USP2 Data Analysis

HGNC Gene Name
ubiquitin specific peptidase 2
HGNC Gene Symbol
USP2
Identifiers
hgnc:12618 NCBIGene:9099 uniprot:O75604
Orthologs
mgi:1858178 rgd:621073
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for USP2
Number of Papers
198 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
CDON cell adhesion associated, oncogene regulated 0.214 Reactome (1)
OR2M2 olfactory receptor family 2 subfamily M member 2 0.21
KCNJ1 potassium inwardly rectifying channel subfamily J member 1 0.209
NRXN3 neurexin 3 -0.199
C11orf52 chromosome 11 open reading frame 52 0.19
PTPRB protein tyrosine phosphatase receptor type B -0.184
THYN1 thymocyte nuclear protein 1 0.184

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with USP2using 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 USP2 using CRISPR-Cas9.

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
RPS21 ribosomal protein S21 9.75e-01 1.58e-11 1.75e-08
RPL19 ribosomal protein L19 3.53e-01 2.08e-09 1.15e-06
RPL22 ribosomal protein L22 5.56e-01 1.13e-05 4.17e-03
RPL14 ribosomal protein L14 4.05e-01 1.22e-04 2.81e-02
RPL31 ribosomal protein L31 3.36e-01 1.27e-04 2.81e-02
ADAM10 ADAM metallopeptidase domain 10 -4.93e-01 2.46e-04 4.10e-02
ARPC3 actin related protein 2/3 complex subunit 3 2.81e-01 3.40e-04 4.10e-02
ATP5MJ ATP synthase membrane subunit j 2.92e-01 4.21e-04 4.10e-02
PPP1CB protein phosphatase 1 catalytic subunit beta -5.02e-01 5.20e-04 4.10e-02
S100A6 S100 calcium binding protein A6 3.05e-01 4.39e-04 4.10e-02
SEC13 SEC13 homolog, nuclear pore and COPII coat complex component 3.56e-01 3.44e-04 4.10e-02
SNRPC small nuclear ribonucleoprotein polypeptide C 2.35e-01 5.13e-04 4.10e-02
TMCO1 transmembrane and coiled-coil domains 1 3.70e-01 4.34e-04 4.10e-02
TMED2 transmembrane p24 trafficking protein 2 -3.53e-01 4.54e-04 4.10e-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 USP2 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
USP2 deubiquitinates MDM2. 4 / 4
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Specifically, protein-protein interaction assays using the bacterial two-hybrid system showed that USP2 can deubiquitinate MDM2 and promotes p53 degradation, showing the association between USP2 and MDM2 (Stevenson et al., 2007).
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USP2 deubiquitinates and stabilizes MDM2 thus inhibiting the proapoptotic activity of p53.

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Review

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USP2 deubiquitinates both MDM2 and MDMX [XREF_BIBR, XREF_BIBR] whereas USP4 deubiquitinates ARF-BP1 [XREF_BIBR], another ubiquitin ligase for p53, thus indirectly destabilizing p53 and inhibiting its function.
USP2 deubiquitinates Cyclin on D1. 4 / 4
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reported that USP2 specifically deubiquitinates and stabilizes cyclin D1, whereas knockdown of this protease causes cyclin D1 degradation and growth arrest in cancer cells dependent on this cell cycle regulator.

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In particular, it has been recently shown that USP-2 deubiquitinates cyclin D1, prevents degradation, accumulates cyclin D1 and finally leads to cell cycle progression from G1 to S phase (Lee et al., [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Cyclin D1 ubiquitination is reversed by the deubiquitinases USP2 and USP22.

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In a screen of potential deubiquitination enzymes, Shan et al. identified USP2 to specifically deubiquitinate cyclin D1, preventing the degradation of cyclin D1, and leading to the accumulation of cyclin D1.
USP2 deubiquitinates LDLR. 4 / 4
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The authors attempt to answer this question by introducing a tripartite complex model, in which USP2 interacts with LDLR at the plasma membrane in an IDOL dependent manner to deubiquitylate and stabilize both LDLR and IDOL.

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Such a temporal expression pattern would leave little opportunity to alleviate the USP2 mediated antagonism of IDOL, and the tripartite complex model would imply that IDOL is constantly engaged in a futile reaction, in which its ubiquitylation of LDLR is immediately reversed by USP2.

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We identify a tri and partite complex encompassing IDOL, USP2, and LDLR and demonstrate that in this context USP2 promotes deubiquitylation of the LDLR and prevents its degradation.

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In summary, USP2 activity leads to the deubiquitylation and stabilization of cell surface LDLR in and IDOL dependent manner, but it remains uncertain exactly why such a phenomenon is accompanied by an extended IDOL protein half-life.
USP2 deubiquitinates PER1. 3 / 3
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Deubiquitination of PER1 by USP2 does not stabilize it.

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In light of the shorter half-life of USP2 (compared to that of PER1) (XREF_FIG) and of its rhythmic expression peaking almost simultaneously with that of PER1, the deubiquitination of PER1 by USP2 could be restricted to a specific circadian time and therefore be altering the function and/or localization of PER1 to fine tune the molecular clock in physiological conditions.

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Recently, we showed that the deubiquitinating enzyme ubiquitin-specific peptidase 2 (USP2) associates with clock proteins and deubiquitinates PERIOD1 (PER1) but does not affect its overall stability.
USP2 deubiquitinates MDM4. 3 / 3
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MdmX, another target of Mdm2, is also deubiquitinated by USP2.

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USP2 deubiquitinates both Mdm2 and MdmX.

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USP2 deubiquitinates both MDM2 and MDMX [XREF_BIBR, XREF_BIBR] whereas USP4 deubiquitinates ARF-BP1 [XREF_BIBR], another ubiquitin ligase for p53, thus indirectly destabilizing p53 and inhibiting its function.
USP2 deubiquitinates Imd. 2 / 2
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USP2, for instance, deubiquitinates Imd, promoting its degradation.

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Identifying USPs regulating immune signals in Drosophila : USP2 deubiquitinates Imd and promotes its degradation by interacting with the proteasome.
USP2 deubiquitinates CRY1. 2 / 2
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In addition to PER1 and BMAL1, USP2 deubiquitinates CRY1 in cultured cells in response to a serum shock, and in the mouse liver, Usp2 knockdown increases CRY ubiquitination and decreases CRY1 protein levels.

