| Different growth factors can stimulate common downstream signaling pathways within the same cell yet produce varying physiological outcomes. Most notably, the Raf/MAP kinase pathway has been shown to mediate growth, differentiation and apoptosis of a given cell. This phenomenon is great relevance to cancer research due to the fact that the very outcomes that MAP kinase mediates are mutated to form the tumorigenic phenotype. Therefore, delineation of the molecules that govern specific growth factor-induced MAP kinase activation is of paramount importance.; The work presented here demonstrates that two protein kinase C (PKC) isoforms mediate Raf/MAP kinase activation by different growth factors within H19-7 and primary rodent cells. The former cell line undergoes differentiation into a neuronal phenotype upon basic fibroblast growth factor (bFGF) stimulation while treatment with epidermal growth factor (EGF) induces mitogenesis, despite the fact that both growth factors activate MAP kinase. PKCδ and &zgr; are required for MAP kinase activation by bFGF and EGF, respectively, and also mediate neurite outgrowth and mitogenesis in H19-7 cells. Furthermore, this work demonstrates that PKCs activate MAP kinase indirectly through RKIP, a Raf-1 kinase inhibitor, a novel mechanism that has remained unknown for many years.; In summary, this work identifies mammalian enzyme isoforms as determinants of growth factor specific MAP kinase activation. In light of this, it is suggested that specific physiological outcomes may be amended by activation or inhibition of these isoforms and present a novel target for the development of anti-cancer therapies. |
