Critical role for the docking-protein FRS2 alpha in FGF receptor-mediated signal transduction pathways

The docking protein FRS2 alpha has been implicated as a mediator of signali ng via fibroblast growth factor receptors (FCFRs). We have demonstrated tha t targeted disruption of FRS2 alpha gene causes severe impairment in mouse development resulting in embryonal lethality at E7.0-E7.5, Experiments with FRS2 alpha -deficient fibroblasts demonstrate that FRS2 alpha plays a crit ical role in FGF-induced mitogen-activated protein (MAP) kinase stimulation , phosphatidylinositol-3 (PI-3) kinase activation, chemotactic response, an d cell proliferation. Following FGF stimulation, tyrosine phosphorylated FR S2 alpha functions as a site for coordinated assembly of a multiprotein com plex that includes Gab1 and the effector proteins that are recruited by thi s docking protein. Furthermore, we demonstrate that different tyrosine phos phorylation sites on FRS2 alpha are responsible for mediating different FGF -induced biological responses. These experiments establish the central role of FRS2 alpha in signaling via FCFRs and demonstrate that FRS2a mediates m ultiple FGFR-dependent signaling pathways critical for embryonic developmen t.