Different protein kinase C isoforms determine growth factor specificity inneuronal cells

Although mitogenic and differentiating factors often activate a number of c ommon signaling pathways, the mechanisms leading to their distinct cellular outcomes have not been elucidated. In a previous report, we demonstrated t hat mitogen-activated protein (MAP) kinase (ERK) activation by the neurogen ic agents fibroblast growth factor (FGF) and nerve growth factor is depende nt on protein kinase C delta (PKC delta), whereas MAP kinase activation in response to the mitogen epidermal growth factor (EGF) is independent of PKC delta in rat hippocampal (H19-7) and pheochromocytoma (PC12) cells. We now show that EGF activates MAP kinase through a PKC zeta-dependent pathway in volving phosphatidylinositol 3-kinase and PDK1 in H19-7 cells, PKC zeta, li ke PKC delta acts upstream of MEK, and PKC zeta can potentiate Raf-l activa tion by EGF. Inhibition of PKC zeta also blocks EGF-induced DNA synthesis a s monitored by bromodeoxyuridine incorporation in H19-7 cells, Finally, in embryonic rat brain hippocampal cell cultures, inhibitors of PRC zeta or PK C delta suppress MAP kinase activation by EGF or FGF. respectively, indicat ing that these factors activate distinct signaling pathways in primary as w ell as immortalized neural cells. Taken together, these results implicate d ifferent PKC isoforms as determinants of growth factor signaling specificit y within the same cell. Furthermore, these data provide a mechanism whereby different growth factors can differentially activate a common signaling in termediate and thereby generate biological diversity.