USP10 Data Analysis

HGNC Gene Name
ubiquitin specific peptidase 10
HGNC Gene Symbol
USP10
Identifiers
hgnc:12608 NCBIGene:9100 uniprot:Q14694
Orthologs
mgi:894652 rgd:1561965
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for USP10
Number of Papers
189 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
ABCD4 ATP binding cassette subfamily D member 4 0.195 0.01 -0.05 9.41e-01
ATP2C2 ATPase secretory pathway Ca2+ transporting 2 0.191 0.04 0.12 7.78e-01
CDK6 cyclin dependent kinase 6 0.181 -0.01 -0.16 8.65e-01
G3BP1 G3BP stress granule assembly factor 1 0.177 BioGRID IntAct INDRA (18) 0.32 1.68 2.72e-09
ZNF146 zinc finger protein 146 0.17 -0.04 -0.30 6.90e-01
GPRIN1 G protein regulated inducer of neurite outgrowth 1 0.167 0.19 0.96 8.99e-04
TGFB3 transforming growth factor beta 3 0.167 0.03 0.10 8.02e-01

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with USP10using 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 USP10 using CRISPR-Cas9.

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
RPL28 ribosomal protein L28 6.22e-01 1.88e-06 4.14e-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 USP10 from literature and knowledge bases. The first section shows only DUB activity and the second shows all other results.

Deubiquitinase Activity

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
USP10 deubiquitinates TP53. 10 / 48
| 47

reach
Because USP10 is a p53 deubiquitinating enzyme, p53 ubiquitination was decreased by transfection of USP10 (compare lanes 3 and 4), whereas deubiquitination of p53 by USP10 was inhibited by co-transfection of USP10 and G3BP1 (compare lanes 4 and 5).

reach
Furthermore, Beclin1 can alter p53 expression by regulating deubiquitination of p53 by USP10 43.

reach
Under stress condition, ATM phosphorylates USP10, which then deubiquitinates and targets cytoplasmic p53 back to the nucleus.

reach
It is likely that USP10 functions to deubiquitinate p53 to counteract the action of E3 ubiquitin ligases such as Mdm2.

reach
These results demonstrate that USP10 deubiquitinates p53 both in vitro and in vivo.

reach
Overall, our study demonstrates that resveratrol directly targets G3BP1, which in turn prevents the G3BP1 and USP10 interaction and consequently increases USP10 regulated deubiquitination of p53 (XREF_FIG).

reach
USP10 is a cytoplasmic ubiquitin-specific protease that deubiquitylates p53, reversing Mdm2-induced p53 nuclear export and degradation [108].

reach
BECN1 also regulates the stability of the proteins USP10 and USP13, which might explain the novel observation 200 that BECN1 regulates p53 levels, as USP10 mediates p53 deubiquitylation.

reach
USP10 deubiquitinates both wild-type p53 and mutp53.

reach
USP10 deubiquitinates p53 and reverses MDM2 mediated nuclear transport and degradation of p53.
USP10 deubiquitinates BECN1. 10 / 10
| 9

reach
Furthermore, the presence of spautin-1 inhibited the deubiquitination of Beclin1 mediated by USP10 and USP13.

reach
Specific and potent autophagy inhibitor-1 (Spautin-1) was identified to inhibit USP10 and USP13, which deubiquitinate the Beclin 1 subunit of Vsp34 complex, and thus promoted the degradation of Vsp34 PI3 kinase complex.

reach
It promotes the degradation of Vps34 complexes by inhibiting USP10 and USP13, two ubiquitin specific peptidases that target the deubiquitination of Beclin-1.

ubibrowser
While A20 inhibits PtdIns3P signaling by removing the TRAF6-dependent Lys63-linked chains from Beclin 1, the enzymes USP10 and USP13 prevent PI3K-III complex components from their degradation and, therefore, support autophagy. Interestingly enough, USP10 also stabilizes p53, which, in turn, triggers the degradation of Beclin 1 and VPS34 in order to prevent autophagy.

reach
Since USP10 mediates the deubiquitination of Beclin1 and reduced levels of USP10 leads to increased ubiquitination and degradation of Vps34 complexes, reduced levels of Vps34 complexes as a result of USP10 reduction may in turn lead to destabilization of USP13.

reach
We demonstrate that USP10 and USP13 can both mediate the deubiquitination of Beclin1.

reach
USP10 has also been shown to enhance autophagy by deubiquitinating beclin-1, a component of class-III PI3K complexes that catalyze the formation of phosphatidylinositol 3-phosphate at both autophagy initiation and autophagosome maturation steps.

reach
USP10 and USP13 have been shown to mediate the deubiquitination of Beclin 1, thereby stabilizing the Vps34 complex XREF_BIBR.

reach
Inhibition of the Deubiquitinating Enzymes USP10 and USP13 Causes Ubiquitination of Beclin 1.

reach
Conversely, it was show that Beclin 1 is deubiquitinated by USP10 and USP13 and adding complexity, Beclin 1 itself controlled the protein stabilities of USP10 and USP13 by regulating their deubiquitinating activities, in turn regulating the levels of tumor suppressor p53 [XREF_BIBR].
USP10 deubiquitinates AMPK_alpha. 9 / 9
| 9

reach
Mechanistically, following the energy deprivation, USP10 largely deubiquitinates AMPKalpha so that its activating phosphorylation by LKB1 could be greatly enhanced.

reach
As shown in XREF_FIG and XREF_SUPPLEMENTARY, knockdown of USP10 increased the ubiquitination of WT AMPKalpha; on the other hand, knockdown of USP10 did not affect ubiquitination levels of the AMPKalpha 4KR mutant (XREF_FIG and XREF_SUPPLEMENTARY).

reach
We further overexpressed WT USP10 or catalytic inactive mutant in USP10 deficient cells and found that WT USP10, but not the CA mutant decreased ubiquitination of AMPKalpha (XREF_FIG and XREF_SUPPLEMENTARY), suggesting that USP10 regulates AMPKalpha ubiquitination in cells.

reach
In this study, we identified that USP10 can deubiquitinate PTEN and AMPKalpha and the stabilization of these two proteins will subsequently suppress the activation of AKT and mTOR in HCC cells.

reach
As shown in Figures 3 E and S3 D, knockdown of USP10 increased the ubiquitination of WT AMPKalpha; on the other hand, knockdown of USP10 did not affect ubiquitination levels of the AMPKalpha 4KR mutan[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

reach
We further overexpressed WT USP10 or CA mutant in USP10 deficient cells and found that WT USP10, but not the CA mutant, decreased ubiquitination of AMPKalpha, suggesting that USP10 regulates AMPKalpha[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

reach
USP10 interacts with AMPK and deubiquitinates AMPKalpha.

reach
In addition, in line with our study, two different groups have also reported that USP10 deubiquitinates and stabilizes PTEN and AMPKalpha in lung cancer and colon cancer cells [16, 27].

reach
Recently, it was established that USP10 deubiquitinates AMPKalpha to promote its interaction with LKB1, its master regulator and thus enhances its activity.
USP10 deubiquitinates CFTR. 7 / 7
| 6

reach
Inhibition of USP10 suppresses post-endocytic de-ubiquitination of CFTR, and the cell targets the ion channel to the lysosome rather than recycling it into the apical membrane.

reach
We previously reported that the DUB USP10 deubiquitinates CFTR in early endosomes of human airway epithelial cells XREF_BIBR.

reach
In a recent study, we demonstrated that USP10, a host cell DUB, deubiquitinates CFTR in endosomes, thereby reducing the lysosomal degradation of CFTR, and maintaining cell and plasma membrane CFTR XREF_BIBR.

ubibrowser
Review

reach
USP10 decreases the ubiquitination of CFTR, whereas the knockdown of USP10 promotes the ubiquitination and reduction of CFTR at the cell surface [XREF_BIBR].
| PMC

reach
Functionally, Cif stabilizes an intracellular complex of a DUB (USP10) and G3BP1, preventing deubiquitylation of CFTR, which is required for recycling the receptor to the plasma membrane XREF_BIBR.

reach
The ability of USP10 to efficiently deubiquitinate CFTR in the early endosome allows for efficient endocytic recycling of CFTR and thus the long half-life of CFTR (approximately 8-24 h in polarized human airway cells) in the plasma membrane.
USP10 deubiquitinates SIRT6. 7 / 7
| 6

reach
As previously mentioned, the peptidase USP10 de-ubiquitinates SIRT6, thereby protecting it from proteasomal degradation.
| PMC

reach
USP10 deubiquitinates and stabilizes the tumor suppressor p53, and SIRT6.

