Phosphorylation of GMFγ by c-Abl coordinates lamellipodial and focal adhesion dynamics

Abstract

During cell migration a critical interdependence between protrusion and focal adhesion dynamics is established and tightly regulated through signaling cascades. Here we demonstrate that c-Abl, a non-receptor tyrosine kinase, can control these migratory structures through the regulation of two actin-associated proteins, glia maturation factor-γ (GMFγ) and Neural Wiskott-Aldrich syndrome protein (N-WASP). Phosphorylation of GMFγ at tyrosine-104 by c-Abl directs activated N-WASP (pY256) to the leading edge, where it can promote protrusion extension. Non-phosphorylated GMFγ guides N-WASP (pY256) to maturing focal adhesions to enhance further growth. Antagonizing this signaling pathway through knockdown or mutation of tyrosine-104 to its non-phosphorylated form attenuates migration, whereas the phospho-mimic mutant GMFγ enhances migration, thus demonstrating c-Abl, GMFγ, and activated N-WASP (pY256) as a critical signaling cascade for regulating migration in a primary human cell line.