title: Regulation of beta 1 integrin-mediated adhesion by T cell receptor signaling involves ZAP-70 but differs from signaling events that regulate transcriptional activity.
abstract: Stimulation of the CD3/TCR results within minutes in an increase in T cell adhesion mediated by beta(1) integrins. The biochemical pathways that control CD3-mediated increases in beta(1) integrin-mediated adhesion remain poorly characterized. In this study, the role of the tyrosine kinase ZAP-70 in the regulation of beta(1) integrin activity by the CD3/TCR was investigated. CD3 stimulation did not increase beta(1) integrin-mediated adhesion of the ZAP-70-deficient Jurkat T cell line, P116, to the beta(1) 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 beta(1) integrin-mediated adhesion. These observations support a model in which the tyrosine kinase activity of ZAP-70 kinase is critical for regulation of beta(1) integrin activity by CD3/TCR. However, the signaling events downstream of ZAP-70 that regulate CD3/TCR-mediated activation of beta(1) integrin function exhibit key differences when compared with the signaling pathways that regulate transcriptional events initiated by CD3/TCR stimulation.
authors.affiliation: Department of Laboratory Medicine and Pathology, Center for Immunology, Cancer Center, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Epler
authors.forename: R
authors.initials: R
authors.lastname: Liu
authors.forename: H
authors.initials: H
authors.lastname: Chung
authors.forename: N C
authors.initials: NC
authors.lastname: Ottoson
authors.forename: Y
authors.initials: Y
authors.lastname: Shimizu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D005353:Fibronectins / Q000502:physiology; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism / Q000502:physiology*; D019169:Jurkat Cells; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000502:physiology; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010649:Phenylalanine / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000276:immunology*; D014443:Tyrosine / Q000235:genetics; D051746:ZAP-70 Protein-Tyrosine Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D005353:Fibronectins; D019012:Integrin beta1; C110810:LAT protein, human; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010750:Phosphoproteins; D017260:Receptor-CD3 Complex, Antigen, T-Cell; C092947:SLP-76 signal Transducing adaptor proteins; D014157:Transcription Factors; D014443:Tyrosine; D010649:Phenylalanine; D008156:Luciferases; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human