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

Min Sup Song1, Arkaitz Carracedo, Leonardo Salmena

  • 1Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Cell
|January 19, 2011
PubMed

Insights

Nuclear PTEN protein interacts with APC/C, enhancing its tumor-suppressive activity. This discovery explains PTEN

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • PTEN (Phosphatase and tensin homolog) is a critical tumor suppressor gene opposing the PI3K/AKT pathway.
  • Nuclear localization of PTEN is essential for its tumor-suppressive functions, but its specific nuclear role is not well understood.

Purpose of the Study:

  • To elucidate the nuclear function of PTEN and its role in tumor suppression.
  • To investigate the interaction of nuclear PTEN with the Anaphase-Promoting Complex/Cyclosome (APC/C) complex.

Main Methods:

  • Investigated the interaction between nuclear PTEN and APC/C components (e.g., CDH1).
  • Assessed the impact of PTEN nuclear exclusion versus phosphatase inactivation on APC/C function.
  • Analyzed PTEN mutant and null states' sensitivity to inhibitors of APC/C targets (PLK1, Aurora kinases).

Main Results:

  • Nuclear PTEN directly interacts with APC/C and promotes its association with CDH1, enhancing APC-CDH1 complex activity.
  • Nuclear exclusion of PTEN, not its phosphatase activity, impairs APC-CDH1 function, explaining senescence responses to PTEN loss.
  • PTEN mutant and null states exhibit differential sensitivity to PLK1 and Aurora kinase inhibitors.

Conclusions:

  • Nuclear PTEN functions as a crucial regulator of the APC-CDH1 complex, contributing to its tumor-suppressive role.
  • This mechanism explains PTEN's role in cellular senescence and the tumor-suppressive activity of catalytically inactive PTEN.
  • Findings offer a basis for stratifying cancer patients and optimizing targeted therapies based on PTEN status.

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