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USP2a protein deubiquitinates and stabilizes the circadian protein CRY1 in response to inflammatory signals.
USP2 deubiquitinates MYLIP. 2 / 2
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In summary, USP2 activity leads to the deubiquitylation and stabilization of cell surface LDLR in and IDOL dependent manner, but it remains uncertain exactly why such a phenomenon is accompanied by an extended IDOL protein half-life.

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The authors attempt to answer this question by introducing a tripartite complex model, in which USP2 interacts with LDLR at the plasma membrane in an IDOL dependent manner to deubiquitylate and stabilize both LDLR and IDOL.
USP2 leads to the deubiquitination of MMP2. 2 / 2
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Review

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It has been proven that USP2 promotes breast cancer metastasis by deubiquitinating MMP2 XREF_BIBR.
USP2 deubiquitinates TWIST1. 2 / 2
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Furthermore, TJP1 recruited USP2, which deubiquitinated TWIST1, thereby protecting TWIST1 from proteasome-mediated protein degradation.

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USP2 regulates Bmi1 and EMT by Twist stabilization and prevents Twist ubiquitination driven by beta-TrCP and subsequent proteasome mediated protein degradation.
USP2 deubiquitinates ARIH2. 1 / 1
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Indeed, USP2 but not heat inactivated USP2 depleted the slower migrating, and hence ubiquitylated, form of TRIAD1 (XREF_FIG E).
Modified USP2 leads to the deubiquitination of ENaC. 1 / 1
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Likewise, overexpression of USP2 causes decreased ubiquitination of ENaC and increases its activity at the plasma membrane.
Modified USP2 leads to the deubiquitination of TWIST1. 1 / 1
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Our data showed that beta-TrCP-driven Twist ubiquitination is abolished by overexpression of USP2.
USP2 deubiquitinates SCNN1B. 1 / 1
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The surface expression of ENaC components is directed by the ubiquitination of ENaC by NEDD4L, an ENaC-specific E3 ubiquitin ligase, and is regulated by the deubiquitination of ENaC by USP2.?
Modified USP2 leads to the deubiquitination of MYLIP. 1 / 1
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USP2 overexpression was shown to decrease IDOL ubiquitylation, but it remains unknown which type of ubiquitin linkages on IDOL are edited by USP2.
USP2 deubiquitinates PTH1R. 1 / 1
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Usp2 is a deubiquitination enzyme targeting various factors including CyclinD1 in cancer cells and PTH receptor 1 in osteoblasts.
USP2 deubiquitinates SCNN1A. 1 / 1
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Fine-tuning of renal sodium reabsorption and excretion depends on the epithelial sodium channel protein (ENaC: protein complex of SCNN1A, SCNN1B, and SCNN1G). The surface expression of ENaC components is directed by the ubiquitination of ENaC by NEDD4L, an ENaC-specific E3 ubiquitin ligase, and is regulated by the deubiquitination of ENaC by USP2.
USP2 deubiquitinates SKP2. 1 / 1
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We first screened a panel of DUBs and found that both USP2 and USP21 bound to endogenous SKP2, but only USP2 deubiquitylated and stabilized SKP2 protein.
USP2 deubiquitinates SLC22A1. 1 / 1
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We also suggest that the deubiquitination of Oct-1 transcription factors by USP2 is involved in the transcriptional regulation of cytokine genes.
USP2 deubiquitinates TRAF2. 1 / 1
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USP2a similarly de-ubiquitinates TRAF2, a ubiquitin-ligase recruited to the TNFR1 complex.?
USP2 deubiquitinates ELOVL6. 1 / 1
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In various cancers, including prostate cancer and ovarian carcinoma, upregulation of USP2 leads to an increase in the levels of deubiquitinated substrates such as fatty acid synthase, MDM2, cyclin D1 and Aurora-A.
USP2 deubiquitinates ARNTL. 1 / 1
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Accordingly, other investigators have shown that UBP41, a truncated form of USP2, can deubiquitinate BMAL1 in vitro, and that in the presence of USP2b, BMAL1 appears less ubiquitinated and more stable.
USP2 deubiquitinates SIRT1. 1 / 1
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USP2 deubiquitinates AURKA. 1 / 1
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In various cancers, including prostate cancer and ovarian carcinoma, upregulation of USP2 leads to an increase in the levels of deubiquitinated substrates such as fatty acid synthase, MDM2, cyclin D1 and Aurora-A.
USP2 leads to the deubiquitination of CRYL1. 1 / 1
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In addition to PER1 and BMAL1, USP2 deubiquitinates CRY1 in cultured cells in response to a serum shock, and in the mouse liver, Usp2 knockdown increases CRY ubiquitination and decreases CRY1 protein levels.
USP2 deubiquitinates CCND1. 1 / 1
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Usp2 is a deubiquitination enzyme targeting various factors including CyclinD1 in cancer cells and PTH receptor 1 in osteoblasts.
USP2 deubiquitinates FASN. 1 / 1
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Here we show that the isopeptidase USP2a (ubiquitin-specific protease-2a) interacts with and stabilizes fatty acid synthase (FAS),?
USP2 leads to the deubiquitination of GRIA. 1 / 1
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Given the same type of deubiquitinating enzyme (USP46) is able to deubiquitinate AMPA receptors, and knockdown of USP46 elevated AMPA receptor ubiquitination and reduced AMPA receptor expression in hi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
USP2 deubiquitinates TP53. 1 / 1
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Unlike USP7, USP2 does not deubiquitinate p53 (9).
USP2 deubiquitinates RIPK1 on K377. 1 / 1
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biopax:reactome
No evidence text available
USP2 deubiquitinates IL32. 1 / 1
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USP2 deubiquitinated and stabilized tAIF, thus promoting AIF mediated cell death.
USP2 deubiquitinates SCNN1G. 1 / 1
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The surface expression of ENaC components is directed by the ubiquitination of ENaC by NEDD4L, an ENaC-specific E3 ubiquitin ligase, and is regulated by the deubiquitination of ENaC by USP2.?
USP2 deubiquitinates FAS. 1 / 1
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USP2a can also deubiquitinate Fas preventing apoptosis in PCa
USP2 deubiquitinates RIPK1. 1 / 1
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?We have found that the ubiquitin-specific protease USP2a has a pivotal role in the decision for cell death or survival by the TNFR1 complex. This enzyme is a novel component of the TNFR1 complex that is recruited upon ligand binding and controls the signalling activity of the TNFR1-interacting protein RIP1 by removing its K63-linked ubiquitin chains.?

