USP9X Data Analysis

HGNC Gene Name
ubiquitin specific peptidase 9 X-linked
HGNC Gene Symbol
USP9X
Identifiers
hgnc:12632 NCBIGene:8239 uniprot:Q93008
Orthologs
mgi:894681 rgd:1560056
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for USP9X
Number of Papers
319 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
UCHL5 ubiquitin C-terminal hydrolase L5 0.24 Reactome (6) -0.04 -0.31 5.72e-01
RNF25 ring finger protein 25 0.225 0.30 1.58 5.77e-08
TUBD1 tubulin delta 1 0.22
FAAP24 FA core complex associated protein 24 0.202
UBE2N ubiquitin conjugating enzyme E2 N 0.196 Reactome (3) 0.24 1.25 1.40e-05
USP7 ubiquitin specific peptidase 7 0.195 IntAct Pathway Commons INDRA (5) Reactome (10) 0.07 0.30 2.73e-01
CEP120 centrosomal protein 120 0.188 -0.00 -0.11 9.61e-01

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with USP9Xusing 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
GO:0032435 negative regulation of proteasomal ubiquitin-dependent protein catabolic process Biological Process 6.51e-05 1.15e-02 3.68e-03
GO:2000059 negative regulation of ubiquitin-dependent protein catabolic process Biological Process 1.25e-04 2.21e-02 3.68e-03
GO:1901799 negative regulation of proteasomal protein catabolic process Biological Process 1.78e-04 3.15e-02 3.68e-03

Transcriptomics

The following table shows the significantly differentially expressed genes after knocking out USP9X using CRISPR-Cas9.

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
MMP1 matrix metallopeptidase 1 3.41e-01 2.46e-06 4.59e-02
PSMB4 proteasome 20S subunit beta 4 -4.17e-01 4.16e-06 4.59e-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 USP9X 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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USP9X deubiquitinates MCL1. 10 / 19
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USP9X deubiquitylation of MCL1 inhibits its proteasomal degradation, thus promoting its anti-apoptotic functions.

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USP9X deubiquitinates and stabilizes MCL1 in distinct human cancers including human follicular lymphomas, diffuse large B cell lymphomas, glioblastoma, colon and lung cancers 19.

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Deubiquitination of Mcl-1 by USP9X.

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USP9X deubiquitylates poly-ubiquitylated MCL1, protecting it from proteasomal degradation, thus increasing its stability and thereby promoting cell survival.

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USP9X interacts with and deubiquitinates MCL-1, thereby stabilising it.

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Conversely, the deubiquitinase USP9X reverses polyubiquitination of Mcl-1 and promotes its stability [XREF_BIBR].

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Thus in multiple cancer cell types, the level at which USP9X is able to deubiquitylate and stabilise MCL1 dictates its anti-apoptotic function.

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Two DUBs USP9X and USP13 deubiquitinate and stabilise MCL1, and hypomorphic mutations in both have been linked to neurodevelopmental disorders and neurodegenerative disease [XREF_BIBR, XREF_BIBR].

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It has been reported that Usp9x deubiquitinates Mcl-1 by removing the conjugated ubiquition.

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The overexpression of USP9X stabilizes the MCL1 protein in human lymphomas, and the depletion of USP9X increases MCL1 ubiquitination, which leads to MM cell apoptosis [31].
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USP9X deubiquitinates SMAD4. 10 / 12
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For example USP9X may upregulate ID2 gene expression by deubiquitinating and stabilizing the transcription factor SMAD4 (Dupont et al., 2009).

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USP9X reverses Smad4 ubiquitination to reactivate the pathway and reinstate TGFbeta signaling.

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The deubiquitination of Smad4 by FAM is direct.

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FAM and USP9X is required for TGFbeta induced migration of MDA-MB-231 breast cancer cells; mechanistically, FAM and USP9X inhibits the monoubiquitination of SMAD4, a modification that blocks the association of SMAD4 with phospho-SMAD2 [XREF_BIBR] (XREF_FIG).

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Subsequently it was shown that USP9X deubiquitylates SMAD4 that is monoubiquitylated at K519 (XREF_FIG).

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Usp9x promotes TGFbeta pathway signalling by deubiquitylating Smad4, allowing it to complex with phosphorylated receptor Smads and then shuttle into the nucleus to execute transcriptional responses to TGFbeta family ligands [XREF_BIBR].

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Taken together, these results demonstrate that USP9x selectively binds to SMAD4 in competition with TIF1gamma and deubiquitinates SMAD4, promoting nuclear SMAD4 retention, SMAD3 and SMAD4 complex formation and target gene expression.

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USP9X (also known as FAM) deubiquitylates SMAD4 and thereby sustains TGF-beta signaling (Dupont etal.

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Multiple mono-ubiquitination of SMAD3 can be removed by USP15 and mono-ubiquitination of SMAD4 seems to be removed by FAM/USP9X.

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This inhibitory event is readily reversed by FAM and USP9x, which deubiquitinates Smad4 and restores its responsiveness to TGF-beta [XREF_BIBR].
USP9X deubiquitinates ERG. 7 / 7
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Previously, we found that ERG undergoes ubiquitination and then is deubiquitinated by USP9X in prostate cancer cells to prevent its proteasomal degradation.

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A role for ERG ubiquitination in prostate cancer cells was also demonstrated by Wang et al. who showed that the enzyme USP9X, which is highly expressed in ERG positive prostate tumours, mediates ERG deubiquitination and thus its stabilization XREF_BIBR.

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Indeed, previous reports have shown Usp9x deubiquitinates and stabilizes ERG, and our previously described DUB inhibitor (WP1130) demonstrated anti-tumour efficacy in ERG driven prostate cancer XREF_BIBR.

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Here, we show that ubiquitin specific peptidase 9, X linked (USP9X), a deubiquitinase enzyme, binds ERG in VCaP prostate cancer cells expressing TMPRSS2-ERG and deubiquitinates ERG in vitro.

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USP9X binds to the ETS domain in ERG protein; therefore, USP9X deubiquitinates and stabilizes full-length ERG and TMPRSS2 - ERG fusion gene products.

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we show that ubiquitin-specific peptidase 9, X-linked (USP9X), a deubiquitinase enzyme, binds ERG in VCaP prostate cancer cells expressing TMPRSS2-ERG and deubiquitinates ERG in vitro.

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Wang et al. demonstrated that ubiquitin specific peptidase 9, X linked (USP9X), a deubiquitinase enzyme, binds ERG in VCaP prostate cancer cells expressing TMPRSS2-ERG and deubiquitinates ERG in vitro XREF_BIBR.
USP9X deubiquitinates SNCA. 7 / 7
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Deubiquitination of α-synuclein by USP9X impairs SIAH-dependent α-synuclein proteasomal degradation and promotes degradation by autophagy

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We recently found that USP9X deubiquitinates α-synuclein, and that this process determines the partition of α-synuclein between the proteasomal and autophagy pathways.

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We recently found that USP9X deubiquitinates alpha-synuclein, and that this process determines the partition of alpha-synuclein between the proteasomal and autophagy pathways.

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Usp9x also deubiquitylates mono-ubiquitylated alpha-synuclein raising the possibility it may play a role in the progression of neurodegenerative diseases such as Parkinson 's disease XREF_BIBR.

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Moreover, USP9X can increase MAPT phosphorylation via a second mechanism, by deubiquitinating the protein alpha-synuclein (SNCA) [XREF_BIBR], which functions as a connecting mediator between the glycogen synthase kinase 3beta (GSK3B) and MAPT and has been shown to stimulate MAPT phosphorylation via GSK3B in vitro [XREF_BIBR].

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We now report that the deubiquitinase USP9X interacts in vivo with and deubiquitinates alpha-synuclein.

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In the brain tissues of PD patients, USP9X colocalises with alpha-synuclein inclusions, and in vitro studies show a functional interaction; whilst monoubiquitylated alpha-synuclein is degraded by the proteasome, USP9X deubiquitylation of alpha-synuclein directs its degradation by the less efficient autophagy pathway [XREF_BIBR].
USP9X deubiquitinates IRS2. 6 / 6
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In addition, USP9X in LNCaP cells was not co-immunoprecipitated with IRS-2 (XREF_SUPPLEMENTARY), suggesting that USP9X does not deubiquitinate IRS-2 in LNCaP cells.

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Thus, it is possible that USP9X preferentially deubiquitinates IRS-2 much more than IRS-1 because of the difference of such ubiquitination patterns.

