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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 the matrix ligand laminin-5. A second integrin ligand, the urokinase receptor (uPAR), associates with {alpha}3ß1 via a surface loop within the {alpha}3 ß-propeller (residues 242–246) but outside the laminin binding region, suggesting that uPAR–integrin interactions could signal differently from matrix engagement. To explore this, {alpha}3-/- epithelial cells were reconstituted with wild-type (wt) {alpha}3 or {alpha}3 with Ala mutations within the uPAR-interacting loop (H245A or R244A). Wt or mutant-bearing cells showed comparable expression and adhesion to laminin-5. Cells expressing wt {alpha}3 and 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 1–251 restored the epithelial phenotype. The H245A and R244A mutants were unaffected by coexpression of uPAR. We conclude that {alpha}3ß1 regulates 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 pathway for 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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