Model for adhesion-dependent cell edge protrusion. (Step 1) Arg localizes to the cell periphery and binds the SH3 domain of cortactin via its PXXP1 motif. (Step 2) The kinase activity of Arg is activated upon adhesion. Arg phosphorylates cortactin, creating an additional binding site to the Arg SH2 domain. In the absence of Arg, Abl can phosphorylate cortactin in the presence of soluble growth factors. (Step 3a) Cortactin phosphorylation leads to a remodeling of the Arg–cortactin complex, allowing the cortactin SH3 domain to interact with N-WASp. These interactions lead to actin remodeling and protrusion formation. (Step 3b) Alternatively or in addition, cortactin phosphorylation recruits other SH2 domain–containing proteins such as Nck1. Nck1 contains three SH3 domains, which can interact with and activate N-WASp to promote actin polymerization. GBD, GTPase-binding domain; MT, microtubule; VCA, verprolin-cofilin-acidic domain.