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
Ubiquitin affects USP2
| 3 11 8
| 3 11 8

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While ubiquitin inhibits USP2 with a K i of 2.8 mM, mutants lacking residues Arg74-Gly75-Gly76 or Leu73-Arg74-Gly75-Gly76 affect the proteolytic activity of USP2 only marginally even at the highest inhibitor concentration.

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While ubiquitin inhibits USP2 with a K i of 2.8 mM, mutants lacking residues Arg74-Gly75-Gly76 or Leu73-Arg74-Gly75-Gly76 affect the proteolytic activity of USP2 only marginally even at the highest inhibitor concentration.

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USP2 is inhibited by ubiquitin with a Ki of 2.8 μM, which is in the same range as the Ki of 3 μM for the related enzyme USP5, also known as isopeptidase T (Dang et al., 1998).

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While ubiquitin inhibits USP2 with a Ki of 2.8 μM, mutants lacking residues Arg74-Gly75-Gly76 or Leu73-Arg74-Gly75-Gly76 affect the proteolytic activity of USP2 only marginally even at the highest inhibitor concentration.

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While ubiquitin inhibits USP2 with a K i of 2.8 muM, mutants lacking residues Arg74-Gly75-Gly76 or Leu73-Arg74-Gly75-Gly76 affect the proteolytic activity of USP2 only marginally even at the highest i[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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USP2 is inhibited by ubiquitin with a K i of 2.8 mM, which is in the same range as the K i of 3 mM for the related enzyme USP5, also known as isopeptidase T (Dang et al., 1998) .

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USP2 is inhibited by ubiquitin with a K i of 2.8 mM, which is in the same range as the K i of 3 mM for the related enzyme USP5, also known as isopeptidase T (Dang et al., 1998) .

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While ubiquitin inhibits USP2 with a K of 2.8 μM, mutants lacking residues or affect the proteolytic activity of USP2 only marginally even at the highest inhibitor concentration.

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While ubiquitin inhibits USP2 with a Ki of 2.8 μM, mutants lacking residues Arg74-Gly75-Gly76 or Leu73-Arg74-Gly75-Gly76 affect the proteolytic activity of USP2 only marginally even at the highest inhibitor concentration.

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Substrate Binding Region of USP2 and USP7 USP2 Inhibition by Full-Length Ubiquitin and the C-Terminally Truncated Mutants, Ubiquitin 1-74 and 1-73 Steady-State Kinetic Parameters for the Hydrolysis of AMC Substrates by UCH-L3 and USP2 Inhibition of USP2 Crystallographic Data and Refinement Statistics Data Set Statistics
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USP2 activates apoptotic process.
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Our studies indicate that apoptosis can be modulated by peroxisomal import of USP2, resulting in its spatial separation from its target proteins in the cytosol and nucleus.

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Significantly , siRNA knockdown of USP2 resulted in apoptosis , which could be reversed by overexpression of fatty acid synthase ( FAS ) ( 8) .

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Caspase dependent apoptosis caused by overexpression of USP2 was first described for USP2-2 [XREF_BIBR] but also for isoform 1 [XREF_BIBR].

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We have previously shown that the 41 kDa USP2 isoform induces apoptosis [3] and that the 69 kDa USP2a isoform mediates the apoptosis signal of the TNF receptor [5].

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Hence, the USP2 variants seem to cause the activation of apoptosis pathways by the specific stabilising of their RIP1 substrate.Based on the pro apoptotic effect when USP2c was targeted by RNAi, we fo[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Knockdown of USP2 did not increase cell apoptosis in Hut-78 cells compared to cells with control siRNA, further suggesting the pivotal role of p53 in USP2 function.

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In vitro an artificial knockdown of USP2 inhibited actinomycin D/TNFalpha induced hepatocyte apoptosis, which was associated with elevated levels of the anti-apoptotic protein c-Flip (L/S) and a concomitant decrease of cellular levels of the ubiquitinligase Itch, a negative regulator of c-Flip.
| 1 5

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Stevenson, et al. showed that USP2 prevents cell apoptosis induced by stabilizing MDM2, in turn leading to p53 reduction XREF_BIBR, XREF_BIBR.

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USP2 reduces cell apoptosis via p53 signaling.

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In vitro an artificial knockdown of USP2 inhibited actinomycin D/TNFalpha-induced hepatocyte apoptosis, which was associated with elevated levels of the anti-apoptotic protein c-Flip(L/S) and a concomitant decrease of cellular levels of the ubiquitinligase Itch, a negative regulator of c-Flip.

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Moreover, USP2 silencing enhanced apoptosis after PUVA treatment in MyLa2000 suggesting that USP2 enhanced therapeutic resistance.

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Here, we found that USP2 showed decreased expression in advanced CTCL compared with the early stage disease and blocked apoptosis in malignant p53 wt T-lymphocytes.

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Finally, the knockdown of USP2 in Hut-78 cells did not increase apoptosis after PUVA, in contrast to what was observed in MyLa2000 with intact p53.
USP2 affects Cyclin
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USP2 activates Cyclin.
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USP2 activates Cyclin. 7 / 7
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As expected, the half-life of cyclin D1 protein in MCF-7 cells was longer than that of other cancer lines such as HCT116; however, USP2 knockdown drastically reduced the cyclin D1 half-life from 60 to 20 minutes (XREF_FIG and XREF_SUPPLEMENTARY).

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Again, knockdown of USP2 in MCF-7 and PC3 cells significantly reduced the steady state levels of cyclin D1 protein (XREF_FIG, also in XREF_SUPPLEMENTARY) and also induced cell growth suppression (XREF_FIG).

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Pharmacological inhibition of USP2 accelerates cyclin D1 degradation and leads to cell cycle arrest in several cancer cell lines among which the HCT116 colon cancer cell line and MCF7 breast cancer cell line.

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Our results reveal that USP2 specifically modulates cyclin D1 function in vivo and demonstrate the importance of this regulation in human cancer cell growth.

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APN can inhibit the expression of USP2 in tumor cells and promote the degradation of cyclin D1 [XREF_BIBR].

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Although, USP-2, as a deubiquitinating enzyme, is well known to prevent degradation of cyclins, including cyclin A1 and cyclin D1 (Kim et al., 2012; Shan et al., 2009), no studies have been reported r[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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The ubiquitin dependent proteolysis of cyclin D1 is antagonized by the deubiquitinating enzyme USP2, thus increasing cyclin D1 half-life.
USP2 inhibits Cyclin.
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USP2 inhibits Cyclin. 3 / 3
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The ubiquitin dependent proteolysis of cyclin D1 is antagonized by the deubiquitinating enzyme USP2, thus increasing cyclin D1 half-life.

