LAUSR

Alpha-ACTN4, a member of alpha-actinin family is critical for cell motility through its regulated binding of actin filaments. We previously found that EGF exposure of cells triggers the tyrosyl-phosphorylation of ACTN4 in fibroblasts that dramatically downregulates its binding to actin filaments. However, the exact kinase remained uncertain. In the present study, we report that the phosphorylation of ACTN4 occurs within seconds upon EGF treatments and is accomplished via direct interaction of ACTN4 with the EGF receptor. The major binding domain of ACTN4 for EGF receptor is mapped to the N-terminal 32 amino acids. A second domain minimizes the interaction, as truncation of the C-terminal tail enhances ACTN4 binding to EGF receptor. A mimetic phosphorylated ACTN4, Y4/31E, presents low binding to EGF receptor. Overexpression of EGF receptor in melanoma cell lines, also accomplishes the phosphorylation of ACTN4 in the presence of EGF. These findings suggest that the binding of ACTN4 to EGFR enables its direct and rapid phosphorylation resulting in dissociation from EGFR and decreased binding to actin filaments.