Src family kinases are required for integrin but not PDGFR signal transduction

Src family kinases (SFKs) have been implicated as important regulators of l igand-induced cellular responses including proliferation, survival, adhesio n and migration. Analysis of SFK function has been impeded by extensive red undancy between family members. We have generated mouse embryos harboring f unctional null mutations of the ubiquitously expressed SFKs Src, Yes and Fy n, This triple mutation leads to severe developmental defects and lethality by E9.5. To elucidate the molecular mechanisms underlying this phenotype, SYF cells (deficient for Src, Yes and Fyn) were derived and tested for thei r ability to respond to growth factors or plating on extracellular matrix. Our studies reveal that while Src, Yes and Fyn are largely dispensable for platelet-derived growth factor (PDGF)-induced signaling, they are absolutel y required to mediate specific functions regulated by extracellular matrix proteins. Fibronectin-induced tyrosine phosphorylation of focal adhesion pr oteins, including the focal adhesion kinase FAK, was nearly eliminated in t he absence of Src, Yes and Fyn, Furthermore, consistent with previous repor ts demonstrating the importance of FAK for cell migration, SYF cells displa yed reduced motility in vitro. These results demonstrate that SFK activity is essential during embryogenesis and suggest that defects observed in SYF triple mutant embryos may be linked to deficiencies in signaling by extrace llular matrix-coupled receptors.