A REQUIREMENT FOR FIBROBLAST GROWTH-FACTOR IN REGULATION OF SKELETAL-MUSCLE GROWTH AND DIFFERENTIATION CANNOT BE REPLACED BY ACTIVATION OF PLATELET-DERIVED GROWTH-FACTOR SIGNALING PATHWAYS

The distinct effects of cytokines on cellular growth and differentiati on suggest that specific signaling pathways mediate these diverse biol ogical activities. Fibroblast growth factors (FGFs) are well-establish ed inhibitors of skeletal muscle differentiation and may operate via a ctivation of specific signaling pathways distinct from recently identi fied mitogen signaling pathways. We examined whether platelet-derived growth factor (PDGF)-activated signaling pathways are sufficient to me diate FGF-dependent repression of myogenesis by introducing the PDGF b eta receptor into a mouse skeletal muscle cell line, Addition of PDGF- BB to cells expressing the PDGF beta receptor activated the PDGF beta receptor tyrosine kinase, stimulated mitogen activated protein (MAP) k inase, and increased the steady-state levels of junB and c-fos mRNAs. Despite the activation of these intracellular signaling molecules. PDG F beta receptor activation elicited no detectable effect on cell proli feration or differentiation. In contrast to PDGF-BB, addition of FGF-2 to myoblasts activated signaling pathways that resulted in DNA synthe sis and repression of differentiation. Because of the low number of en dogenous FGF receptors expressed, FGF-stimulated signaling events, inc luding tyrosine phosphorylation and activation of MAP kinase, could be detected only in cells expressing higher levels of a transfected FGF receptor cDNA. As the PDGF beta receptor- and FGF receptor-stimulated signaling pathways yield different biological responses in these skele tal muscle cells, we hypothesize that FGF-mediated repression of skele tal muscle differentiation activates signaling pathways distinct from those activated by the PDGF beta receptor. Activation of PDGF beta rec eptor tyrosine kinase activity, stimulation of MAP kinase, and upregul ation of immediate early gene expression are not sufficient to repress skeletal muscle differentiation.