ubibrowser
Review

reach
USP10 suppresses SIRT6 ubiquitination to protect SIRT6 from proteasomal degradation.

reach
Second, USP10 suppresses SIRT6 ubiquitination and protects SIRT6 from proteasome mediated degradation.

reach
USP10 deubiquitinates and stabilizes SIRT6, which amplifies the tumor-suppressive activity of SIRT6.

reach
USP10 negatively regulates SIRT6 ubiquitination.
USP10 deubiquitinates IKBKG. 6 / 6
| 5

ubibrowser
Review

reach
MCPIP1 induction serves as a negative feedback mechanism for attenuating NF-kappaB activation in genotoxic response by mediating USP10 dependent deubiquitination of NEMO [13].

reach
By mediating USP10 dependent deubiquitination of NEMO, MCPIP1 serves in a negative feedback mechanism for attenuation of NF-kappaB activation [XREF_BIBR].

reach
One example is USP10 that requires the protein MCPIP-1 (monocyte chemotactic protein induced protein 1) to interact with and deubiquitinate its substrate NEMO inhibiting the NF-kappaB signalling cascade [XREF_BIBR].

reach
USP10 deubiquitinates IKKgamma and NEMO, thereby inhibiting IKKgamma mediated nuclear factor kappaB (NF-kappaB) activation after genotoxic stress.

reach
Thus, by mediating USP10 dependent deubiquitination of NEMO, MCPIP1 induction serves as a negative feedback mechanism for attenuating genotoxic NF-kappaB activation.
USP10 deubiquitinates PCNA. 5 / 5
| 5

reach
Moreover, USP10 could induce PCNA deubiquitination to promote HCC cell growth.

reach
And USP10 could strengthen cell proliferative and migratory abilities through deubiquitinating PCNA.

reach
Recent research has shown that PCNA is also modified by ISG15, and ISGylation of PCNA recruits USP10 to deubiquitinate PCNA, thereby regulating PCNA ubiquitination under UV irradiation induced stress.

reach
An interesting study has recently shown that the deubiquitylation of mammalian PCNA, at least in the context of DNA damage induced by ultraviolet irradiation (UV), is aided by the deubiquitylating activity of USP10.

reach
This modification in turn recruits USP10 that de-ubiquitylates PCNA in order to block TLS and resume normal replication.
USP10 deubiquitinates NLRP7. 4 / 4
| 1 3

reach
NLRP7 deubiquitination by USP10 promotes tumor progression and tumor associated macrophage polarization in colorectal cancer.

reach
Collectively, the present results indicated that NLRP7 in CRC cells interacts with and is deubiquitinated by USP10, resulting in increased NLRP7 protein stability.

reach
Co-IP experiments showed that USP10 knockdown increased the ubiquitination of NLRP7 in HCT116 cells.

trips
NLRP7 deubiquitination by USP10 promotes tumor progression and tumor-associated macrophage polarization in colorectal cancer.
USP10 deubiquitinates PTEN. 4 / 4
| 3

ubibrowser
We further demonstrated that USP10 directly interacted with and stabilized PTEN via deubiquitination.

reach
Additionally, we found that USP10 stabilized PTEN protein in a dose dependent manner, and inhibited Lys-48-linked polyubiquitylation of PTEN.

reach
In addition, in line with our study, two different groups have also reported that USP10 deubiquitinates and stabilizes PTEN and AMPKalpha in lung cancer and colon cancer cells [16, 27].

reach
In this study, we identified that USP10 can deubiquitinate PTEN and AMPKalpha and the stabilization of these two proteins will subsequently suppress the activation of AKT and mTOR in HCC cells.
USP10 deubiquitinates Histone. 3 / 3
| 3

reach
USP10 deubiquitylates the histone variant H2A.Z and both are required for androgen receptor mediated gene activation.

reach
Moreover, USP10 not only binds AR, resulting in increased transcriptional activity, but also deubiquitinates the histone variant H2A.Z, both of which are required for AR - mediated gene activation [XREF_BIBR, XREF_BIBR].

reach
In addition, more bulky structures, SUMO (small ubiquitin related modifier) and ubiquitin are conjugated to histones (Galanty et al., 2009; Morris et al., 2009; Shioo and Eisenman, 2003; Thakar et al.[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
USP10 deubiquitinates His2Av. 3 / 3
| 3

reach
USP10 specifically deubiquitylates H2A.Z and H2A.

reach
USP10 directly deubiquitylates H2A.Z in vitro and in vivo, and reducing USP10 expression in prostate cancer cells results in elevated steady-state levels of mono-ubiquitylated H2A.Z (H2A.Zub1).

reach
In addition, the deubiquitination of H2A.Z by USP10 is required for the androgen-receptor mediated transcriptional activation of hormone regulated genes [XREF_BIBR].
USP10 deubiquitinates TBP. 3 / 3
| 2

reach
To test whether USP10 deubiquitinates and stabilizes TBP in mammalian cells, we overexpressed USP10 in 293T cells and monitored TBP ubiquitination levels in these cells.

reach
To test whether USP10 deubiquitinates TBP through direct protein protein interactions, we used HA-TBP to co-IP with Flag-USP10 co-expressed in 293T cells.

ubibrowser
Huwe1 as an E3 ligase targeting TBP for K48-linked ubiquitination and proteasome-mediated degradation; We found that Huwe1 activity on TBP is antagonized by the deubiquitinase USP10, which protects TBP from degradation.
USP10 deubiquitinates TRAF6. 3 / 3
| 2

ubibrowser
We found TANK formed a complex with MCPIP1 (also known as ZC3H12A) and a deubiquitinase, USP10, which was essential for the USP10-dependent deubiquitination of TRAF6 and the resolution of genotoxic NF-κB activation upon DNA damage.

reach
TRAF Family Member associated NF-kappaB Activator (TANK) Inhibits Genotoxic Nuclear Factor kappaB Activation by Facilitating Deubiquitinase USP10 dependent Deubiquitination of TRAF6 Ligase.

reach
We found TANK formed a complex with MCPIP1 (also known as ZC3H12A) and a deubiquitinase, USP10, which was essential for the USP10 dependent deubiquitination of TRAF6 and the resolution of genotoxic NF-kappaB activation upon DNA damage.
USP10 deubiquitinates SKP2. 2 / 2
| 2

reach
Additionally, Liao and colleagues [XREF_BIBR] found that USP10 can promote leukemic cell proliferation by deubiquitinating and stabilizing the S-phase kinase associated protein 2 (SKP2) that acts as a co-regulator of BCR-ABL mediating its K63 linked ubiquitination and activation in CML cells [XREF_BIBR].

reach
USP10 deubiquitinates and stabilizes SKP2.
USP10 deubiquitinates RPS3. 2 / 2
| 1

reach
Subsequent deubiquitination of RPS2 and RPS3 by USP10 is critical for recycling of stalled ribosomes in a process known as ribosome associated quality control.

ubibrowser
No evidence text available
USP10 deubiquitinates HDAC6. 2 / 2
| 2

reach
XREF_FIG, wild-type USP10, but not the catalytically-inactive USP10CA mutant, significantly reduces HDAC6 ubiquitination in 293T cells (comparing lanes 3 and 4 in the top panel).

reach
Next, we tested whether USP10 could deubiquitinate HDAC6.
USP10 deubiquitinates MSH2. 2 / 2
| 1

reach
USP10 deubiquitinates MSH2 in vitro and in vivo Moreover, the protein level of MSH2 is positively correlated with the USP10 protein level in a panel of lung cancer cell lines.

ubibrowser
Here we report that ubiquitin-specific peptidase 10 (USP10) interacts with and stabilizes MSH2.
USP10 leads to the deubiquitination of CDKN2A. 2 / 2
| 1

reach
USP10, in turn, mediated the deubiquitination of p14ARF, preventing its proteasome dependent degradation.

ubibrowser
Oncogene-induced senescence mediated by c-Myc requires USP10 dependent deubiquitination and stabilization of p14ARF.
USP10 leads to the deubiquitination of mutated TP53. 2 / 2
| 2

reach
However, it is unclear whether USP10 antagonizes ubiquitination of mutp53 by other ubiquitin ligases, USP10 alters subcellular localization of mutp53, and USP10 plays a role in deubiquitination of different TP53 mutants.

