Traction Forces Mediated by α6β4 Integrin: Implications for Basement Membrane Organization and Tumor Invasion

Abstract

The integrin α6β4, a laminin receptor that stabilizes epithelial cell adhesion to the basement membrane (BM) through its association with cytokeratins, can stimulate the formation and stabilization of actin-rich protrusions in carcinoma cells. An important, unresolved issue, however, is whether this integrin can transmit forces to the substrate generated by the acto-myosin system. Using a traction-force detection assay, we detected forces exerted through α6β4 on either laminin-1 or on an anti-α6 antibody, demonstrating that this integrin can transmit forces without the need to engage other integrins. These α6β4-dependent traction forces were organized into a compression machine localized to the base of lamellae. We hypothesized that the compression forces generated by α6β4 result in the remodeling of BMs because this integrin plays a major role in the interaction of epithelial and carcinoma cells with such structures. Indeed, we observed that carcinoma cells are able to remodel a reconstituted BM through α6β4-mediated compression forces by a process that involves the packing of BM material under the cells and the mechanical removal of BM from adjacent areas. The distinct signaling functions of α6β4, which activate phosphoinositide 3-OH kinase and RhoA, also contribute to remodeling. Importantly, we demonstrate remodeling of a native BM by epithelial cells and the involvement of α6β4 in this remodeling. Our findings have important implications for the mechanism of both BM organization and tumor invasion.