Synergistic Promotion of c-Src Activation and Cell Migration by Cas and AND-34/BCAR3

Rebecca B Riggins,Lawrence A Quilliam,Amy H Bouton

doi:10.1074/jbc.m303535200

Abstract

The adapter molecule p130Cas (Cas) plays a role in cellular processes such as proliferation, survival, cell adhesion, and migration. The ability of Cas to promote migration has been shown to be dependent upon its carboxyl terminus, which contains a bipartite binding site for the protein tyrosine kinase c-Src (Src). The association between Src and Cas enhances Src kinase activity, and like Cas, Src plays an important role in cell proliferation and migration. In this study, we show that Src and Cas function cooperatively to promote cell migration in a manner that depends upon kinase-active Src. Another carboxyl-terminal binding partner of Cas, AND-34/BCAR3 (AND-34), functions synergistically with Cas to enhance Src activation and cell migration. The carboxyl-terminal guanine nucleotide exchange factor domain of AND-34, as well as the activity of its putative target Rap1, contribute to these events. A mechanism through which AND-34 may regulate Cas-dependent cell migration is suggested by the finding that Cas becomes redistributed from focal adhesions to lamellipodia located at the leading edge of AND-34 overexpressing cells. These data thus provide insight into how Cas and AND-34 may function together to stimulate Src signaling pathways and promote cell migration.

Highlights

One of the major initiating events for cell migration is engagement of integrin receptors by extracellular matrix (ECM) ligands
Functions Associated with the guanine nucleotide exchange factors (GEFs) Domain of AND-34 — Because the GEF domain located at the carboxyl terminus of AND-34 has been reported to have activity toward RalA, Rap1, and R-Ras [37], we hypothesized that enhancement of Src activation and Src/Cas-dependent cell migration by AND-34 may occur through a mechanism that involves activation of one or more of these GTPases
This study focuses on elucidating mechanisms by which two molecules, Cas and AND-34, modulate Src kinase activity and promote cell migration

Summary

Introduction

One of the major initiating events for cell migration is engagement of integrin receptors by ECM ligands. The ability of Cas to promote migration has been shown to be dependent upon its carboxyl terminus, which contains a bipartite binding site for the protein tyrosine kinase c-Src (Src).

Results

Conclusion