USP12 Data Analysis

HGNC Gene Name
ubiquitin specific peptidase 12
HGNC Gene Symbol
USP12
Identifiers
hgnc:20485 NCBIGene:219333 uniprot:O75317
Orthologs
mgi:1270128 rgd:1308045
INDRA Statements
deubiquitinations all statements
Pathway Commons
Search for USP12
Number of Papers
58 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

Dependency GO Term Enrichment

Gene set enrichment analysis was done on the genes correlated with USP12using 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 USP12 using CRISPR-Cas9.

Knockout Differential Expression

Symbol Name log2-fold-change p-value p-value (adj.)
RPS24 ribosomal protein S24 5.05e-01 1.33e-06 2.94e-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 USP12 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
USP12 deubiquitinates AR. 6 / 6
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USP12 in the presence of its cofactors Uaf-1 and WDR20 deubiquitinates AR to enhance AR protein stability and transcriptional activity [71] USP12 in complex with Uaf-1 and WDR20 also abrogates phospho[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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The AR is known to be regulated by a number of post-translational modifications and we have recently identified the deubiquitinating enzyme Usp12 as a positive regulator of AR.

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We determined that Usp12 deubiquitinates the AR resulting in elevated receptor stability and activity.

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We have recently reported that AR is deubiquitinated and stabilised by Usp12 resulting in increased transcriptional activity.

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In this report we demonstrate that Usp12, in complex with Uaf-1 and WDR20, deubiquitinates the AR to enhance receptor stability and transcriptional activity.

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We find that USP12 deubiquitinates MDM2 and AR, which in turn controls the levels of the TP53 tumour suppressor and AR oncogene in prostate cancer.
USP12 deubiquitinates Histone_H2B. 5 / 5
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It has also been reported that USP12 and USP46 deubiquitinate histone H2A and H2B thereby playing a role in Xenopus development.

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USP12 and USP46 prefer nucleosomal substrates and deubiquitinate both histone H2A and H2B in vitro and in vivo.

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Both USP12 and USP46 deubiquitinate histone H2A and H2B, affecting Xenopus development (Joo et al., 2011), and, unlike USP1, these smaller USPs can simultaneously bind WDR20 in addition to WDR48 (Joo [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Usp12 and Usp46 deubiquitinate both H2A and H2B and Uaf-1 is required for this reaction [XREF_BIBR].

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Joo et al. demonstrated that USP46 and USP12 containing fractions from HeLa cells can deubiquitinate histones H2A and H2B to control cell fate and gastrulation during Xenopus development [XREF_BIBR].
USP12 deubiquitinates PHLPP1. 4 / 4
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Usp12 deubiquitinates and stabilises PHLPP and PHLPPL and controls Akt activation status.

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Further analysis using denaturing immunoprecipitation experiments revealed that Usp12 can also deubiquitinate and stabilise both PHLPP and PHLPPL.

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USP11 stabilizes IKK-α?to stabilize and activate p53

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Secondly, Usp12 deubiquitinates and stabilises PHLPP and PHLPPL proteins which enhances dephosphorylation and deactivation of Akt.
USP12 deubiquitinates PHLPP2. 4 / 4
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we demonstrate that Usp12, in complex with Uaf-1 and WDR20, directly deubiquitinates and stabilises the Akt phosphatases PHLPP and PHLPPL resulting in decreased levels of active pAkt.

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Secondly, Usp12 deubiquitinates and stabilises PHLPP and PHLPPL proteins which enhances dephosphorylation and deactivation of Akt.

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Usp12 deubiquitinates and stabilises PHLPP and PHLPPL and controls Akt activation status.

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Further analysis using denaturing immunoprecipitation experiments revealed that Usp12 can also deubiquitinate and stabilise both PHLPP and PHLPPL.
USP12 deubiquitinates EP300. 2 / 2
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De-ubiquitination of p300 by USP12 Critically Enhances METTL3 Expression and Ang II induced Cardiac Hypertrophy.

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De-ubiquitination of p300 by USP12 Critically Enhances METTL3 Expression and Ang II-induced Cardiac Hypertrophy.
USP12 deubiquitinates MDM2. 2 / 2
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We find that USP12 deubiquitinates MDM2 and AR, which in turn controls the levels of the TP53 tumour suppressor and AR oncogene in prostate cancer.

