The lipid phosphatase activity of PTEN is critical for its tumor supressor function

Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13513-8. doi: 10.1073/pnas.95.23.13513.

Abstract

Since their discovery, protein tyrosine phosphatases have been speculated to play a role in tumor suppression because of their ability to antagonize the growth-promoting protein tyrosine kinases. Recently, a tumor suppressor from human chromosome 10q23, called PTEN or MMAC1, has been identified that shares homology with the protein tyrosine phosphatase family. Germ-line mutations in PTEN give rise to several related neoplastic disorders, including Cowden disease. A key step in understanding the function of PTEN as a tumor suppressor is to identify its physiological substrates. Here we report that a missense mutation in PTEN, PTEN-G129E, which is observed in two Cowden disease kindreds, specifically ablates the ability of PTEN to recognize inositol phospholipids as a substrate, suggesting that loss of the lipid phosphatase activity is responsible for the etiology of the disease. Furthermore, expression of wild-type or substrate-trapping forms of PTEN in HEK293 cells altered the levels of the phospholipid products of phosphatidylinositol 3-kinase and ectopic expression of the phosphatase in PTEN-deficient tumor cell lines resulted in the inhibition of protein kinase (PK) B/Akt and regulation of cell survival.

Publication types

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

MeSH terms

  • Cell Line
  • Escherichia coli
  • Genes, Tumor Suppressor*
  • Germ-Line Mutation*
  • Humans
  • PTEN Phosphohydrolase
  • Phosphoric Monoester Hydrolases / chemistry
  • Phosphoric Monoester Hydrolases / genetics*
  • Phosphoric Monoester Hydrolases / metabolism
  • Protein Tyrosine Phosphatases*
  • Tumor Suppressor Proteins*

Substances

  • Tumor Suppressor Proteins
  • Phosphoric Monoester Hydrolases
  • Protein Tyrosine Phosphatases
  • PTEN Phosphohydrolase
  • PTEN protein, human