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IRS-2 deubiquitination by USP9X maintains anchorage independent cell growth via Erk1/2 activation in prostate carcinoma cell line.

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In addition, the interaction between USP9X and IRS-2 was not observed in LNCaP cells (XREF_SUPPLEMENTARY), suggesting that USP9X in LNCaP does not deubiquitinate and stabilize IRS-2 because of the absence of interaction between them.

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Knockdown of USP9X dramatically reduced IRS-2 protein level, increased IRS-2 ubiquitination, and promoted the proteasomal degradation of IRS-2 in PC3 cells, suggesting that USP9X also deubiquitinates IRS-2 to prevent its proteasomal degradation.

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These data suggest that USP9X deubiquitinates IRS-2 and prevents its proteasomal degradation.
USP9X deubiquitinates CTNNB1. 5 / 5
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As shown in Figure XREF_FIG, knockdown of USP9X increased the ubiquitination of beta-catenin and subsequent degradation.

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In the Wnt pathway, FAM deubiquitinates betacatenin, preventing its degradation in mammalian cells, but the effect of FAM activity on Wnt signaling was not noted.

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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

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Deubiquitinase USP9X deubiquitinates beta-catenin and promotes high grade glioma cell growth.

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Deubiquitinase USP9X deubiquitinates β-catenin and promotes high grade glioma cell growth.
USP9X deubiquitinates YAP1. 5 / 5
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Here we demonstrate that the deubiquitination enzyme USP9X deubiquitinates and stabilizes YAP1, thereby promoting cancer cell survival.

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Mechanistically, USP9X deubiquitinates and stabilizes YAP1.

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Here we demonstrate that the deubiquitination enzyme USP9X deubiquitinates and stabilizes YAP1, thereby promoting cancer cell survival.

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Since YAP1 plays a key role in human cancer development, it is possible that USP9X promotes deubiquitination and stabilization of YAP1 in human cancers.

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Mechanistically, it was found that hsa_circ_0024093 could regulate the expression of USP9X, which further induced YAP1 deubiquitination to stabilize YAP1 protein.
USP9X deubiquitinates ZBTB38. 5 / 5
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Together these data show that USP9X deubiquitinates ZBTB38, both in basal conditions, and in conditions where ZBTB38 ubiquitination is augmented by RBBP6.

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USP9X deubiquitinates ZBTB38.

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We thus conclude that USP9X activity triggers the deubiquitination of ZBTB38 in cells.

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By poly-ubiquitination assays, we observed that USP9X causes deubiquitination of ZBTB38, even in cells over-expressing RBBP6 and conversely that inactivation of USP9X amplifies the polyubiquitination induced by RBBP6 over-expression (XREF_SUPPLEMENTARY).

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Molecularly, these functions depend on a deubiquitinase, USP9X, which interacts with ZBTB38, deubiquitinates it, and stabilizes it.
USP9X deubiquitinates SMURF1. 4 / 4
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Moreover, USP9X deubiquitinates and stabilizes SMURF1, a member of the NEDD4 family of ubiquitin ligases; silencing USP9X expression in MDA-MB-231 breast cancer cells destabilized SMURF1 and inhibited SMURF1 dependent cell migration [XREF_BIBR].

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In another study, in breast cancer cells ubiquitination of Smurf1 could be reversed by the deubiquitinating enzyme USP9X through Smurf1 WW domain binding, which improved Smurf1 's stability.

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USP9X (FAM) deubiquitylates the autoubiquitylated E3 ligases Itch and SMURF1 and, thereby, increases their stability XREF_BIBR - XREF_BIBR.
USP9X deubiquitinates TDRD3. 4 / 4
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To test whether USP9X de-ubiquitinates TDRD3 in cells, we transfected HeLa cells with either control or USP9X specific siRNA, and measured TDRD3 ubiquitination.

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USP9X prevents TDRD3 ubiquitination.

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USP9X prevents polyubiquitination of TDRD3 in cells.

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We observed that when the cellular levels of USP9X were reduced by siRNA, the TDRD3 ubiquitination levels markedly increased (XREF_FIG, upper panel -- compare lane 2 to lane 5) and inhibition of the proteasome greatly augmented this difference (XREF_FIG, upper panel -- compare lane 3 to lane 6), suggesting that USP9X is necessary to suppress TDRD3 ubiquitination.
USP9X deubiquitinates PRC2_complex. 3 / 3
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We report here that Usp9x deubiquitinates and stabilizes PRC2, acting as a gatekeeper to the switch in H3K27me3 deposition patterns during mouse development.

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Usp9x deubiquitinates and stabilizes PRC2.

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This finding led us to hypothesize that Usp9x deubiquitinates and stabilizes PRC2 components to drive H3K27me3 deposition.
USP9X deubiquitinates EPS15. 3 / 3
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We identify the endocytic protein Eps15 as one of the critical substrates of USP9X

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USP9X Controls EGFR Fate by Deubiquitinating the Endocytic Adaptor Eps15

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Interestingly, recent findings further demonstrate that EPS15 de-ubiquitination by USP9X affects EGFR internalization and its trafficking to lysosomes.
USP9X deubiquitinates STIL. 3 / 3
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As USP9X interacts with and deubiquitylates the MD3 domain (aa 715-988) of STIL and removal of the MD3 domain destabilized STIL, USP9X controls STIL levels via the MD3 antidegron of STIL.

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To test whether USP9X deubiquitylates the STIL MD3 domain, we incubated immunoprecipitated full-length STIL or the MD3 domain of STIL with recombinant GST, GST-USP7, or GST fused to the catalytic domain of USP9X (USP9X CD).

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USP9X directly deubiquitylates STIL.
USP9X deubiquitinates SOX2. 3 / 3
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Usp9x knockdown in melanoma increased SOX2 ubiquitination, leading to its depletion, and enhanced apoptotic effects of BRAF inhibitor and MEK inhibitors.

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We identified that Usp9x deubiquitinates SOX2 and can increaseSOX2 levels, but additional studies are needed to confirm the specific ubiquitin sites among the 16 lysine residues in SOX2 that could be putative ubiquitin acceptors.

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USP9X deubiquitinates IGF1R. 3 / 3
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Furthermore, knockdown of USP9X significantly increased IGF-IR ubiquitination in HEK293T cells.

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These results raise the possibility that USP9X deubiquitinates IGF-IR to prevent its degradation.

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We found that USP9X interacted with IGF-IR, and that knockdown of USP9X decreases IGF-IR protein level and increased ubiquitination of IGF-IR.
USP9X deubiquitinates IQCB1. 3 / 3
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Because USP9X deubiquitinates NPHP5 (XREF_FIG), we hypothesize that NPHP5 is prone to ubiquitination when its association with USP9X is compromised in G2/M.

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NPHP5 directly binds to a deubiquitinating enzyme USP9X/FAM and two E3 ubiquitin ligases BBS11/TRIM32 and MARCH7/axotrophin. NPHP5 undergoes K63 ubiquitination in a cell cycle dependent manner and K48/K63 ubiquitination upon USP9X depletion or inhibition.

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Only wild type USP9X could robustly deubiquitinate NPHP5 (XREF_FIG).
USP9X deubiquitinates CEP131. 3 / 3
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USP9X deubiquitinates CEP131.

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USP9X can also regulate and stabilize CEP131, a centriolar satellite protein, ultimately promoting breast carcinogenesis, indicating that USP9X is a significant regulator of centrosome biogenesis and revealing a critical role for the USP9X/CEP131 axis in breast carcinogenesis

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USP9X gain-of-function leads to CEP131 deubiquitylation, stabilisation and centrosome amplification [XREF_BIBR].
USP9X deubiquitinates MIB1. 3 / 3
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USP9x in turn stimulates JAG1 activity through two mechanisms: (1) through TRB3 deubiquitination and stabilization, and (2) through deubiquitination and activation of Mind Bomb 1, an E3 ligase required for JAG1 ubiquitination-mediated endocytosis and Notch activation.

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Further, in human breast cancer cell lines, USP9X deubiquitinates and stabilizes MIB1, an activator of ligand dependent canonical NOTCH1 signaling that is important for cardiac development.

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Therefore, we postulated that nitrosylated USP9X deubiquitinates and stabilizes MIB1 in valvular interstitial cells, which potentiates the ability of a ligand producing cell to activate NOTCH on a neighboring cell.
Modified USP9X leads to the deubiquitination of SMAD4. 3 / 3
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Loss of USP9X therefore prevents deubiquitination of SMAD4, enhancing tumour progression.

