ROLE OF GLYCOGEN-SYNTHASE KINASE-3 IN THE PHOSPHATIDYLINOSITOL 3-KINASE AKT CELL-SURVIVAL PATHWAY/

Growth factor-dependent survival of a variety of mammalian cells is de pendent on the activation of phosphatidylinositol (PI) 3-kinase and it s downstream effector, the protein kinase Akt. Glycogen synthase kinas e-3 (GSK-3) has been previously identified as a physiological target o f Akt, which is inhibited by phosphorylation, so we have investigated the role of GSK-3 in cell survival. Overexpression of catalytically ac tive GSK-3 induced apoptosis of both Rat-1 and PC12 cells, whereas dom inant-negative GSK-3 prevented apoptosis following inhibition of PI 3- kinase. GSK-3 thus plays a critical role in regulation of apoptosis an d represents a key downstream target of the PI 3-kinase/Akt survival s ignaling pathway.