Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC

Curr Biol. 1998 Oct 22;8(21):1195-8. doi: 10.1016/s0960-9822(07)00493-9.

Abstract

Glioblastomas are highly malignant tumors of the central nervous system that are resistant to radiation and chemotherapy [1]. We explored the role of the phosphatidylinositol (PI) 3-kinase signal transduction pathway in glioblastomas, as this pathway has been shown to inhibit apoptosis induced by cytokine withdrawal and the detachment of cells from the extracellular matrix [2]. Components of this pathway have been implicated in tumor development [3-6]. We show that glioblastoma cells, in contrast to primary human astrocytes, contain high endogenous protein kinase B (PKB/Akt) activity and high levels of PI 3,4,5-triphosphate (PI(3,4,5)P3) and PI(3,4)P2, the lipid products of PI 3-kinase. These glioblastoma cells express mutant forms of the putative 3' phospholipid phosphatase PTEN, also known as MMAC. Expression of wild-type PTEN derived from primary astrocytes, but not of mutant forms of PTEN, reduced the levels of 3' phosphoinositides and inhibited PKB/Akt activity. PTEN antagonized the activation of PKB/Akt by growth factors, by activated PI 3-kinase and by PI-dependent protein kinase-1 (PDK1), but did not antagonize the phospholipid-independent activation of PKB/Akt lacking the pleckstrin homology (PH) domain. These results suggest a role for PTEN in regulating the activity of the PI 3-kinase pathway in malignant human cells.

Publication types

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

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases
  • 3T3 Cells
  • Animals
  • Astrocytes / metabolism
  • COS Cells
  • Enzyme Activation
  • Genes, Tumor Suppressor*
  • Glioblastoma / enzymology*
  • Glioblastoma / genetics*
  • Humans
  • Mice
  • Mutation*
  • PTEN Phosphohydrolase
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositol Phosphates / metabolism
  • Phospholipids / metabolism
  • Phosphoric Monoester Hydrolases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Recombinant Proteins / metabolism
  • Transfection
  • Tumor Suppressor Proteins*

Substances

  • Phosphatidylinositol Phosphates
  • Phospholipids
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • Tumor Suppressor Proteins
  • Phosphatidylinositol 3-Kinases
  • Protein-Tyrosine Kinases
  • 3-Phosphoinositide-Dependent Protein Kinases
  • AKT1 protein, human
  • PDPK1 protein, human
  • Pdpk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human