α₄β₁-dependent adhesion strengthening under mechanical strain is regulated by paxillin association with the α₄-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 α₄-integrin adhesiveness is regulated by the cytoskeletal adaptor paxillin. A mutation of the α₄ tail that disrupts paxillin binding, α₄(Y991A), reduced talin association to the α₄β₁ heterodimer, impaired integrin anchorage to the cytoskeleton, and suppressed α₄β₁-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 α₄-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.