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Rac recruits high-affinity integrin αvβ3 to lamellipodia in endothelial cell migration

Nature Cell Biology volume 3, pages 316–320 (2001)Cite this article

Abstract

Integrin αvβ3 has an important role in the proliferation, survival, invasion and migration of vascular endothelial cells1,2. Like other integrins, αvβ3 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 αvβ3 and αvβ5 from several species3, to investigate the role of αvβ3 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.

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Figure 1: Localization of high-affinity αvβ3 to cell edges.
Figure 2: Effects of manganese and matrix composition on localization of high-affinity αvβ3.
Figure 3: PI(3)K and Rac in localization of high-affinity αvβ3 to cell edges.
Figure 4: Effect of WOW-1 on cell migration.

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Acknowledgements

We thank M. Ginsberg for providing polyclonal and LIBS anti-αvβ3 antibodies, and B. Cessna for secretarial assistance. This work was supported by US Public Health Service grants to M.A.S. and S.J.S., and an American Heart Association fellowship to W.B.K.

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Authors and Affiliations

  1. Department of Vascular Biology, and Department of Experimental Medicine, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    William B. Kiosses, Sanford J. Shattil, Nisar Pampori & Martin Alexander Schwartz

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  1. William B. Kiosses
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  2. Sanford J. Shattil
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  3. Nisar Pampori
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  4. Martin Alexander Schwartz
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Correspondence to Martin Alexander Schwartz.

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Kiosses, W., Shattil, S., Pampori, N. et al. Rac recruits high-affinity integrin αvβ3 to lamellipodia in endothelial cell migration. Nat Cell Biol 3, 316–320 (2001). https://doi.org/10.1038/35060120

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