Nerve growth factor induces survival and differentiation through two distinct signaling cascades in PC12 cells

Nerve growth factor induces differentiation and survival of rat PC12 pheochromocytoma cells. The activation of the erk cascade has been implicated in transducing the multitude of signals induced by NGF. In order to explore the role of this signaling cascade in NGF mediated survival, differentiation and proliferation, we generated recombinant adenoviruses which express the intermediates of the erk cascade in their wild type, dominant negative and constitutively activated forms. We show that differentiation of PC12 cells requires activity of the ras/erk pathway, whereas inhibition of this pathway had no effect on survival or proliferation. Constitutively active forms of ras, raf and mek induced PC12 cell differentiation, while dominant interfering forms inhibited differentiation. Survival of PC12 cells in serum-free medium did not require activity of the ras/erk pathway. Instead, PI3 Kinase signaling was necessary for PC12 cell survival. Interestingly, constitutively activated versions of raf and mek were able to promote survival, but again this was dependent on activation of PI3 Kinase. Therefore, at least two distinct signaling pathways are required in PC12 cells for mediation of NGF functions.