reach
USP10 deubiquitinates and stabilizes both wt and mutant p53.
USP10 deubiquitinates TOP2A. 1 / 1
| 1

reach
In contrast, USP10, also a cytosolic DUB [XREF_BIBR], deubiquitylates TOP2A in complex with the E3 ligase RNF168 [XREF_BIBR], which is also important in DNA damage response signalling for double-strand break repair [XREF_BIBR].
USP10 deubiquitinates AMPK. 1 / 1
| 1

reach
Deubiquitination and activation of AMPK by USP10.
USP10 deubiquitinates PRKAA2. 1 / 1
|

ubibrowser
The deubiquitinase USP10 specifically removes ubiquitination on AMPKalpha to facilitate AMPKalpha phosphorylation by LKB1.
USP10 deubiquitinates PDLIM5. 1 / 1
| 1

reach
Research on the endothelium revealed that USP10, as a regulatory protein, delayed the rate of NICD1 degradation by deubiquitinating the Notch1 receptor (Lim et al., 2019).
| PMC
Unubiquitinated USP10 leads to the deubiquitination of CFTR. 1 / 1
| 1

reach
In P. aeruginosa, the OMV associated toxin CFTR-inhibitory factor (Cif) controls the host deubiquitylating enzyme USP10 to cause increased ubiquitylation of cystic fibrosis transmembrane conductance regulator (CFTR), which is involved in mucus production.
USP10 deubiquitinates H2AZ1. 1 / 1
|

ubibrowser
Review
USP10 leads to the deubiquitination of SLC9A3. 1 / 1
| 1

reach
Ubiquitin specific peptidase 7 (USP7) and USP10 mediate deubiquitination of human NHE3 regulating its expression and activity.
USP10 deubiquitinates MDM4. 1 / 1
| 1

reach
Another DUB, USP10 deubiquitinates p53, but not MDM2 or MDMX.
USP10 deubiquitinates AR. 1 / 1
| 1

reach
Together, these data provide novel insights into how H2A.Z ubiquitylation and deubiquitylation and USP10 function in AR regulated gene expression.
Modified USP10 leads to the deubiquitination of AMPK_alpha. 1 / 1
| 1

reach
In contrast, overexpression of USP10 significantly inhibited polyubiquitylation of PTEN and AMPKalpha.
USP10 deubiquitinates ITGB1. 1 / 1
|

ubibrowser
?Silencing of the DUB USP10 induces a buildup of ubiquitin on integrins beta1 and beta5 in cell lysates, whereas recombinant USP10 removes ubiquitin from these integrin subunits.
USP10-C424A deubiquitinates TP53. 1 / 1
| 1

reach
We confirmed that wild-type USP10 but not USP10 C424A deubiquitinates the p53 protein (XREF_SUPPLEMENTARY C).
Modified USP10 leads to the deubiquitination of PTEN. 1 / 1
| 1

reach
In contrast, overexpression of USP10 significantly inhibited polyubiquitylation of PTEN and AMPKalpha.
USP10 deubiquitinates ULK1. 1 / 1
| 1

reach
However, a direct deubiquitination of ULK1 by USP10 remains to be demonstrated.
Mutated USP10 leads to the deubiquitination of BECN1. 1 / 1
| 1

reach
As shown in XREF_FIG, the coincubation of ubiquitinated Beclin1 with USP10 or USP13 but not a catalytically inactive USP10 mutant reduced the levels of Beclin1 ubiquitination.
USP10 deubiquitinates NOTCH1. 1 / 1
| 1

reach
Research on the endothelium revealed that USP10, as a regulatory protein, delayed the rate of NICD1 degradation by deubiquitinating the Notch1 receptor (Lim et al., 2019).
| PMC
USP10 deubiquitinates AICDA. 1 / 1
| 1

reach
USP10 regulates B cell response to SARS-CoV-2 or HIV-1 nanoparticle vaccines through deubiquitinating AID.
USP10 deubiquitinates TBX21. 1 / 1
|

ubibrowser
Review
USP10 deubiquitinates ITGB5. 1 / 1
|

ubibrowser
?Silencing of the DUB USP10 induces a buildup of ubiquitin on integrins beta1 and beta5 in cell lysates, whereas recombinant USP10 removes ubiquitin from these integrin subunits.
USP10 deubiquitinates ENaC. 1 / 1
| 1

reach
Yet, overexpressed USP10 does not deubiquitinate the bulk of the ENaC pool.
USP10 deubiquitinates H2BC10. 1 / 1
|

ubibrowser
The deubiquitinase (DUB) Ubp10 is thought to promote heterochromatic silencing by maintaining low H2B-Ub at sub-telomeres
USP10 deubiquitinates PRKAA1. 1 / 1
|

ubibrowser
The deubiquitinase USP10 specifically removes ubiquitination on AMPKa to facilitate AMPKa phosphorylation by LKB1.
USP10 deubiquitinates FLT3. 1 / 1
|

ubibrowser
USP10, a primary cytoplasmic DUB, acts as an oncogene or a tumor suppressor by regulating various protein substrates, including FLT3, p53, AMPK, PTEN, etc.
USP10 leads to the deubiquitination of mutated FLT3. 1 / 1
| 1

reach
Given our recent finding that USP10 deubiquitinates mutant FLT3, 18 coupled with reported studies showing that FLT3 and SYK are interacting partners with each other and are targets of the same E3 ligase c-CBL, XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR we hypothesised that USP10 may play a role in stabilisation of SYK.
USP10 deubiquitinates SNX3. 1 / 1
|

ubibrowser
?A two-hybrid screen identified sorting nexin 3 (SNX3) as a novel substrate of Usp10.
Modified USP10 leads to the deubiquitination of TBP. 1 / 1
| 1

reach
Strikingly, overexpression of USP10 significantly inhibited TBP ubiquitination (XREF_FIG).
Modified USP10 leads to the deubiquitination of mutated TP53. 1 / 1
| 1

reach
Coexpression of USP10 together with Mdm2 decreased mutant p53 ubiquitination (XREF_SUPPLEMENTARY), while downregulation of USP10 increased mutant p53 ubiquitination (XREF_SUPPLEMENTARY), suggesting that USP10 also regulates mutant p53 ubiquitination.
USP10 deubiquitinates RPS2. 1 / 1
| 1

reach
Subsequent deubiquitination of RPS2 and RPS3 by USP10 is critical for recycling of stalled ribosomes in a process known as ribosome associated quality control.
USP10 deubiquitinates SNAI2. 1 / 1
|

ubibrowser
Here, by using a genome wide siRNA screen for human deubiquitinating enzymes (DUBs), we identified USP10 as a deubiquitinase for Slug in cancer cells.
Modified USP10 leads to the deubiquitination of SIRT6. 1 / 1
| 1

reach
The results showed that overexpression of wild-type USP10 promoted the deubiquitination of Sirt6 and inhibited the activation of downstream Akt signaling pathway, while mutant USP10 lost this function.
USP10 deubiquitinates Nucleoproteins. 1 / 1
| 1

reach
The result showed that both USP10 and USP11 specifically co-precipitated with NP-HA (lanes 1, 3 and 4, lower panel), consistent with the published result, and NP could be deubiquitinated by only USP11 but not USP10 (lanes 3 and 4, upper panel).
USP10 deubiquitinates TAP1. 1 / 1
|

ubibrowser
Review
USP10 deubiquitinates MDM2. 1 / 1
| 1

reach
Another DUB, USP10 deubiquitinates p53, but not MDM2 or MDMX.

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
USP10 affects TP53
| 3 1 44
USP10 activates TP53.
| 3 1 17
USP10 activates TP53. 10 / 24
| 3 1 15

reach
We identify 9 direct binding partners of p53 in the nuclear RNA interactome, including USP10, which deubiquitinates and activates p53 in response to DNA damage, and Sumo1, which can itself become covalently coupled to p53 to regulate its activity and subcellular localization (XREF_SUPPLEMENTARY) XREF_BIBR XREF_BIBR XREF_BIBR.

reach
Upon DNA damage, USP10 deubiquitylates and activates p53.

eidos
USP10 , upon ATM-dependent phosphorylation at threonine 42 and serine 337 residues , is stabilized and translocated to the nucleus to activate p53 through deubiquitinating activity , inducing tumor cell suppression [ 53 ] .
| PMC

reach
Overall, these results suggest that USP10 potentiates p53 function in cells.

eidos
Thus , depletion of USP10 would cause a decrease in p53 levels and lead to cisplatin resistance .

reach
For example, USP7 regulates the stability of both p53 and Mdm2 and maintains p53 ubiquitination levels; 120 USP2 mediates the stability of Mdm2; 121 USP10 modulates p53 localization and stability; 122 OTUB1 abrogates p53 ubiquitination and activates p53.

reach
USP10 modulates anterograde and retrograde vesicular trafficking, the localization and stability of p53 and binds Dengue virus RNA.

