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Selective Inhibition of Fibroblast Growth Factor (FGF)-stimulated Mitogenesis by a FGF Receptor-1-derived Phosphopeptide¹

Molecular Neurobiology Group, MRC Centre for Developmental Neurobiology, Kings College London, London Bridge, London SE1 1UL, United Kingdom

The activated fibroblast growth factor receptor (FGFR)-1 is phosphorylated on five tyrosine residues outside the catalytic site. Although one such residue, Tyr⁷³⁰, is flanked by potential binding sites for phosphotyrosine-interacting molecules, a physiological role for this region is still controversial. We report that a cell-permeant phosphopeptide mimic of this site, FGFR⁷³⁰(p)Y, inhibits FGF-mediated mitogenesis in cells with no effect on responses stimulated by other growth factors. A similar phosphopeptide corresponding to the phospholipase C binding site on the receptor had no effect on the mitogenic response. The FGFR⁷³⁰(p)Y peptide did not inhibit phosphorylation of p90/FRS2 or Erk, suggesting that it does not act by inhibiting the Erk-kinase cascade. However, the FGFR⁷³⁰(p)Y peptide bound Shc in a manner requiring both phosphorylated tyrosine and a putative PTB domain binding determinant. These data suggest that the peptide might inhibit mitogenesis by competing with the corresponding site on the FGFR for the ability to bind Shc.

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