THE CYTOPLASMIC RAF ONCOGENE INDUCES A NEURONAL PHENOTYPE IN PC12 CELLS - A POTENTIAL ROLE FOR CELLULAR RAF KINASES IN NEURONAL GROWTH-FACTOR SIGNAL-TRANSDUCTION

The neuron-like differentiation of PC12 cells is induced by nerve grow th factor (NGF) through stimulation of a membrane-bound protooncoprote in signaling pathway containing the NGF receptor Trk, the tyrosine kin ase Src, and the GTP-binding protein Ras. The Raf-1 and B-raf protoonc ogenes encode cytoplasmic serine/threonine kinases that are stimulated by NGF in a Ras-dependent manner. To investigate the possible roles o f cytoplasmic Raf kinases in eliciting neuronal differentiation, we ha ve expressed the activated Raf-1 oncogene in PC12 cells. Expression of the raf oncogene results in the elaboration of a neuron-like phenotyp e, including neurite growth and the induction of the NGF-responsive ge nes NGFI-A and transin. The actions of activated Raf-1 and NGF are not additive. Furthermore, activated Raf-1 oncoprotein can prime cells fo r transcription-independent neurite growth by NGF and can elicit rapid neurite growth from NGF-primed cells. Our data indicate that the path ways utilized by NGF and activated raf to effect PC12 differentiation overlap and lead to the suggestion that cellular raf kinase activities play significant roles in transducing the differentiating signals of neuronal growth factors.