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We find that USP12 deubiquitinates MDM2 and AR, which in turn controls the levels of the TP53 tumour suppressor and AR oncogene in prostate cancer.
USP12 deubiquitinates MDK. 1 / 1
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Collectively, our study identified that USP12 is responsible for deubiquitinating and stabilizing MDK and leads to metastasis by promoting angiogenesis.
USP12 deubiquitinates Histone-H2A. 1 / 1
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Joo et al. demonstrated that USP46 and USP12 containing fractions from HeLa cells can deubiquitinate histones H2A and H2B to control cell fate and gastrulation during Xenopus development [XREF_BIBR].
USP12 deubiquitinates H2BC21. 1 / 1
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USP12 and USP46 prefer nucleosomal substrates and deubiquitinate both histone H2A and H2B in vitro and in vivo.
USP12 deubiquitinates GRIA. 1 / 1
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Knock-down of USP46, but not USP12, results in increased levels of ubiquitinated GluA1, decreased surface and total levels of GluA1, and reduced mEPSC amplitudes, consistent with a role for USP46 in deubiquitinating mammalian AMPARs (Huo et al., 2015).
USP12 deubiquitinates WDR48. 1 / 1
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Usp12 and Usp46 deubiquitinate both H2A and H2B and Uaf-1 is required for this reaction [XREF_BIBR].
USP12 deubiquitinates H2AC17. 1 / 1
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It was shown that USP12 deubiquitinates histones H2A and H2B both in vitro and in vivo
USP12 deubiquitinates H2AC20. 1 / 1
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USP12 and USP46 prefer nucleosomal substrates and deubiquitinate both histone H2A and H2B in vitro and in vivo.
USP12 deubiquitinates TCR. 1 / 1
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Similarly, the ubiquitin specific peptidase 12 (USP12) can deubiquitinate LAT at the proximal TCR (Figure 2), to protect it from ubiquitin-dependent lysosomal degradation [146].
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USP12 deubiquitinates H2BC10. 1 / 1
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It was shown that USP12 deubiquitinates histones H2A and H2B both in vitro and in vivo
USP12 deubiquitinates Notch. 1 / 1
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At the biochemical level, USP12 with its activator UAF1 deubiquitinate the nonactivated form of Notch in cell culture and in vitro.
USP12 deubiquitinates LAT. 1 / 1
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Similarly, the ubiquitin specific peptidase 12 (USP12) can deubiquitinate LAT at the proximal TCR (Figure 2), to protect it from ubiquitin-dependent lysosomal degradation [146].
| PMC

Other Statements

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WDR48 affects USP12
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WDR48 activates USP12.
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WDR48 activates USP12. 10 / 63
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Wild type UAF1 was unable to activate USP12 E190K to similar levels as compared to USP12 WT ( xref d, e) and similarly, the UAF1 3X mutant did no longer activate.

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Uaf-1 and WDR20 have previously been shown to stimulate Usp12 catalytic activity [XREF_BIBR, XREF_BIBR].

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Together, UAF1 and WDR20 are able to synergistically stimulate the enzymatic activities of USP12 and USP46 to a peak level.

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To delineate the mechanism by which UAF1 activates USP12, we next determined the crystal structure of USP12 in complex with full-length human UAF1 in F222 space group at 3.2 A (XREF_SUPPLEMENTARY).

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Activation of USP12 by UAF1 requires structural fine tuning at the junction of the Ub globular domain and it tail through BL1, whereas WDR20 acts independently of this site and directly affects the ca[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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UAF1 activates USP12 by binding to the tip of its Fingers domain and transmitting a long-range allosteric signal to BL1.

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This result clearly indicates that UAF1 and WDR20 indeed allosterically activate USP12 through two distinct pathways.

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Activation of USP12 by UAF1 requires structural fine-tuning at the junction of the Ub globular domain and it tail through BL1, whereas WDR20 acts independently of this site and directly affects the ca[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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For example, USP1, USP12, and USP46 are activated by the WD40-repeat containing UAF1, and USP7 is activated by GMPS (Cohn et al., 2007, 2009; Faesen et al., 2011; van der Knaap et al., 2005).

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This study confirmed that the modulator UAF1 activates USP1, USP12, and USP46, and GMPS activates USP7.
WDR48 activates USP12-E190K. 1 / 1
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Wild type UAF1 was unable to activate USP12 E190K to similar levels as compared to USP12 WT (XREF_FIG d, e) and similarly, the UAF1 3X mutant did no longer activate.
WDR48 decreases the amount of USP12.
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WDR48 decreases the amount of USP12. 1 / 3
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As Uaf-1 and WDR20 depletion reduces Usp12 levels their silencing has a comparable effect on the AR as the Usp12 depletion alone.
WDR48 deubiquitinates USP12.
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WDR48 deubiquitinates USP12. 1 / 1
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The E1 protein from anogenital HPV types interacts with the UAF1 associated deubiquitinating enzymes USP1, USP12, and USP46 to stimulate replication of the viral genome.
WDR20 affects USP12
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WDR20 activates USP12.
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WDR20 activates USP12. 10 / 55
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To investigate the mechanism by which WDR20 activates USP12 , we next determined the crystal structure of a ternary complex consisting of USP12 , UAF1 lacking its SLD , and WDR20 at a 3 .

