 5 / 5
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USP4 increased the level of beta-catenin by inducing its deubiquitinylation.

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

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

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

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beta-Catenin protein stability was significantly lower in USP4 silenced PC14PE6 and LvBr4 cells than in PC14PE6 cells (XREF_FIG), demonstrating that USP4 positively regulated beta-catenin expression in metastatic lung cancer cells.
Modified USP4 increases the amount of CTNNB1. 1 / 1
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To examine whether USP4 overexpression increases beta-catenin expression and invasiveness, PC14PE6 cells were transfected with blank (FLAG) and USP4-overexpression vector (FLAG-USP4).
USP4 inhibits CTNNB1.
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USP4 inhibits CTNNB1. 1 / 1
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In this study, we found ubiquitin specific peptidase 4 (USP4) to strongly inhibit the Wnt and beta-catenin signaling by removing Lysine 63 linked poly-ubiquitin chain from Dishevelled (Dvl).
Modified USP4 inhibits CTNNB1. 1 / 1
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Ectopic expression of USP4 promoted beta-catenin poly-ubiquitination and thus inhibited Wnt induced accumulation of cytosolic beta-catenin and counteracted Wnt induced transcriptional activity.
| 1 21
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USP4 accelerates the growth, invasion, and metastasis of colorectal cancer [XREF_BIBR, XREF_BIBR].

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

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

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

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

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

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

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

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

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USP4 accelerates HCC cell proliferation, migration, and invasion in vitro.
Modified USP4 activates Neoplasm Invasiveness. 1 / 1
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To examine whether USP4 overexpression increases beta-catenin expression and invasiveness, PC14PE6 cells were transfected with blank (FLAG) and USP4-overexpression vector (FLAG-USP4).
| 1

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Interestingly, we were also able to observe that USP4 knockdown in SW480 cells increased invasion activity under the same experimental conditions as used in HCT116 cells, suggesting that the role of U[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
USP4 affects HDAC2
| 4
USP4 activates HDAC2.
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USP4 activates HDAC2. 3 / 8
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In fact, expression of USP4 significantly prolonged the half-life of HDAC2 (XREF_FIG).

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

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By promoting activation of the relaxin and TGF-beta 1/Smad2/matrix metalloproteinase 9 axis and transcriptional repression activity of HDAC2, USP4 induces breast cell invasion, migration, and proliferation both in vitro and in vivo.
USP4 inhibits HDAC2.
| 1
USP4 inhibits HDAC2. 1 / 7
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Therefore, our studies reveal USP4 suppresses p53 and NF-kappaB activation by stabilizing HDAC2.
USP4 affects TGFB
| 15
USP4 activates TGFB.
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USP4 activates TGFB. 10 / 11
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By promoting activation of the relaxin and TGF-beta 1/Smad2/matrix metalloproteinase 9 axis and transcriptional repression activity of HDAC2, USP4 induces breast cell invasion, migration, and proliferation both in vitro and in vivo.

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

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

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

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

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

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USP4 promotes invasion of breast cancer cells via Relaxin and TGF-beta 1/Smad2/MMP -9 signal.

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

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

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USP4, when overexpressed, potently enhanced TGF-beta signaling.
USP4 bound to TGFBR1 activates TGFB. 2 / 2
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Mechanistically, we revealed that USP4 interacted directly with and deubiquitinated TGF-beta receptor type I (TGFR-1) to activate the TGF-beta signaling pathway, and subsequently induced the Epithelial-Mesenchymal Transition (EMT) in HCC cells.

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Taken together, our results elucidate that USP4 is highly expressed in HCC and promotes the tumor invasion and metastasis, the underlying mechanism is that USP4 directly interacts with and deubiquitinates TGFR-1 to increase TGF-beta signaling Induced EMT.
USP4 inhibits TGFB.
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USP4 inhibits TGFB. 2 / 2
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In this context, to achieve a certain biological outcome, the same DUB can regulate the pathway at different levels (e.g., USP15 and USP4 promote signaling by targeting the TGF-beta receptor and the effector SMADs) or multiple DUBs can act on the same target (e.g., USP15 and OTUB1 promote signaling through stabilizing R-SMADs).

