Deubiquitylation and stabilization of PTEN by USP13

Nat Cell Biol. 2013 Dec;15(12):1486-1494. doi: 10.1038/ncb2874. Epub 2013 Nov 24.

Abstract

The tumour 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 ubiquitylation, in the regulation of PTEN stability, activity and localization. However, the deubiquitylase that regulates PTEN polyubiquitylation and protein stability remains unknown. Here we screened a total of 30 deubiquitylating enzymes (DUBs) and identified five DUBs that physically associate with PTEN. One of them, USP13, stabilizes the PTEN protein through direct binding and deubiquitylation of PTEN. Loss of USP13 in breast cancer cells promotes AKT phosphorylation, cell proliferation, anchorage-independent growth, glycolysis and tumour 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 tumours and correlates with PTEN protein levels. These findings identify USP13 as a tumour-suppressing protein that functions through deubiquitylation and stabilization of PTEN.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Endopeptidases / genetics
  • Endopeptidases / metabolism*
  • Female
  • Gene Expression
  • Glycolysis
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • PTEN Phosphohydrolase / metabolism*
  • Protein Stability
  • Protein Transport
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction
  • Tumor Burden
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitination*

Substances

  • Tumor Suppressor Proteins
  • Proto-Oncogene Proteins c-akt
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Endopeptidases
  • USP13 protein, human