Negative feedback regulation of the tumor suppressor PTEN by phosphoinositide-induced serine phosphorylation

J Immunol. 2002 Jul 1;169(1):286-91. doi: 10.4049/jimmunol.169.1.286.

Abstract

The PTEN tumor suppressor phosphatase directly counteracts the multiple functions of phosphatidylinositol 3-kinase by removing phosphate from the D3 position of inositol phospholipids. Like many lymphomas and leukemias, the Jurkat T cell line lacks PTEN protein due to frame-shift mutations in both PTEN alleles and therefore survives in long-term cell culture. We report that PTEN reintroduced into Jurkat was highly phosphorylated on serines 380 and 385 in its C terminus, particularly the former site. Phosphate was also detected at Ser(380) in PTEN in untransformed human T cells. Treatments that reduced the levels of D3-phospholipids in the cells resulted in reduced phosphorylation and accelerated degradation of PTEN. In contrast, expression of inactive PTEN-C124G or coexpression of a constitutively active protein kinase B led to increased phosphorylation and slower degradation of PTEN. These results suggest that PTEN normally is subjected to a feedback mechanism of regulation aimed at maintaining homeostatic levels of D3-phosphoinositides, which are crucial for T cell survival and activation.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alanine / genetics
  • Amino Acid Sequence
  • Amino Acid Substitution / genetics
  • Cells, Cultured
  • Down-Regulation / genetics
  • Down-Regulation / immunology*
  • Feedback
  • Half-Life
  • Humans
  • Jurkat Cells / enzymology
  • Jurkat Cells / metabolism
  • Molecular Sequence Data
  • PTEN Phosphohydrolase
  • Phosphatidylinositol Phosphates / metabolism
  • Phosphatidylinositol Phosphates / physiology
  • Phosphatidylinositols / metabolism
  • Phosphatidylinositols / physiology*
  • Phosphoric Monoester Hydrolases / antagonists & inhibitors*
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism*
  • Phosphorylation
  • Serine / genetics
  • Serine / metabolism*
  • T-Lymphocytes / enzymology*
  • T-Lymphocytes / metabolism
  • Tumor Suppressor Proteins / antagonists & inhibitors*
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • Phosphatidylinositol Phosphates
  • Phosphatidylinositols
  • Tumor Suppressor Proteins
  • phosphatidylinositol 3,4,5-triphosphate
  • Serine
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Alanine