Coordination of cell polarization and migration by the Rho family GTPases requires Src tyrosine kinase activity

Background: The ability of a cell to polarize and move is governed by remod eling of the cellular adhesion/cytoskeletal network that is in turn control led by the Rho family of small GTPases. However, it is not known what signa ls lie downstream of Rac1 and Cdc42 during peripheral actin and adhesion re modeling that is required for directional migration. Results: We show here that individual members of the Rho family, RhoA, Rac1 , and Cdc42, direct the specific intracellular targeting of c-Src tyrosine kinase to focal adhesions, lamellipodia, or filopodia, respectively, and th at the adaptor function of c-Src (the combined SH3/SH2 domains coupled to g reen fluorescent protein) is sufficient for targeting. Furthermore, Src's c atalytic activity is absolutely required at these peripheral cell-matrix at tachment sites for remodeling that converts RhoA-dependent focal adhesions into smaller focal complexes along Rac1-induced lamellipodia (or Cdc42-indu ced filopodia). Consequently, cells in which kinase-deficient c-Src occupie s peripheral adhesion sites exhibit impaired polarization toward migratory stimuli and reduced motility. Furthermore, phosphorylation of FAK, an Sro a dhesion substrate, is suppressed under these conditions. Conclusions: Our findings demonstrate that individual Rho GTPases specify S rc's exact peripheral localization and that Rac1- and Cdc42-induced adhesio n remodeling and directed cell migration require Src activity at peripheral adhesion sites.