reach
Wildtype TP53 is usually rescued from proteasomal degradation by USP10.

reach
As shown in XREF_FIG, downregulation of USP10 increased cancer cell proliferation in p53 +/+ cells, while USP10 expression levels have no apparent effect on proliferation in cells lacking p53.

reach
It will be interesting to discover whether overexpression of USP7 could also rescue the diminished DNA damage induced p53 response caused by USP10 depletion.
USP10 activates mutated TP53. 2 / 2
| 2

reach
Paradoxically, USP10 could promote cancer cell proliferation in mutant p53 background.

reach
Furthermore, expression of USP10 increased mutant p53 stability (XREF_SUPPLEMENTARY), while downregulation of USP10 decreased mutant p53 stability (XREF_SUPPLEMENTARY), suggesting that USP10 regulates mutant p53 stability.
USP10 inhibits TP53.
| 14
USP10 inhibits TP53. 10 / 20
| 12

reach
Expression of USP10 significantly suppressed c-Myc transcriptional activity in p53 wildtype and p53 -/- HCT116 cells, but the levels of USP10 mediated suppression in c-Myc target gene transcription in p53-null cells were partially reversed.

reach
In addition, USP10 suppresses the tumour cell growth in cells with wild-type p53, and USP10 expression is down-regulated in a high percentage of clear cell carcinomas known to have few p53 mutations [108].

reach
It also binds USP10, a key p53 regulator, reducing p53 stability and its anti-cancer functions.

reach
Indeed, USP10 depletion attenuates DNA damage induced stabilization of p53, an effect that was rescued by overexpression of wild-type USP10 but not by mutant USP10 lacking ATM phosphorylation sites.

reach
Consistent with this notion, USP10 expression is frequently lost in renal cell carcinoma, and overexpression of USP10 suppresses cell transformation and tumorigenesis in a p53 dependent fashion.

reach
Coexpression of WT USP10 with Mdm2 reversed Mdm2 induced cytoplasmic translocation of p53.

reach
Association of USP10 with G3BP2 Inhibits p53 Signaling and Contributes to Poor Outcome in Prostate Cancer.

reach
It also binds USP10, a key p53 regulator, reducing p53 stability and anti-cancer functions.

reach
Downregulation of p53 abolished the inhibitory effect of USP10 on tumor growth (XREF_FIG and data not shown), confirming that USP10 inhibits cancer cell growth by stabilizing p53.

reach
Usp10 overexpression abolished the estrogen mediated regulation of p53 and the downstream transcriptional gene p21.
USP10 inhibits mutated TP53. 1 / 1
| 1

reach
Furthermore, expression of USP10 increased mutant p53 stability (XREF_SUPPLEMENTARY), while downregulation of USP10 decreased mutant p53 stability (XREF_SUPPLEMENTARY), suggesting that USP10 regulates mutant p53 stability.
USP10 bound to G3BP2 inhibits TP53. 1 / 1
| 1

reach
For example, USP10 interacts with G3BP2 to block p53 signal transduction, leading to poor prognosis in prostate cancer [XREF_BIBR]; USP44 promotes the development of prostate cancer by stabilizing EZH2 [XREF_BIBR], and USP2a enhances c-Myc expression via microRNA related regulation and thus promotes tumourigenesis [XREF_BIBR].
USP10 increases the amount of TP53.
| 9
USP10 increases the amount of TP53. 5 / 6
| 5

reach
Reconstitution of USP10 in CAKI-1 and CAKI-2 (WT p53 cell lines) restored p53 expression and increased p21 and BAX expression (XREF_SUPPLEMENTARY).

reach
In accordance with published work, we detected that knockdown of USP10 is sufficient to reduce p53 protein levels.

reach
Both, the DUB HAUSP (herpesvirus associated ubiquitin specific protease) and USP10 (ubiquitin specific protease 10), targeting poly-ubiquitinated p53, have been shown to restore p53 levels even when Hdm2 is overexpressed.

reach
These results suggest that USP10 can upregulate p53 levels, most likely by deubiquitinating and consequently stabilizing p53.

reach
In accordance with published work, we detected that knockdown of USP10 is sufficient to reduce p53 protein levels (Yuan et al., 2010).
Modified USP10 increases the amount of TP53. 3 / 3
| 3

reach
Furthermore, overexpression of USP10 in 786-O cells increases levels of mutp53, leading to enhanced colony formation and proliferation, which is nullified by depletion of mutp53.

reach
Overexpression of USP10 significantly increased the levels of endogenous p53, with no effect on p53 mRNA levels (XREF_FIG).

reach
Consistent with this study, we show that increased USP10 expression in mutant p53 background increases p53 levels and promotes cancer cell proliferation, while downregulation of USP10 inhibits cancer cell growth.
USP10 increases the amount of mutated TP53. 1 / 1
| 1

reach
Inhibition of USP10 by the protein spautin-1 reduces mutant p53 levels under glucose restricted conditions.
USP10 decreases the amount of TP53.
| 4
USP10 decreases the amount of TP53. 4 / 4
| 4

reach
Interestingly, downregulation of USP10 significantly decreased p53 stabilization and the expression of p53 target genes p21 and Bax after DNA damage (XREF_FIG).

reach
On the other side, the ubiquitinated TP53 could be reversed and stabilized by USP7 and USP10, to keep the amount of TP53 in check.

reach
Thus, depletion of USP10 would cause a decrease in p53 levels and lead to cisplatin resistance.

reach
To confirm the role of USP10 in regulating p53 levels, we depleted USP10 using USP10 specific shRNA, and found that downregulation of USP10 decreased p53 protein levels with no effect on p53 mRNA levels (XREF_FIG).
| 8 30
| 8 26

reach
USP10 Is an Essential Deubiquitinase for Hematopoiesis and Inhibits Apoptosis of Long-Term Hematopoietic Stem Cells.

reach
Collectively, these results indicate that USP10 inhibits cytokine deprivation induced apoptosis of IVC-LSK cells in a deubiquitinase dependent but ROS independent manner.

reach
XREF_FIG, overexpression of either HDAC6 or USP10 in USP10 knockdown cells significantly increased cell survival post-cisplatin treatment and reduced apoptosis as shown by the level of cleaved PARP-1.

reach
Thus, USP10 induced aggregates and aggresomes might inhibit apoptosis by reducing the amount of ubiquitinated protein oligomers.

reach
USP10 also has deubiquitinase independent functions, such that USP10 inhibits apoptosis by reducing reactive oxygen species (ROS) production induced by an oxidative stress inducer arsenite.

sparser
A deubiquitinase-inactive USP10 mutant (USP10/C418A) did not inhibit cytokine deprivation-induced apoptosis of IVC-LSK cells, indicating that a factor deubiquitinated by USP10 inhibits apoptosis of IVC-LSK cells.

sparser
We previously reported that USP10 inhibits oxidant-induced apoptosis by reducing ROS production in mouse embryonic fibroblasts (MEFs) ( xref ).

sparser
However, we could not exclude the possibility that USP10 inhibits apoptosis by promoting degradation of pro-apoptotic protein(s) by aggresome-mediated autophagy.

sparser
Upon exposure to an oxidant, USP10 inhibits ROS-dependent apoptosis by reducing ROS production ( xref ).

reach
On exposure to arsenic, an oxidative stress inducer, USP10 is recruited into stress granules (SGs), and USP10 containing SGs reduce reactive oxygen species (ROS) production and inhibit ROS dependent apoptosis.
USP10 bound to G3BP1 inhibits apoptotic process. 1 / 1
| 1

reach
Studies using USP10 mutants, including USP10/77 -792 and USP10/95-792, indicate that USP10 's interaction with G3BP1 is essential for inhibition of ROS dependent apoptosis and for USP10 incorporation into stress granules.
| 4

reach
In conclusion, these results suggest that USP10 promotes proliferation and migration and inhibits apoptosis of endometrial stromal cells in endometriosis through activating the Raf-1/MEK/ERK pathway.

reach
USP10-knockout indicated that USP10, through augmenting formation of SGs, reduced reactive oxygen species (ROS) production and inhibited ROS dependent apoptosis.
| PMC

reach
USP10 promotes proliferation and migration and inhibits apoptosis of endometrial stromal cells in endometriosis through activating the Raf-1/MEK/ERK pathway.

reach
USP10 Heterozygote mice exhibited exacerbated hepatic I/R injury, as evidenced by enhanced liver inflammation via the NF-kappaB signalling pathway and increased hepatocyte apoptosis.

reach
Two independent USP10 short hairpin RNAs (shRNAs) both promoted cell proliferation of HCCLM3 and HUH7 cells.

