title: Alpha 6 beta 4 integrin regulates keratinocyte chemotaxis through differential GTPase activation and antagonism of alpha 3 beta 1 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 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.
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Russell
authors.forename: Edgar F
authors.initials: EF
authors.lastname: Fincher
authors.forename: Linda
authors.initials: L
authors.lastname: Millman
authors.forename: Robyn
authors.initials: R
authors.lastname: Smith
authors.forename: Veronica
authors.initials: V
authors.lastname: Vela
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Waterman
authors.forename: Clara N
authors.initials: CN
authors.lastname: Dey
authors.forename: Shireen
authors.initials: S
authors.lastname: Guide
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Weaver
authors.forename: M Peter
authors.initials: MP
authors.lastname: Marinkovich
mesh_terms: D015815:Cell Adhesion Molecules / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D002633:Chemotaxis / Q000502:physiology*; D003001:Cloning, Molecular; D004815:Epidermal Growth Factor / Q000378:metabolism; D004820:Epidermolysis Bullosa / Q000378:metabolism; D006801:Humans; D039201:Integrin alpha3beta1 / Q000378:metabolism*; D039161:Integrin alpha6beta4 / Q000378:metabolism*; D007365:Intercellular Junctions / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011554:Pseudopodia / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology*; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000097794:Kalinin
chemical_list: D015815:Cell Adhesion Molecules; D004815:Epidermal Growth Factor; D039201:Integrin alpha3beta1; D039161:Integrin alpha6beta4; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D000097794:Kalinin