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Published 19 December 2005. doi:10.1083/jcb.200503155
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 171, Number 6, 1073-1084
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Article

 {alpha}4ß1-dependent adhesion strengthening under mechanical strain is regulated by paxillin association with the {alpha}4-cytoplasmic domain

Ronen Alon1, Sara W. Feigelson1, Eugenia Manevich1, David M. Rose2, Julia Schmitz3, Darryl R. Overby4,5, Eitan Winter1, Valentin Grabovsky1, Vera Shinder1, Benjamin D. Matthews4,5,6, Maya Sokolovsky-Eisenberg1, Donald E. Ingber4,5, Martin Benoit3, and Mark H. Ginsberg2

1 Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel
2 Department of Medicine, University of California, San Diego, La Jolla, CA 9209
3 Center for Nano Science, Ludwigs-Maximilians-Universität, Munich D-80799, Germany
4 Department of Pathology, Vascular Biology Program, Children's Hospital
5 Department of Surgery, Vascular Biology Program, Children's Hospital
6 Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115

Correspondence to Ronen Alon: ronen.alon{at}weizmann.ac.il

The capacity of integrins to mediate adhesiveness is modulated by their cytoplasmic associations. In this study, we describe a novel mechanism by which {alpha}4-integrin adhesiveness is regulated by the cytoskeletal adaptor paxillin. A mutation of the {alpha}4 tail that disrupts paxillin binding, {alpha}4(Y991A), reduced talin association to the {alpha}4ß1 heterodimer, impaired integrin anchorage to the cytoskeleton, and suppressed {alpha}4ß1-dependent capture and adhesion strengthening of Jurkat T cells to VCAM-1 under shear stress. The mutant retained intrinsic avidity to soluble or bead-immobilized VCAM-1, supported normal cell spreading at short-lived contacts, had normal {alpha}4-microvillar distribution, and responded to inside-out signals. This is the first demonstration that cytoskeletal anchorage of an integrin enhances the mechanical stability of its adhesive bonds under strain and, thereby, promotes its ability to mediate leukocyte adhesion under physiological shear stress conditions.

D.R. Overby's present address is Department of Biomedical Engineering, Tulane University, New Orleans, LA 70118.

Abbreviations used in this paper: AFM, atomic force microscopy; HUVEC, human umbilical vein endothelial cell; siRNA, short inhibitory RNA; wt, wild type.


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