Stimulation of the CD3/TCR results within minutes in an increase in T cell adhesion mediated by β1 integrins. The biochemical pathways that control CD3-mediated increases in β1 integrin-mediated adhesion remain poorly characterized. In this study, the role of the tyrosine kinase ZAP-70 in the regulation of β1 integrin activity by the CD3/TCR was investigated. CD3 stimulation did not increase β1 integrin-mediated adhesion of the ZAP-70-deficient Jurkat T cell line, P116, to the β1 integrin ligand fibronectin. Reintroduction of wild-type ZAP-70, but not a kinase-inactive variant, K369R, corrected the adhesive defect observed in P116 T cells. In addition, the kinase-inactive ZAP-70 mutant inhibited CD3-induced adhesion of primary human T cell blasts. Interestingly, a ZAP-70 mutant with a tyrosine to phenylalanine substitution at position 319 (Y319F) restored the adhesive defect in P116 T cells, even though Y319F ZAP-70 failed to fully reconstitute CD3-initiated NF-AT-dependent transcription and tyrosine phosphorylation of the LAT adapter protein. Finally, expression of mutants of LAT and the SLP-76 adapter protein that modulate CD3-mediated activation of an NF-AT reporter gene failed to block CD3-induced increases in β1 integrin-mediated adhesion. These observations support a model in which the tyrosine kinase activity of ZAP-70 kinase is critical for regulation of β1 integrin activity by CD3/TCR. However, the signaling events downstream of ZAP-70 that regulate CD3/TCR-mediated activation of β1 integrin function exhibit key differences when compared with the signaling pathways that regulate transcriptional events initiated by CD3/TCR stimulation.
Brugge, 1995;Schwartz et al., 1995;Shimizu et al., 1999;Hynes and Bader, 1997;Hynes, 1996). Several aspects of integrin structure and function lead to their prominent role in regulating the ability of a T cell to interact with and respond to the extracellular environment. First, the short cytoplasmic tails associate with cytoskeletal proteins, such as talin, o-actinin and paxillin (Clark and Brugge, 1995). In this way, integrins act as a cell surface bridge that links the structure of the extracellular matrix environment around a cell with its own cytoskeletal scaffold. In adherent cells, this linkage with the cytoskeleton results in the formation of a structure known as a focal adhesion at the point of contact of a cell with the underlying ECM (Schwartz et al., 1995;Guan, 1997). In addition to providing cell anchorage, focal adhesions are now known to be centers of signaling activity. Kinases, such as src kinase and focal adhesion
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