Deubiquitinase ubiquitin‐specific protease 9X regulates the stability and function of E3 ubiquitin ligase ring finger protein 115 in breast cancer cells

Lu, Qiong; Lu, Da Yong; Shao, Zhi‐Ming; Li, Da‐Qiang

doi:10.1111/cas.13953

Cited by 20 publications

(15 citation statements)

References 47 publications

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“…Ubiquitin specific peptidase 9 X-linked (Usp9x) is a prominently known for acting as the DUB to protect SMURF1 and RNF115 from proteolysis [ 71 , 72 ], and there is emerging evidence that Usp9x can also interact with other AR-containing proteins to regulate intracellular events. For instance, Usp9x has been observed to interact with the cytoskeletal protein ankyrin-3 (ANK3) to promote spine morphogenesis [ 38 , 73 ].…”

Section: Ankyrin Repeats and The Usp—working Together To Regulate mentioning

confidence: 99%

Structural Insights into Ankyrin Repeat-Containing Proteins and Their Influence in Ubiquitylation

Kane

Spratt

2021

IJMS

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Ankyrin repeat (AR) domains are considered the most abundant repeat motif found in eukaryotic proteins. AR domains are predominantly known to mediate specific protein–protein interactions (PPIs) without necessarily recognizing specific primary sequences, nor requiring strict conformity within its own primary sequence. This promiscuity allows for one AR domain to recognize and bind to a variety of intracellular substrates, suggesting that AR-containing proteins may be involved in a wide array of functions. Many AR-containing proteins serve a critical role in biological processes including the ubiquitylation signaling pathway (USP). There is also strong evidence that AR-containing protein malfunction are associated with several neurological diseases and disorders. In this review, the structure and mechanism of key AR-containing proteins are discussed to suggest and/or identify how each protein utilizes their AR domains to support ubiquitylation and the cascading pathways that follow upon substrate modification.

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Section: Ankyrin Repeats and The Usp—working Together To Regulate mentioning

confidence: 99%

Structural Insights into Ankyrin Repeat-Containing Proteins and Their Influence in Ubiquitylation

Kane

Spratt

2021

IJMS

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“… 34 , 35 In order to detect whether the protein degradation of RUNX2 was mediated by proteasome, proteasome inhibitors MG-132 was used in this study. 36 It was found that MG-132 could effectively increase the expression of RUNX2 protein, in addition, the protein level of RUNX2 in the absence of MAPK14 protein could be recovered to some extent. It has been reported that MAPK14 could also be degraded by ubiquitination, 37 but this phenomenon was not found in our study.…”

Section: Discussionmentioning

confidence: 96%

<p>Phosphorylated MAPK14 Promotes the Proliferation and Migration of Bladder Cancer Cells by Maintaining RUNX2 Protein Abundance</p>

Liu

et al. 2020

CMAR

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Background: Mitogen-activated protein kinase 14 (MAPK14) acts as an integration point for multiple biochemical signal pathways. High expressions of MAPK14 have been found in a variety of tumors. Runt-related transcription factor 2 (RUNX2) is related to many tumors, especially in tumor invasion and metastasis. However, the mechanism of these two genes in bladder cancer remains unclear. Methods: TCGA database and Western blot were used to analyze the mRNA and protein levels of the target gene in bladder cancer tissues and adjacent tissues. The proliferation ability of bladder cancer cells was tested by colony forming and EdU assay. The migration ability of cells was detected by transwell assay. Immunoprecipitation was utilized to detect protein-protein interaction. Cycloheximide chase assay was used to measure the half-life of RUNX2 protein. Results: Phosphorylated mitogen-activated protein kinase 14 (P-MAPK14, Thr180/Tyr182) was highly expressed in bladder cancer tissues and bladder cancer cell lines. Accordingly, P-MAPK14 could be combined with RUNX2 and maintain its protein stability and promote the proliferation and migration of bladder cancer cells. In addition, the functional degradation caused by the downregulation of MAPK14 and P-MAPK14 could be partially compensated by the overexpression of RUNX2. Conclusion: These results suggest that P-MAPK14 might play an important role in the development of bladder cancer and in the regulation of RUNX2 protein expression. P-MAPK14 might become a potential target for the treatment of bladder cancer.

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“…In vivo ubiquitination assay was performed as described previously . Briefly, HEK293T cells were seeded into 10‐cm dish overnight.…”

Section: Methodsmentioning

confidence: 99%

“…Immunoblotting analysis, immunoprecipitation assays, and immunofluorescent staining were performed as described previously in details. [39][40][41]…”

Section: Antibodies Immunoblotting Immunoprecipitation Assays Anmentioning

confidence: 99%

USP9X stabilizes BRCA1 and confers resistance to DNA‐damaging agents in human cancer cells

Zhang

et al. 2019

Cancer Medicine

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BRCA1, a multifunctional protein with an important role in DNA double‐strand break repair by homologous recombination (HR), is subjected to ubiquitin‐dependent degradation. To date, several E3 ubiquitin ligases have been identified to govern BRCA1 stability, but the deubiquitinase that counteracts its turnover remains undefined. In this study, we report that the ubiquitin‐specific protease 9X (USP9X) is a bona fide deubiquitinase for BRCA1 in human cancer cells. Reciprocal immunoprecipitation assays demonstrated that USP9X interacted with BRCA1. Depletion of USP9X by short interfering RNAs or inhibition of USP9X by the small‐molecular inhibitor WP1130 significantly reduced BRCA1 protein abundance, without affecting its mRNA levels. In contrast, overexpression of wild‐type USP9X, but not its deubiquitinase activity‐defective mutant (C1566S), resulted in an upregulation of BRCA1 protein levels. Moreover, USP9X depletion reduced the half‐life of BRCA1, accompanied by an increase in its ubiquitination. HR assays showed that knockdown of USP9X significantly reduced HR efficiency, which was partially rescued by reintroduction of BRCA1 into USP9X‐depleted cells. In support of these findings, USP9X knockdown significantly enhanced sensitivity to PARP inhibitor Olaparib and methyl methanesulfonate (MMS). Collectively, these results establish USP9X as a deubiquitinase for BRCA1 and reveal a previously unrecognized role of USP9X in the regulation of HR repair and the sensitivity of cancer cells to DNA‐damaging agents.

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Deubiquitinase ubiquitin‐specific protease 9X regulates the stability and function of E3 ubiquitin ligase ring finger protein 115 in breast cancer cells

Cited by 20 publications

References 47 publications

Structural Insights into Ankyrin Repeat-Containing Proteins and Their Influence in Ubiquitylation

Structural Insights into Ankyrin Repeat-Containing Proteins and Their Influence in Ubiquitylation

<p>Phosphorylated MAPK14 Promotes the Proliferation and Migration of Bladder Cancer Cells by Maintaining RUNX2 Protein Abundance</p>

USP9X stabilizes BRCA1 and confers resistance to DNA‐damaging agents in human cancer cells

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