α(4)β(1)-dependent adhesion strengthening under mechanical strain is regulated by paxillin association with the α(4)-cytoplasmic domain

The capacity of integrins to mediate adhesiveness is modulated by their cytoplasmic associations. In this study, we describe a novel mechanism by which α(4)-integrin adhesiveness is regulated by the cytoskeletal adaptor paxillin. A mutation of the α(4) tail that disrupts paxillin binding, α(4)(Y991A), reduced talin association to the α(4)β(1) heterodimer, impaired integrin anchorage to the cytoskeleton, and suppressed α(4)β(1)-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 α(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.