α6β4 integrin regulates keratinocyte chemotaxis through differential GTPase activation and antagonism of α3β1 integrin

Abstract

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 α6β4 integrin. We investigated the role of α6β4 integrin in laminin-5-dependent keratinocyte migration by re-expressing normal or attachment-defective β4 integrin in β4 integrin null keratinocytes. We found that expression of β4 integrin in either a ligand bound or ligand unbound state was necessary and sufficient for EGF-induced cell migration. In a ligand bound state, β4 integrin supported EGF-induced cell migration though sustained activation of Rac1. In the absence of α6β4 integrin ligation, Rac1 activation became tempered and EGF chemotaxis proceeded through an alternate mechanism that depended upon α3β1 integrin and was characterized by cell scattering. α3β1 integrin also relocalated from cell-cell contacts to sites of basal clustering where it displayed increased conformational activation. The aberrant distribution and activation of α3β1 integrin in attachment-defective β4 cells could be reversed by the activation of Rac1. Conversely, in WT β4 cells the normal cell-cell localization of α3β1 integrin became aberrant after the inhibition of Rac1. These studies indicate that the extracellular domain of β4 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.