THE PI 3-KINASE AKT SIGNALING PATHWAY DELIVERS AN ANTI-APOPTOTIC SIGNAL/

Serum and certain growth factors have the ability to inhibit programme d cell death (apoptosis) and promote survival. The mechanism by which growth factors deliver an anti-apoptotic signal and the mechanism by w hich this survival signal is uncoupled from mitogenesis are not clear. We studied five downstream effectors of growth factor receptors-Ras, Raf, Src, phosphoinositide 3-kinase (PI 3-kinase), and Akt (PKB)-for t heir abilities to block apoptosis. Activated forms of Pas, Raf, and Sr c, although transforming, were not sufficient to deliver a survival si gnal upon serum withdrawal. In contrast, inhibition of PI S-kinase acc elerated apoptosis, and an activated form of the serine/threonine kina se Akt, a downstream effector of PI 3-kinase, blocked apoptosis. The a bility of Akt to promote survival was dependent on and proportional to its kinase activity. In Rat1a fibroblasts, activated Akt did not alte r Bcl-2 or Bcl-X(L), expression but inhibited Ced3/ICE-like activity. Thus, the PI 5-kinase/Akt (PKB) signaling pathway transduces a surviva l signal that ultimately blocks Ced3/ICE-like activity. These results suggest that uncoupling of survival and mitogenesis can be explained b y differing abilities of distinct mitogens to efficiently induce the P I 3-kinase/Akt signaling pathway.