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Strikingly, overexpression of wild-type FAM, but not of the catalytically inactive FAM mutant, inhibited Smad4 monoubiquitination in vivo.

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Overexpression of FAM also inhibits monoubiquitination of endogenous Smad4.
USP9X deubiquitinates XIAP. 3 / 3
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We reasoned that USP9X deubiquitylates XIAP to regulate mitotic survival.

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Engel et al. [XREF_BIBR] demonstrate that USP9X is the mitotic deubiquitinase of the X linked inhibitor of apoptosis protein (XIAP) and that deubiquitylation and stabilization of XIAP by USP9X lead to increased resistance toward mitotic spindle poisons.

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These studies revealed a mitosis specific function for the ubiquitin specific protease 9X (USP9X), which we show to deubiquitylate and stabilize XIAP in order to promote mitotic survival.
USP9X deubiquitinates ITCH. 3 / 3
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USP9X (FAM) deubiquitylates the autoubiquitylated E3 ligases Itch and SMURF1 and, thereby, increases their stability XREF_BIBR - XREF_BIBR.

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USP8 and USP9X deubiquitinate ITCH to induce ubiquitination and degradation of the anti-apoptotic protein c-FLIP, leading to apoptosis in glioblastoma [XREF_BIBR], or to anoikis in pancreatic ductal adenocarcinoma [XREF_BIBR].

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USP9X deubiquitinates SMAD4 on K519. 3 / 3
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Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4.

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Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4.

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Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4.
USP9X deubiquitinates CDC20. 2 / 2
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We hypothesize that USP9X deubiquitinates Cdc20 directly; however, we can not rule out the possibility that USP9X loss enhances Cdc20 ubiquitination and degradation indirectly.

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In summary, the data presented here show that USP9X antagonizes Cdc20 auto-ubiquitination and degradation to limit the turnover of MCC complexes by APC/C.
USP9X leads to the deubiquitination of ETS1. 2 / 2
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A recent report demonstrated that USP9X prevents ETS1 ubiquitination and thereby stabilizes the protein [XREF_BIBR].

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Ets-1 deubiquitination blocks its proteasomal destruction and enhances tumorigenicity, which could be reversed by Usp9x knockdown or inhibition.
USP9X leads to the deubiquitination of MARK4. 2 / 2
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An investigation of the polyubiquitination of AMPK-RKs showed that the deubiquitinating enzyme USP9X (ubiquitin specific protease-9) modulates the deubiquitination of NUAK1 (AMPK related kinase 5) and MARK4 (microtubule-affinity-regulating kinase 4) in cells XREF_BIBR.

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USP9X deubiquitinates F2R. 2 / 2
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To test whether FAF directly de-ubiquitinates PAR-1, we used affinity purified FAF and HA-Ub-labelled PAR-1 in an in vitro reaction.

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FAF clearly reduced poly-ubiquitinated PAR-1 level in vitro (XREF_FIG), supporting that FAF directly de-ubiquitinates PAR-1.
USP9X deubiquitinates BCL9. 2 / 2
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The USP9X mediated BCL9 deubiquitination promotes formation of the beta, catenin, BCL9, and PYGO complex, increasing the transcriptional activity of the Wnt and beta-catenin target genes.

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Additionally, the deubiquitination of BCL9 by USP9X increases proliferation and invasion of breast cancer cells.
USP9X deubiquitinates CD274. 2 / 2
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Indeed, USP9X induces PD-L1 deubiquitination and regulates its stabilization by ubiquitin specific protease activity.

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Our data indicate that USP9X deubiquitinates and stabilizes PD-L1.
USP9X deubiquitinates LATS2. 2 / 2
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We further demonstrated that USP9X deubiquitinates LATS2 and thus prevents LATS2 degradation by the proteasome.

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Deubiquitylase USP9X suppresses tumorigenesis by stabilizing large tumor suppressor kinase 2 (LATS2) in the Hippo pathway
USP9X leads to the deubiquitination of BCL10. 2 / 2
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Finally, the ubiquitin specific protease 9X (USP9X) interacts with BCL10 in activated T cells and silencing of USP9X augments BCL10 ubiquitination and impairs NF-kappaB signaling in T cells.

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Mechanistically, USP9X interacts with Bcl10 of the Carma1-Bcl10-Malt1 (CBM) complex and removes the TCR-induced ubiquitin chain from Bcl10, which facilitates the association of Carma1 with Bcl0-Malt1.
USP9X deubiquitinates epnA. 2 / 2
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It was recently shown that silencing Fam by siRNA abrogated ionomycin induced decrease in Epsin ubiquitylation, indicating that Fam plays a role in regulating levels of Epsin ubiquitylation [15].

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However, in vitro data on direct deubiquitylation of Epsin by Fam are lacking, and the ~ 50% identity between Faf and Fam suggests different specificities for substrates [49]; indeed, the only reporte[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
USP9X leads to the deubiquitination of ARNTL. 2 / 2
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Through biochemical experiments, we discover that USP9X reduces BMAL1 ubiquitination, enhances its stability, and increases its protein level, leading to the elevated transcriptional activity.

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Here, we use affinity purification and mass spectrometry analysis to identify probable ubiquitin carboxyl-terminal hydrolase FAF-X (USP9X) as an interacting protein of the core clock protein aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL or BMAL1).
USP9X leads to the deubiquitination of NUAK1. 2 / 2
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An investigation of the polyubiquitination of AMPK-RKs showed that the deubiquitinating enzyme USP9X (ubiquitin specific protease-9) modulates the deubiquitination of NUAK1 (AMPK related kinase 5) and MARK4 (microtubule-affinity-regulating kinase 4) in cells XREF_BIBR.

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USP9X leads to the deubiquitination of FBXW7. 2 / 2
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USP9X antagonized FBW7 ubiquitylation and protected mice from CRC.

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USP9X antagonized FBW7 ubiquitylation, and Usp9x deletion caused Fbw7 destabilization.
USP9X leads to the deubiquitination of TP53. 2 / 2
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USP9X inhibited p53 ubiquitination mediated degradation.
USP9X deubiquitinates GJA1. 2 / 2
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USP9X deubiquitinates connexin43 to prevent high glucose-induced epithelial-to-mesenchymal transition in NRK-52E cells.

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The following findings were observed : (1) Expression of USP9X was down-regulated in the kidney tissue of db/db diabetic mice; (2) overexpression of USP9X suppressed high glucose (HG)-induced expressions of EMT markers and extra cellular matrix (ECM) in NRK-52E cells; (3) depletion of USP9X further aggravated EMT process and ECM production in NRK-52E cells; (4) USP9X deubiquitinated Cx43 and suppressed its degradation to regulate EMT process; (5) USP9X deubiquitinated Cx43 by directly binding to the C-terminal Tyr 286 of Cx43.
USP9X deubiquitinates MARCHF7. 2 / 2
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Exogenous expression and short interfering RNA depletion experiments demonstrate that MARCH7 can be stabilized by both USP9X and USP7, which deubiquitylate MARCH7 in the cytosol and nucleus, respectively.
USP9X deubiquitinates AMOTL2. 2 / 2
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we report for the first time that USP9X is a deubiquitinase of Angiomotin-like 2 (AMOTL2) and that AMOTL2 mono-ubiquitination is required for YAP inhibition.

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These results indicate that deubiquitination of AMOTL2 by USP9X depresses LATS1/2 activity and subsequently activates YAP.
USP9X deubiquitinates AMOT on K496. 2 / 2
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USP9x acts to deubiquitylate Angiomotin at lysine 496, resulting in stabilization of Angiomotin and lower YAP and TAZ activity.

