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Summary: The α4 integrins (α4β1 and α4β7) play multiple roles in the immune system. α4 integrins impact hematopoiesis, leukocyte trafficking in immune surveillance and inflammation, and leukocyte activation and survival. To perform these functions, α4 integrins act as both adhesive and signaling receptors. Paxillin, a signaling adapter molecule, binds directly to the α4 subunit cytoplasmic domain, and its binding is regulated by serine phosphorylation of the α4 subunit. This regulated interaction of paxillin with the α4 subunit is likely to regulate the diverse functions of α4 integrins in the immune system. Furthermore, this protein–protein interaction may provide novel targets for the modulation of the immune response.