A new class of cancer-associated PTEN mutations defined by membrane translocation defects

H. N. Nguyen, J. M. Yang, M. Rahdar, M. Keniry, K. F. Swaney, R. Parsons, B. H. Park, H. Sesaki, P. N. Devreotes, M. Iijima

Research output: Contribution to journalArticle

Abstract

Phosphatase and tensin homolog (PTEN), which negatively regulates tumorigenic phosphatidylinositol (3,4,5)-trisphosphate (PIP3) signaling, is a commonly mutated tumor suppressor. The majority of cancer-associated PTEN mutations block its essential PIP3 phosphatase activity. However, there is a group of clinically identified PTEN mutations that maintain enzymatic activity, and it is unknown how these mutations contribute to tumor pathogenesis. Here, we show that these enzymatically competent PTEN mutants fail to translocate to the plasma membrane where PTEN converts PIP3 to PI(4,5)P2. Artificial membrane tethering of the PTEN mutants effectively restores tumor suppressor activity and represses excess PIP3 signaling in cells. Thus, our findings reveal a novel mechanism of tumorigenic PTEN deficiency.

Original languageEnglish (US)
Pages (from-to)3737-3743
Number of pages7
JournalOncogene
Volume34
Issue number28
DOIs
StatePublished - Jul 1 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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