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USP9X leads to deubiquitinate AMOT at Lys 496, resulting in stabilization of AMOT and reduced YAP and TAZ activity.
USP9X deubiquitinates AMOT. 2 / 2
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USP9X in the DUBs (ubiquitin-specific protease family) could bind to and deubiquitinate AMOT.
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Thus, it appears that the direct effect of limiting deubiquitylation of AMOT by USP9x offsets the reduced potential for ubiquitylation due to lower E3 ligase levels.
USP9X deubiquitinates SNRPN. 1 / 1
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Usp9x deubiquitinates SMN that is mostly mono- and di ubiquitinated.
USP9X leads to the deubiquitination of pygo. 1 / 1
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The USP9X mediated BCL9 deubiquitination promotes formation of the beta, catenin, BCL9, and PYGO complex, increasing the transcriptional activity of the Wnt and beta-catenin target genes.
USP9X deubiquitinates MTOR. 1 / 1
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USP9X deubiquitinates KCNH2. 1 / 1
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USP9X deubiquitinates CDH1. 1 / 1
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Modified USP9X leads to the deubiquitination of XIAP. 1 / 1
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Indeed, ubiquitylation of XIAP was substantially increased upon silencing or chemical inhibition of USP9X (Figs XREF_FIG E and XREF_FIG A) in mitotic cells, while forced expression of USP9X attenuated XIAP ubiquitylation (Fig XREF_FIG A).
USP9X deubiquitinates ALDH1A3. 1 / 1
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USP9X deubiquitinates ALDH1A3 and maintains mesenchymal identity in glioblastoma stem cells.
USP9X deubiquitinates EIF4A2. 1 / 1
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Our results provide evidence that USP9X is a novel regulator of the translation initiation process via deubiquitination of eIF4A1
USP9X deubiquitinates FOXO3. 1 / 1
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Hydroxylation of these sites prevents the binding of USP9x deubiquitinase, thereby promoting the proteasomal degradation of FOXO3a.
USP9X deubiquitinates STMN1. 1 / 1
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In this report, we find that Usp9x, a deubiquitinating enzyme, stably associates with the SMN complex via directly interacting with SMN.| Usp9x deubiquitinates SMN that is mostly mono- and di-ubiquitinated.
USP9X deubiquitinates EIF4A1. 1 / 1
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These data suggested that the deubiquitination of eIF4A1 by USP9X is required for eIF4A1 protein stability.
Modified USP9X leads to the deubiquitination of AMOT. 1 / 1
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We demonstrate that loss of USP9x leads to increased ubiquitylation of AMOT, resulting in reduced AMOT levels.
USP9X deubiquitinates BECN1. 1 / 1
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Interestingly, Beclin1 and the Bcl-2 family member, MCL-1, compete for their interaction with USP9X, which contributes to their stabilization by protecting them from proteasomal degradation in HEK293T cells
USP9X deubiquitinates TTK. 1 / 1
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Conclusions: In summary, our data demonstrated that the USP9X-TTK axis may play a critical role in NSCLC, and could be considered as a potential therapeutic target.
USP9X deubiquitinates F3. 1 / 1
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Usp9x deubiquitinates and stabilizes the TF, ERG, in prostate, and we previously published that DUB inhibitor (WP1130) has anti-tumor activity in ERG fusion driven prostate cancer [XREF_BIBR, XREF_BIBR, XREF_BIBR].
USP9X deubiquitinates ERBB2. 1 / 1
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?In contrast, ErbB2 immunoprecipitates were found to contain significant USP9x relative to control immunoprecipitates prepared using anti-ERalpha IgG
USP9X deubiquitinates DDI1. 1 / 1
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Identification of USP9X as the DUB Responsible for Deubiquitination of Human DDI1
USP9X deubiquitinates PEX5. 1 / 1
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In addition, Pex5p can be deubiquitinated by the deubiquitinase USP9X
USP9X deubiquitinates TRIB3. 1 / 1
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USP9x in turn stimulates JAG1 activity through two mechanisms: (1) through TRB3 deubiquitination and stabilization, and (2) through deubiquitination and activation of Mind Bomb 1, an E3 ligase required for JAG1 ubiquitination-mediated endocytosis and Notch activation.
USP9X deubiquitinates ubiquitinated SMAD4. 1 / 1
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FAM and Usp9x deubiquitinates the monoubiquitinated SMAD4 (which is exported from the nucleus (XREF_FIG)) and thereby enables SMAD2 and SMAD4 complex formation.
USP9X deubiquitinates DVL2. 1 / 1
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Our findings indicate that USP9X-mediated deubiquitylation of DVL2 is required for canonical WNT activation, while increased DVL2 ubiquitylation is associated with localization to actin-rich projections and activation of the planar cell polarity (PCP) pathway.
USP9X deubiquitinates PCM1. 1 / 1
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?Collectively, our experiments identified USP9X as an integral component of the centrosome where it functions to stabilize PCM1 and CEP55 and promote centrosome biogenesis.
USP9X deubiquitinates EPN. 1 / 1
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Agonist stimulation of Notch leads to the recruitment of USP9X, a deubiquitinating enzyme, which deubiquitinates epsin and enables it to promote Notch internalization.
USP9X leads to the deubiquitination of NFE2L2. 1 / 1
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Taken together, USP9X reduced Nrf2 ubiquitination level and promoted Nrf2-ARE pathway activation to prevent the accumulation of extracellular matrix, eventually alleviated the pathological process of diabetic renal fibrosis.
USP9X deubiquitinates GPSM1. 1 / 1
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USP9X deubiquitinates SMAD1. 1 / 1
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USP9X deubiquitinates ALKBH3. 1 / 1
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Instead, it seemed to act as a scaffold protein, recruiting two further DUBs, USP7 and USP9x, which then de-ubiquitylated ALKBH3.
USP9X deubiquitinates PRICKLE1. 1 / 1
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[XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR] We postulated the physical interaction between the PRICKLEs and USP9X might indicate that PRICKLE was a USP9X substrate, and that USP9X deubiquitinates and stabilizes both PRICKLE1 and PRICKLE2.
USP9X deubiquitinates NFX1. 1 / 1
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In addition, we identified STAM and NFX1, which are known to be deubiquitylated by USP8 and USP9 respectively.
USP9X deubiquitinates TMPRSS2. 1 / 1
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USP9X binds to the ETS domain in ERG protein; therefore, USP9X deubiquitinates and stabilizes full-length ERG and TMPRSS2 - ERG fusion gene products.
USP9X deubiquitinates IQCB1 on K48. 1 / 1
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On the basis of our findings that NPHP5 is deubiquitinated by USP9X, K48 ubiquitinated by MARCH7 and K63 ubiquitinated by BBS11, we asked whether simultaneous ablation of MARCH7 and/or BBS11 might override the effects of USP9X loss on NPHP5.
USP9X deubiquitinates IRS1. 1 / 1
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On the other hand, the reduction of IRS-1 protein level was relatively small, suggesting that deubiquitination of IRS-1 by USP9X is not so active as for IRS-2.
USP9X deubiquitinates EIF4B. 1 / 1
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USP9X controls translation efficiency via deubiquitination of eukaryotic translation initiation factor 4A1
USP9X leads to the deubiquitination of FN1. 1 / 1
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Importantly, USP9x depletion augmented and maintained the FN induced integrin alpha5beta1 complex ubiquitination and led to a slower migration rate, suggesting that USP9x contributes to deubiquitinati[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
USP9X leads to the deubiquitination of APC_C. 1 / 1
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Because USP9X is a DUB and the SAC signal relies on inhibition of the APC/C ubiquitin ligase, USP9X might antagonize APC/C dependent ubiquitination to help maintain the SAC.
USP9X deubiquitinates CEP55. 1 / 1
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?Collectively, our experiments identified USP9X as an integral component of the centrosome where it functions to stabilize PCM1 and CEP55 and promote centrosome biogenesis.
USP9X deubiquitinates TAS2R13. 1 / 1
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USP9x in turn stimulates JAG1 activity through two mechanisms: (1) through TRB3 deubiquitination and stabilization, and (2) through deubiquitination and activation of Mind Bomb 1, an E3 ligase required for JAG1 ubiquitination-mediated endocytosis and Notch activation.
USP9X deubiquitinates MAP3K5. 1 / 1
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USP9X deubiquitinates STAM. 1 / 1
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In addition, we identified STAM and NFX1, which are known to be deubiquitylated by USP8 and USP9 respectively.
USP9X leads to the deubiquitination of EGFR. 1 / 1
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However, silencing of USP9X did not increase EGFR ubiquitination, arguing that the receptor itself is not the direct target.
Modified USP9X leads to the deubiquitination of CD274. 1 / 1
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In Oral Squamous Cell Carcinoma (OSCC) cells, the high expression of USP9X increases the deubiquitination of PD-L1 and reduces its degradation, resulting in protein accumulation in these cells.
USP9X deubiquitinates PSD. 1 / 1
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USP9x-mediated deubiquitination of EFA6 regulates de novo tight junction assembly
USP9X deubiquitinates BIRC5 on lysine. 1 / 1
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Lysine 63 de-ubiquitination of survivin by hFAM is required for the dissociation of survivin from centromeres.
USP9X deubiquitinates SMN1. 1 / 1
1 |

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Ubiquitin-specific Protease 9x Deubiquitinates and Stabilizes the Spinal Muscular Atrophy Protein-Survival Motor Neuron
USP9X deubiquitinates PRICKLE2. 1 / 1
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[XREF_BIBR, XREF_BIBR, XREF_BIBR - XREF_BIBR] We postulated the physical interaction between the PRICKLEs and USP9X might indicate that PRICKLE was a USP9X substrate, and that USP9X deubiquitinates and stabilizes both PRICKLE1 and PRICKLE2.
USP9X deubiquitinates ZAP70. 1 / 1
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Usp9X becomes competent to deubiquitinate ZAP70 through TCR-dependent phosphorylation and enhancement of its catalytic activity and association with the LAT signalosome.
USP9X deubiquitinates LATS1. 1 / 1
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In addition, USP9X can also function as a tumor suppressor. USP9X strongly interacts with LATS, a core kinase in the Hippo pathway. Increased USP9X expression significantly up-regulates and stabilizes LATS and leads to a decrease in the transport of YAP/TAZ into the nucleus as well as inhibiting of their target genes.

