Selective inhibition of fibroblast growth factor (FGF)-stimulated mitogenesis by a FGF receptor-1-derived phosphopeptide.
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 Cgamma 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.
Dunican
D J
DJ
Molecular Neurobiology Group, MRC Centre for Developmental Neurobiology, Kings College London, London Bridge, London SE1 1UL, United Kingdom.
Williams
E J
EJ
Howell
F V
FV
Doherty
P
P
D016475:3T3 Cells; D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D051380:GRB2 Adaptor Protein; D007527:Isoenzymes / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D008934:Mitogens / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D008969:Molecular Sequence Data; D051966:Phospholipase C gamma; D010748:Phosphopeptides / Q000378:metabolism* / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D012455:Salamandridae; D010738:Type C Phospholipases / Q000378:metabolism; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D007527:Isoenzymes; D008934:Mitogens; D010748:Phosphopeptides; D011506:Proteins; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; C496349:Fgfr1 protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma