Chemokine-Induced Zap70 Kinase-Mediated Dissociation of the Vav1-Talin Complex Activates α4β1 Integrin for T Cell Adhesion

Summary Lymphocyte integrins mediate cell arrest on endothelium during immune surveillance after activation by chemokine-stimulated inside-out signals. Here we show that a Vav1-talin complex in T cells is a key target for chemokine-triggered inside-out signaling leading to integrin α4β1 activation. Thus, Vav1 dissociation from talin was required to generate high-affinity α4β1 conformations. Assembly of the Vav1-talin complex required PtdIns(4,5)P 2 , which was provided by talin-bound phosphatidylinositol phosphate kinase Iγ. Chemokine-promoted Vav1 dissociation from talin followed an initial increase in talin binding to α4β1. This process was dependent on ZAP-70, which binds to and phosphorylates Vav1 in the complex, leading to further α4β1 activation and cell adhesion strengthening. Moreover, Vav1-talin dissociation was needed for Rac1 activation, thus indicating that α4β1 and Rac1 activation can be coupled by chemokine-stimulated ZAP-70 function. Our data suggest that Vav1 might function as a repressive adaptor of talin that must dissociate from α4β1-talin complexes for efficient integrin activation.