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Based on our results, it is highly likely that USP-2 suppression by adiponectin enhanced proteasomal activity, thereby increasing cyclin D1 degradation, whereas enhancement in USP-2 expression by lept[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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These data demonstrate that inactivation of USP2 downregulates the levels of endogenous cyclin D1 and suppresses cell growth by delaying G1/S progression.
USP2 increases the amount of Cyclin.
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USP2 increases the amount of Cyclin. 2 / 2
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Furthermore, the role of USP-2 induction in cyclin D1 expression was examined by gene silencing of USP-2.

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We found that USP2 knockdown consistently downregulated cyclin D1 expression in multiple TNBC cells.
USP2 decreases the amount of Cyclin.
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Modified USP2 decreases the amount of Cyclin. 1 / 1
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Importantly, USP-2 overexpression restored suppression of cyclin D1 expression and cell number (Figs. 3B and 5A), directly indicating an important role of USP-2 deubiquitinase in anti-proliferative ef[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
LEP affects USP2
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LEP increases the amount of USP2.
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LEP increases the amount of USP2. 9 / 10
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Leptin increases expression of p53 and USP2 in HepG2 tumor Xenograft model.

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Herein, we present the evidence that changes in USP-2 expression by adiponectin and leptin contribute to the regulation of cyclin D1 degradation by proteasomes that impacts cell cycle modulation in ca[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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In the present study, we clearly demonstrated that adiponectin and leptin modulates expression of USP-2 expression in the opposite manner, which in turn directly impacts cyclin D1 degradation (Figs. 3[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Treatment with globular adiponectin (gAcrp) decreased, whereas leptin increased USP-2 expression both in human hepatoma and breast cancer cells.

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Based on our results, it is highly likely that USP-2 suppression by adiponectin enhanced proteasomal activity, thereby increasing cyclin D1 degradation, whereas enhancement in USP-2 expression by lept[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Similarly, leptin also increased USP-2 protein expression in a dose- and time dependent manner in HepG2 cells and MCF-7 cells.

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Although USP-2 seems to play a critical role in USP-2 expression modulated by adiponectin and leptin, the only little information regarding molecular mechanisms underlying USP-2 expression is availabl[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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As shown in Fig. 4C, transfection with siRNA targeting USP-2 significantly suppressed leptin induced cyclin D1 protein expression in HepG2 cells, suggesting that increase in USP-2 expression by leptin[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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While it has been shown that USP2 is involved in the regulation of cancer growth and leptin induces USP2 expression, the functional role of USP2 in leptin induced p53 expression has not been explored.
LEP activates USP2.
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LEP activates USP2. 2 / 2
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We next examined whether USP-2 modulation affects proteasomal activity in HepG2 cells treated with globular adiponectin and leptin.

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We therefore next inquired the role of USP-2 in cyclin D1 expression in cancer cells treated with leptin.
USP2 affects Ubiquitin
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USP2 activates Ubiquitin.
| 6
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Moreover, P5091 inhibits USP7-, but not USP2- or USP8 mediated cleavage of poly K48 linked ubiquitin chains (visualized by the presence or absence of mono-ubiquitin) (XREF_SUPPLEMENTARY).

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At the molecular level, the simplest explanation for this result is that USP2 drives the Ub K48 -Imd molecules to the proteasome and/or ensures the removal of Ub K48 from Imd at the level of the proteasome, then allowing for Imd degradation by the proteasome machinery.

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USP2 promotes stabilization of cyclinD1 via direct interaction with cyclin D1 and antagonizes ubiquitin dependent degradation (Shan et al., 2009).

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The specificity of SJB was confirmed by various experiments : first, we show that SJB potently and selectively block USP1 activity without inhibiting other DUBs (USP2/USP5/USP7/USP14/UCH37); second, SJB inhibited binding of USP1 with HA-Ub-VS probe, but it did not affect labeling of other DUBs with probe; and third, SJB inhibited USP1, but not USP2 or USP7, triggered cleavage of ubiquitin tetramer chains.

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As shown in XREF_FIG, USP2, a DUB that non specifically targets all ubiquitin linkages, completely reduced polyubiquitinated TLR2.
USP2 bound to Imd activates Ubiquitin. 1 / 1
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Focusing on USP2 biochemical function, we show that USP2 binds to Imd and promotes the cleavage of Ub K48 chains from the protein in both cultured cells and flies.
USP2 inhibits Ubiquitin.
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USP2 directly interacts with cyclin D1 and promotes its stabilization by antagonizing ubiquitin dependent degradation.

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Moreover, USP2 directly interacts with cyclin D1 and promotes its stabilization by antagonizing ubiquitin dependent degradation.

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The ubiquitin dependent proteolysis of cyclin D1 is antagonized by the deubiquitinating enzyme USP2, thus increasing cyclin D1 half-life.
USP2 decreases the amount of Ubiquitin.
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USP2 decreases the amount of Ubiquitin. 1 / 2
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Immunoblot analyses showed that USP2 treatment reduced the amount of associated ubiquitin by ~ 44% (XREF_FIG).
USP2 affects cell cycle
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USP2 activates cell cycle.
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USP2 inhibition causes cell cycle arrest in activated cardiac fibroblasts .

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USP2 modulates cell cycle progression , and therefore carcinogenesis , via the deubiquitination of cyclins and Aurora-A .

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To test this hypothesis, we first examined cell cycle distribution in cells treated with control versus USP2 siRNAs.

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In addition, USP2 inhibition suppressed CFs proliferation, collagen synthesis and cell cycle progression.

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In addition , USP2 inhibition suppressed CFs proliferation , collagen synthesis and cell cycle progression .

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Taken together, these results demonstrate that USP2 mediated cell cycle control occurs primarily through its effect on cyclin D1, regardless of p53 status.

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Within this group, Usp2 activates Wnt signaling [17]; Rab35 is a GTPase that regulates phosphoinositides and F-actin on endosomes [18]; Grtp1 is a Rab-GAP with broad specificity [19]; and Casp6 regula[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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USP2 modulates cell cycle progression, and therefore carcinogenesis, via the deubiquitination of cyclins and Aurora-A.
USP2 inhibits cell cycle.
| 1
| 1

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Strikingly, ectopic overexpression of cyclin D1 in USP2-knockdown cells effectively reverses the changes in cell cycle distribution caused by USP2 knockdown (XREF_FIG).
USP2 affects TP53
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USP2 inhibits TP53.
| 1 6
USP2 inhibits TP53. 7 / 7
| 1 6

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USP2 additionally prevents p53 signaling .