Other Statements

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USP9X affects MCL1
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USP9X activates MCL1.
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USP9X activates MCL1. 10 / 27
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Recent reports have suggested also that USP9X enhances Mcl-1 stability by preventing its proteasomal destruction through de-ubiquitination [XREF_BIBR].

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We therefore investigated the effect of Usp9X knockdown in Mcl1 -/- MEFs to rule out the possibility that USP9X mediates its mitosis specific effects by stabilizing MCL1.

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In contrast, the deubiquitinase USP9x prevented Mcl-1 degradation and stabilized Mcl-1 levels by removing the poly-ubiquitin chain [XREF_BIBR].

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In addition, ionising radiation-induced activation of USP9x inhibits Mcl-1 degradation, resulting in increased radio-resistance and apoptosis [106].

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For example, by removing K48 linked polyubiquitin chains from MCL1, USP9X inhibits the proteasomal degradation of MCL1, a pro survival BCL2 family member that is overexpressed in multiple cancer types and contributes to chemoresistance and tumor recurrence [XREF_BIBR].

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Together, our results indicate that radiation induced activation of USP9x inhibits Mcl-1 degradation and apoptosis resulting in increased radioresistance.

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USP9x expression correlated moderately but significantly with Mcl-1 expression in glioblastoma, supporting our hypothesis that USP9x stabilizes Mcl-1 in glioblastoma cells.

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Importantly, examination of USP9X targets MCL1 and beta-catenin by western blot analysis did not reveal a change in their protein levels when USP9X was knocked down in DAOY cells.

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Furthermore, the chemical inhibition of USP9X increased the sensitivity of the human lung carcinoma lines A549 and H1299 to an anti-apoptotic inhibitor (ABT-737, targets BCL-xl, but not MCL1).

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In Jurkat T lymphoma and K562 chronic myelogenous cells, USP9X is enzymatically activated in response to ionising radiation and causes MCL1 stabilisation, in turn inhibiting apoptosis and resulting in radioresistance [XREF_BIBR].
USP9X increases the amount of MCL1.
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USP9X increases the amount of MCL1. 10 / 12
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We have shown previously that USP9X inhibition by WP1130 reduces MCL-1 levels, promotes apoptosis and increases tumor cell sensitivity to chemotherapy [XREF_BIBR].

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While Usp9X is known to modulate Mcl-1 expression, our observed effects of Usp9X manipulation on Bag3 and Bcl-2 have not been previously described and may suggest that Usp9X also interacts with Bag3 as well as Bcl-2.

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XREF_BIBR More recently, in non small cell lung carcinoma, inhibition of USP9X by either siRNA knockdown or via a small molecule inhibitor WP1130 decreased MCL1 expression and sensitized cells to radiation therapy.

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Furthermore, knockdown of Usp9X or Bag3 depleted endogenous Mcl-1 protein levels and in turn enhanced apoptosis induced through Bcl-2 and Bcl-xL inhibition [XREF_BIBR].

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Usp9X modulates Mcl-1 levels and counteracts apoptosis in cancer cells [XREF_BIBR].

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Similar distinction was also observed for Mcl-1, one observed substrate of Usp9x, where Usp9x KD increased Mcl-1 levels in 8041 cells but decreased Mcl-1 in MIAPACA2 cells.

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These isothiocyanates increased Mcl-1 ubiquitination and either isothiocyanate treatment, or RNAi mediated silencing of USP9x decreased Mcl-1 levels, consistent with the notion that USP9x is a primary target of isothiocyanate activity.

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These ITCs increased Mcl-1 ubiquitination and either ITC treatment or RNAi mediated silencing of USP9x decreased Mcl-1 levels, consistent with the notion that USP9x is a primary target of ITC activity.

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We also observed that Usp9x KD decreased Mcl-1 levels in MIAPACA2 cells but increased Mcl-1 levels in 8041 cells.

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Mechanistically, Usp9X knockdown caused concomitant suppression of Bag3, Mcl-1 and Bcl-2 expression, which remarkably recapitulates the effects of CP-d and n-ATF 5-S1 on these molecules.
Modified USP9X increases the amount of MCL1. 1 / 1
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Overexpression of Usp9x increased 3D growth and invasion in PANC1 cells and up-regulated the expression of known Usp9x substrates Mcl-1 and ITCH.
USP9X bound to MCL1 increases the amount of MCL1. 1 / 1
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Additionally, Schwickart et al. demonstrated that in hematologic malignancies 51, the expression of deubiquitinase USP9X expression correlates with that of Mcl-1, and USP9X binds to Mcl-1, stabilizes it and thereby promotes Mcl-1 overexpression and cell survival.
USP9X inhibits MCL1.
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USP9X inhibits MCL1. 5 / 8
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Although USP9X depletion did not cause an obvious change in Mcl-1 degradation during mitosis, it did increase the loss of other mitotic APC/C substrates, in particular cyclin A, but also cyclin B and NEK2A (XREF_FIG A).

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Therefore, the indirectly supported, USP9X mediated degradation of MCL-1 can be regarded as a novel autophagy independent, oncosuppressive function of BECLIN 1 [XREF_BIBR].

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Indeed, knock-down of USP9X reduced the half-life of Mcl-1 and increased its conjugation to Lys48 linked poly-ubiquitin chains [XREF_BIBR] that generally target proteins for proteasomal degradation.

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Indeed, knockdown of Usp9X increased mitotic cell death in Mcl1 -/- cells to a similar extent as in WT MEFs, thus indicating independence of MCL1 (Fig XREF_FIG A and B).

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The USP9X inhibitor WP1130 or depletion of USP9X by its specific shRNAs induces MCL-1 degradation in cells and increases tumor cell sensitivity to chemo and radiotherapies 39.
USP9X decreases the amount of MCL1.
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USP9X decreases the amount of MCL1. 3 / 7
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Moreover, knock-down of Usp9X or Bag3 depleted endogenous Mcl-1 protein levels and in turn enhanced apoptosis induced through Bcl-2 and Bcl-xL inhibition.

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Usp9x siRNA transfection downregulated Mcl-1 levels and increased the activated levels of apoptosis related proteins (caspase-9, caspase-3 and PARP) (XREF_FIG).

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We also observed that Usp9x KD decreased Mcl-1 levels in MIAPACA2 cells but increased Mcl-1 levels in 8041 cells.

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So, knockdown of USP9X not only inhibited the proliferation of glioma cells in vitro, but also suppressed the tumorigenicity of primary glioma cells in vivo.

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It is worth noting that the proliferation defect caused by Usp9X deficiency was observed in CD8 + T cells as well as CD4 + T cells (XREF_FIG).

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In breast cancer, USP9X deubiquitinates and stabilizes YAP to promote breast cancer cell proliferation and chemoresistance to therapeutic drugs XREF_BIBR.

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FAF enhanced the proliferation of human gingival fibroblasts, human skin fibroblasts, and human umbilical vein endothelial cells in subconfluent and confluent cells, suggesting that FAF might be functioning as a competence factor.

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USP9X possibly promotes head and neck cancer cell proliferation through the mTOR pathway.

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In contrast, in immortalized but non tumorigenic HaCaT keratinocytes, USP9X depletion led to increase in cell proliferation, maintaining direct regulation of Notch activity.

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These data demonstrate that loss of USP9X decreases the proliferation of ReNcell VM cells but does not alter their morphology, cell death or differentiation.

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In addition, USP9X activates glycolysis and promotes cell proliferation through pVHL.

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By these results, we concluded that USP9X contributes to proliferation of PC3 cells through maintenance of IRS-2-Erk1/2 axis.