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These results strongly suggest that WDR20 can activate USP12 by allosterically optimizing its catalytic cleft, whereas the effect of UAF1 binding can not be directly transmitted to the catalytic cysteine through USP12.

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USP12 can be further activated by WDR20 [ 179,180 ] .

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Although mammalian USP46 and USP12 DUB activity can be stimulated by two proteins UAF-1 and WDR20, the C. elegans homologs of these genes have not yet been identified.

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In agreement with our enzyme kinetics data, our binding studies revealed negligible changes in the substrate binding affinity of USP12 induced by UAF1 or WDR20 (XREF_FIG and XREF_SUPPLEMENTARY).

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These results suggest that even though fine-tuning the Ub globular domain-tail junction is not critical for WDR20 to activate USP12 , interaction between BL1 and the Ub globular domain is still important for the full WDR20-stimulated USP12 activity .

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In agreement with our enzyme kinetics data, our binding studies revealed negligible changes in the substrate binding affinity of USP12 induced by UAF1 or WDR20.

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In agreement with our enzyme kinetics data, our binding studies revealed negligible changes in the substrate binding affinity of USP12 induced by UAF1 or WDR20 (Figures 6A and S6) .

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Overall, our two UAF1-USP12 structures not only reveal a series of structural changes of the enzyme that are connected to the binding site of UAF1 but also highlight the dynamic nature of three key lo[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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In USP12, this loop is important for activation, as mutation of a stretch of glycine residues within the loop leads to loss in activation of USP12 by either UAF1 or WDR20.
WDR20 decreases the amount of USP12.
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WDR20 decreases the amount of USP12. 1 / 1
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As Uaf-1 and WDR20 depletion reduces Usp12 levels their silencing has a comparable effect on the AR as the Usp12 depletion alone.
USP12 affects AR
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USP12 activates AR.
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USP12 activates AR. 8 / 10
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This data suggests that AR co-activation by Usp12 and Uaf-1 is largely driven through negating AR phosphorylation by Akt inactivation.

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Cell lines used in this study express low levels of endogenous Usp12 and Uaf-1, consequently even without the addition of Uaf-1 overexpression of WDR20 alone was enough to significantly enhance the AR activity.

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Deubiquitinating enzyme Usp12 is a novel co-activator of the androgen receptor.

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Our previous observations for the LNCaP cell line that express AR FL but not AR Vs have demonstrated that USP12 silencing causes a decrease in transcript expression of all the AR target genes [XREF_BIBR] supporting our data that AR Vs are not targeted by USP12 in the AR V expressing CWR22Rv1 cell line.

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This further confirms that each complex member alone has a limited effect on AR activity but in combination the Usp12 complex significantly increases AR transcriptional activity implying that targeting any of the binding partners should offer the same efficacy as targeting Usp12 alone.

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We have recently reported that Usp12, in combination with Uaf-1, can increase the transcriptional activity of AR [XREF_BIBR], and hence we wanted to analyse the importance of Akt phosphorylation sites in this process.

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Interestingly, Usp12 and WDR20 alone significantly increased AR activity but this effect was greatest when Usp12, Uaf-1 and WDR20 were overexpressed simultaneously.

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Also, USP12 co-localizes with AR in the cytoplasm and promotes AR transcriptional activity by confronting the ubiquitin dependent degradation of AR [XREF_BIBR].
USP12 inhibits AR.
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USP12 inhibits AR. 2 / 3
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Also, USP12 co-localizes with AR in the cytoplasm and promotes AR transcriptional activity by confronting the ubiquitin dependent degradation of AR [XREF_BIBR].

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USP12 inhibition in AR V positive lines drives the AR V expression profile.
USP12 increases the amount of AR.
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USP12 increases the amount of AR. 2 / 2
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Our data suggests that USP12 is unable to modulate AR V levels or activity but is capable of targeting AR FL.

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Our previous observations for the LNCaP cell line that express AR FL but not AR Vs have demonstrated that USP12 silencing causes a decrease in transcript expression of all the AR target genes [XREF_BIBR] supporting our data that AR Vs are not targeted by USP12 in the AR V expressing CWR22Rv1 cell line.
USP12 affects autophagy
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Usp12 stimulation of autophagy, in the context of mHTT, could lead to more efficient cargo loading in autophagosomes, and thereby reduce mHTT associated toxicity.

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Another possibility is that Usp12 stimulation of autophagy confers neuroprotection primarily by clearing cargo other than mHTT.

