title: Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC.
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.
authors.affiliation: Department of Radiation Oncology University of California San Francisco, California, 94115, USA. hkogan@radonc17.ucsf.edu
authors.forename: D
authors.initials: D
authors.lastname: Haas-Kogan
authors.forename: N
authors.initials: N
authors.lastname: Shalev
authors.forename: M
authors.initials: M
authors.lastname: Wong
authors.forename: G
authors.initials: G
authors.lastname: Mills
authors.forename: G
authors.initials: G
authors.lastname: Yount
authors.forename: D
authors.initials: D
authors.lastname: Stokoe
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D016475:3T3 Cells; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D019556:COS Cells; D004789:Enzyme Activation; D016147:Genes, Tumor Suppressor; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D051379:Mice; D009154:Mutation; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D010743:Phospholipids; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; C494918:AKT1 protein, human; C578562:PDPK1 protein, human; C578564:Pdpk1 protein, mouse; C494929:PTEN protein, human