Traction forces mediated by alpha6beta4 integrin: implications for basement membrane organization and tumor invasion.
The integrin alpha6beta4, 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 alpha6beta4 on either laminin-1 or on an anti-alpha6 antibody, demonstrating that this integrin can transmit forces without the need to engage other integrins. These alpha6beta4-dependent traction forces were organized into a compression machine localized to the base of lamellae. We hypothesized that the compression forces generated by alpha6beta4 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 alpha6beta4-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 alpha6beta4, 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 alpha6beta4 in this remodeling. Our findings have important implications for the mechanism of both BM organization and tumor invasion.
Rabinovitz
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Department of Pathology, Division of Cancer Biology and Angiogenesis, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA. irabinov@caregroup.harvard.edu
Gipson
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Mercurio
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D000954:Antigens, Surface / Q000378:metabolism*; D001485:Basement Membrane / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D001943:Breast Neoplasms / Q000378:metabolism; D002448:Cell Adhesion; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D039161:Integrin alpha6beta4; D016023:Integrins / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D009361:Neoplasm Invasiveness; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011554:Pseudopodia / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D000954:Antigens, Surface; D039161:Integrin alpha6beta4; D016023:Integrins; D007797:Laminin