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Both alpha-synuclein and TDP-43 are substrates for autophagic degradation XREF_BIBR, XREF_BIBR, XREF_BIBR, and so, we might predict that stimulation of autophagy by Usp12 overexpression would also be neuroprotective in the related PD and ALS neuron models.

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Publisher Correction : Deubiquitinase Usp12 functions noncatalytically to induce autophagy and confer neuroprotection in models of Huntington 's disease.

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Deubiquitinase Usp12 functions noncatalytically to induce autophagy and confer neuroprotection in models of Huntington 's disease.

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Usp12 induction of autophagy is a potential mechanism by which Usp12 confers neuroprotection in HD models.

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Author Correction : Deubiquitinase Usp12 functions noncatalytically to induce autophagy and confer neuroprotection in models of Huntington 's disease.

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Surprisingly, the catalytic activity of Usp12 is not required to protect against neurodegeneration or induce autophagy.

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Publisher Correction : Deubiquitinase Usp12 functions noncatalytically to induce autophagy and confer neuroprotection in models of Huntington 's disease.

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Also , USP12 causes autophagy and confer neuroprotection in Huntington 's disease ( HD ) [ 184 ] .

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As a result, depleting Usp12 decreased PC cellular proliferation and increased cellular apoptosis suggesting it may be a potential target for CRPC therapy [XREF_BIBR].

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Functionally, we show that WDR48 and USP12 suppress proliferation of tumor cells.

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In contrast, overexpression of WDR48 and USP12 (XREF_FIG C) suppressed cell proliferation similarly to PHLPP1 (XREF_FIG D).

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As shown in XREF_FIG B, knockdown of WDR48 and USP12 by shRNA accelerated the rate of cell proliferation compared with control shRNA transfected cells.

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We further established that Usp12 depletion reduced PC cell proliferation and induced apoptosis, furthermore Usp12 levels are increased in PC tissue [XREF_BIBR].

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Furthermore, Usp12 silencing was shown to reduce proliferation of PC cells.
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Thus, these results suggest that WDR48 and USP12 negatively regulate Akt signaling and thereby induce apoptosis in conjunction with PHLPP1.

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As a result, depleting Usp12 decreased PC cellular proliferation and increased cellular apoptosis suggesting it may be a potential target for CRPC therapy [XREF_BIBR].

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WDR48 and USP12 Negatively Regulate Akt Signaling and Promote Apoptosis.

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In vivo experiments showed that USP12-knockdown could suppress tumor growth in mice , and immuno-blotting revealed that USP12 could induce G2 / M arrest through the cyclin dependent kinase 1 / cyclinB1 axis , and trigger apoptosis via the p38 / mitogen-activated protein kinase pathway .

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Invivo experiments showed that USP12-knockdown could suppress tumor growth in mice, and immuno blotting revealed that USP12 could induce G2/M arrest through the cyclin dependent kinase1 and cyclinB1 axis, and trigger apoptosis via the p38 and mitogen activated protein kinase pathway.

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In fact, overexpression of WDR48 and USP12 induced apoptosis similarly to PHLPP1.
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We further established that Usp12 depletion reduced PC cell proliferation and induced apoptosis, furthermore Usp12 levels are increased in PC tissue [XREF_BIBR].
USP12 affects TGFB
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USP12 activates TGFB. 6 / 6
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The dauer larva-constitutive C. elegans phenotype caused by defective DAF-7 and TGF-beta signaling was enhanced and suppressed, respectively, by ubh-1 deletion and overexpression in the loss-of-function genetic backgrounds of daf7, daf-1 and TGF-betaRI, and daf4 and R-SMAD, but not of daf-8 and R-SMAD.

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This suggested that UBH-1 may stimulate DAF-7 and TGF-beta signaling via DAF-8 and R-SMAD.

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Here, we show that the deubiquitinating enzyme UBH-1 in Caenorhabditis elegans and its human homolog, ubiquitin C-terminal hydrolase-L1 (UCH-L1), stimulate DAF-7 and TGF-beta signaling, suggesting that this mode of regulation of TGF-beta signaling is conserved across animal species.

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This suggested that UBH-1 may stimulate DAF-7 and TGF-beta signaling via DAF-8 and R-SMAD.

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Here, we show that the deubiquitinating enzyme UBH-1 in Caenorhabditis elegans and its human homolog, ubiquitin C-terminal hydrolase-L1 (UCH-L1), stimulate DAF-7 and TGF-beta signaling, suggesting that this mode of regulation of TGF-beta signaling is conserved across animal species.