reach
In vitro data showed that USP10 deficiency reduced proliferation and migration of rat thoracic aorta smooth muscle cells (A7r5) and human aortic smooth muscle cells (HASMCs).

reach
Indeed, downregulation of USP10 decreases p53 stability and increases cancer cell proliferation XREF_BIBR, thus projecting a role as a tumor suppressor.

reach
Proliferation inhibition by loss of USP10 depends on SKP2 functional status.

reach
In conclusion, these results suggest that USP10 promotes proliferation and migration and inhibits apoptosis of endometrial stromal cells in endometriosis through activating the Raf-1/MEK/ERK pathway.

reach
USP10 promotes proliferation and migration and inhibits apoptosis of endometrial stromal cells in endometriosis through activating the Raf-1/MEK/ERK pathway.

reach
For example, in hepatocellular carcinoma, Zhu et al. reported that USP10 promotes proliferation [XREF_BIBR], whereas Lu et al. found that USP10 suppresses tumor progression by inhibiting mTOR activation [XREF_BIBR].

reach
Specifically, USP10 activates PTEN by preventing its K63 linked polyubiquitination mediated by TRIM25 and suppresses the AKT and mTOR signaling pathway thereby inhibiting NSCLC proliferation, indicating that it may be a potential drug target for cancer treatment.

reach
USP10 overexpression promoted ectopic endometrial stromal cell migration and proliferation, suppressed cell apoptosis, and activated MEK and ERK signaling that is a critical downstream target of the serine/threonine protein kinase Raf-1, which was significantly blocked by PD98059.

reach
USP10 regulates Musashi-2 stability via deubiquitination and promotes tumour proliferation in colon cancer.

reach
Consistent with this study, we show that increased USP10 expression in mutant p53 background increases p53 levels and promotes cancer cell proliferation, while downregulation of USP10 inhibits cancer cell growth.

reach
Conversely, downregulation of USP10 inhibited cell proliferation (XREF_FIG and data not shown).

reach
As expected, USP10 over expression inhibited the proliferation of colon cancer cells with either a wildtype p53 or with p53-deficency.

reach
The deubiquitinase USP10 restores PTEN activity and inhibits non small cell lung cancer cell proliferation.

reach
Furthermore, the double knock-down of G3BP1 and USP10 rescued the inhibition of proliferation induced by G3BP1 depletion in HCT116 (XREF_FIG) and SK-MEL-5 cells (XREF_SUPPLEMENTARY).

reach
Furthermore, we provide evidence that USP10 inhibits cancer cell proliferation in cells with WT p53.

reach
Consistent with its molecular activity, re-expression of USP10 suppressed NSCLC cell proliferation and migration while knockout of USP10 promoted NSCLC cell proliferation and migration.

reach
On the other hand, reconstitution of USP10 in cells with USP10 downregulation inhibited cancer cell proliferation (XREF_FIG), suggesting the effect of USP10 knockdown is specific.

reach
In contrast, overexpressing USP10 expression in MHCC97L and BEL-7402 cells reduced the cell proliferation.

sparser
Furthermore, we provide evidence that USP10 inhibits cancer cell proliferation in cells with WT p53.

sparser
Conversely, downregulation of USP10 inhibited cell proliferation ( xref and data not shown).
USP10 affects MYC
| 21
USP10 inhibits MYC.
| 18
USP10 inhibits MYC. 10 / 22
| 18

reach
Third, USP10 antagonizes c-Myc transcriptional activity and cell cycle progression through both SIRT6 and p53.

reach
Previous studies have shown that USP10 antagonizes c-Myc transcriptional activation that could promote Sirt6 stabilization to suppress tumor formation.

reach
It has been reported that one of the molecular mechanisms underlying USP10 tumor-suppressive functions is that it protects p53 from degradation, raising the possibility that USP10 also antagonizes c-Myc transcriptional activity through p53.

reach
In addition, p53 knockdown partially abolished USP10 over-expression-mediated suppression in c-Myc target gene expression in SIRT6 +/+ MEFs, and p53 knockdown in SIRT6 -/- MEFs fully reversed USP10 mediated suppression of c-Myc targets expression (XREF_FIG).

reach
To further prove the principle that USP10 suppresses c-Myc transcriptional activity through both SIRT6 and p53, we tested whether knockdown of SIRT6 rescues this USP10 suppressive activity.

reach
USP10 suppresses c-Myc transcriptional activity through SIRT6 and p53.

reach
We then used SIRT6-null mouse embryonic fibroblasts (MEFs) to prove the principle that SIRT6 is another downstream factor in USP10 mediated c-Myc suppression.

reach
USP10 inhibits c-Myc transcriptional activity.

reach
Therefore, USP10 might antagonize c-Myc activity to inhibit tumor cell growth though SIRT6 and p53.

reach
We then used in vitro anchorage independent colony formation assay and analyzed the role of USP10 mediated c-Myc suppression in tumor formation.
USP10 activates MYC.
| 2
USP10 activates MYC. 2 / 2
| 2

reach
Thus, we determined whether USP10 functions as a tumor suppressor through SIRT6 mediated c-Myc inactivation.

reach
To our surprise, SIRT6 gene suppression resulted in a lower level of increase in c-Myc target gene expression than that of USP10 knockdown, implying that additional factors may contribute to USP10 mediated c-Myc suppression.
USP10 decreases the amount of MYC.
| 1
USP10 decreases the amount of MYC. 1 / 1
| 1

reach
USP10 also antagonizes c-myc transcription through deubiquitination of SIRT6, a histone deacetylase, and NF-kappaB signaling through deubiquitination of NEMO [XREF_BIBR].
USP10 affects SIRT6
| 1 8
USP10 inhibits SIRT6.
| 1
USP10 inhibits SIRT6. 1 / 13
| 1

reach
Accordingly, inactivation of USP10 reduced Sirt6 abundance and stability and diminished Sirt6 induced downstream signaling in cardiomyocytes.
USP10 activates SIRT6.
| 1 4
USP10 activates SIRT6. 5 / 8
| 1 4

reach
Furthermore, USP10 directly regulates Sirt6 during the pathogenesis of CH.

reach
These studies suggest the possibility that the association with RBM5-AS1 may reinforce USP10 dependent suppression of SIRT6 degradation.
| PMC

reach
In contrast, knockdown of USP10 but not USP22 in RKO cells promoted SIRT6 degradation.

eidos
It was shown that knockdown of USP10 decreased Sirt6 expression , whereas overexpression of USP10 increased Sirt6 protein expression in primary cardiomyocytes after Ang II stimulation ( Figure 6C and 6D ) .

reach
Therefore, it seems that USP10 mediated SIRT6 stabilization is largely involved in regulating c-Myc transcriptional activity.
USP10 increases the amount of SIRT6.
| 3
USP10 increases the amount of SIRT6. 2 / 2
| 2

reach
It was shown that knockdown of USP10 decreased Sirt6 expression, whereas overexpression of USP10 increased Sirt6 protein expression in primary cardiomyocytes after Ang II stimulation.

reach
Conversely, shRNA mediated knockdown of USP10 decreased the endogenous SIRT6 protein levels without affecting SIRT6 mRNA levels (XREF_FIG).
Modified USP10 increases the amount of SIRT6. 1 / 1
| 1

reach
It was shown that knockdown of USP10 decreased Sirt6 expression, whereas overexpression of USP10 increased Sirt6 protein expression in primary cardiomyocytes after Ang II stimulation.
USP10 affects cell growth
| 19
USP10 inhibits cell growth.
| 18
| 17

reach
In addition, USP10 suppresses the tumour cell growth in cells with wild-type p53, and USP10 expression is down-regulated in a high percentage of clear cell carcinomas known to have few p53 mutations [108].

reach
Downregulation of p53 abolished the inhibitory effect of USP10 on tumor growth (XREF_FIG and data not shown), confirming that USP10 inhibits cancer cell growth by stabilizing p53.

reach
In addition, USP10 suppresses the tumour cell growth in cells with wild-type p53, and USP10 expression is down-regulated in a high percentage of clear cell carcinomas known to have few p53 mutations [XREF_BIBR].

reach
Given USP10 also regulates p53 expression and suppresses tumor cell growth, phosphorylation of USP10 under energy stress might contribute to p53 level increase and tumor suppression.

reach
On the other hand, shRNA mediated USP10 knockdown caused more vigorous tumor cell growth of both wildtype and p53-null cells, confirming the tumor-suppressive function of USP10 (XREF_FIG, XREF_SUPPLEMENTARY).

reach
Moreover, USP10 inhibited cell growth and invasion in lung cancer [XREF_BIBR], and was an independent factor for the prognosis of gastric carcinoma [XREF_BIBR].
| PMC

reach
Consistent with this study, we show that increased USP10 expression in mutant p53 background increases p53 levels and promotes cancer cell proliferation, while downregulation of USP10 inhibits cancer cell growth.

reach
3.2 Spautin-1, a dual USP10 and USP13 antagonist, inhibits melanoma cell growth in vitro.
| PMC

reach
Our study demonstrated that USP10 suppresses tumor cell growth through potentiating both SIRT6- and p53 mediated suppression of the oncogene c-myc.

reach
The same study shows that USP10 suppresses tumor cell growth in cells expressing wild-type p53.
Modified USP10 inhibits cell growth. 1 / 1
| 1

reach
Consistent with this study, we show that increased USP10 expression in mutant p53 background increases p53 levels and promotes cancer cell proliferation, while downregulation of USP10 inhibits cancer cell growth.
USP10 activates cell growth.
| 1
| 1

reach
On the other hand, in cancer cells with mutant p53, USP10 could promote cancer cell growth, and inhibition of USP10 is called for.
USP10 affects cell death
| 5 16
USP10 inhibits cell death.
| 5 12
| 5 10

reach
To obtain information describing how USP10 inhibits MG-132-induced cell death, we measured cell death of USP10-KD cells expressing several USP10 mutants.

sparser
USP10 inhibited cell death induced by PI, and the inhibition correlated with aggresome/aggregate-inducing activity ( xref and xref ).

reach
Given that USP10-WT, USP10 C424A, and USP10 96-798, but not USP10 1-214, in USP10-KD cells promoted p62 aggregation and aggresome formation (XREF_FIG G and XREF_SUPPLEMENTARY A-S5C), these results suggested that USP10 inhibits cell death induced by MG-132 by promoting aggresome formation and p62 aggregation.

reach
Thus, we examined whether USP10 inhibits MG-132-induced cell death by measuring activated caspase-3 (cleaved caspase-3).

sparser
Thus, we examined whether USP10 inhibits MG-132-induced cell death by measuring activated caspase-3 (cleaved caspase-3).

reach
USP10 Inhibits Cell Death Induced by MG-132.

reach
USP10 C424A and USP10 96-798, but not USP10 1-214, reduced cell death of USP10-KD cells (XREF_FIG G and XREF_SUPPLEMENTARY A-S5C).

reach
USP10 inhibited cell death induced by PI, and the inhibition correlated with aggresome and aggregate inducing activity (XREF_FIG and XREF_SUPPLEMENTARY).

reach
Similar to Beclin 1 knockdown, we found that suppression of the ubiquitin specific peptidase, USP10, or a small molecule inhibitor of the deubiquitinases USP10 and USP13, i.e., spautin-1 XREF_BIBR, can increase radiation induced DSBs and promote tumor cell death.

sparser
These results indicated that USP10 and p62 cooperatively inhibit MG-132-induced cell death by promoting the formation of aggresomes and p62 aggregates.
USP10-C424A inhibits cell death. 1 / 1
| 1

reach
USP10 C424A and USP10 96-798, but not USP10 1-214, reduced cell death of USP10-KD cells (XREF_FIG G and XREF_SUPPLEMENTARY A-S5C).
Mutated USP10 inhibits cell death. 1 / 1
| 1

reach
While USP10/77 -792 and USP10/95 -792 mutants inhibited cell death of IVC-LSK cells as efficiently as USP10-WT, a deubiquitinase inactive mutant USP10 and C418A showed minimal activity and failed to inhibit cytokine deprivation induced cell death after 44and 62hr of starvation.
USP10 activates cell death.
| 4
| 4

reach
Similar to Beclin 1 knockdown, we found that suppression of the ubiquitin specific peptidase, USP10, or a small molecule inhibitor of the deubiquitinases USP10 and USP13, i.e., spautin-1 XREF_BIBR, can increase radiation induced DSBs and promote tumor cell death.

reach
Consistent with our screening results on the effect of USP10 siRNA, pretreatment with spautin-1, a specific inhibitor of USP10, markedly inhibited curcumin induced morphological changes of mitochondria and subsequent paraptotic cell death in various breast cancer cells.

reach
Additional work will be needed to investigate the detailed underlying mechanism by which USP10 contributes to paraptotic cell death in malignant breast cancer cells.

reach
Additional work is needed to investigate the detailed underlying mechanism by which USP10 contributes to mitochondrial dilation and subsequent paraptotic cell death in malignant breast cancer cells.
G3BP1 affects USP10
| 3 13
G3BP1 inhibits USP10.
| 3 12
| 3 9

reach
discovered the interaction of G3BP1 with ubiquitin specific protease 10 (USP10), and they concluded that G3BP1 might restrict the deubiquitinating activity of USP10.

reach
It should be remarked that G3BP1 is also a perturbator for the PD-VPs USP10 [91], GiGYF2 [99], EIF4G1 [100], and TIAL1 [101].

reach
G3BP1 disrupts the interaction of USP10 with p53.

sparser
Anisonov et al. [91] also found that USP10 is inhibited by G3BP1 in a mechanism similar to that for NUP62, which indicates an analogous cascading route from SARS-CoV-2 to PD for this protein.

reach
One of the reported functions of G3BP1 is to bind to and inhibit USP10 XREF_BIBR.

reach
Surprisingly, the human homolog of Bre5, G3BP1, inhibits the activity of USP10, at least in vitro, indicating that cofactors can either restrict or enhance protease activity.

reach
Notably, siRNA mediated knockdown of G3BP1 significantly increased the abundance of CFTR, most likely because endogenous G3BP1 inhibits USP10 (XREF_FIG).

reach
It appears therefore that the FGDF mediated G3BP and USP10 complex is mutually inhibitory, with G3BP inhibiting the DUB activity of USP10 and USP10 inhibiting the SG nucleating function of G3BP.

reach
Anisonov et al. [91] also found that USP10 is inhibited by G3BP1 in a mechanism similar to that for NUP62, which indicates an analogous cascading route from SARS-CoV-2 to PD for this protein.

sparser
In airway epithelial cells treated with the CFTR inhibitory factor (Cif), the Ras GTPase-activating protein-binding protein 1 (G3BP1) inhibits the ubiquitin-specific protease USP10.
G3BP1 bound to USP10 inhibits USP10. 3 / 3
| 3

reach
G3BP1 binds to USP10 and therefore disrupts the interaction of USP10 with p53, leading to suppression of p53 deubiquitination.

reach
Second, in U2OS bladder cancer cells, the interaction between G3BP1 and USP10 inactivates the deubiquitinating enzyme activity of USP10 XREF_BIBR.

reach
G3BP1 binds to USP10 and inhibits the deubiquitination activity of USP10.
G3BP1 activates USP10.
| 1
G3BP1 activates USP10. 1 / 1
| 1

reach
Interestingly G3BP1 modulates USP10 deubiquitinase activity, as well as interacts and co-localizes with HCV NS5B protein and RNA to modulate HCV replication.
USP10 affects AR
| 12
USP10 activates AR.
| 10
USP10 activates AR. 10 / 12
| 10

reach
For example, USP10 stimulates AR transcriptional activity in the presence of its synthetic agonist R1881 [67].

reach
Usp10 is known to enhance AR transcriptional activity [XREF_BIBR, XREF_BIBR] and Usp22 and Usp26 have been found in complexes with AR [XREF_BIBR, XREF_BIBR].

reach
Overexpression of wild-type USP10 stimulated AR activity as revealed by reporter constructs harbouring selective androgen response elements, non selective steroid response elements or the mouse mammary tumour virus promoter.

reach
USP10 overexpression enhanced AR transcriptional activity whereas knock-down by specific siRNAs had the opposite effect.

reach
, confirming that USP10 is a bonafide co-activator of AR regulated transcription.

reach
Usp10, another DUB reported to target AR, was also shown to enhance AR activity by combining both direct and indirect activity.

reach
USP10 appeared to modulate AR function.

reach
Cell based transactivation assays in PC-3/AR cells revealed that overexpression of wild-type USP10, but not of an enzymatically inactive form, stimulated AR activity mediated by reporter constructs harbouring selective androgen response elements (AREs), non selective steroid response elements (SREs) or the mouse mammary tumour virus (MMTV) promoter.

reach
RNF6 and USP10, which modulate androgen receptor function, showed correlated genomic loss and lower expression in a subset of tumors and gain and higher expression in others.

