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JCS ePress online publication date 15 Jul 2003
doi: 10.1242/jcs.00663

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Research Article

{alpha}6{beta}4 integrin regulates keratinocyte chemotaxis through differential GTPase activation and antagonism of {alpha}3{beta}1 integrin


Alan J. Russell, Edgar F. Fincher, Linda Millman, Robyn Smith, Veronica Vela, Elizabeth A. Waterman, Clara N. Dey, Shireen Guide, Valerie M. Weaver, and M. Peter Marinkovich*
* Author for correspondence (e-mail: mpm{at}stanford.edu)

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}6{beta}4 integrin. We investigated the role of {alpha}6{beta}4 integrin in laminin-5-dependent keratinocyte migration by re-expressing normal or attachment-defective {beta}4 integrin in {beta}4 integrin null keratinocytes. We found that expression of {beta}4 integrin in either a ligand bound or ligand unbound state was necessary and sufficient for EGF-induced cell migration. In a ligand bound state, {beta}4 integrin supported EGF-induced cell migration though sustained activation of Rac1. In the absence of {alpha}6{beta}4 integrin ligation, Rac1 activation became tempered and EGF chemotaxis proceeded through an alternate mechanism that depended upon {alpha}3{beta}1 integrin and was characterized by cell scattering. {alpha}3{beta}1 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}3{beta}1 integrin in attachment-defective {beta}4 cells could be reversed by the activation of Rac1. Conversely, in WT {beta}4 cells the normal cell-cell localization of {alpha}3{beta}1 integrin became aberrant after the inhibition of Rac1. These studies indicate that the extracellular domain of {beta}4 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.


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