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First published online 15 July 2003
doi: 10.1242/jcs.00663

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Journal of Cell Science 116, 3543-3556 (2003)
doi: 10.1242/jcs.00663

Research Article

{alpha}6ß4 integrin regulates keratinocyte chemotaxis through differential GTPase activation and antagonism of {alpha}3ß1 integrin

Alan J. Russell1,*, Edgar F. Fincher1, Linda Millman1, Robyn Smith1, Veronica Vela1, Elizabeth A. Waterman1, Clara N. Dey1, Shireen Guide1, Valerie M. Weaver2 and M. Peter Marinkovich1,{ddagger}

1 Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
2 Pathology & Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA 19104, USA

{ddagger} Author for correspondence (e-mail: mpm{at}stanford.edu)

Accepted 12 May 2003

Growth factor-induced cell migration and proliferation are essential for epithelial wound repair. Cell migration during wound repair also depends upon expression of laminin-5, a ligand for {alpha}6ß4 integrin. We investigated the role of {alpha}6ß4 integrin in laminin-5-dependent keratinocyte migration by re-expressing normal or attachment-defective ß4 integrin in ß4 integrin null keratinocytes. We found that expression of ß4 integrin in either a ligand bound or ligand unbound state was necessary and sufficient for EGF-induced cell migration. In a ligand bound state, ß4 integrin supported EGF-induced cell migration though sustained activation of Rac1. In the absence of {alpha}6ß4 integrin ligation, Rac1 activation became tempered and EGF chemotaxis proceeded through an alternate mechanism that depended upon {alpha}3ß1 integrin and was characterized by cell scattering. {alpha}3ß1 integrin also relocalated from cell-cell contacts to sites of basal clustering where it displayed increased conformational activation. The aberrant distribution and activation of {alpha}3ß1 integrin in attachment-defective ß4 cells could be reversed by the activation of Rac1. Conversely, in WT ß4 cells the normal cell-cell localization of {alpha}3ß1 integrin became aberrant after the inhibition of Rac1. These studies indicate that the extracellular domain of ß4 integrin, through its ability to bind ligand, functions to integrate the divergent effects of growth factors on the cytoskeleton and adhesion receptors so that coordinated keratinocyte migration can be achieved.

Key words: {alpha}6ß4 Integrin, EGF, Laminin-5, Keratinocyte, Chemotaxis




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