TY - JOUR
T1 - Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC
AU - Haas-Kogan, Daphne
AU - Shalev, Noga
AU - Wong, Michelle
AU - Mills, Gordon
AU - Yount, Garret
AU - Stokoe, David
N1 - Funding Information:
This work was supported by NIH grant number M01RR01271 and an award from the Radiological Society of North America (D.H-K.) and grant number IRG-97-150-01-IRG from the American Cancer Society (to D.S.). We thank Frank McCormick for support and encouragement, Pablo Rodriguez-Viciana for helpful discussion, and Boudewijn Burgering, Phil Hawkins and Nicholas Tonks for reagents.
PY - 1998/10/22
Y1 - 1998/10/22
N2 - 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.
AB - 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.
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U2 - 10.1016/s0960-9822(07)00493-9
DO - 10.1016/s0960-9822(07)00493-9
M3 - Article
C2 - 9799739
AN - SCOPUS:0032558822
SN - 0960-9822
VL - 8
SP - 1195
EP - 1198
JO - Current Biology
JF - Current Biology
IS - 21
ER -