Selective inhibition of fibroblast growth factor (FGF)-stimulated mitogenesis by a FGF receptor-1-derived phosphopeptide

Cell Growth Differ. 2001 May;12(5):255-64.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Adaptor Proteins, Signal Transducing*
  • Amino Acid Sequence
  • Animals
  • Cells, Cultured
  • Fibroblast Growth Factors / antagonists & inhibitors
  • Fibroblast Growth Factors / metabolism*
  • Fibroblast Growth Factors / pharmacology
  • GRB2 Adaptor Protein
  • Isoenzymes / metabolism
  • MAP Kinase Signaling System
  • Mice
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogens / antagonists & inhibitors
  • Mitogens / metabolism*
  • Mitogens / pharmacology
  • Molecular Sequence Data
  • Phospholipase C gamma
  • Phosphopeptides / metabolism*
  • Phosphopeptides / pharmacology
  • Proteins / metabolism
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptors, Fibroblast Growth Factor / metabolism*
  • Salamandridae
  • Type C Phospholipases / metabolism
  • src Homology Domains

Substances

  • Adaptor Proteins, Signal Transducing
  • GRB2 Adaptor Protein
  • Grb2 protein, mouse
  • Isoenzymes
  • Mitogens
  • Phosphopeptides
  • Proteins
  • Receptors, Fibroblast Growth Factor
  • Fibroblast Growth Factors
  • Fgfr1 protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Fibroblast Growth Factor, Type 1
  • Mitogen-Activated Protein Kinases
  • Type C Phospholipases
  • Phospholipase C gamma