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H19 functions as a competing endogenous RNA (ceRNA) by sponging miR-148a and maintaining the expression levels of ubiquitin specific protease 4 (USP4), a key miR-148a target that stabilizes TGFbetaRI and promotes TGF-beta signalling.
| 1 12
USP4 activates cell migration.
| 1 7
| 1 7

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

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

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

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

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

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

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

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

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

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

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

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

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However, in breast cancer, USP4 was also recognized as a tumour suppressor for its up-regulatory effect on programmed cell death 4 (PDCD4) to restrain tumour growth.20 Moreover, USP4 was able to target TRAF2 and TRAF6 for deubiquitination and thereafter inhibited TNFalpha induced cancer cell migration.34 In the present study, we proved that USP4 expression was drastically increased in melanoma.
| 12
USP4 activates apoptotic process.
| 7

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

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

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

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

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

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

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USP4 knockout mice exhibited exacerbated hepatic I/R injury, as evidenced by enhanced liver inflammation via the NF-kappaB signalling pathway and increased hepatocyte apoptosis.
| 5

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

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

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

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

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It was found that over-expression of USP4 enhanced the ability of RD cells to fight against invading EV71, and also reduced cell apoptosis.
| 1 12
| 1 10

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

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

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

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

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

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

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

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Inhibition of USP4 would be expected to inhibit the invasion and metastasis of breast cancer and drugs that target USP15 could reduce the oncogenic potential of glioblastomas.

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Further, we investigated the mechanism by which USP4 promotes growth and metastasis in HCC cells.

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USP4 can promote TGF-beta-induced invasion and metastasis of breast cancer cells in a zebrafish xenograft model.
| 2

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

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Knockdown of USP4 dramatically suppressed the metastasis of PC14PE6 and LvBr5-Luc cells to the whole body and brain, as reflected by bioluminescence signals at 19 and 22 days post-injection (XREF_FIG).
USP4 affects MAP3K7
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USP4 inhibits MAP3K7.
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USP4 inhibits MAP3K7. 4 / 10
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We also found that overexpression of USP4 inhibited TAK1 but not IKKβ-induced NF-κB activation in a reporter assay ( xref ).

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

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

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XREF_BIBR showed that USP4 could block Dox induced activation of NF-kappaB at the early stage of the treatment by preventing TAK1 from conjugating K63 linked polyubiquitin chains.
USP4 activates MAP3K7.
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USP4 activates MAP3K7. 2 / 2
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Molecular analysis revealed that USP4 deficiency augmented the activation of the transforming growth factor beta activated kinase 1 (TAK1)-(JNK1/2)/P38 signaling in response to hypertrophic stress, and blockage of TAK1 activation abolished the pathological effects of USP4 deficiency in vivo.

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Previous study also showed that USP4 targets TAK1 by removing K63 linked polyubiquitination and then recruit IkappaB kinase (IKK) complex to simulate TNF-alpha -induced NF-kappaB activation 49.
USP4 affects TRAF6
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USP4 activates TRAF6.
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USP4 activates TRAF6. 7 / 7
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USP4 has also been shown to target TRAF2 and TRAF6 inhibiting nuclear factor-kappaB (NF-kB) signalling and antagonizing lung cancer cell migration XREF_BIBR XREF_BIBR XREF_BIBR, suggesting a context dependent role in cancer.

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

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

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

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USP4 targets TRAF6 through its USP domain.

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

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However, in breast cancer, USP4 was also recognized as a tumour suppressor for its up-regulatory effect on programmed cell death 4 (PDCD4) to restrain tumour growth.20 Moreover, USP4 was able to target TRAF2 and TRAF6 for deubiquitination and thereafter inhibited TNFalpha induced cancer cell migration.34 In the present study, we proved that USP4 expression was drastically increased in melanoma.
USP4 activates ubiquitinated TRAF6. 1 / 1
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USP4 specifically targets ubiquitinated TRAF6 and then cleaves the polyubiquitin chains.
USP4 inhibits TRAF6.
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USP4 inhibits TRAF6. 3 / 3
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Overexpression of USP4 inhibits EV71 replication by stabilizing TRAF6 to activate NF-kappaB inflammatory signaling.

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

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55 Ubiquitin specific peptidase 4 (USP4) negatively regulates TRAF6, suppressing IL-1beta-induced NF-kappaB activation by removing polyubiquitin chains on TRAF6 in a deubiquitin activity dependent manner.
USP4 decreases the amount of TRAF6.
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USP4 decreases the amount of TRAF6. 1 / 1
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USP4 silencing in LPS induced activation of microglia promoted the expression of p-p65 and TRAF6 and the secretion of TNF-alpha and IL-1beta.
USP4 affects USP4
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USP4 activates USP4.
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USP4 activates USP4. 4 / 6
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Ubiquitination of USP4 could physically block its interaction with CtIP or induce conformational change of USP4.

