Distinct ligand binding sites in integrin {alpha}3{beta}1 regulate matrix adhesion and cell-cell contact

doi:10.1083/jcb.200304065

Published 13 October 2003. doi:10.1083/jcb.200304065

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© The Rockefeller University Press, 0021-9525/2003/10/177 $8.00
The Journal of Cell Biology, Volume 163, Number 1, 177-188

Article

Distinct ligand binding sites in integrin ${alpha}$ 3ß1 regulate matrix adhesion and cell–cell contact

Feng Zhang¹, Clifford C. Tom¹, Matthias C. Kugler¹, Tsui-Ting Ching¹, Jordan A. Kreidberg², Ying Wei¹ and Harold A. Chapman¹

¹ Department of Medicine and Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA 94143
² Department of Medicine, Harvard Medical School, Boston, MA 02115

Address correspondence to Harold A. Chapman, Pulmonary and Critical Care Division, University of California San Francisco, 513 Parnassus Ave., San Francisco, CA 94143-0130. Tel.: (415) 514-1210. Fax: (415) 502-4995. email: halchap{at}itsa.ucsf.edu; or Ying Wei, Tel.: (415) 514-3435. email: yingwei{at}itsa.ucsf.edu

The integrin ${alpha}$ 3ß1 mediates cellular adhesion to thematrix ligand laminin-5. A second integrin ligand, the urokinasereceptor (uPAR), associates with ${alpha}$ 3ß1 via a surfaceloop within the ${alpha}$ 3 ß-propeller (residues 242–246)but outside the laminin binding region, suggesting that uPAR–integrininteractions could signal differently from matrix engagement.To explore this, ${alpha}$ 3^-/- epithelial cells were reconstituted withwild-type (wt) ${alpha}$ 3 or ${alpha}$ 3 with Ala mutations within the uPAR-interactingloop (H245A or R244A). Wt or mutant-bearing cells showed comparableexpression and adhesion to laminin-5. Cells expressing wt ${alpha}$ 3and uPAR dissociated in culture, with increased Src activity,up-regulation of SLUG, and down-regulation of E-cadherin and ${gamma}$ -catenin. Src kinase inhibition or expression of Src 1–251restored the epithelial phenotype. The H245A and R244A mutantswere unaffected by coexpression of uPAR. We conclude that ${alpha}$ 3ß1regulates both cell–cell contact and matrix adhesion,but through distinct protein interaction sites within its ß-propeller.These studies reveal an integrin- and Src-dependent pathwayfor SLUG expression and mesenchymal transition.

Key Words: integrin ${alpha}$ 3ß1; urokinase receptor; Src; SLUG; epithelial and mesenchymal transition

The online version of this article includes supplemental material.

Abbreviations used in this paper: uPAR, urokinase receptor;wt, wild type.

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