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When FRT tagged USP9X was introduced into USP9X -/- cells, the cell proliferation rate nearly recovered to that of WT cells, whereas overexpression of USP9X in WT cells slightly promoted cell proliferation as well.
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Knockdown of USP9X inhibited cell proliferation and cell cycle progression and increased apoptosis.

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In addition, depletion of USP9X decreases breast cancer proliferation, tumorigenesis, and chemoresistance in a YAP1 dependent manner.

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Down-regulation of Usp9X inhibits proliferation in glioblastoma cell lines.

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Knockdown of FAM196B Inhibited Cell Proliferation of A549and H1299 cell lines.

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Depletion of USP9X led to decreased cell proliferation (XREF_FIG), while depletion of both USP9X and YAP1 did not cause a further decrease in cell proliferation compared with cells depleted of YAP1 alone.

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The expression of USP9X in cholangiocarcinoma inhibited cell proliferation and colony formation in vitro as well as xenograft tumorigenicity in vivo .

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Recent studies have demonstrated that FAM134B inhibits colon cancer cells proliferation, migration, wound healing, colony formation and tumour formation in vivo [21,39] .

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USP9X null neurospheres have reduced neural progenitor proliferation but not stem cell self-renewal.

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Knockdown of USP9X suppresses cell proliferation, inhibits G1/S phase conversion, and induces apoptosis in U251 and A172 cells.

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Importantly, knockdown of EGLN3 impaired USP9X mediated suppression of proliferation.
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As inhibition of USP9X resulted in caspase 3 and caspase 8 activation and increased the rates of apoptosis, USP9X might promote cell survival by inhibiting apoptosis in glioma cells.

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Furthermore, we demonstrated that knockdown of USP24 but not USP9X could significantly induce growth inhibition and apoptosis of T-ALL cells.

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In contrast, USP9x knockdown slightly increased apoptosis in IR resistant A172 cells and significantly in Ln229 cells and reduced clonogenic survival after irradiation only on these two cell lines.

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Usp9X knockdown induces apoptosis, caspase activation and recapitulates effects of CP-d and n-ATF 5-S1.

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Inhibition of USP9X induces apoptosis in FLT3-ITD-positive AML cells cooperatively by inhibiting the mutant kinase through aggresomal translocation and inducing oxidative stress.

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FAM129A inhibited apoptosis and promoted migration and proliferation in human cancers.

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Furthermore, ectopic expression of USP9X prevented c-FLIP downregulation and apoptosis upon combined treatment.

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Although both Usp9X and Mcl-1 knockdown elicited some features of apoptosis, broad spectrum caspase inhibition was ineffective in preventing knockdown induced MPNST cell death suggesting that caspase independent death pathways were also activated.

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Although USP9x knockdown reduced Mcl-1 levels and increased apoptosis in A172 cells, USP9x regulated radiosensitivity independently of Mcl-1 in Ln229 cells.

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Considering our observations with respect to Bcl-2 family members and IAPs, Usp9X appears to block death-receptor-mediated apoptosis most likely at the level of initiator- as well as effector caspases, involving a combination of factors.
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Down-regulation of USP24 but not USP9X induces growth inhibition and apoptosis of T-ALL cells.

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Knockdown of endogenous USP9X expression evidently inhibited the migration and invasion of PANC-1 cells, and promoted cell apoptosis.

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Whole-genome transcriptome analysis revealed that FAM induced up-regulation of apoptosis related genes and genes that encode for mediators of oxidative stress resistance and heat shock proteins.

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Previous studies have suggested that deubiquitinase USP9X stabilizes myeloid cell leukemia sequence 1 (MCL1) and promotes tumor cell survival and apoptosis resistance [XREF_BIBR, XREF_BIBR].

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Specific knock-down of Usp9X induces apoptosis in glioblastoma cells.

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USP9X promotes apoptosis in cholangiocarcinoma by modulation expression of KIF1Bbeta via deubiquitinating EGLN3 .

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Knockdown of USP9X suppresses cell proliferation, inhibits G1/S phase conversion, and induces apoptosis in U251 and A172 cells.

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These results show that expression of USP9X is upregulated in hepatoma cells SMMC7721 and HepG2, and that downregulating USP9X by siRNA may induce cell apoptosis, inhibit cell growth and cell migration in the HCC SMMC7721 and HepG2 cell lines.

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Expression levels of ARF-BP1 and Mule and Usp9x appears to be critical for the maintenance of proper cellular balance of anti- and pro apoptotic proteins, and contributes to cell sensitivity to apoptosis and is linked to tumor formation [XREF_BIBR, XREF_BIBR].

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USP9X promotes apoptosis in cholangiocarcinoma by modulation expression of KIF1Bbeta via deubiquitinating EGLN3.
USP9X affects CTNNB1
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USP9X activates CTNNB1.
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USP9X activates CTNNB1. 8 / 13
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At molecular level , USP9X induces beta-catenin signaling to mediate HCC progression.124 Therefore , mediating GSK-3beta degradation and triggering beta-catenin nuclear translocation can significantly enhance proliferation rate of HCC cells.125 Besides , activation of beta-catenin signaling induces resistance of HCC cells toward apoptosis.126 Histone deacetylase 6 ( HDAC6 ) acts as tumor-suppressor and diminishes beta-catenin expression to induce apoptosis in HCC cells .
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By evaluating signaling in U251 cells treated with a Wnt ligand, we found that USP9X knockdown partly blocked the activation of Wnt and beta- catenin pathway by regulating the stability of beta-catenin.

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In summary, these results indicate that USP9X stabilizes beta-catenin and activates Wnt and beta-catenin signal pathway to promote glioma cell proliferation and survival.

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The results of the western blot suggested that knockdown of USP9X decreased beta-catenin protein, but the results of RT-PCR suggested that beta-catenin mRNA expression levels did not change (XREF_SUPPLEMENTARY).

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Previous studies have suggested that USP9X is co-immunoprecipitated with beta-catenin and inhibits the degradation of beta-catenin through the deubiquitination of beta-catenin in mouse lymphocyte cells [XREF_BIBR].

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USP9X promotes the progression of hepatocellular carcinoma by regulating beta-catenin.

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Down-regulation of USP9X also consistently inhibits the tumorigenicity of primary glioma cells in vivo.In summary, these results indicate that USP9X stabilizes beta-catenin and activates Wnt and beta-catenin signal pathway to promote glioma cell proliferation and survival.

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At molecular level, USP9X induces β-catenin signaling to mediate HCC progression.124 Therefore, mediating GSK-3β degradation and triggering β-catenin nuclear translocation can significantly enhance proliferation rate of HCC cells.125 Besides, activation of β-catenin signaling induces resistance of HCC cells toward apoptosis.126 Histone deacetylase 6 (HDAC6) acts as tumor-suppressor and diminishes β-catenin expression to induce apoptosis in HCC cells.
| PMC
USP9X bound to CTNNB1 activates CTNNB1. 1 / 1
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It was found that USP9x interacted with beta-catenin and inhibited the degradation of beta-catenin through the deubiquitination of beta-catenin.
USP9X increases the amount of CTNNB1.
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USP9X increases the amount of CTNNB1. 3 / 3
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Mechanically, USP9X promotes HCC cell proliferation by regulating the expression of beta-catenin.

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USP9X has also been reported to increase the levels of beta-catenin, a transcription factor linked to the growth of brain tumors XREF_BIBR, XREF_BIBR, and overexpression of USP9X has been reported to enhance the half-life and expression of beta-catenin in mouse L cells and MCF7 cells, respectively XREF_BIBR, XREF_BIBR.

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However, in contrast to previous studies, which indicated Usp9x positively regulates beta-catenin protein levels, significantly increased pbeta-catenin33/37/41 and Tyr654 pbeta-catenin levels observed in Usp9x -/Y neocortices implied a novel regulatory mechanism in NPs.
Modified USP9X increases the amount of CTNNB1. 2 / 2
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Overexpression of Dvl, ATDC, and deubiquitinating enzyme Fam, which also affects the degradation of beta-catenin, has been reported to elevate beta-catenin level.

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In MDCK cells, overexpression of the USP9X catalytic domain increased the steady-state levels of beta-catenin, presumably by its ability to deubiquitylate and hence rescue from proteasomal degradation.
USP9X inhibits CTNNB1.
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USP9X inhibits CTNNB1. 1 / 3
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Deletion of Usp9x increases the levels of beta-catenin protein in Neural Progenitors.
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USP9X activates Cell Survival.
| 16
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Usp9x expression increases cell survival and 3D growth, and induces invasion in human PDAC cell line PANC1.