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The dauer larva-constitutive C. elegans phenotype caused by defective DAF-7 and TGF-beta signaling was enhanced and suppressed, respectively, by ubh-1 deletion and overexpression in the loss-of-function genetic backgrounds of daf7, daf-1 and TGF-betaRI, and daf4 and R-SMAD, but not of daf-8 and R-SMAD.
USP12 affects PHLPP1
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USP12 increases the amount of PHLPP1.
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USP12 increases the amount of PHLPP1. 1 / 2
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Our data demonstrates that Usp12 increases the levels of PHLPP and PHLPPL that in turn decreases the active pAkt pool and inhibits AR S213 phosphorylation by Akt.
Modified USP12-C48A increases the amount of PHLPP1. 1 / 1
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Importantly, overexpression of Usp12 deubiquitinated both PHLPP and PHLPPL and this elevated the steady-state levels of the enzymes, while overexpression of an enzymatically inactive Usp12 C48A mutant failed to elevate PHLPP and PHLPPL levels suggesting the importance of Usp12 enzymatic activity for phosphatase regulation.
USP12 activates PHLPP1.
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USP12 activates PHLPP1. 1 / 2
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In fact, overexpression of WDR48 and USP12 induced apoptosis similarly to PHLPP1.
USP12 inhibits PHLPP1.
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USP12 inhibits PHLPP1. 1 / 1
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Because PHLPP1 is a potent negative regulator of the PI3-kinase and Akt pathway, we hypothesized that WDR48 and USP12 might suppress Akt signaling by stabilizing PHLPP1.
USP12 affects daf-7
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USP12 activates daf-7. 4 / 4
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This suggested that UBH-1 may stimulate DAF-7 and TGF-beta signaling via DAF-8 and R-SMAD.

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This suggested that UBH-1 may stimulate DAF-7 and TGF-beta signaling via DAF-8 and R-SMAD.

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Here, we show that the deubiquitinating enzyme UBH-1 in Caenorhabditis elegans and its human homolog, ubiquitin C-terminal hydrolase-L1 (UCH-L1), stimulate DAF-7 and TGF-beta signaling, suggesting that this mode of regulation of TGF-beta signaling is conserved across animal species.

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Here, we show that the deubiquitinating enzyme UBH-1 in Caenorhabditis elegans and its human homolog, ubiquitin C-terminal hydrolase-L1 (UCH-L1), stimulate DAF-7 and TGF-beta signaling, suggesting that this mode of regulation of TGF-beta signaling is conserved across animal species.
USP12 affects AKT
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USP12 inhibits AKT. 4 / 4
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WDR48 and USP12 Negatively Regulate Akt Signaling and Promote Apoptosis.

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As knockdown of WDR48 and USP12 increased Akt activation, we next tested whether WDR48 and USP12 could potentiate the suppression of Akt signaling by PHLPP1.

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Thus, these results suggest that WDR48 and USP12 negatively regulate Akt signaling and thereby induce apoptosis in conjunction with PHLPP1.

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Because PHLPP1 is a potent negative regulator of the PI3-kinase and Akt pathway, we hypothesized that WDR48 and USP12 might suppress Akt signaling by stabilizing PHLPP1.
USP12 affects METTL3
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USP12 increases the amount of METTL3.
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USP12 increases the amount of METTL3. 2 / 2
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Furthermore, we discover that USP12 promote the expression of METTL3 via upregulating p300.

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Finally, our data show that USP12 is partially dependent on the stabilization of p300 to activate METTL3 expression and promote myocardial hypertrophy.
USP12 bound to EP300 increases the amount of METTL3. 1 / 1
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Mechanistically, USP12 binds and stabilizes p300, thereby activating the transcription of its downstream gene METTL3.
USP12 activates METTL3.
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USP12 activates METTL3. 1 / 1
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Furthermore , we discover that USP12 promote the expression of METTL3 via upregulating p300 .
USP12 affects PHLPP2
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USP12 increases the amount of PHLPP2. 1 / 2
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Our data demonstrates that Usp12 increases the levels of PHLPP and PHLPPL that in turn decreases the active pAkt pool and inhibits AR S213 phosphorylation by Akt.
Modified USP12-C48A increases the amount of PHLPP2. 1 / 1
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Importantly, overexpression of Usp12 deubiquitinated both PHLPP and PHLPPL and this elevated the steady-state levels of the enzymes, while overexpression of an enzymatically inactive Usp12 C48A mutant failed to elevate PHLPP and PHLPPL levels suggesting the importance of Usp12 enzymatic activity for phosphatase regulation.
USP12 affects Notch
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USP12 inhibits Notch.
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USP12 inhibits Notch. 2 / 2
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CG7023 and USP12 was shown to negatively regulate Notch signaling in flies.

