Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner

Cell. 2011 Jan 21;144(2):187-99. doi: 10.1016/j.cell.2010.12.020.

Abstract

PTEN is a frequently mutated tumor suppressor gene that opposes the PI3K/AKT pathway through dephosphorylation of phosphoinositide-3,4,5-triphosphate. Recently, nuclear compartmentalization of PTEN was found as a key component of its tumor-suppressive activity; however its nuclear function remains poorly defined. Here we show that nuclear PTEN interacts with APC/C, promotes APC/C association with CDH1, and thereby enhances the tumor-suppressive activity of the APC-CDH1 complex. We find that nuclear exclusion but not phosphatase inactivation of PTEN impairs APC-CDH1. This nuclear function of PTEN provides a straightforward mechanistic explanation for the fail-safe cellular senescence response elicited by acute PTEN loss and the tumor-suppressive activity of catalytically inactive PTEN. Importantly, we demonstrate that PTEN mutant and PTEN null states are not synonymous as they are differentially sensitive to pharmacological inhibition of APC-CDH1 targets such as PLK1 and Aurora kinases. This finding identifies a strategy for cancer patient stratification and, thus, optimization of targeted therapies. PAPERCLIP:

Publication types

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

MeSH terms

  • Anaphase-Promoting Complex-Cyclosome
  • Animals
  • Antigens, CD
  • Aurora Kinases
  • Cadherins / metabolism*
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cellular Senescence*
  • Humans
  • Male
  • Mice
  • Neoplasm Transplantation
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism*
  • Phosphoric Monoester Hydrolases / metabolism
  • Prostatic Neoplasms / metabolism
  • Prostatic Neoplasms / pathology
  • Protein-Serine-Threonine Kinases / metabolism
  • Transplantation, Heterologous
  • Ubiquitin-Protein Ligase Complexes / metabolism*

Substances

  • Antigens, CD
  • CDH1 protein, human
  • Cadherins
  • Ubiquitin-Protein Ligase Complexes
  • Anaphase-Promoting Complex-Cyclosome
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human