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However, in established human pancreatic tumor cells, Usp9x supports tumor cell survival and the malignant phenotype, illustrating wide distinctions in function in murine tumor cell models and bona fide human pancreatic cancer while also highlighting the potential for Usp9x inhibitors to be used in the treatment of human PDAC.

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Here we show that the deubiquitinase USP9X stabilizes MCL1 and thereby promotes cell survival.

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The deubiquitinase USP9X promotes tumor cell survival and confers chemoresistance through YAP1 stabilization.

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The hypothesis that UBP43 is an anti-neoplastic target is consistent with recent work reported with the deubiquitinase USP9X, which promoted cancer cell survival by regulating stability of a pro survival BCL2 family member.

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From these results we conclude that USP9X and ZBTB38 both contribute to cell survival upon oxidative stress, and that they act in the same pathway.

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Furthermore, USP9X knockdown increased the inhibition of cell viability after cisplatin administration.

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On the contrary, USP9X acts as an oncogene and stabilizes MCL1, a critical antiapoptotic member of the BCL-2 family, and thereby promotes cell survival of multiple myeloma XREF_BIBR.

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USP9X has, however, also been proposed to promote tumor cell survival by limiting the degradation of the anti-apoptotic protein Mcl-1.

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Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival.
USP9X bound to MCL1 activates Cell Survival. 1 / 1
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Additionally, Schwickart et al. demonstrated that in hematologic malignancies 51, the expression of deubiquitinase USP9X expression correlates with that of Mcl-1, and USP9X binds to Mcl-1, stabilizes it and thereby promotes Mcl-1 overexpression and cell survival.
USP9X inhibits Cell Survival.
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FAm significantly decreased cell viability and increased intracellular lipid accumulation, whereas LF significantly recovered cell viability without affecting lipid accumulation.

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As inhibition of USP9X resulted in caspase 3 and caspase 8 activation and increased the rates of apoptosis, USP9X might promote cell survival by inhibiting apoptosis in glioma cells.
USP9X affects SMAD4
3 | 11
USP9X activates SMAD4.
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USP9X activates SMAD4. 10 / 12
3 | 9

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A recent study reported that USP9X activates SMAD4 by deubiquitination at K519, resulting in the activation of SMAD2/3, and promotion of TGFbeta pathway, which will induce cell apoptosis.

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USP9x has been reported to increase SMAD4 activity by removing an inhibitory ubiquitin moiety [XREF_BIBR].

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USP9X was previously reported to regulate Smad4 transcriptional activity positively, thus we hypothesized that decreased USP9X expression would attenuate Smad4 function and TGF-beta responsiveness in HCC cell lines [XREF_BIBR].

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Removal of the mono-ubiquitin by the de-ubiquitinase FAM and USP9x restores Smad4 function [XREF_BIBR].

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Since USP9X was previously reported to positively regulate SMAD4 transcriptional activity 17 and SMAD4 is commonly mutated in PDA 4, we hypothesized that Usp9x loss would attenuate Smad4 function or TGFbeta responsiveness in PDA cell lines.

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Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4.

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Sall4 shows an interaction with Usp9x (XREF_FIG B), an essential component of the TGF-beta and BMP signaling pathway, which activates Smad4 by removing a monoubiquitin group.

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Thus, the de-ubiquitylase FAM and USP9 can remove K519 mono-ubiquitylation of Smad4 imposed by TIF1gamma, and thus restore Smad4 function.

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Loss of the USP9x homologue Fat facets in Drosophila inhibits the activity of the Smad4 homologue Medea through ubiquitination of Medea on K738 (equivalent to K519 in human Smad4) (Stinchfield et al.,[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Smad4 is monoubiquitinated in lysine 519 in vivo, a modification that inhibits smad4 by impeding association with phospho-smad2. Fam reverts this negative modification, re-empowering smad4 function;control of smad4 is a good way to regulate bone formation. Fam and ectodermin/tif1gamma (ecto) were reported to respectively regulate the de-ubiquitination and ubiquitination of smad4.
USP9X inhibits SMAD4.
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USP9X inhibits SMAD4. 1 / 3
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USP9x shRNA delivery significantly inhibits TGF-beta-induced SMAD4 nuclear retention and eliminates PA promotion of TGF-beta-induced SMAD4 nuclear retention.
USP9X increases the amount of SMAD4.
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USP9X increases the amount of SMAD4. 1 / 1
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A recent report shows that USP9X modulates Smad4 levels in cells through reduction of its mono-ubiquitination.
USP9X affects VHL
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USP9X inhibits VHL.
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USP9X inhibits VHL. 8 / 8
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USP9X degrades pVHL through protection of its substrate, the newly identified pVHL E3 ligase Smurf1.

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Our findings show pVHL is induced by USP9X knockdown, raising the possibility a suitable USP9X inhibitor may exert a similar effect.

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Smurf1 thus mediates downregulation of pVHL by USP9X.

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USP9X down-regulates pVHL through Smurf1.

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USP9X negatively regulates pVHL.

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In order to demonstrate USP9X negatively regulates pVHL in clear cell renal cell carcinoma (ccRCC) which is a VHL disease associated neoplasm, USP9X was knocked down in 786-0 cells stably expressing HA tagged pVHL.

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USP9X knockdown up-regulated pVHL, while HUWE1 showed no evidence of pVHL regulation at the protein level (XREF_SUPPLEMENTARY).

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Previous results demonstrated USP9X decreases the protein stability of pVHL, raising a question as to how USP9X destabilizes pVHL.
USP9X inhibits mutated VHL. 1 / 1
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Newly identified unstable pVHL mutants maintain partial pVHL function and are negatively regulated by USP9X.
USP9X decreases the amount of VHL.
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USP9X decreases the amount of VHL. 3 / 3
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As knockdown of USP9X in HEK293T cells significantly increased pVHL levels, both mRNA levels and protein half-life of pVHL were evaluated in HEK293T cells to further investigate the mechanism by which USP9X regulates pVHL.

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This study shows that inhibition of USP9X function by either shRNA or a chemical inhibitor significantly enhances pVHL levels and suppresses tumor cell proliferation.

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USP9X negatively regulates pVHL levels and consequently protects HIF and NF-kappaB activity.
USP9X activates VHL.
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USP9X activates VHL. 1 / 1
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Knockdown of USP9X caused induction of pVHL, and protein levels of HIF-2alpha were consequently decreased in HepG2 cells and PC3 cells.
USP9X affects CEP131
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USP9X activates CEP131.
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To investigate whether and how other substrates of USP9X might affect the cellular function of USP9X promoted CEP131 stabilization, we analysed by WB analysis the expression of IPO5, PRMT5 and PPM1B, which were also identified as interactors of USP9X (XREF_SUPPLEMENTARY), and the results indicate that the protein abundance of these proteins was essentially unchanged upon USP9X knockdown (XREF_SUPPLEMENTARY).

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Collectively, these observations suggest a potential role for USP9X promoted CEP131 stabilization in breast carcinogenesis.

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Since centrosome dysregulation associated mitotic defects could result in genome instability and cell apoptosis XREF_BIBR XREF_BIBR XREF_BIBR, we examined whether USP9X promoted CEP131 stabilization plays a role in genome stability and cell death.

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We next asked the question how USP9X promoted CEP131 stabilization has an impact on centrosome biogenesis.

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In vitro deubiquitination assays revealed that, while USP9X was able to remove ubiquitins of CEP131 and K504R, but not that of CEP131 and K254R (XREF_FIG), favouring the argument that USP9X targets K254 of CEP131 for deubiquitination, although polyubiquitin chains conjugated onto CEP131 and K254R and CEP131 and K504R were both dramatically reduced (XREF_FIG).

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These results indicate that USP9X promoted CEP131 stabilization is required for breast cancer cell survival.

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Combining the findings that mildly disrupted centrosomal localization of PCM1 has minimal effect on CEP131 recruitment and the observations that USP9X directly interacts with CEP131 and opposes its polyubiquitin linkages in vitro, we get the conclusion that the effect of USP9X on CEP131 stabilization is attributed to the interplay between these two molecules but not through USP9X targeting other substrates like PCM1, and USP9X regulated PCM1 stabilization on centrosome activity, if it does so, seems to be independent of USP9X promoted CEP131 stabilization.

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On the other hand, Li and colleagues demonstrated that USP9X, a well studied protein with oncogenic potential (Schwickart et al., 2010), promotes CEP131 stabilization through deubiquitination (Li et a[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Together, these results indicate that overexpression of USP9X promotes centrosome amplification and mitotic defects in a CEP131 dependent manner.

