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A more recent version of this article appeared on August 1, 2002
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Submitted on February 25, 2002
Revised on April 23, 2002
Accepted on May 15, 2002
1 Department of Genetics and Pathology, Uppsala University, Rudbeck Laboratory, S-751 85, Uppsala, Sweden
2 Department of Medical Cell Biology, Uppsala University, Biomedical Center, S 751 23, Uppsala, Sweden
3 Department of Medical Cell Biology, Uppsala University, Biomedical Center, S-751 23, Uppsala, Sweden
* Corresponding author. E-mail address: Michael.Cross{at}genpat.uu.se.
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-
(PLC-). 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-
and the intracellular domain of FGFR-1. Mutation of tyrosine 766 to phenylalanine prevented PLC- 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- 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.
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