Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN

Cell. 1998 Oct 2;95(1):29-39. doi: 10.1016/s0092-8674(00)81780-8.

Abstract

PTEN is a tumor suppressor with sequence homology to protein tyrosine phosphatases and the cytoskeletal protein tensin. mPTEN-mutant mouse embryos display regions of increased proliferation. In contrast, mPTEN-deficient immortalized mouse embryonic fibroblasts exhibit decreased sensitivity to cell death in response to a number of apoptotic stimuli, accompanied by constitutively elevated activity and phosphorylation of protein kinase B/Akt, a crucial regulator of cell survival. Expression of exogenous PTEN in mutant cells restores both their sensitivity to agonist-induced apoptosis and normal pattern of PKB/Akt phosphorylation. Furthermore, PTEN negatively regulates intracellular levels of phosphatidylinositol (3,4,5) trisphosphate in cells and dephosphorylates it in vitro. Our results show that PTEN may exert its role as a tumor suppressor by negatively regulating the PI3'K/PKB/Akt signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Cell Division
  • Cell Survival
  • Cells, Cultured
  • Female
  • Fibroblasts / cytology
  • Genes, Tumor Suppressor*
  • Mice
  • Mutagenesis
  • PTEN Phosphohydrolase
  • Phosphatidylinositol Phosphates / metabolism
  • Phosphoric Monoester Hydrolases*
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / physiology*
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Substrate Specificity
  • Tumor Suppressor Proteins*

Substances

  • Phosphatidylinositol Phosphates
  • Proto-Oncogene Proteins
  • Tumor Suppressor Proteins
  • phosphatidylinositol 3,4,5-triphosphate
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphoric Monoester Hydrolases
  • Protein Tyrosine Phosphatases
  • PTEN Phosphohydrolase