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