Requirement for Phosphatidylinositol-3 Kinase in the Prevention of Apoptosis by Nerve Growth Factor

TLDR

NGF promotes neuronal differentiation and survival through binding to the Trk receptor tyrosine kinase. NGF blocks apoptosis via a phosphatidylinositol 3‑kinase pathway, as inhibition with wortmannin or LY294002 abolishes this effect. Survival of PC‑12 cells depends on PI3K signaling rather than Ras, and this pathway is distinct from the one driving differentiation.

Abstract

Nerve growth factor (NGF) induces both differentiation and survival of neurons by binding to the Trk receptor protein tyrosine kinase. Although Ras is required for differentiation, it was not required for NGF-mediated survival of rat pheochromocytoma PC-12 cells in serum-free medium. However, the ability of NGF to prevent apoptosis (programmed cell death) was inhibited by wortmannin or LY294002, two specific inhibitors of phosphatidylinositol (Pl)-3 kinase. Moreover, platelet-derived growth factor (PDGF) prevented apoptosis of PC-12 cells expressing the wild-type PDGF receptor, but not of cells expressing a mutant receptor that failed to activate Pl-3 kinase. Cell survival thus appears to be mediated by a Pl-3 kinase signaling pathway distinct from the pathway that mediates differentiation.