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CG7023/USP12 was shown to negatively regulate Notch signaling in flies (Moretti et al., 2012).
USP12 activates Notch.
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USP12 activates Notch. 1 / 1
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The Ubiquitin specific Protease 12 (USP12) is a negative regulator of Notch signaling as USP12 directly targets Notch and directs it to lysosomal degradation.
USP12 affects MAP1LC3
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USP12 inhibits MAP1LC3.
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Usp12 and Usp12-C48S overexpression significantly decreased the mean half-life of LC3, but did not affect the half-life of the control protein Dendra2.

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Conversely, Usp12 knockdown increased the mean half-life of LC3, while also significantly right shifting the distribution of LC3 half-lives in individual neurons.
USP12 activates MAP1LC3.
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Mutated USP12 activates MAP1LC3. 1 / 1
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Since a non catalytic mutant of Usp12, Usp12-C48S, stimulated LC3 clearance as efficiently as Usp12, we additionally conclude that this function of Usp12 is independent of its deubiquitinating activity.
USP12 affects USP46
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USP12 activates USP46.
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USP12 activates USP46. 1 / 1
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Identification of Usp12 as a modifier of HD suggested that Usp12 could rescue neurodegeneration in related disorders, such as amyotrophic lateral sclerosis (ALS) and Parkinson 's disease (PD) that are characterized by proteotoxic stress.
USP12 bound to WDR48 activates USP46. 1 / 1
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In C. elegans, USP46 and USP12 both bind to USP1 associated factor 1 (UAF1 and WDR48) and the binding dramatically enhances the activity of USP12 and USP46.
USP12 inhibits USP46.
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USP12 inhibits USP46. 1 / 1
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We propose a mechanism by which Usp12 suppresses HD related neurodegeneration via induction of autophagy.
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Valproic acid decreases the amount of USP12. 2 / 2
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No evidence text available

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No evidence text available
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Pirinixic acid decreases the amount of USP12. 2 / 2
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No evidence text available

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No evidence text available

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Deubiquitinase USP12 promotes LPS induced macrophage responses through inhibition of IkappaBalpha.

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Most of the deubiquitinases, including A20 and CYLD, can inhibit NF-kappaB activation [XREF_BIBR], while USP12 positively regulates the LPS signal [XREF_BIBR].
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Knockdown of USP12 decreased the lung metastasis ability of 4T1 cells, while USP12 overexpression increased the lung metastasis ability of these cells in vivo.

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Collectively , our study identified that USP12 is responsible for deubiquitinating and stabilizing MDK and leads to metastasis by promoting angiogenesis .
USP12 affects Interferon
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Interestingly, USP12 positively regulates interferon (IFN) antiviral signaling independently of its deubiquitinase activity.

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Additionally, USP12 positively regulates IFN antiviral signaling independently of its deubiquitinase activity.
USP12 affects GRIA1
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USP12 decreases the amount of GRIA1. 2 / 2
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Knock-down of USP46, but not USP12, results in increased levels of ubiquitinated GluA1, decreased surface and total levels of GluA1, and reduced mEPSC amplitudes, consistent with a role for USP46 in deubiquitinating mammalian AMPARs.

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Knock-down of USP46, but not USP12, results in increased levels of ubiquitinated GluA1, decreased surface and total levels of GluA1, and reduced mEPSC amplitudes, consistent with a role for USP46 in deubiquitinating mammalian AMPARs (Huo et al., 2015).
RFX1 affects USP12
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RFX1 decreases the amount of USP12. 2 / 2
2 |

biopax:msigdb
No evidence text available

biopax:msigdb
No evidence text available
AR affects USP12
| 2
AR activates USP12. 2 / 2
| 2

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USP12 in the presence of its cofactors Uaf-1 and WDR20 deubiquitinates AR to enhance AR protein stability and transcriptional activity [71] USP12 in complex with Uaf-1 and WDR20 also abrogates phospho[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

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Akt inhibition abrogated S213 phosphorylation of AR and decreased the ability of Usp12 to stabilise AR protein levels.
USP12 affects cell cycle
| 1 1
USP12 inhibits cell cycle.
| 1
| 1

eidos
Flow cytometry analysis also showed that USP12 could induce cell cycle arrest at the G2 / M stage .
USP12 activates cell cycle.
| 1
| 1

reach
Flow cytometry analysis also showed that USP12 could induce cell cycle arrest at the G2/Mstage.
| 2
USP12 inhibits angiogenesis.
| 1
| 1

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Overexpression of MDK rescued the loss of angiogenesis ability mediated by knockdown of USP12 in breast cancer cells in vitro and in vivo.
USP12 activates angiogenesis.
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| 1

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USP12 promotes breast cancer angiogenesis by maintaining midkine stability.
USP12 is modified
| 1 1
USP12 is produced.
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USP12 is produced. 1 / 1
| 1

