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The Journal of Immunology, 2003, 170: 5912-5918.
Copyright © 2003 by The American Association of Immunologists

Paxillin Binding to the {alpha}4 Integrin Subunit Stimulates LFA-1 (Integrin {alpha}L{beta}2)-Dependent T Cell Migration by Augmenting the Activation of Focal Adhesion Kinase/Proline-Rich Tyrosine Kinase-21

David M. Rose2,3,*, Shouchun Liu2,{dagger}, Darren G. Woodside{dagger}, Jaewon Han{dagger}, David D. Schlaepfer{ddagger} and Mark H. Ginsberg{dagger}

* Division of Rheumatology, Allergy, and Immunology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093; and {dagger} Division of Vascular Biology, Department of Cell Biology, and {ddagger} Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037

Engagement of very late Ag-4 (integrin {alpha}4{beta}1) by ligands such as VCAM-1 markedly stimulates leukocyte migration mediated by LFA-1 (integrin {alpha}L{beta}2). This form of integrin trans-regulation in T cells requires the binding of paxillin to the {alpha}4 integrin cytoplasmic domain. This conclusion is based on the abolition of trans-regulation in Jurkat T cells by an {alpha}4 mutation ({alpha}4(Y991A)) that disrupts paxillin binding. Furthermore, cellular expression of an {alpha}4-binding fragment of paxillin that blocks the {alpha}4-paxillin interaction, selectively blocked VCAM-1 stimulation of {alpha}L{beta}2-dependent cell migration. The {alpha}4-paxillin association mediates trans-regulation by enhancing the activation of tyrosine kinases, focal adhesion kinase (FAK) and/or proline-rich tyrosine kinase-2 (Pyk2), based on two lines of evidence. First, disruption of the paxillin-binding site in the {alpha}4 tail resulted in much less {alpha}4{beta}1-mediated phosphorylation of Pyk2 and FAK. Second, transfection with cDNAs encoding C-terminal fragments of Pyk2 and FAK, which block the function of the intact kinases, blocked {alpha}4{beta}1 stimulation of {alpha}L{beta}2-dependent migration. These results define a proximal protein-protein interaction of an integrin cytoplasmic domain required for trans-regulation between integrins, and establish that augmented activation of Pyk2 and/or FAK is an immediate signaling event required for the trans-regulation of integrin {alpha}L{beta}2 by {alpha}4{beta}1.




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