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Since Mdm2 is responsible for p53 degradation, USP2 could negatively regulate the p53 pathway activity through up-regulation of Mdm2.

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Overexpression of USP2 was also shown to reduce p53 stability [XREF_BIBR], and another de-ubiquitylase USP8 (also called UBPY) promotes epithelial growth factor receptor degradation [XREF_BIBR, XREF_BIBR, XREF_BIBR].

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Overexpression of USP2 was shown to reduce p53 stability, conversely suppression led to destabilisation of MDM2 and increased p53 level and activation (9).

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To test whether USP2 could block p53 via Mdm2, we silenced USP2 and measured Mdm2 level by western blot in MyLa2000 cells after nutlin3a treatment.

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We postulate that upregulation of USP2 antagonizes p53 effect via deubiquitination of Mdm2.

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USP2 additionally prevents p53 signaling.
USP2 activates TP53.
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USP2 activates TP53. 1 / 1
| 1

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On the other hand , USP2 has also been shown to increase p53 in a hepatoma cell line ( HepG2 ) and a breast cancer cell line ( MCF7 ) after leptin stimulation [ 36 ] .
USP2 affects LDLR
| 1 4
USP2 activates LDLR.
| 3
USP2 activates LDLR. 3 / 5
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USP2 not only interacts with and stabilises the sterol regulated E3-ligase IDOL but also rescues LDLR from lysosomal degradation, recalling the example of USP7 described in detail below 53.

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USP2 promoting LDLR activity was not simply an artefact of overexpression, as convincingly demonstrated by the Usp2 siRNA experiments, which showed a 70% reduction in surface LDLR levels and a halving of LDL uptake.

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Conversely, loss of USP2 reduces LDLR protein in an IDOL dependent manner and limits LDL uptake.
USP2 inhibits LDLR.
| 1 1
USP2 inhibits LDLR. 2 / 2
| 1 1

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Both USP2-1 and USP2-4 deubiquitinate and stabilize IDOL , suggesting that USP2 promotes LDLR degradation [ 110 ] .

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Using a genetic screening approach, we identify the ubiquitin specific protease 2 (USP2) as a post-transcriptional regulator of IDOL mediated LDLR degradation.
USP2 affects CLOCK
| 7
USP2 activates CLOCK.
| 6
USP2 activates CLOCK. 6 / 6
| 6

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Thus, the USP2 deubiquitinating enzyme modulates the two major features of clock function - its intrinsic circadian rhythm and its capacity to respond to external cues.

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By its action on the ubiquitination status of PER1, and possibly other clock proteins it interacts with, USP2 appears to exert a broad function, modulating both SCN central clock function (as seen by effects on both period length and response to photic stimuli) as well as peripheral clocks (as exemplified by our observations in embryonic fibroblasts).

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The ability of USP2 to modulate these central functions of the clock suggested that it acts on the molecular clock machinery.

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USP2 may also mediate the response of the clock to inflammation, as the expression of the gene is increased in response to TNFalpha treatment, and CRY1 protein induction in response to this cytokine is abrogated when Usp2 expression is knocked down.

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Our group showed that USP2 modulates the response of the clock to light [XREF_BIBR].

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Apart from its functions within the clock, USP2 also mediates clock output.
USP2 decreases the amount of CLOCK.
| 1
USP2 decreases the amount of CLOCK. 1 / 1
| 1

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We show that USP2 acts as an integral component of the circadian clock through deubiquitination of PER1, and that Usp2 gene deletion in mice leads to altered circadian behavior and expression of core clock components.
2,3,7,8-tetrachlorodibenzodioxine decreases the amount of USP2.
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2,3,7,8-tetrachlorodibenzodioxine increases the amount of USP2.
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USP2 affects Imd
| 7
USP2 inhibits Imd.
| 4
USP2 inhibits Imd. 4 / 4
| 4

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However, while USP2 is also required to prevent excessive activation of the Imd pathway in infected flies, USP34 displays differential requirement depending on the antimicrobial peptide gene analysed : silencing Usp34 enhanced the activation of AttA, Drs and IM1.

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We report here that USP2 and USP34 and Puf, in addition to the previously described USP36 and Scny, prevent inappropriate activation of Imd dependent immune signal in unchallenged conditions.

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USP2 promotes Imd degradation by the proteasome.

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However, while USP2 also prevents excessive Imd dependent signalling in vivo, USP34 shows differential requirement depending on NF-kappaB target genes, in response to fly infection by either Gram positive or Gram negative bacteria.
USP2 activates Imd.
| 3
USP2 activates Imd. 2 / 2
| 2

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Surprisingly, USP2 also targets Imd for degradation, a function which, from our proteomic analysis of USP2 partners and subsequent co-immunoprecipitation experiments, likely occurs at the level of the proteasome.

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We further show that USP2 prevents the constitutive activation of signalling by promoting Imd proteasomal degradation.
USP2 bound to Imd activates Imd. 1 / 1
| 1

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USP2 interacts with Imd and promotes cleavage of Imd linked Ub K48.
ADIPOQ affects USP2
| 7
ADIPOQ increases the amount of USP2.
| 5
ADIPOQ increases the amount of USP2. 5 / 5
| 5

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In the present study, we clearly demonstrated that adiponectin and leptin modulates expression of USP-2 expression in the opposite manner, which in turn directly impacts cyclin D1 degradation (Figs. 3[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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It would be interesting to examine the role of AMPK and JAK and STAT signaling in the modulation of USP-2 expression by adiponectin and leptin for the future study.Cyclin D1, an important regulator of[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Although USP-2 seems to play a critical role in USP-2 expression modulated by adiponectin and leptin, the only little information regarding molecular mechanisms underlying USP-2 expression is availabl[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Herein, we present the evidence that changes in USP-2 expression by adiponectin and leptin contribute to the regulation of cyclin D1 degradation by proteasomes that impacts cell cycle modulation in ca[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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As expected from our microarray data, adiponectin did not trigger elevated transcript levels of TR2, CASP1 and USP2 in MCF-7 breast cancer cells, but a significantly reduced USP2 expression by approximately 60%.
ADIPOQ inhibits USP2.
| 1
ADIPOQ inhibits USP2. 1 / 1
| 1

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Based on our results, it is highly likely that USP-2 suppression by adiponectin enhanced proteasomal activity, thereby increasing cyclin D1 degradation, whereas enhancement in USP-2 expression by lept[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
ADIPOQ decreases the amount of USP2.
| 1
ADIPOQ decreases the amount of USP2. 1 / 1
| 1

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As expected from our microarray data, adiponectin did not trigger elevated transcript levels of TR2, CASP1 and USP2 in MCF-7 breast cancer cells, but a significantly reduced USP2 expression by approximately 60%.
USP2 affects TWIST1
| 7
USP2 activates TWIST1.
| 3
USP2 activates TWIST1. 3 / 3
| 3

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In addition, USP2 activates Bmi1 and EMT by stabilizing Twist through removing ubiquitylation mediated by beta-transducin repeats containing proteins (beta-TrCP), a cellular E3 ubiquitin ligase.