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

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Together, these findings provided support for USP4 interactions with CtIP and MRN being critical for its DDR functions and for a model wherein USP4 auto-deubiquitylation promotes these interactions and thereby USP4 functions in DSB repair.

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Furthermore, gastrodin significantly upregulated the expression of USP4 and increased the binding of USP4 to the insulin receptor.Considering the importance of the PI3K-Akt pathway in the pathogenesis of T2DM, we detected the effects of gastrodin on the PI3K-Akt pathway to further explore the underlying mechanism of gastrodin in ameliorating insulin resistance.
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USP4 increases the amount of USP4.
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USP4 increases the amount of USP4. 2 / 2
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Specific inhibitory siRNA of USP4 reduced USP4 level and the parameters mentioned above.

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By inhibiting the expression of USP4, down-regulation of USP4 inhibited the proliferation, migration, and apoptosis of hypertrophic scar fibroblasts through the TGF-beta and Smad7 signaling pathway.
USP4 decreases the amount of USP4.
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USP4 decreases the amount of USP4. 1 / 1
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Transient transfection of USP4 siRNA effectively reduced the expression of USP4 protein (XREF_FIG).
USP4 affects TNF
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USP4 inhibits TNF.
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USP4 inhibits TNF. 4 / 6
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Moreover, we found that USP4 targets HDAC2 to downregulate tumor necrosis factor-alpha (TNFalpha)-induced NF-kappaB activation.

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

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USP4 negatively regulates TNFalpha induced, K63 linked TAK1 polyubiquitination and TAK1 mediated IKK and NF-kappaB activation [XREF_BIBR].

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USP4 was identified by studies to negatively regulate both TNF-alpha- and IL-1beta-induced NF-kappaB activation [XREF_BIBR, XREF_BIBR, XREF_BIBR].
USP4 activates TNF.
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USP4 activates TNF. 1 / 2
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Ubiquitin specific protease 4 (USP4) targets TRAF2 and TRAF6 for deubiquitination and inhibits TNFalpha induced cancer cell migration.
TNF affects USP4
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TNF activates USP4.
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TNF activates USP4. 6 / 7
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To further determine the molecular interaction of USP4 and TAK1 in TNFalpha induced signal transduction, we overexpressed expression vector encoding MYC-USP4 in HEK-293T cells and treated with TNFalpha for the time points as indicated (XREF_FIG).

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

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We found that TNFalpha induced co-immunoprecipitation of MYC-USP4 and TAK1 as well as IKKbeta and RIPK1 within 10 min of stimulation (XREF_FIG).

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

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To determine whether USP4 inhibits TNFalpha induced TAK1 polyubiquitination, we overexpressed MYC-USP4-WT and -C311A mutant with HA-Ub in HEK293T cells and treated with TNFalpha for the time points indicated.

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Consistently, we also found that TNFalpha induced co-immunoprecipitation of endogenous USP4 and TAK1 as well as IKKbeta and RIPK1 (XREF_FIG).
TNF inhibits USP4.
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TNF inhibits USP4. 1 / 1
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To determine the role of USP4 in the regulation of TNFalpha induced IL-6 gene expression, we extracted total RNAs from the control and USP4 knockdown HeLa cell lines treated with TNFalpha for the time points indicated and performed quantitative RT-PCR to examine the effect of USP4 knockdown on TNFalpha induced IL-6 expression.
USP4 affects Wnt
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USP4 activates Wnt.
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USP4 activates Wnt. 4 / 5
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In addition to these newly identified nuclear functions, both USP4 and USP15 are well known to function in the cytosol, i.e. USP4 modulates the Wnt and beta-catenin, NF-kappaB, p53 and TGF-beta signaling pathways while USP15 performs functions in the TGF-beta receptor and NF-kappaB signaling pathways.

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

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However , later studies demonstrated that USP4 enhanced Wnt signaling through stabilizing and facilitating nuclear localization of beta-catenin , especially in cancer ( Yun et al ., 2015 ; Hwang et al ., 2016 ) .

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However, later studies demonstrated that USP4 enhanced Wnt signaling through stabilizing and facilitating nuclear localization of beta-catenin, especially in cancer.
USP4 inhibits Wnt.
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USP4 inhibits Wnt. 2 / 2
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In this study, we found ubiquitin specific peptidase 4 (USP4) to strongly inhibit the Wnt and beta-catenin signaling by removing Lysine 63 linked poly-ubiquitin chain from Dishevelled (Dvl).

