CALCIUM INFLUX INDUCES NEURITE GROWTH THROUGH A SRC-RAS SIGNALING CASSETTE

We find that calcium influx through voltage-dependent calcium channels causes extensive neu rite outgrowth in PC12 cells. The calcium signal transduction pathway promoting neurite outgrowth causes the rapid act ivation of protein tyrosine kinases, which include Src. Protein tyrosi ne phosphorylation results in the formation of an Shc/Grb2 complex, re ading to Ras activation, MAP kinase activation, and the subsequent ind uction of the immediate early gene NGFI-A. Protein tyrosine phosphoryl ation, gene induction, and neurite outgrowth are inhibited by the expr ession of dominant negative forms of both Src and Ras, indicating a re quirement for both proto-oncoproteins in calcium signaling. Our result s suggest that a signaling cassette which includes Src and Ras is like ly to underlie it broad range of calcium actions in the nervous system .