Fibroblast growth factor receptor-1 regulation of Src family kinases.
Fibroblast growth factors (FGFs) induce proliferation and differentiation of a wide variety of cells by stimulation of cell surface expressed high affinity-binding receptor tyrosine kinases. Members of the Src family of cytoplasmic tyrosine kinases are substrates for certain growth factor receptors. We have examined interactions between FGF receptor-1 (FGFR-1) and Src, Fyn and Yes. In lung capillary endothelial cells and murine fibroblasts, bFGF stimulation led to increased autophosphorylation of Src family members. In contrast, in porcine aortic endothelial 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 cells showed that FGFR-1/Y766F mediated an increased autophosphorylation 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-gamma, 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 phorbol 12-myristate 13-acetate (PMA) and Src was phosphorylated in vitro by purified recombinant PKC alpha. Moreover, inhibition of PKC attenuated the bFGF induced decrease in autophosphorylation of Src family members. These data indicate a negative regulatory role for PKC on Src kinase activity in certain cell types.
Landgren
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E
Ludwig Institute for Cancer Research, Uppsala Branch, Sweden.
Blume-Jensen
P
P
Courtneidge
S A
SA
Claesson-Welsh
L
L
D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology*; D013552:Swine
D011518:Proto-Oncogene Proteins; D017468:Receptors, Fibroblast Growth Factor; D015688:Oncogene Protein pp60(v-src); D011493:Protein Kinase C