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Further analysis showed that LPS reduced the levels of Sp1 which enhanced the transcriptional levels of USP12.
USP12 is deubiquitinated.
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USP12 is deubiquitinated. 1 / 1
| 1

trips
Deubiquitinating enzyme Usp12 is a novel co-activator of the androgen receptor.
Vorinostat affects USP12
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Vorinostat decreases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
Vincristine affects USP12
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Vincristine increases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
Urethane affects USP12
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Urethane increases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available

ctd
No evidence text available
1 |
Titanium dioxide increases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
1 |
Testosterone decreases the amount of USP12. 1 / 1
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ctd
No evidence text available
Sunitinib affects USP12
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Sunitinib increases the amount of USP12. 1 / 1
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ctd
No evidence text available
1 |
Silicon dioxide decreases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
Rotenone affects USP12
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Rotenone decreases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
Potassium chromate decreases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
1 |
Pirimiphos-methyl decreases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
1 |

ctd
No evidence text available
Oxycodone affects USP12
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Oxycodone decreases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
Medroxyprogesterone acetate increases the amount of USP12. 1 / 1
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ctd
No evidence text available
Lipopolysaccharide decreases the amount of USP12. 1 / 1
| 1

reach
Further analysis showed that LPS reduced the levels of Sp1 which enhanced the transcriptional levels of USP12.
Leflunomide affects USP12
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Leflunomide increases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
Lead atom affects USP12
1 |
Lead atom increases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
Jinfukang affects USP12
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Jinfukang decreases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
Ionomycin affects USP12
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Ionomycin increases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
1 |
Hypochlorous acid increases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
1 |
Hsa-miR-9500 decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-92a-2-5p decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-8083 decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-7515 decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-744-5p decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-7109-5p decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-6887-5p decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-6885-5p decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-6876-5p decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-6795-5p decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-6780b-5p decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-625-5p decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-5196-5p decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-4747-5p decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-4725-3p decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-4533 decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-4476 decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-4472 decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-4447 decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-4271 decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-373-3p decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-328-5p decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-3202 decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-215-5p decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-192-5p decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-1260b decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Hsa-miR-1252-5p decreases the amount of USP12. 1 / 1
1 |

biopax:mirtarbase
No evidence text available
1 |
Geldanamycin increases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
1 |
Formaldehyde increases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
Doxorubicin affects USP12
1 |
Doxorubicin decreases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
Dicrotophos affects USP12
1 |
Dicrotophos decreases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
Clofibrate affects USP12
1 |
Clofibrate increases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
Cisplatin affects USP12
1 |
Cisplatin decreases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
Bun107 affects USP12
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Bun107 activates USP12. 1 / 1
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Moreover, the human ortholog of Bun107 activates USP12 and USP46 XREF_BIBR.
Bucladesine affects USP12
1 |
Bucladesine increases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
Bisphenol A affects USP12
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Bisphenol A decreases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
Avobenzone affects USP12
1 |
Avobenzone increases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
1 |
Aluminium atom increases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
1 |
Aflatoxin M1 decreases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
Abrine affects USP12
1 |
Abrine increases the amount of USP12. 1 / 1
1 |

ctd
No evidence text available
WD40 affects USP12
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WD40 activates USP12. 1 / 1
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For example, GMP synthetase (GMPS) interacts and activates USP7 (Faesen et al., 2011; Sarkari et al., 2009; van der Knaap et al., 2005), whereas the WD40 repeat containing UAF1 (WDR48) activates USP1,[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]

eidos
Highlights d Free USP12 deubiquitinase is inactive and has several flexible structural elements d UAF1 and WDR20 can both activate USP12 without increasing its substrate affinity d UAF1 and WDR20 bind USP12 at two distinct sites away from its catalytic center d Two distinct allosteric mechanisms underlie USP12 activation by UAF1 and WDR20 Ubiquitin-specific proteases ( USPs ) constitute the largest family of deubiquitinating enzymes , whose catalytic competency is often modulated by their binding partners through unknown mechanisms .
USP46 affects USP12
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USP46 bound to WDR48 activates USP12. 1 / 1
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In C. elegans, USP46 and USP12 both bind to USP1 associated factor 1 (UAF1 and WDR48) and the binding dramatically enhances the activity of USP12 and USP46.
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| 1

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Thus, USP12 and OTUD7B counterbalance inhibitory E3 ligases to stabilize TCR signaling.Aside from acting at the proximal signalosome, E3 ligases also inhibit T-cell activation by acting further downstream, controlling the key transduction events that lead to the nuclear translocation of the T-cell activating transcription factors.
| PMC
USP12 affects ribH2
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USP12 inhibits ribH2. 1 / 1
| 1

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The largely constant substrate affinity of USP12 in different forms negates a role of the BLs in controlling the accessibility of the Ub-binding surface of the enzyme.

