Deubiquitylation and stabilization of PTEN by USP13

Abstract

The tumor suppressor PTEN is frequently lost in human cancers. In addition to gene mutations and deletions, recent studies have revealed the importance of post-translational modifications, such as ubiquitination, in the regulation of PTEN stability, activity and localization. However, the deubiquitinase that regulates PTEN poly-ubiquitination and protein stability remains unknown. Here we screened a total of 30 deubiquitinating enzymes (DUBs) and identified five DUBs that physically associate with PTEN. One of them, USP13, stabilizes PTEN protein via direct binding and deubiquitination of PTEN. Loss of USP13 in breast cancer cells promotes AKT phosphorylation, cell proliferation, anchorage-independent growth, glycolysis and tumor growth through downregulation of PTEN. Conversely, overexpression of USP13 suppresses tumorigenesis and glycolysis in PTEN-positive but not PTEN-null breast cancer cells. Importantly, USP13 protein is downregulated in human breast tumors and correlates with PTEN protein levels. These findings identify USP13 as a tumor-suppressing protein that functions through deubiquitination and stabilization of PTEN.

SIPL1-facilitated PTEN ubiquitination contributes to its association with PTEN

“…Down-53 regulation of NEDD4-1 via SCFβ-TRCP-mediated degradation inhibited 54 tumorigenesis through enhancing PTEN function [4]. Deubiquitination 55 of PTEN by USP13, a deubiquitinating enzyme, stabilized PTEN, and 56 thereby inhibited breast cancer tumorigenesis [5]. Conversely, by pro-57 moting NEDD4-1-mediated PTEN polyubiquitination, a 34 kDa protein, 58 p34SEI-1 exhibited oncogenic activities [6,7].…”

Deubiquitylase OTUD3 regulates PTEN stability and suppresses tumorigenesis

“…A recent study, through a screen of 30 USP members, identified USP13 as a candidate that de-polyubiquitylates and stabilizes PTEN (ref. 24). However, depletion of USP13 in cells reduced but did not abolish the PTEN ubiquitylation 24 , suggesting that other DUB(s) might exist to function as the DUB for PTEN.…”

“…24). However, depletion of USP13 in cells reduced but did not abolish the PTEN ubiquitylation 24 , suggesting that other DUB(s) might exist to function as the DUB for PTEN. It is not surprising that such an important tumour suppressor is controlled by multiple DUBs.…”

Protein monoubiquitylation: targets and diverse functions

“…2008), whereas USP13 removes polyubiquitin from and thereby stabilizes PTEN (Zhang et al . 2013). The different subcellular localizations of these DUBs—USP7 in the nucleus and USP13 in the cytosol—may allow the targeting of different populations of ubiquitylated PTEN, a scenario that is again reminiscent of p53 regulation by DUBs.…”