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Vol. 12, Issue 12, 4030-4043, December 2001
6
4 Integrin:
Implications for Basement Membrane Organization and Tumor
Invasion
§ and
*Department of Pathology, Division of Cancer Biology and
Angiogenesis, Beth Israel Deaconess Medical Center, Boston,
Massachusetts 02115; §Schepens Eye Research Institute,
Boston, Massachusetts 02115; and The integrin Harvard Medical School,
Boston, Massachusetts 02115
6
4, 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 64 on either laminin-1 or on an anti-6
antibody, demonstrating that this integrin can transmit forces
without the need to engage other integrins. These
64-dependent traction forces were organized into a compression machine localized to the base of lamellae. We hypothesized that the
compression forces generated by 64 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 64-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
64, 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 64 in
this remodeling. Our findings have important implications for the
mechanism of both BM organization and tumor invasion.
Online version of this article contains video
material for certain figures. Online version available at
www.molbiolcell.org.
Corresponding author. E-mail address:
irabinov{at}caregroup.harvard.edu.
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