STIMULATION OF C2C12 MYOBLAST GROWTH BY BASIC FIBROBLAST GROWTH-FACTOR AND INSULIN-LIKE GROWTH-FACTOR-1 CAN OCCUR VIA MITOGEN-ACTIVATED PROTEIN KINASE-DEPENDENT AND KINASE-INDEPENDENT PATHWAYS

It is now well-recognized that the mitogen-activated protein (MAP) kin ase cascade facilitates signaling from an activated tyrosine kinase re ceptor to the nucleus. In fact, an increasing number of extracellular effecters have been reported to activate the MAP kinase cascade, with a significant number of cellular responses attributed to this activati on. We set out to explore how two extracellular effectors, basic fibro blast growth factor (bFGF) and insulin-like growth factor 1 (IGF-1), w hich have both been reported to activate MAP kinase, generate quite di stinct cellular responses in C2C12 myoblasts. We demonstrate here that bFGF, which is both a potent mitogen and inhibitor of myogenic differ entiation, is a strong MAP kinase agonist. By contrast, IGF-1, which i s equally mitogenic for C2C12 cells but ultimately enhances the differ entiated phenotype, is a weak activator of the MAP kinase cascade. We further demonstrate that IGF-1 is a potent activator of both insulin r eceptor substrate IRS-1 tyrosyl phosphorylation and association of IRS -1 with activated phosphatidylinositol 3-kinase (PI3-kinase). Finally, use of the specific MAP kinase kinase inhibitor, PD098059, and wortma nnin, a PI3-kinase inhibitor, suggests the existence of an IGF-1-induc ed, MAP kinase-independent signaling event which contributes to the mi togenic response of this factor, whereas bFGF-induced mitogenesis appe ars to a strongly correlate with activation of the MAP kinase cascade.