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Indeed, MG132 treatment reverted Twist downregulation mediated by USP2 depletion.

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Our work reveals that USP2 mediated Twist and Bmi1 pathway represents a cell-intrinsic mechanism crucial for CSC regulation besides EMT and provides pre-clinical evidence that targeting USP2 is indeed a promising approach for anti-CSC therapy.
USP2 decreases the amount of TWIST1.
| 3
USP2 decreases the amount of TWIST1. 1 / 1
| 1

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USP2 depletion was found to considerably reduce Twist protein levels in the tumorspheres.
Modified USP2 decreases the amount of TWIST1. 1 / 1
| 1

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Western blot assays illustrated that ablating USP2 expression in BT549 and MDA-MB-157 cells considerably reduced protein expression of Twist as expected.
USP2-C276A decreases the amount of TWIST1. 1 / 1
| 1

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Western blot and tumorsphere formation assays showed that the decreased Twist protein level and tumorspheres mediated by USP2 knockdown were rescued by WT but not the C276A mutant of USP2.
USP2 increases the amount of TWIST1.
| 1
Modified USP2 increases the amount of TWIST1. 1 / 1
| 1

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Altogether, our study illustrates that USP2 overexpression in TNBC promotes Twist and Bmi1 expression, CSC expansion, cancer cell migration and tumor development.
JUN affects USP2
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JUN decreases the amount of USP2. 6 / 6
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USP2 affects MDM2
| 3
USP2 decreases the amount of MDM2.
| 1
USP2 decreases the amount of MDM2. 1 / 3
| 1

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Knockdown of USP2 decreases Mdm2 protein level and increases p53 transcriptional activity.
USP2 inhibits MDM2.
| 1
USP2 inhibits MDM2. 1 / 2
| 1

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However, our Western blot assays demonstrated that depleting USP2 expression in multiple TNBC cells neither downregulated MDM2 nor upregulated p53 expression, suggesting that the MDM2 and p53 axis is not involved in USP2 's functions in CSCs.
USP2 increases the amount of MDM2.
| 1
USP2 increases the amount of MDM2. 1 / 1
| 1

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As such, USP2 knockdown could potentially reduce Mdm2 levels and thereby activate p53 mediated cell growth repression.
5 |
Benzo[a]pyrene increases the amount of USP2. 5 / 5
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In addition, USP2 inhibition suppressed CFs proliferation, collagen synthesis and cell cycle progression.

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Mutations in the CYLD deubiquitinating enzyme leads to familial cylindromatosis XREF_BIBR and overexpression of USP2 has been reported to increase prostate cancer cell proliferation through the stabilization of fatty acid synthase XREF_BIBR.

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These results suggest that USP-2 promotes cell proliferation pertinent to the features of human hepatic and breast cancers.
USP2 affects EGFR
| 1
USP2 inhibits EGFR. 1 / 5
| 1

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USP2 has also been shown to localise to endosomes and negatively regulate EGFR down-regulation 52.
MEF2A affects USP2
5 |
MEF2A decreases the amount of USP2. 5 / 5
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USP2 affects KCNQ1
| 4
USP2 activates KCNQ1.
| 2
USP2 activates KCNQ1. 2 / 3
| 2

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Immunocytochemistry confirmed that USP2 restores the membrane localization of KCNQ1.

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In contrast to previous observations with the ENaC, coexpression of the 2 isoforms of USP2 in the present study did not increase the KCNQ1 and KCNE1 mediated current in Xenopus oocytes per se.
USP2 inhibits KCNQ1.
| 1
USP2 inhibits KCNQ1. 1 / 1
| 1

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Having found that USP2 antagonized the Nedd4-2-mediated downregulation of KCNQ1, we aimed to test whether USP2 interacted directly with the channel.
USP2 increases the amount of KCNQ1.
| 1
USP2 increases the amount of KCNQ1. 1 / 1
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The catalytically inactive USP2 (CA) did not restore the KCNQ1 level.
Tioguanine affects USP2
| 3 1
| 3 1

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Previous studies indicated that 6-TG could non-competitively inhibit human USP2 ( xref ) thus plays a critical role in tumor cells survival.

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( C ) Noncompetitive inhibition of USP2 by 6TG .

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Slow-binding inhibition of USP2 by 6TG .

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Overall , the ternary complex structure of USP2-Ub-6TG suggests the existence of an enzyme-substrate-inhibitor ( ESI ) complex and confirms the noncompetitive mechanism of USP2 inhibition by 6TG .
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Valproic acid increases the amount of USP2.
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Valproic acid increases the amount of USP2. 3 / 3
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Valproic acid decreases the amount of USP2.
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Valproic acid decreases the amount of USP2. 1 / 1
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USP2 affects cell growth
| 3
USP2 activates cell growth.
| 2
| 2

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Again, knockdown of USP2 in MCF-7 and PC3 cells significantly reduced the steady state levels of cyclin D1 protein (XREF_FIG, also in XREF_SUPPLEMENTARY) and also induced cell growth suppression (XREF_FIG).

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To completely exclude the possibility that the cell growth repression induced by USP2 knockdown is p53 dependent, we performed the same experiments in isogenic p53 knockout cells (HCT116 p53-/-).
USP2 inhibits cell growth.
| 1
| 1

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These data demonstrate that inactivation of USP2 downregulates the levels of endogenous cyclin D1 and suppresses cell growth by delaying G1/S progression.
USP2 affects SLC22A2
| 4
USP2 activates SLC22A2.
| 3
USP2 activates SLC22A2. 3 / 3
| 3

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USP2 Modulates Oct-1 and Oct-2 in LPS Stimulated HL-60 Cells.

