A novel function for the Tec family tyrosine kinase Itk in activation of beta 1 integrins by the T-cell receptor

Stimulation of T cells via the CD3-T-cell receptor (TCR) complex results in rapid increases in beta1 integrin-mediated adhesion via poorly defined int racellular signaling events. We demonstrate that TCR-mediated activation of beta1 integrins requires activation of the Tec family tyrosine kinase Itk and phosphatidylinositol 3-kinase (PI 3-K)-dependent recruitment of Itk to detergent-insoluble glycosphingolipid-enriched microdomains (DIGs) via bind ing of the pleckstrin homology domain of Itk to the PI 3-K product PI(3,4,5 )-P-3. Activation of PI 3-K and the src family kinase Lck, via stimulation of the CD4 co-receptor, can initiate beta1 integrin activation that is depe ndent on Itk function. Targeting of Itk specifically to DIGs, coupled with CD4 stimulation, can also activate beta1 integrin function independently of TCR stimulation. Changes in beta1 integrin function mediated by TCR activa tion of Itk are also accompanied by Itk-dependent modulation of the actin c ytoskeleton, Thus, TCR-mediated activation of beta1 integrins involves memb rane relocalization and activation of Itk via coordinate action of PI 3-K a nd a src family tyrosine kinase.