Alpha 6 beta 4 integrin regulates keratinocyte chemotaxis through differential GTPase activation and antagonism of alpha 3 beta 1 integrin.
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.
Russell
Alan J
AJ
Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Fincher
Edgar F
EF
Millman
Linda
L
Smith
Robyn
R
Vela
Veronica
V
Waterman
Elizabeth A
EA
Dey
Clara N
CN
Guide
Shireen
S
Weaver
Valerie M
VM
Marinkovich
M Peter
MP
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
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