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Activated Integrin VLA-4 Localizes to the Lamellipodia and Mediates T Cell Migration on VCAM-1¹

Young-Min Hyun^*, Hung-Li Chung, James L. McGrath, Richard E. Waugh and Minsoo Kim^2,*

^* Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology and Department of Biomedical Engineering, University of Rochester, Rochester, NY 14642

Lymphocyte migration from blood into lymphoid tissues or to sites of inflammation occurs through interactions between cell surface integrins and their ligands expressed on the vascular endothelium and the extracellular matrix. VLA-4 (₄β₁) is a key integrin in the effective trafficking of lymphocytes. Although it has been well established that integrins undergo functionally significant conformational changes to mediate cell adhesion, there is no mechanistic information that explains how these are dynamically and spatially regulated during lymphocyte polarization and migration. Using dynamic fluorescence resonance energy transfer analysis of a novel VLA-4 FRET sensor under total internal reflection fluorescence microscopy, we show that VLA-4 activation localizes to the lamellipodium in living cells. During T cell migration on VCAM-1, VLA-4 activation concurs with spatial redistribution of chemokine receptor and active Rap1 at the leading edge. Selective inhibition of the activated VLA-4 at the leading edge with a small molecule inhibitor is sufficient to block T cell migration. These data suggest that a subpopulation of activated VLA-4 is mainly localized to the leading edge of polarized human T cells and is critical for T cell migration on VCAM-1.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This project was supported by the American Heart Association (to M.K.) and by National Institutes of Health Grants HL087088 and HL18208 (to M.K.).

² Address correspondence and reprint requests to Dr. Minsoo Kim, Department of Microbiology and Immunology, David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY 14642. E-mail address: minsoo_kim{at}urmc.rochester.edu

³ Abbreviations used in this paper: FRET, fluorescence resonance energy transfer; TIRF, total internal reflection fluorescence; PLL, poly-L-lysine; LIBS, ligand-induced binding site; wt, wild type; PTX, pertussis toxin; DIC, differential interference contrast; PKA, protein kinase A; RIAM, Rap1-GTP-interacting molecule.

⁴ The online version of this article contains supplemental material.

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The JI 2009 183: 1-2. [Full Text]  

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