reach
The coactivating effects were observed with selective and non selective response elements, indicating that USP10 was a broad coactivator of the AR.
USP10 inhibits AR.
| 1
USP10 inhibits AR. 1 / 3
| 1

reach
In contrast, the siRNA luciferase screen in LNCaP cells showed that transfection with validated siRNAs targeting USP10 potentiated AR transcriptional activity.
USP10 increases the amount of AR.
| 1
USP10 increases the amount of AR. 1 / 1
| 1

reach
However, it is not clear if inhibition or shRNA knockdown of USP10 lowers AR protein levels.
Spautin-1 affects USP10
1 | 10
1 | 10

reach
Indeed, a recent study showed that a small molecule, Spautin-1, promoted the degradation of Vps34 by inhibiting two ubiquitin specific proteases USP10 and USP13 that regulate the stability of the Vps34 complex [XREF_BIBR].

reach
SBI blocks the kinase activity of ULK1, diminishing the phospho regulated capacity of beclin-1 to engage with its binding partners (Egan et al., 2015) and Spautin-1 inhibits the USP10 and USP13 hydrol[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

reach
A previous study reported that Spautin-1 also inhibits USP10 activity XREF_BIBR.

reach
Spautin-1 inhibits the catalytic activity of both USP10 and USP13 with an IC 50 of ~ 0.6-0.7 microM.

reach
Molecular analysis revealed that Spautin-1 directly inhibits the activity of the deubiquitinating enzymes (DUBs) ubiquitin specific protease 10 (USP10) and USP13.

reach
58 Spautin-1 promotes the degradation of BECN1 by inhibiting 2 USPs (ubiquitin-specific peptidases), USP10 and USP13, which target BECN1.

tas
No evidence text available

reach
To further determine whether USP10 could be a druggable target in these patients, we evaluated the ex vivo antineoplastic effect of pharmacological inhibition of USP10 by Spautin-1 on primary monocytes from 16 patients with CML.

reach
Spautin-1 inhibits the activity of the deubiquitinating enzymes USP13 and USP10.

reach
Spautin-1 inhibits the activity of two ubiquitin specific peptidases, USP10 and USP13, causing an increase in proteasomal degradation of class III PI3 kinase complexes, which have been shown to regulate autophagy [XREF_BIBR].
SIRT6 affects USP10
| 11
SIRT6 activates USP10.
| 8
SIRT6 activates USP10. 8 / 8
| 8

reach
32 These findings present evidence that Sirt6 mediates the effect of USP10 in the regulation of CH in response to Ang II stimulation.

reach
Ang II induced cardiac hypertrophy potentiated by USP10 knockdown was also completely blocked by Sirt6 activity upregulation.

reach
Our study has presented evidence that Sirt6 mediates the effect of USP10 in the regulation of CH in response to Ang II stimulation.

reach
These findings present evidence that Sirt6 mediates the effect of USP10 in the regulation of CH in response to Ang II stimulation.

reach
These findings demonstrated that the Sirt6 mediated the effect of USP10 in regulation of CH in response to Ang II stimulation.

reach
Sirt6 Mediates USP10 Regulated Cardiac Hypertrophy.

reach
To further prove the principle that USP10 suppresses c-Myc transcriptional activity through both SIRT6 and p53, we tested whether knockdown of SIRT6 rescues this USP10 suppressive activity.

reach
Furthermore, USP10 physically binds to sirtuin 6 (Sirt6) and Sirt6 mediates the effect of USP10 on the regulation of CH.
SIRT6 inhibits USP10.
| 1
SIRT6 inhibits USP10. 1 / 1
| 1

reach
Indeed, knockdown of SIRT6 in p53 +/+ cells partially reversed the suppressive activity of USP10.
SIRT6 increases the amount of USP10.
| 1
SIRT6 increases the amount of USP10. 1 / 1
| 1

reach
Similarly, knockdown of SIRT6 partially reversed USP10 stable expression mediated tumor suppression in wildtype but not p53-null HCT116 cells.
SIRT6 decreases the amount of USP10.
| 1
SIRT6 decreases the amount of USP10. 1 / 1
| 1

reach
Conversely, Sirt6 deficiency decreased the ameliorative effects of USP10 overexpression in response to HFD treatment.
USP10 affects CFTR
| 10
USP10 decreases the amount of CFTR.
| 5
USP10 decreases the amount of ubiquitinated CFTR. 3 / 3
| 3

reach
Overexpressing USP-10 decreased the amount of ubiquitinated CFTR and increased its abundance in the plasma membrane of human airway epithelial cells [XREF_BIBR].

reach
small interference RNA mediated knockdown of USP10 increased the amount of ubiquitinated CFTR and its degradation in lysosomes, and reduced both apical membrane CFTR and CFTR mediated chloride secretion.

reach
Moreover, a dominant negative USP10 (USP10-C424A) increased the amount of ubiquitinated CFTR and its degradation, whereas overexpression of wt-USP10 decreased the amount of ubiquitinated CFTR and increased the abundance of CFTR.
Modified USP10 decreases the amount of ubiquitinated CFTR. 2 / 2
| 2

reach
siRNA mediated reduction of USP10 protein expression (by 76 +/-4%, XREF_FIG) increased the amount of ubiquitinated CFTR.

reach
Moreover, a dominant negative USP10 (USP10-C424A) increased the amount of ubiquitinated CFTR and its degradation, whereas overexpression of wt-USP10 decreased the amount of ubiquitinated CFTR and increased the abundance of CFTR.
USP10 activates CFTR.
| 2
USP10 activates CFTR. 1 / 2
| 1

reach
For example, UCH-L3 localizes to endosomes and regulates the surface levels of ENaC in kidney cells, USP-10 localizes to endosomes and promotes CFTR recycling to the epithelial cell surface, USP20 and USP33 control recycling of beta 2 ARs, and both AMSH and USP8 and UBPY are endosome associated DUBs implicated in regulating EGFR degradation.
Modified USP10 activates CFTR. 1 / 1
| 1

reach
Moreover, a dominant negative USP10 (USP10-C424A) increased the amount of ubiquitinated CFTR and its degradation, whereas overexpression of wt-USP10 decreased the amount of ubiquitinated CFTR and increased the abundance of CFTR.
USP10 increases the amount of CFTR.
| 2
USP10 increases the amount of ubiquitinated CFTR. 1 / 1
| 1

reach
Thus, the goal of this study was to test the hypothesis that Cif inhibits USP10, which increases the amount of ubiquitinated CFTR that is degraded in lysosomes, thereby reducing cell and plasma membrane CFTR level.
USP10 increases the amount of CFTR. 1 / 1
| 1

reach
Thus, the goal of this study was to test the hypothesis that Cif inhibits USP10, which increases the amount of ubiquitinated CFTR that is degraded in lysosomes, thereby reducing cell and plasma membrane CFTR level.
USP10 inhibits CFTR.
| 1
USP10 inhibits ubiquitinated CFTR. 1 / 1
| 1

reach
Finally, if Cif stabilizes an inhibitory interaction between G3BP1 and USP10, silencing G3BP1 should reduce the Cif induced decrease in USP10 activity as well as the Cif induced increase in ubiquitinated CFTR, and its degradation in lysosomes.
USP10 affects Neoplasms
| 4 3
USP10 inhibits Neoplasms.
| 2 1
| 2 1

eidos
Additionally , USP10 blocks tumor formation via p53 and SIRT6-mediated degradation of c-Myc , thereby stopping cell cycle progression and cancer cell growth [ 53 ] .
| PMC

eidos
For example , in hepatocellular carcinoma , Zhu et al. reported that USP10 promotes proliferation [ 40 ] , whereas Lu et al. found that USP10 suppresses tumor progression by inhibiting mTOR activation [ 41 ] .

reach
USP10, upon ATM-dependent phosphorylation at threonine 42 and serine 337 residues, is stabilized and translocated to the nucleus to activate p53 through deubiquitinating activity, inducing tumor cell suppression [53].
| PMC
USP10 activates Neoplasms.
| 2 2
| 2 2

reach
We next found that USP10 coordinately promotes tumor progression with G3BP1.

reach
For instance, USP10 promotes tumor metastasis through deubiquitination and stabilization of Smad4 in advanced HCC [8].
| PMC

eidos
On the other hand , USP10 , a p53 deubiquitinase , serves as a positive regulator of p53 ; inhibition of USP10 could suppress cancer by degrading oncogenic p53 mutants ( Figure 2b ) [ 32 ] .

eidos
It has been reported that USP10 mediates cancer progression via stabilizing some substrates , such as p53 , STRT6 , AMPK , FLT3 and androgen receptor [ 20-24 ] .
USP10 affects G3BP1
| 4
USP10 inhibits G3BP1.
| 2
USP10 inhibits G3BP1. 2 / 6
| 2

reach
USP10 may prevent G3BP from nucleating SG assembly by locking G3BP in a conformation that influences the NTF2 like domain and mediates or prevents G3BP oligomerization.

