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-{gamma} (GMF{gamma}) and Neural Wiskott-Aldrich syndrome protein (N-WASP). Phosphorylation of GMF{gamma} at tyrosine-104 by c-Abl directs activated N-WASP (pY256) to the leading edge, where it can promote protrusion extension. Non-phosphorylated GMF{gamma} 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 GMF{gamma} enhances migration, thus demonstrating c-Abl, GMF{gamma}, and activated N-WASP (pY256) as a critical signaling cascade for regulating migration in a primary human cell line.