FIBROBLAST GROWTH-FACTOR RECEPTORS DISPLAY BOTH COMMON AND DISTINCT SIGNALING PATHWAYS

We compared the mitogenic and signaling pathways of three Fibroblast G rowth Factor Receptors (FGFRs), FGFR1, KGFR and FGFR4 in the same cell line. Each receptor was expressed in L6E9 rat myoblasts that do not n ormally express detectable levels of FGFRs and clones that express com parable levels of each receptor were selected. Our results show that F GFs induce an effective survival and growth of FGFR1 and KGFR expressi ng cells. In addition, these cells exhibit a morphology that is remini scent of that of malignantly transformed cells and display anchorage i ndependent growth in a ligand dependent manner. Unlike KGFR and FGFR1, FGFR4 mediates a less effective growth, and cells overexpressing this receptor do not undergo any morphological changes nor do they display an anchorage independent growth in response to FGFs, All three recept ors exhibit both quantitative and qualitative differences in their abi lity to induce tyrosine phosphorylation of cellular substrates, Both F GFR1 and KGFR induce strong phosphorylation of phospholipase C-gamma a nd a 90 kDa protein, while FGFR4 induces a relatively weak phosphoryla tion of phospholipase C-gamma and completely fails to induce phosphory lation of the 90 kDa. The three receptors also induce phosphorylation of the mitogen activated protein kinases (MAPK) but the effect of FGFR 1 is far stronger than that of the other two receptors, Since FGFR4 is expressed in myoblasts in vivo, we examined whether this receptor can function in the differentiation pathway of myoblasts. Contrary to its weak mitogenic activity, FGFR4 effectively mediates the inhibition of myogenic differentiation in L6E9 cells and also suppresses the expres sion of the myogenic regulatory protein myogenin, Taken together, our results suggest that the signaling mechanism of FGFR4 differs from tha t of FGFR1 and KGFR, and that the primary role of FGFR4 in myoblasts m ay be the maintenance of their non differentiated state.