Rac recruits high-affinity integrin alphavbeta3 to lamellipodia in endothelial cell migration.
Integrin alphavbeta3 has an important role in the proliferation, survival, invasion and migration of vascular endothelial cells. Like other integrins, alphavbeta3 can exist in different functional states with respect to ligand binding. These changes involve both affinity modulation, by which conformational changes in the integrin heterodimer govern affinity for individual extracellular matrix proteins, and avidity modulation, by which changes in lateral mobility and integrin clustering affect the binding of cells to multivalent matrices. Here we have used an engineered monoclonal antibody Fab (antigen-binding fragment) named WOW-1, which binds to activated integrins alphavbeta3 and alphavbeta5 from several species, to investigate the role of alphavbeta3 activation in endothelial cell behaviour. Because WOW-1 is monovalent, it is insensitive to changes in integrin clustering and therefore reports only changes in affinity. WOW-1 contains an RGD tract in its variable region and binds only to unoccupied, high-affinity integrins. By using WOW-1, we have identified the selective recruitment of high-affinity integrins as a mechanism by which lamellipodia promote formation of new adhesions at the leading edge in cell migration.
Department of Vascular Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
W B
WB
Kiosses
S J
SJ
Shattil
N
N
Pampori
M A
MA
Schwartz
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002417:Cattle; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D003094:Collagen / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017930:Genes, Reporter; D007128:Immunoglobulin Fragments / Q000378:metabolism; D008845:Microinjections; D008856:Microscopy, Fluorescence; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D011554:Pseudopodia / Q000378:metabolism*; D019030:Receptors, Vitronectin / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection; D000077191:Wortmannin; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
D000730:Androstadienes; D000911:Antibodies, Monoclonal; D002867:Chromones; D004791:Enzyme Inhibitors; D007128:Immunoglobulin Fragments; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D019030:Receptors, Vitronectin; D011993:Recombinant Fusion Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D003094:Collagen; D020744:rac GTP-Binding Proteins; D000077191:Wortmannin