Evidence for ras-Dependent and Independent Pathways in NGF-Induced Neuronal Differentiation of PC12 Cells

PC12 cells expressing a dominant inhibitory mutant Ha-Ras protein [p21 (Asn-17) Ha-ras] were used to study signaling pathways involved in neuronal differentiation. Expression of the mutant protein completely blocks NGF-induced neurite outgrowth in these subclones. In contrast, NGF is able to potentiate the effect of dibutyryl cyclic AMP or ionomycin in inducing process formation in PC12 cells expressing the mutant Ras protein. These results suggest that (i) a Ras-independent signaling pathway exists in PC12 cells that is not sufficient for, but can contribute to NGF-induced neuritogenesis; (ii) the block of neuronal differentiation by the mutant Ras protein can be bypassed by either one of two second messengers, cyclic AMP and Ca++.