FIBROBLAST GROWTH-FACTOR RECEPTOR-1 REGULATION OF SRC FAMILY KINASES

Fibroblast growth factors (FGFs) induce proliferation and differentiat ion of a wide variety of cells by stimulation of cell surface expresse d high affinity-binding receptor tyrosine kinases. Members of the Src family of cytoplasmic tyrosine kinases are substrates for certain grow th factor receptors, We have examined interactions between FGF recepto r-1 (FGFR-1) and Src, Fyn and Yes. In lung capillary endothelial cells and murine fibroblasts, bFGF stimulation led to increased autophospho rylation of Src family members, In contrast, in porcine aortic endothe lial cells (FGFR-1/PAE) and lung fibroblasts from chinese hamster (CCL 39), activation of FGFR caused reduced autophosphorylation of Src and Fyn. In neither case could complex-formation between Src members and FGFR be seen, Analysis of a panel of mutated FGFR-1 expressed in PAE c ells showed that FGFR-1/Y766F mediated an increased autophosphorylatio n of Src members and upregulation of their kinase activities, Y766 in FGFR-1 has been shown to serve as a binding site for phospholipase C-g amma, which regulates Ca2+ fluxes and protein kinase C (PKC) activity. The negative effect on Src kinase activity upon FGFR stimulation was mimicked by activation of PKC in FGFR-1/PAE or CCL 39 cells using phor bol 12-myristate 13-acetate (PMA) and Src was phosphorylated in vitro by purified recombinant PKC alpha. Moreover, inhibition of PBC attenua ted the bFGF induced decrease in autophosphorylation of Src family mem bers, These data indicate a negative regulatory role for PRC on Src ki nase activity in certain cell types.