Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN.
PTEN is a tumor suppressor with sequence homology to protein tyrosine phosphatases and the cytoskeletal protein tensin. mPTEN-mutant mouse embryos display regions of increased proliferation. In contrast, mPTEN-deficient immortalized mouse embryonic fibroblasts exhibit decreased sensitivity to cell death in response to a number of apoptotic stimuli, accompanied by constitutively elevated activity and phosphorylation of protein kinase B/Akt, a crucial regulator of cell survival. Expression of exogenous PTEN in mutant cells restores both their sensitivity to agonist-induced apoptosis and normal pattern of PKB/Akt phosphorylation. Furthermore, PTEN negatively regulates intracellular levels of phosphatidylinositol (3,4,5) trisphosphate in cells and dephosphorylates it in vitro. Our results show that PTEN may exert its role as a tumor suppressor by negatively regulating the PI3'K/PKB/Akt signaling pathway.
Amgen Institute, and Department of Medical Biophysics, University of Toronto, Ontario, Canada.
V
V
Stambolic
A
A
Suzuki
J L
JL
de la Pompa
G M
GM
Brothers
C
C
Mirtsos
T
T
Sasaki
J
J
Ruland
J M
JM
Penninger
D P
DP
Siderovski
T W
TW
Mak
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D002470:Cell Survival; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D016147:Genes, Tumor Suppressor; D051379:Mice; D016296:Mutagenesis; D051059:PTEN Phosphohydrolase; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D013379:Substrate Specificity; D025521:Tumor Suppressor Proteins
D018129:Phosphatidylinositol Phosphates; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; C060974:phosphatidylinositol 3,4,5-triphosphate; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D017027:Protein Tyrosine Phosphatases; D051059:PTEN Phosphohydrolase