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© The Rockefeller University Press, 0021-9525/1997//1873 $5.00
The Journal of Cell Biology, Volume 139, Number 7, , 1997 1873-1884

Article

The Integrin {alpha}6β4 Functions in Carcinoma Cell Migration on Laminin-1 by Mediating the Formation and Stabilization of Actin-containing Motility Structures



Isaac Rabinovitz and Arthur M. Mercurio

Department of Medicine (GI Division), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

Functional studies on the {alpha}6β4 integrin have focused primarily on its role in the organization of hemidesmosomes, stable adhesive structures that associate with the intermediate filament cytoskeleton. In this study, we examined the function of the {alpha}6β4 integrin in clone A cells, a colon carcinoma cell line that expresses {alpha}6β4 but no {alpha}6β1 integrin and exhibits dynamic adhesion and motility on laminin-1. Time-lapse videomicroscopy of clone A cells on laminin-1 revealed that their migration is characterized by filopodial extension and stabilization followed by lamellae that extend in the direction of stabilized filopodia. A function-blocking mAb specific for the {alpha}6β4 integrin inhibited clone A migration on laminin-1. This mAb also inhibited filopodial formation and stabilization and lamella formation. Indirect immunofluorescence microscopy revealed that the {alpha}6β4 integrin is localized as discrete clusters in filopodia, lamellae, and retraction fibers. Although β1 integrins were also localized in the same structures, a spatial separation of these two integrin populations was evident. In filopodia and lamellae, a striking colocalization of the {alpha}6β4 integrin and F-actin was seen. An association between {alpha}6β4 and F-actin is supported by the fact that {alpha}6β4 integrin and actin were released from clone A cells by treatment with the F-actin– severing protein gelsolin and that {alpha}6β4 immunostaining at the marginal edges of clone A cells on laminin-1 was resistant to solubilization with Triton X-100. Cytokeratins were not observed in filopodia and lamellipodia. Moreover, {alpha}6β4 was extracted from these marginal edges with a Tween-40/deoxycholate buffer that solubilizes the actin cytoskeleton but not cytokeratins. Three other carcinoma cell lines (MIP-101, CCL-228, and MDA-MB-231) exhibited {alpha}6β4 colocalized with actin in filopodia and lamellae. Formation of lamellae in these cells was inhibited with an {alpha}6-specific antibody. Together, these results indicate that the {alpha}6β4 integrin functions in carcinoma migration on laminin-1 through its ability to promote the formation and stabilization of actin-containing motility structures.

Address all correspondence to Arthur M. Mercurio, Beth Israel Deaconess Medical Center-Dana 601, 330 Brookline Ave., Boston, MA 02215. Tel.: (617) 667-7714. Fax: (617) 975-5071. E-mail: amercuri{at}bih.harvard.edu


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