The Shb adaptor protein binds to tyrosine 766 in the FGFR-1 and regulates the Ras/MEK/MAPK pathway via FRS2 phosphorylation in endothelial cells.

Stimulation of fibroblast growth factor receptor-1 (FGFR-1) is known to result in phosphorylation of tyrosine 766 and the recruitment and subsequent activation of phospholipase C-gamma (PLC-gamma). To assess the role of tyrosine 766 in endothelial cell function, we generated endothelial cells expressing a chimeric receptor, composed of the extracellular domain ...
of the PDGF receptor-alpha and the intracellular domain of FGFR-1. Mutation of tyrosine 766 to phenylalanine prevented PLC-gamma activation and resulted in a reduced phosphorylation of FRS2 and reduced activation of the Ras/MEK/MAPK pathway relative to the wild-type chimeric receptor. However, FGFR-1-mediated MAPK activation was not dependent on PKC activation or intracellular calcium, both downstream mediators of PLC-gamma activation. We report that the adaptor protein Shb is also able to bind tyrosine 766 in the FGFR-1, via its SH2 domain, resulting in its subsequent phosphorylation. Overexpression of an SH2 domain mutant Shb caused a dramatic reduction in FGFR-1-mediated FRS2 phosphorylation with concomitant perturbment of the Ras/MEK/MAPK pathway. Expression of the chimeric receptor mutant and the Shb SH2 domain mutant resulted in a similar reduction in FGFR-1-mediated mitogenicity. We conclude, that Shb binds to tyrosine 766 in the FGFR-1 and regulates FGF-mediated mitogenicity via FRS2 phosphorylation and the subsequent activation of the Ras/MEK/MAPK pathway.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Animals, Cell Line, Cyclic AMP-Dependent Protein Kinases, Endothelium, Vascular, Fibroblast Growth Factor 2, Helminth Proteins, MAP Kinase Kinase Kinase 1, MAP Kinase Signaling System, Membrane Proteins, Mice, Mitogen-Activated Protein Kinases, Mutation, Phospholipase C gamma, Phosphoproteins, Phosphorylation, Platelet-Derived Growth Factor, Protein Binding, Protein Kinase C, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Receptor Protein-Tyrosine Kinases, Receptor, Fibroblast Growth Factor, Type 1, Receptor, Platelet-Derived Growth Factor alpha, Receptors, Fibroblast Growth Factor, Recombinant Fusion Proteins, Type C Phospholipases, Tyrosine, ras Proteins, src Homology Domains, src-Family Kinases
Mol. Biol. Cell
Date: Aug. 01, 2002
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