THE FGF RECEPTOR-1 TYROSINE KINASE DOMAIN REGULATES MYOGENESIS BUT ISNOT SUFFICIENT TO STIMULATE PROLIFERATION

Ligand-stimulated activation of FGF receptors (FGFRs) in skeletal musc le cells represses terminal myogenic differentiation. Skeletal muscle cell lines and subsets of primary cells are dependent on FGFs to repre ss myogenesis and maintain growth. To understand the intracellular eve nts that transduce these signals, MM14 skeletal muscle cells were tran sfected with expression vectors encoding chimeric receptors. The chime ras are comprised of the PDGF beta receptor (PDGF beta R) extracellula r domain, the FGFR-1 intracellular domain, and either the PDGF beta R or FGFR-1 transmembrane domain. The chimeric receptors were autophosph orylated upon PDGF-BB stimulation and are capable of stimulating mitog en-activated protein kinase activity. Activation of the tyrosine kinas e domain of either chimera repressed myogenesis, suggesting intracellu lar responses regulating skeletal muscle differentiation are transduce d by activation of the FGFR-1 tyrosine kinase. Unexpectedly, we found that activation of either chimeric receptor failed to stimulate cellul ar proliferation. Thus, it appears that regulation of skeletal muscle differentiation by FGFs requires only activation of the FGFR-1 tyrosin e kinase. In contrast, stimulation of proliferation may require additi onal, as yet unidentified, signals involving the receptor ectodomain, the FGF ligand, and heparan sulfate either alone, or in combination.