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 e mbryos display regions of increased proliferation. In contrast, mPTEN- deficient immortalized mouse embryonic fibroblasts exhibit decreased s ensitivity to cell death in response to a number of apoptotic stimuli, accompanied by constitutively elevated activity and phosphorylation o f protein kinase B/Akt, a crucial regulator of cell survival. Expressi on of exogenous PTEN in mutant cells restores both their sensitivity t o agonist-induced apoptosis and normal pattern of PKB/Akt phosphorylat ion. Furthermore, PTEN negatively regulates intracellular levels of ph osphatidylinositol (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 pathw ay.