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Transient depletion of USP12, USP46, and USP53 did not induce a senescence arrest.
USP12 affects WDR48
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USP12 bound to WDR20 inhibits WDR48. 1 / 1
| 1

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The partial overlap of the binding interfaces and the high affinity of WDR20 suggests that WDR20 binding to USP12 and UAF1 can either prevent binding of the second UAF1 molecule or it can actively compete out UAF1 if it is bound to the USP12 and UAF1 complex.
USP12 affects WDR20
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USP12 inhibits WDR20. 1 / 1
| 1

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Consistent with an important role in binding USP12, mutations of W306 and F262 effectively abolish the ability of WDR20 to interact with and activate USP12 ( Figures 4C and S4D ).
USP12 affects Val-Ser
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USP12 activates Val-Ser. 1 / 1
| 1

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Our previous observations for the LNCaP cell line that express AR FL but not AR Vs have demonstrated that USP12 silencing causes a decrease in transcript expression of all the AR target genes [XREF_BIBR] supporting our data that AR Vs are not targeted by USP12 in the AR V expressing CWR22Rv1 cell line.
USP12 affects Ubiquitin
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| 1

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Also, USP12 co-localizes with AR in the cytoplasm and promotes AR transcriptional activity by confronting the ubiquitin dependent degradation of AR [XREF_BIBR].
USP12 affects USP12
| 1
USP12 bound to WDR48 activates USP12. 1 / 1
| 1

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In C. elegans, USP46 and USP12 both bind to USP1 associated factor 1 (UAF1 and WDR48) and the binding dramatically enhances the activity of USP12 and USP46.
USP12 affects TCR
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USP12 activates TCR. 1 / 1
| 1

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In contrast, USP12 has been found to stabilize the TCR complex and promote TCR signaling through deubiquitylating TCR adaptor proteins LAT and Trat1 in primary mouse T lymphocytes.
| 1

reach
Thus, USP12 and OTUD7B counterbalance inhibitory E3 ligases to stabilize TCR signaling.Aside from acting at the proximal signalosome, E3 ligases also inhibit T-cell activation by acting further downstream, controlling the key transduction events that lead to the nuclear translocation of the T-cell activating transcription factors.
| PMC
USP12 affects STAT1
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USP12 inhibits STAT1. 1 / 1
| 1

reach
Other studies have shown that USP12 suppresses the PH domain and leucine rich repeat protein phosphatases, which restrains the activation of macrophages through the dephosphorylation of transcription factor STAT1 [XREF_BIBR].
USP12 affects PRRC2A
| 1
USP12 inhibits PRRC2A. 1 / 1
| 1

eidos
In vivo experiments showed that USP12-knockdown could suppress tumor growth in mice , and immuno-blotting revealed that USP12 could induce G2 / M arrest through the cyclin dependent kinase 1 / cyclinB1 axis , and trigger apoptosis via the p38 / mitogen-activated protein kinase pathway .
USP12 affects NLRP3
| 1
USP12 increases the amount of NLRP3. 1 / 1
| 1

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Additionally, the study also found out that the UAF1/USP12 and UAF1/USP46 complexes increase p65 expression, which promotes NF-κB activation and increases NLRP3 and IL-1β expression levels.
| PMC
USP12 affects MYC
| 1
USP12 increases the amount of MYC. 1 / 1
| 1

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In this study, we showed that knockdown of USP12 effectively induced cell cycle arrest in HeLa cells and decreased BMI-1, c-Myc and cyclin D2 transcription levels.
USP12 affects MON2
| 1
USP12 increases the amount of MON2. 1 / 1
| 1

reach
USP1, USP12, and UAF1 were produced using Sf9 and Sf21 insect cell expression.
USP12 affects MAPK
| 1
USP12 activates MAPK. 1 / 1
| 1

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Invivo experiments showed that USP12-knockdown could suppress tumor growth in mice, and immuno blotting revealed that USP12 could induce G2/M arrest through the cyclin dependent kinase1 and cyclinB1 axis, and trigger apoptosis via the p38 and mitogen activated protein kinase pathway.

reach
Thus, in this study we probed the involvement of USP12 in macrophage mediated inflammatory responses using bacterial endotoxin, LPS, as the model system.
USP12 affects KLK3
| 1
USP12 increases the amount of KLK3. 1 / 1
| 1

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For example, USP26 physically interacts with AR and influences AR ubiquitination and transcriptional activation; 17 USP12 stabilizes AR, enhances its cellular function, and thereby triggers the gene expression of PSA.
USP12 affects IL6