J. Cell Biol., Volume 141, Number 2, April 20, 1998 515-526

Integrin and Cadherin Synergy Regulates Contact Inhibition of Migration and Motile Activity

Anna Huttenlocher,^* Margot Lakonishok,^* Melissa Kinder,^* Stanley Wu,^* Tho Truong,^* Karen A. Knudsen,^§ and Alan F. Horwitz^*

^* Department of Cell and Structural Biology,  Department of Pediatrics, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801; and ^§ Lankenau Medical Research Center, Wynnewood, Pennsylvania 19096

Integrin receptors play a central role in cell migration through their roles as adhesive receptors for both other cells and extracellular matrix components. In this study, we demonstrate that integrin and cadherin receptors coordinately regulate contact-mediated inhibition of cell migration. In addition to promoting proliferation (Sastry, S., M. Lakonishok, D. Thomas, J. Muschler, and A. Horwitz. 1996. J. Cell Biol. 133:169-184), ectopic expression of the 5 integrin in cultures of primary quail myoblasts promotes a striking contact-mediated inhibition of cell migration. Myoblasts ectopically expressing 5 integrin (5 myoblasts) move normally when not in contact, but upon contact, they show inhibition of migration and motile activity (i.e., extension and retraction of membrane protrusions). As a consequence, these cells tend to grow in aggregates and do not migrate to close a wound. This phenotype is also seen with ectopic expression of 1 integrin, paxillin, or activated FAK (CD2 FAK) and therefore appears to result from enhanced integrin-mediated signaling. The contact inhibition observed in the 5 myoblasts is mediated by N-cadherin, whose expression is upregulated more than fivefold. Perturbation studies using low calcium conditions, antibody inhibition, and ectopic expression of wild-type and mutant N-cadherins all implicate N-cadherin in the contact inhibition of migration. Ectopic expression of N-cadherin also produces cells that show inhibited migration upon contact; however, they do not show suppressed motile activity, suggesting that integrins and cadherins coordinately regulate motile activity. These observations have potential importance to normal and pathologic processes during embryonic development and tumor metastasis.

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