Focal adhesion kinase facilitates platelet-derived growth factor-BB-stimulated ERK2 activation required for chemotaxis migration of vascular smooth muscle cells

The focal adhesion (FAK) non-receptor protein-tyrosine kinase (PTR) links b oth extracellular matrix/integrin and growth factor stimulation to intracel lular signals promoting cell migration. Here we show that both transient an d stable overexpression of the FAR C-terminal domain termed FRNK (FAK-relat ed non-kinase) inhibits serum and platelet-derived growth factor (PDGF)HE-i nduced vascular smooth muscle cell (SMC) migration in wound healing and in vitro Boyden Chamber chemotaxis assays, respectively. Expression of FRNK, b ut not a point mutant of FRNK (FRNK L1034S), disrupted the formation of a c omplex containing both FAK and the activated PDGF-beta receptor and resulte d in reduced tyrosine phosphorylation of endogenous FAK at the Tyr-397 bind ing site for Src family PTKs. As demonstrated using:FAK-deficient and FAR-r econstituted fibroblasts, FAK positively contributed to PDGF-BB-stimulated ERK2/MAP kinase activity, and in SMCs, ERR2/MAP kinase activity was require d for PDGF-BB-stimulated chemotaxis, Stable expression of FRNK but not FRNK L1034S expression in SMCs lowered the extent and duration of stimulated ER K2/MAP kinase activation at low but not at high PDGF-BB concentrations. Imp ortantly, stable expression of FRNK in SMCs did not affect SMC morphology o r proliferation in culture. Because the increased migration of vascular SMC s in response to extracellular matrix proteins and growth factors contribut es to neointima formation, our results show that FAR inhibition by FRNK exp ression may provide a novel approach to regulate abnormal vascular SMC migr ation in vivo.