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Overexpression of USP2 did not cause modification of the K48 linked polyubiquitination of Oct-2 protein, suggesting that USP2 is unlikely to modulate Oct-2 digestion in a direct manner.

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Therefore, USP2 potentiates nuclear accumulation of Oct-1 and Oct-2 proteins.
USP2 decreases the amount of SLC22A2.
| 1
USP2 decreases the amount of SLC22A2. 1 / 1
| 1

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USP2 decreased nuclear Oct-2 protein levels in addition to decreasing the polyubiquitination of Oct-1.
USP2 affects NFkappaB
| 3
USP2 inhibits NFkappaB.
| 2
| 2

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The ubiquitin #specific proteases system 2 (USP2) stabilizes the ubiquitin-E3-ligase ITCH and lowers NF-kappaB basal activity, which leads to reduced c-FLIP mRNA production; proteasomal degradation of c- FLIP isoforms is also elevated by its negative regulator proteasome ITCH [XREF_BIBR].

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USP2a, a 69-kDa splice variant of USP2, also known as USP9 and UBP41, negatively regulates NF-kappaB activation and proinflammatory cytokine production by interacting with TRAF6.
USP2 activates NFkappaB.
| 1
USP2 activates NFkappaB. 1 / 1
| 1

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To date, several studies have demonstrated that USP2 modulates the NF-kappaB signaling pathway [XREF_BIBR, XREF_BIBR, XREF_BIBR].
USP2 affects NEDD4L
| 4
USP2 inhibits NEDD4L.
| 2
USP2 inhibits NEDD4L. 2 / 2
| 2

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The biochemical experiments show an augmented surface expression and reduced ubiquitylation level of KCNQ1 when catalytically active USP2 is coexpressed with Nedd4-2, suggesting that USP2 may counter [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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In cells coexpressing USP2-45/-69, the amount of ubiquitylated KCNQ1 was significantly decreased and the total amount of KCNQ1 was increased, demonstrating that USP2 antagonizes the effect of Nedd4-2 [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
USP2 activates NEDD4L.
| 2
USP2 activates NEDD4L. 2 / 2
| 2

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However, coexpression of USP2 together with Nedd4-2 and KCNQ1 augments the binding efficiency of Nedd4-2, indicating that either both USP2-45 and USP-69 stabilize the binding to the KCNQ1 protein or N[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Interestingly, Nedd4-2 coimmunoprecipitation with wild-type KCNQ1 was increased when USP2 was coexpressed, suggesting that USP2 may augment the binding of Nedd4-2 to the channel complex.
USP2 affects BMI1
| 1 1 2
USP2 activates BMI1.
| 1 1 1
USP2 activates BMI1. 3 / 3
| 1 1 1

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In addition, USP2 activates Bmi1 and EMT by stabilizing Twist through removing ubiquitylation mediated by beta-transducin repeats-containing proteins (β-TrCP), a cellular E3 ubiquitin ligase ( xref ).

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In addition , USP2 activates Bmi1 and EMT by stabilizing Twist through removing ubiquitylation mediated by beta-transducin repeats-containing proteins ( beta-TrCP ) , a cellular E3 ubiquitin ligase ( 104 ) .

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In addition, USP2 activates Bmi1 and EMT by stabilizing Twist through removing ubiquitylation mediated by beta-transducin repeats containing proteins (beta-TrCP), a cellular E3 ubiquitin ligase.
USP2 increases the amount of BMI1.
| 1
Modified USP2 increases the amount of BMI1. 1 / 1
| 1

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Altogether, our study illustrates that USP2 overexpression in TNBC promotes Twist and Bmi1 expression, CSC expansion, cancer cell migration and tumor development.
TP53 affects USP2
| 4
TP53 activates USP2.
| 3
TP53 activates USP2. 3 / 3
| 3

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USP2 is upregulated by PUVA and a p53 activator, nutlin3a.

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These results suggested that activated p53 increased USP2, which in turn counteracted the pro apoptotic activity of p53, forming a negative feedback loop.

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It would be interesting to investigate whether USP2 aggravates the resistance to other therapeutic modalities, such as ionizing radiation or ultraviolet B. Mechanistically we were able to demonstrate that the activation of p53 upregulated USP2.
TP53 inhibits USP2.
| 1
TP53 inhibits USP2. 1 / 1
| 1

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Interestingly, leptin induced increase in p53 expression was significantly suppressed by gene silencing of USP2 in both HepG2 and MCF-7 cells (XREF_FIG), suggesting the crucial role of USP2 and probably modulation of ubiquitination in leptin induced p53 expression.
PTH affects USP2
| 4
PTH increases the amount of USP2.
| 2
PTH increases the amount of USP2. 2 / 2
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Parathyroid hormone (hPTH 1-38) stimulates the expression of UBP41, an ubiquitin specific protease, in bone.

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PTH (1-31), which stimulates intracellular cAMP, and PTHrP (1-34) both induced UBP41 mRNA expression; whereas PTH analogs (3-34) and (7-34), that do not stimulate cAMP, had no effect on UBP41 expression.
PTH activates USP2.
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PTH activates USP2. 2 / 2
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Together, these results demonstrate that UBP41, an ubiquitin specific protease, is selectively upregulated in bone by the osteotropic agents PTH, PTHrP, and PGE2, possibly via the PKA and cAMP pathway.

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In contrast, PTH (7-34) does not increase USP2.
| 3

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Since our study is the first to uncover USP2 's novel function in CSCs, future studies will be needed to delineate the contribution of cyclin D1 to USP2 mediated CSC expansion in TNBC.
Modified USP2 activates Neoplastic Stem Cells. 1 / 1
| 1

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Altogether, our study illustrates that USP2 overexpression in TNBC promotes Twist and Bmi1 expression, CSC expansion, cancer cell migration and tumor development.
| 1

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Moreover, the enzymatically inactive mutant of USP2 failed to promote CSC renewal, suggesting that the CSC promoting effect mediated by USP2 depends on its deubiquitinase activity.
| 1

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In line with these observations, the ALDEFLUO assay illustrated that USP2 depletion significantly reduced the CSC population.
ZEB1 affects USP2
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ZEB1 decreases the amount of USP2. 3 / 3
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USP2 affects proteolysis
| 3
| 3

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Seventh, alcohol induced dramatic reduction of USP2, the major deubiquitinating enzyme may provide mechanistic perspectives underlying caveolar protein depletion and/or degradation as USP2 depletion has been documented to significantly enhance protein degradation.

