Cortactin regulates cell migration through activation of N-WASP

Abstract

Cortactin is an actin-associated scaffolding protein that regulates cell migration. Amplification of the human gene, EMS1, has been detected in breast, head and neck tumors, where it correlates with increased invasiveness. Cortactin can regulate actin dynamics directly via its N-terminal half, which can bind and activate the Arp2/3 complex. The C-terminal portion of cortactin, however, is thought to have limited function in its regulation of the actin polymerization machinery. In this report, we identify a role for the cortactin C-terminus in regulating cell migration and, more specifically, actin dynamics. Overexpression of either full-length cortactin or cortactin C-terminus is sufficient to enhance migration of mammary epithelial cells. In vitro, cortactin binds to and activates, via its SH3 domain, a regulator of the Arp2/3 complex, neural Wiskott Aldrich Syndrome protein (N-WASP). This in vitro activation of N-WASP is likely to be important in vivo, as cortactin-enhanced migration is dependent upon N-WASP. Thus, our results suggest that cortactin has multiple mechanisms by which it can recruit and modulate the actin machinery and ultimately regulate cell migration.

Abl2/Abl-related Gene Stabilizes Actin Filaments, Stimulates Actin Branching by Actin-related Protein 2/3 Complex, and Promotes Actin Filament Severing by Cofilin

“…Effects of Arg on Branch Formation by Arp2/3 ComplexCortactin weakly activates branch formation by the Arp2/3 complex on its own, but it robustly stimulates branch formation when combined with the nucleation-promoting factor N-WASp (9,(35)(36)(37). We confirmed that 1 M cortactin increased branching by Arp2/3 complex and N-WASp GST-VCA ϳ3-fold (Fig.…”

Neural Wiskott-Aldrich Syndrome Protein (N-WASP)-mediated p120-Catenin Interaction with Arp2-Actin Complex Stabilizes Endothelial Adherens Junctions

“…p120-catenin has emerged as a master regulator of VE-cadherin stability as it prevents VE-cadherin endocytosis by clathrin-coated adaptor AP1 (17,37,39) and restricts RhoA activity (40,41). A recent study showed that in fibroblasts, p120-catenin also induces the activation of cortactin, a well known partner of N-WASP (42), to induce lamellipodia formation for their migratory events (33). We ruled out the role of p120-catenin as the activator of N-WASP because knockdown of p120-catenin had no effect on N-WASP activity or the interaction of N-WASP with Arp2 and actin.…”

Dynamics between actin and the VE-cadherin/catenin complex

“…79,80,83,85,99,100 Furthermore, cortactin has multiple functions in cell motility and is able to activate N-WASP. 101 For further readings to cortactin, please see recent reviews. [102][103][104][105] Both WASP and cortactin are targeted and activated by a number of cellular signals.…”