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Selective inhibition of fibroblast growth factor (FGF)-stimulated mitogenesis by a FGF receptor-1-derived
D J Dunican1, E J Williams, F V Howell
1Molecular Neurobiology Group, MRC Centre for Developmental Neurobiology, Kings College London, London Bridge, London SE1 1UL, United Kingdom.
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.
Insights
A novel phosphopeptide targeting fibroblast growth factor receptor (FGFR)-1 inhibits FGF-mediated cell growth. This peptide, FGFR730(p)Y, may block Shc protein binding, impacting mitogenesis.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Fibroblast growth factor receptor (FGFR)-1 activation involves tyrosine phosphorylation outside its catalytic site.
- The physiological role of phosphorylation at Tyr730 on FGFR-1 remains debated, despite potential binding sites for phosphotyrosine-interacting molecules.
Purpose of the Study:
- To investigate the functional significance of the Tyr730 residue in FGFR-1 signaling.
- To determine if a phosphopeptide mimic of Tyr730 can inhibit FGF-mediated cellular responses.
Main Methods:
- Synthesis of a cell-permeant phosphopeptide mimic of the FGFR-1 Tyr730 site (FGFR730(p)Y).
- Assessing the effect of FGFR730(p)Y on FGF-mediated mitogenesis and responses to other growth factors.
- Investigating the interaction of FGFR730(p)Y with intracellular signaling proteins, including Shc and components of the Erk-kinase cascade.
Main Results:
- FGFR730(p)Y specifically inhibited FGF-mediated mitogenesis without affecting other growth factor responses.
- The peptide did not inhibit phosphorylation of p90/FRS2 or Erk, indicating it does not block the Erk-kinase cascade.
- FGFR730(p)Y demonstrated binding to Shc, dependent on both phosphorylated tyrosine and a PTB domain binding determinant.
Conclusions:
- The Tyr730 site on FGFR-1 plays a role in FGF-mediated mitogenesis.
- FGFR730(p)Y peptide inhibits mitogenesis likely by competing with the native FGFR-1 Tyr730 site for Shc binding.
- These findings provide insights into FGFR-1 signaling pathways and potential therapeutic targets.