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Knockdown of USP2 or USP14 accelerated protein degradation of TNF-alpha, and abolished the effect of miR-124 on TNF-alpha protein stability.

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The ubiquitin dependent proteolysis of cyclin D1 is antagonized by the deubiquitinating enzyme USP2, thus increasing cyclin D1 half-life.

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USP2a, a 69-kDa splice variant of USP2, also known as USP9 and UBP41, negatively regulates NF-kappaB activation and proinflammatory cytokine production by interacting with TRAF6.

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In this study, we demonstrated that USP2KD promotes 25 of 104 cytokines in macrophage like cells after LPS stimulation, while ectopic expression of USP2 represses most cytokine production following this stimulation.

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In LPS stimulated macrophage like cell line J774.1, the knockdown of USP2 promoted cytokine production, whereas the ectopic expression of USP2 repressed cytokine production.
USP2 affects FASN
| 1
USP2 activates FASN. 1 / 3
| 1

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Usp2 enhances the stability of fatty acid synthase (FASN) by impeding proteasome-dependent degradation in human HCC (Calvisi et al., 2011; Kitamura and Hashimoto, 2021).
| PMC
TFDP1 affects USP2
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TFDP1 decreases the amount of USP2. 3 / 3
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TCF3 affects USP2
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TCF3 decreases the amount of USP2. 3 / 3
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Dietary Fats affects USP2
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Dietary Fats increases the amount of USP2. 3 / 3
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CLOCK affects USP2
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CLOCK activates USP2. 3 / 3
| 3

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This suggests a scenario in USP2 -/- mice in which increased turnover of BMAL1 coincides with increased CLOCK and BMAL1 driven gene expression in the USP2 -/- SCN.

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The circadian rhythm of Usp2 is blunted in Clock mutant and Bmal1 KO mice, and the Usp2 promoter is activated by CLOCK and BMAL1, indicating that Usp2 is a direct target of these transcription factors.

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However, the free running period (tau), a key intrinsic characteristic of the central circadian clock, was significantly increased in Usp2 KO mice (XREF_FIG; XREF_TABLE) (also reproduced in an additional group of mice, data not shown), suggesting the involvement of USP2 in the molecular clockwork.
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Pirinixic acid decreases the amount of USP2.
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Pirinixic acid decreases the amount of USP2. 2 / 2
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Pirinixic acid activates USP2.
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Phenobarbital increases the amount of USP2.
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Phenobarbital increases the amount of USP2. 2 / 2
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Phenobarbital decreases the amount of USP2.
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Phenobarbital decreases the amount of USP2. 1 / 1
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Ezogabine affects USP2
| 3
Ezogabine increases the amount of USP2.
| 2
Ezogabine increases the amount of USP2. 2 / 2
| 2

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Indeed, we found that retigabine (8 mg/kg) significantly increased the protein levels of USP2 in hippocampal CA1 area of stressed rats.

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On the other hand, the expression and coexpression of GluA1 and USP2 in hippocampal CA1 area were down-regulated after acute stress, and increased by retigabine treatment.
Ezogabine inhibits USP2.
| 1
| 1

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Yet, the role of deubiquitinating enzymes and its therapeutic potential in cognitive processes have not been reported.The present study aims to examine the effects of acute stress on deubiquitinating [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]
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Carbon nanotube decreases the amount of USP2.
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Carbon nanotube decreases the amount of USP2. 2 / 2
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Carbon nanotube increases the amount of USP2.
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Carbon nanotube increases the amount of USP2. 1 / 1
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Bisphenol A affects USP2
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Bisphenol A decreases the amount of USP2.
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Bisphenol A decreases the amount of USP2. 2 / 2
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Bisphenol A increases the amount of USP2.
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Bisphenol A increases the amount of USP2. 1 / 1
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| 1

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USP2 may also mediate the response of the clock to inflammation, as the expression of the gene is increased in response to TNFalpha treatment, and CRY1 protein induction in response to this cytokine is abrogated when Usp2 expression is knocked down.
| 1

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Macrophage USP2 may therefore selectively prevent age- and/or adiposity related chronic inflammation and subsequent insulin resistance.
USP2 affects USP2
| 2
USP2 activates USP2.
| 1
USP2 activates USP2. 1 / 2
| 1

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On the other hand, a defect of peroxisomal protein import or even release of USP2 from defective peroxisomes because of cell injury or dysfunction would increase the cytosolic pool of USP2, which might contribute to the initiation of apoptosis.
USP2 inhibits USP2.
| 1
USP2 inhibits USP2. 1 / 1
| 1

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In summary, our data show that the ubiquitin core and the ubiquitin C terminus alone bind USP2 very weakly with affinities at best in the high micromolar range, while full-length ubiquitin inhibits USP2 with a K i of 2.8 mM.USP2 is one of 54 human members of the family of ubiquitin-specific proteases (USPs).
USP2 affects Proteasome
| 3
USP2 inhibits Proteasome.
| 2
| 2

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Usp2 enhances the stability of fatty acid synthase (FASN) by impeding proteasome-dependent degradation in human HCC (Calvisi et al., 2011; Kitamura and Hashimoto, 2021).
| PMC

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Ubiquitin specific protease-2 (USP-2), a deubiquitinating enzyme, is known to impair proteasome induced degradation of cyclin D1, a critical cell cycle regulator.
USP2 activates Proteasome.
| 1
| 1

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At the molecular level, the simplest explanation for this result is that USP2 drives the Ub K48 -Imd molecules to the proteasome and/or ensures the removal of Ub K48 from Imd at the level of the proteasome, then allowing for Imd degradation by the proteasome machinery.
USP2 affects MMP2
| 2
USP2 increases the amount of MMP2.
| 1
USP2 increases the amount of MMP2. 1 / 2
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This study also showed that USP2 upregulates MMP2 expression and induces the motility and invasiveness of TNBC cells [XREF_BIBR]; however, it remains unknown whether MMP2 is a direct substrate of USP2.
USP2 decreases the amount of MMP2.
| 1
USP2 decreases the amount of MMP2. 1 / 1
| 1

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Silencing of USP2 expression decreased migration and invasion in LM2-4175 and SCP46 cells in association with the downregulation of matrix metalloproteinase-2 (MMP2) expression, whereas overexpression of USP2 in MDA-MB-468 and MDA-MB-231 cells enhanced migration and invasion and upregulated the expression of MMP2.
USP2 affects ASAH1
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USP2 activates ASAH1.
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USP2 activates ASAH1. 1 / 2
| 1