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USP4 negatively regulates Wnt signaling by interacting with Nemolike kinase [XREF_BIBR] and USP15 promotes beta-catenin degradation through the stabilization of adenomatous polyposis coli (APC), a negative regulator of Wnt mediated transcription [XREF_BIBR].
USP4 increases the amount of Wnt.
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USP4 increases the amount of Wnt. 1 / 1
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Accordingly, USP4 significantly enhanced the expression of the WNT and beta-catenin downstream target genes, Cyclin D1 and Axin2.
USP4 affects Ubiquitin
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USP4 activates Ubiquitin.
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Like other USPs, USP4 also mediates the removal and processing of ubiquitin.

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USP4 DUSP-Ubl promotes ubiquitin release.

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The DUSP-Ubl domain of USP4 enhances its catalytic efficiency by promoting ubiquitin exchange.

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Pulse-chase analysis of Y-betagal degradation in yeast revealed that Y-betagal is degraded at wild-type rates when Unp is expressed (results not shown), consistent with the ONPG assay and reinforcing [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
USP4 inhibits Ubiquitin.
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Mutation of the conserved Cys residue of Unp to Ala (UnpC311A-FLAG and UnpDelta1-168 : C311A, Fig. 2, lanes 5 and 7) abolished the ubiquitin cleaving activity of Unp, as did the mutation of both conse[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
USP4 affects CDH1
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USP4 inhibits CDH1.
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USP4 inhibits CDH1. 3 / 3
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Neither transient nor stable overexpression of USP4 inhibited E-cadherin in Huh7 cells (Figure xref ).

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Through the immunoblotting analysis, we found that the knockdown of USP4 induced drastic down-regulation of N-cadherin and up-regulation of E-cadherin, indicating that USP4 deficiency could reverse the process of EMT.

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Neither transient nor stable overexpression of USP4 inhibited E-cadherin in Huh7 cells.
USP4 decreases the amount of CDH1.
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USP4 decreases the amount of CDH1. 3 / 3
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In line with previous studies, we also showed that USP4 promoted melanoma metastasis by suppressing E-cadherin expression and increasing N-cadherin expression, indicating the ubiquitous existence of the crosstalk between USP4 and EMT in different kinds of cancer.

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

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We found that knockdown of both USP4 and beta-catenin downregulated the expression of ZEB1 and thereby increased the level of E-cadherin, indicating that the USP4 and beta-catenin axis is required for the EMT process and involves the regulation of ZEB1.
USP4 increases the amount of CDH1.
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USP4 increases the amount of CDH1. 1 / 1
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Moreover, we performed RT-PCR experiment, and it also showed that the knockdown of USP4 could significantly decrease N-cadherin and increase E-cadherin expression at the transcriptional level.
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We observed that the activity and protein levels of both HDAC1 and HDAC4 are decreased when myoblast differentiation is promoted by the USP4 knockdown.

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

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USP4 suppresses Wnt3a induced osteoblast differentiation and mineralization by cleaving K63 linked polyubiquitin chains from disheveled (Dvl) and inhibiting the accumulation of beta-catenin and activation of its downstream cascades.

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Naive CD4 + T cells were sorted using flow cytometry based analysis and were induced for Th2 cell differentiation, and were treated with the inhibitor of USP4, vialinin A, and then processed by flow cytometry.
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19 A recent study has demonstrated that USP4 could promote osteoblast differentiation via Activation of Wnt and beta-catenin signalling by inducing Runx2.

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Conversely, deubiquitination of the K48 linked polyubiquitination of RORgammat by the deubiquitinase ubiquitinspecific protease USP4 stabilizes RORgammat and promotes its activation of Th17 associated genes, whereas inhibition of USP4 activity diminishes Th17 differentiation.
USP4 affects PDCD4
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USP4 activates PDCD4.
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USP4 activates PDCD4. 3 / 3
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In addition, proteasome inhibition by the addition of MG132 induced a significant increase in the PDCD4 expression level (XREF_FIG), suggesting that USP4 inhibits PDCD4 degradation.

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To determine whether PDCD4 is involved in the anti-proliferative function of USP4, we further examined the role of PDCD4 in the USP4 induced inhibition of proliferation by knocking down PDCD4 using siRNA.

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The physical interaction between USP4 and PDCD4 indicated that USP4 targets PDCD4 for deubiquitination and subsequent inhibition of its degradation.
USP4 increases the amount of PDCD4.
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Furthermore, the knockdown of USP4 significantly decreased the endogenous PDCD4 protein expression level (XREF_FIG).