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To gain molecular insights into the functional connection between USP9X and CEP131, we examined whether USP9X promoted CEP131 stabilization is dependent on the enzymatic activity of USP9X.
Modified USP9X activates CEP131. 1 / 1
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Moreover, USP9X overexpression was able to restore the expression of CEP131 and prolong the half-life of CEP131 in USP9X deficient cells (XREF_FIG).
USP9X inhibits CEP131.
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USP9X inhibits CEP131. 1 / 1
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Vice versa, depletion of USP9X also decreased cellular pools of CEP131 and PCM1.
USP9X increases the amount of CEP131.
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Modified USP9X increases the amount of CEP131. 1 / 1
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Moreover, USP9X overexpression was able to restore the expression of CEP131 and prolong the half-life of CEP131 in USP9X deficient cells (XREF_FIG).
USP9X affects TGFB
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USP9X activates TGFB.
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USP9X activates TGFB. 8 / 9
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USP9X might also act as a regulator of the TGF-beta pathway, another signaling circuitry of great relevance to cancer, as witnessed by the fact that loss of USP9X abolishes multiple TGF-beta gene responses XREF_BIBR.

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FAM and USP9x activity is required for Smad4 mediated TGFbeta signaling, because it re-enables Smad4 to form complexes with R-Smads and signal in the nucleus.

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The results, exemplified in Figures 1 C, 1D, and S1, show that loss of FAM abolishes multiple TGFbeta gene responses.

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FAM knockdown also blocks TGFbeta mediated induction of a synthetic Smad promoter fused to luciferase (CAGA12-lux, Figure 1 E), in line with the notion that FAM is a critical factor for Smad signaling[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Since USP9X was previously reported to positively regulate SMAD4 transcriptional activity 17 and SMAD4 is commonly mutated in PDA 4, we hypothesized that Usp9x loss would attenuate Smad4 function or TGFbeta responsiveness in PDA cell lines.

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The deubiquitylating enzyme USP9X (also known as FAM) reverts the effects of TRIM33 on Smad4 and restores TGF-beta signaling.

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USP9X positively regulates TGF-beta signaling by deubiquitylating SMAD4 and promoting its association with SMAD2 [XREF_BIBR].

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Loss of Usp9x Disrupts Cortical Architecture, Hippocampal Development and TGFbeta Mediated Axonogenesis.
USP9X inhibits TGFB.
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USP9X inhibits TGFB. 3 / 3
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Where indicated, control cells were supplemented with 5 muM SB431542 (Tocris) in the medium to quench autocrine TGFbeta signaling.For FAM knockdown, the sequences of the siRNA were as follows : # 1 : [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Thus loss of USP9x can increase TGFbeta signaling, potentially contributing to tumorigenesis.

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Depletion of FAM or Smad4 abolished TGFbeta induced migration.
USP9X affects GPSM1
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USP9X activates GPSM1.
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USP9X activates GPSM1. 6 / 7
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The observations that knockdown of USP9x decreases the cellular level of AGS3 (XREF_FIG) and overexpression of USP9x increases the staining intensity of AGS3 (XREF_FIG) imply that USP9x can regulate the level of AGS3.

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These data show that ectopic expression of USP9x at a high level increases the staining signal of AGS3, and that this effect of USP9x requires its deubiquitinating activity.

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Presumably this indicates that low amounts of USP9x are sufficient to prevent AGS3 degradation.

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To test whether the ability of USP9x to enhance AGS3 staining depends on its deubiquitinating activity, we repeated the experiment using the UCH domain of USP9x alone, which is the catalytic domain responsible for the deubiquitinase activity of USP9x XREF_BIBR, XREF_BIBR.

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Relative to the full-length USP9x, which increased the AGS3 staining primarily in cells expressing a high level of transfected USP9x-HA (~ 30% of these cells), the UCH domain led to enhanced AGS3 staining in almost all transfected cells displaying a moderate-to-high level of overexpression (XREF_FIG).

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Taken together, our study suggests that USP9x can modulate the level of a subpopulation of AGS3, and this modulation plays a role in regulating the structure of the late Golgi compartments.
USP9X increases the amount of GPSM1.
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USP9X increases the amount of GPSM1. 3 / 3
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The observations that knockdown of USP9x decreases the cellular level of AGS3 (XREF_FIG) and overexpression of USP9x increases the staining intensity of AGS3 (XREF_FIG) imply that USP9x can regulate the level of AGS3.

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Collectively, our study supports a model in which USP9x can modulate the level of AGS3 (or a pool of it), and that this modulation plays a role in regulating the structure and/or function of the late Golgi compartments.

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Under this scenario, it would be worthwhile to investigate whether USP9x modulates the level of AGS3 associated with the Golgi membrane considering our findings that knockdown of AGS3 or USP9x both affect the late Golgi compartments (XREF_FIG).
Modified USP9X increases the amount of GPSM1. 1 / 1
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In contrast, overexpression of either USP9x or its deubiquitinating domain UCH increases the amount of AGS3, whereas expression of the mutant UCH domain that lacks deubiquitinating activity does not have the same effect.
USP9X decreases the amount of GPSM1.
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USP9X decreases the amount of GPSM1. 1 / 1
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Knockdown of USP9x causes a moderate reduction in the level of AGS3.
USP9X affects cell death
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USP9X activates cell death.
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It is thus possible that USP9X promotes or prevents H 2 O 2 -triggered cell death by acting on different targets at varying levels of oxidative damage.

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Thus, USP9X positively regulates ASK1 activity and ASK1 dependent cell death through the deubiquitination and stabilization of ASK1 [XREF_BIBR].

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Finally, the Usp9X pharmacological inhibitor WP1130 significantly reduced human MPNST growth and induced tumor cell death in an in vivo xenograft model.

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Since centrosome dysregulation associated mitotic defects could result in genome instability and cell apoptosis XREF_BIBR XREF_BIBR XREF_BIBR, we examined whether USP9X promoted CEP131 stabilization plays a role in genome stability and cell death.
USP9X inhibits cell death.
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Interestingly, different from Peterson 's finding that USP9X is an oncogene in B-cell malignancies [XREF_BIBR], we found that knockdown of USP9X did not induce cell death of T-ALL cells, indicating that the role of USP9X is cell type dependent.

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Pharmacological inhibition of USP9X potently induced cell death in OSCC cells in vitro and in vivo.

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Moreover, USP9x silencing resulted in significantly increased cell death in BaF3 and p210 cells (XREF_SUPPLEMENTARY), suggesting that the ITC induced inhibition of USP9x can, at least partially, account for the reduced viability and increased cell death observed upon ITC treatment.

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Indeed, knockdown of Usp9X increased mitotic cell death in Mcl1 -/- cells to a similar extent as in WT MEFs, thus indicating independence of MCL1 (Fig XREF_FIG A and B).
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Usp9x expression increases cell survival and 3D growth, and induces invasion in human PDAC cell line PANC1.

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In brief, USP9X promoted the migration and invasion of PANC-1 cells probably by provoking epithelial-mesenchymal transition, and also inhibited apoptosis.

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Furthermore, USP9X inhibition also reversed the increased migration and invasion mediated by miR-132 inhibition.

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G9 mediated inhibition of Usp9x in pancreatic cancer cells not only reduced the in vitro 3D growth and invasion but also inhibited tumor growth of human pancreatic cancer MIAPACA2 cells in vivo.

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Depletion of USP9X in prostate cancer LNCaP and PC-3 cells by small interfering RNA promoted cell invasion and migration.

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Inhibition of USP9X by its inhibitor WP1130 reduced the migration and invasion of NSCLC cells.

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Importantly, reintroduction of RNF115 in USP9X depleted cells partially rescued the reduced proliferation, migration, and invasion of breast cancer cells by USP9X knockdown.
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Enforced expression of FAM198B inhibited cell invasion, migration, mobility, proliferation and anchorage-independent growth and FAM198B silencing exhibited opposite activities in vitro.

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Knockdown of endogenous USP9X expression evidently inhibited the migration and invasion of PANC-1 cells, and promoted cell apoptosis.

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The invasided cell numbers were reduced after the overexpression of FAM3D-AS1, suggesting that FAM3D-AS1 can inhibit the cell invasion ( xref E), Thus, these results revealed that FAM3D-AS1 possessed the function of inhibition of cell proliferation and invasion.
USP9X affects Notch
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