reach
It is also possible that USP10 blocks the helicase function of G3BP, as helicase activity of some proteins, e.g., DDX6 and RCK, has been shown to be required for RNA granule assembly.
USP10 decreases the amount of G3BP1.
| 1
USP10 decreases the amount of G3BP1. 1 / 3
| 1

reach
However, USP10 KD also reduces expression of G3BP1 and G3BP2 (to 58% and 77% of control values, respectively; XREF_FIG), suggesting that the SG inhibition caused by USP10 KD may be caused by reduced levels of G3BP.
USP10 activates G3BP1.
| 1
USP10 activates G3BP1. 1 / 1
| 1

reach
We next found that USP10 coordinately promotes tumor progression with G3BP1.
USP10 affects CD36
| 4 6
USP10 activates CD36.
| 4 3
USP10 activates CD36. 5 / 5
| 4 1

eidos
Western blot showed that increased expression of CD36 protein was suppressed by USP10 inhibitor or siRNA ( Figure 4A , 4B ) .

reach
In this study, our western blotting and RT-qPCR assays revealed that USP10 inhibition promotes the degradation of CD36 protein but does not change its mRNA level.

eidos
USP10 knockdown also inhibited the expression of CD36 protein ( Figure 3C , 3D ) .

eidos
In this study , our western blotting and RT-qPCR assays revealed that USP10 inhibition promotes the degradation of CD36 protein but does not change its mRNA level .

eidos
We found that USP10 inhibitor significantly reduced CD36 expression ( Figure 3E , 3F ) .
USP10 activates ubiquitinated CD36. 2 / 2
| 2

reach
As shown in XREF_FIG, XREF_FIG, USP10 inhibition or knockdown significantly increased ubiquitinated CD36.

reach
Moreover, the K48-poly-ubiquitinated CD36 was upregulated by Spautin-1 or USP10 siRNA.
USP10 increases the amount of CD36.
| 2
USP10 increases the amount of CD36. 2 / 2
| 2

reach
USP10 knockdown also inhibited the expression of CD36 protein (XREF_FIG, XREF_FIG).

reach
We found that USP10 inhibition decreased the expression of CD36 in THP1 cells (XREF_FIG).
USP10 decreases the amount of CD36.
| 1
USP10 decreases the amount of CD36. 1 / 1
| 1

reach
We have studied what silencing USP10 induced the inhibition of lipid uptake and CD36 expression.
USP10 affects AMPK
| 1 7
USP10 activates AMPK. 8 / 9
| 1 7

reach
These results suggest that USP10 deubiquitinase activity is required for its effects in AMPK activation and cellular metabolism.We then explored the mechanism by which USP10 modulates AMPK activation,[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

reach
The fact that USP10 also positively regulates beclin-1 and AMPK would make pharmacologic activators of USP10 particularly effective as autophagy enhancers.

reach
Only WT USP10, but not the CA mutant could rescue AMPK activation triggered by USP10 RNAi (XREF_FIG), suggesting that USP10 deubiquitinase activity is required for AMPK activation.

reach
As shown in Figure 4 B, the phosphorylation of USP10 increased significantly after glucose starvation, suggesting that USP10 might be a substrate of AMPK.

sparser
Finally, USP10 deubiquitinates and activates the autophagy-promoting kinase AMPK ( xref ).

reach
We then explored the mechanism by which USP10 modulates AMPK activation, first by examining whether USP10 directly interacts with AMPK.

reach
Only WT USP10, but not the CA mutant, could rescue AMPK activation triggered by USP10 RNAi, suggesting that USP10 deubiquitinase activity is required for AMPK activation.

reach
As shown in XREF_FIG, the phosphorylation of USP10 increased significantly after glucose starvation, suggesting that USP10 might be a substrate of AMPK.
USP10 affects SGs
| 9
USP10 inhibits SGs.
| 7
USP10 inhibits SGs. 5 / 5
| 5

reach
Interestingly, the overexpression of USP10 prevents the formation of SGs by directly binding G3BP via an FGDF motif.

reach
Cells with an exon 3 deletion may express an FGDF containing inhibitory fragment of USP10, which would suppress SGs as does USP10 1-40 (XREF_FIG) and explain the apparent contradiction.

reach
Tet induced GFP-USP10 expression prevents AS and CZ induction of SGs (XREF_FIG) but does not alter stress induced polysome disassembly (XREF_FIG), indicating that GFP-USP10 inhibits the cytoplasmic condensation of mRNPs into SGs.

reach
Here, we have shown that overexpression of EGFP-USP10, but not a mutant lacking an intact FGDF-motif, efficiently blocks the formation of SGs (XREF_FIG).

reach
When mCherry tagged USP10 is cotransfected with GFP-G3BP1, both proteins colocalize in SGs (XREF_FIG, 4), but mCherry-USP10 coexpressed with GFP-Caprin1 inhibits SGs even upon AS treatment (XREF_FIG, 5 and 6), suggesting that USP10 and Caprin1 compete for limiting G3BP.
USP10 bound to G3BP1 inhibits SGs. 2 / 2
| 2

reach
USP10 lacking the PAM2 motif does not co-IP PABP or eIF4G, but still binds G3BP and blocks SGs (XREF_FIG, 10-12).

reach
Since the binding of nsP3 and USP10 to G3BP inhibits SGs, we hypothesized that ICP8 binding might do the same.
USP10 activates SGs.
| 2
USP10 activates SGs. 2 / 2
| 2

reach
Rescue experiments using a G3BP1 mutant that lacks the ability to bind Caprin1 or USP10 rescues SGs assembly, whereas other phosphomimetic mutants of G3BP1 (G3BP1-S149E) fail to do that [XREF_BIBR].

reach
In addition, the overexpression of USP10 without stress stimuli in HT22 cells induced TIA1/Tau/USP10 positive SGs in a deubiquitinase independent manner.
USP10 affects SKP2
| 9
USP10 increases the amount of SKP2.
| 5
USP10 increases the amount of SKP2. 3 / 3
| 3

reach
XREF_FIG, only the knockdown of USP10 and USP13 decreased the expression of SKP2.

reach
We further explored whether USP10 modulates the expression of SKP2 and thus activating Bcr-Abl in CML cells.

reach
We further found that only USP10-WT, but not USP10-CA, increased the protein level of SKP2, suggesting that deubiquitinating activity of USP10 is required for SKP2 enrichment.
Modified USP10 increases the amount of SKP2. 2 / 2
| 2

reach
The results showed that overexpression of USP10 increased the protein level of SKP2 in HEK293T and HeLa cells in a manner similar to USP13.

reach
The result showed that loss of USP10 significantly decreased the expression of SKP2, as well as the phosphorylation and downstream signals of Bcr-Abl, suggesting that USP10 is required for the expression of SKP2 and the phosphorylation of Bcr-Abl in CML cells.
USP10 activates SKP2.
| 3
USP10 activates SKP2. 3 / 3
| 3

reach
Notably, genetic or pharmacological inhibition of USP10 using Spautin-1 prominently decreased the stability of endogenous SKP2 protein, suggesting that USP10 inhibits the degradation of SKP2 in vivo.

reach
USP10 modulates the SKP2 and Bcr-Abl axis via stabilizing SKP2 in chronic myeloid leukemia.

reach
Since USP10 is a well characterized DUB in humans, exploring whether USP10 directly regulates the stability of SKP2 protein is attractive.
USP10 decreases the amount of SKP2.
| 1
USP10 decreases the amount of SKP2. 1 / 1
| 1

reach
To our expectation, pharmacological inhibition of USP10 by Spautin-1 significantly increased the poly-ubiquitination level of SKP2.
| 1 4

reach
However, our results using USP10 functional mutants indicated that ROS inhibition by USP10 is dispensable for USP10 to inhibit apoptosis of HSCs.

sparser
However, our results using USP10 functional mutants indicated that ROS inhibition by USP10 is dispensable for USP10 to inhibit apoptosis of HSCs.

reach
Upon exposure to an oxidant, USP10 inhibits ROS dependent apoptosis by reducing ROS production.

reach
Similarly, USP10 and USP13 silencing could induce ROS generation and cause DNA damage.
| PMC

reach
On exposure to arsenic, an oxidative stress inducer, USP10 is recruited into stress granules (SGs), and USP10 containing SGs reduce reactive oxygen species (ROS) production and inhibit ROS dependent apoptosis.