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J. Biol. Chem., Vol. 282, Issue 35, 25338-25348, August 31, 2007

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Talin 1 and Paxillin Facilitate Distinct Steps in Rapid VLA-4-mediated Adhesion Strengthening to Vascular Cell Adhesion Molecule 1^*

From the Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

VLA-4 (₄₁) is a key integrin in lymphocytes, interacting with endothelial vascular cell adhesion molecule 1 (VCAM-1) on blood vessels and stroma. To dissect the contribution of the two cytoskeletal VLA-4 adaptor partners paxillin and talin to VLA-4 adhesiveness, we transiently knocked them down in Jurkat T cells and primary resting human T cells by small interfering RNA silencing. Paxillin was required for VLA-4 adhesiveness to low density VCAM-1 under shear stress conditions and was found to control mechanical stability of bonds mediated by the ₄ subunit but did not affect the integrin affinity or avidity to VCAM-1 in shear-free conditions. Talin 1 maintained VLA-4 in a high affinity conformation, thereby promoting rapid VLA-4 adhesion strengthening to VCAM-1 under both shear stress and shear-free conditions. Talin 1, but not paxillin, was required for VLA-4 to undergo optimal stimulation by the prototypic chemokine, CXCL12, under shear stress conditions. Interestingly, talin 1 and paxillin played the same distinct roles in VLA-4 adhesions of primary T lymphocytes, although VLA-4 affinity to VCAM-1 was at least 200-fold lower in these cells than in Jurkat cells. Collectively, our results suggest that whereas paxillin is a mechanical regulator of VLA-4 bonds generated in the absence of chemokine signals and low VCAM-1 occupancy, talin 1 is a versatile VLA-4 affinity regulator implicated in both spontaneous and chemokine-triggered rapid adhesions to VCAM-1.

Received for publication, January 4, 2007 , and in revised form, June 11, 2007.

^* 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 Incumbent of the Linda Jacobs Chair in Immune and Stem Cell Research. Supported by the Binational Science Foundation, the Israel Science Foundation, and by MAIN, the EU6 Program for Migration and Inflammation. To whom correspondence should be addressed. Tel.: 972-8-9342482; Fax: 972-8-9344141; E-mail: ronen.alon{at}weizmann.ac.il.

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