title: ZAP-70 tyrosine kinase is required for LFA-1-dependent T cell migration.
abstract: The ZAP-70 tyrosine kinase is essential for T cell activation by the T cell receptor. We show that ZAP-70 is also required for migration of T cells that is dependent on the integrin LFA-1. Invasion of TAM2D2 T cell hybridoma cells into fibroblast monolayers, which is LFA-1-dependent, was blocked by overexpression of dominant-negative ZAP-70 and by piceatannol but not by herbimycin A. The Syk inhibitor piceatannol blocks the Syk homologue ZAP-70, which is expressed by TAM2D2 cells, with the same dose dependence as the inhibition of invasion. Dominant-negative ZAP-70 completely inhibited the extensive metastasis formation of TAM2D2 cells to multiple organs upon i.v. injection into mice. Migration of TAM2D2 cells through filters coated with the LFA-1 ligand ICAM-1, induced by 1 ng/ml of the chemokine SDF-1, was blocked by anti-LFA-1 mAb and also abrogated by dominant-negative ZAP-70 and piceatannol. In contrast, migration induced by 100 ng/ml SDF-1 was independent of both LFA-1 and ZAP-70. LFA-1 cross-linking induced tyrosine phosphorylation, which was blocked by dominant-negative ZAP-70 and piceatannol. We conclude that LFA-1 engagement triggers ZAP-70 activity that is essential for LFA-1-dependent migration.
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: R D
authors.initials: RD
authors.lastname: Soede
authors.forename: Y M
authors.initials: YM
authors.lastname: Wijnands
authors.forename: I
authors.initials: I
authors.lastname: Van Kouteren-Cobzaru
authors.forename: E
authors.initials: E
authors.lastname: Roos
mesh_terms: D000818:Animals; D016227:Benzoquinones; D002465:Cell Movement / Q000502:physiology*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D005347:Fibroblasts; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D006825:Hybridomas / Q000378:metabolism; D016023:Integrins / Q000502:physiology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D047029:Lactams, Macrocyclic; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D051379:Mice; D009362:Neoplasm Metastasis / Q000503:physiopathology; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011809:Quinones / Q000494:pharmacology; D051381:Rats; D017828:Rifabutin / Q000031:analogs & derivatives; D013267:Stilbenes / Q000494:pharmacology; D013601:T-Lymphocytes / Q000378:metabolism*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D051746:ZAP-70 Protein-Tyrosine Kinase
chemical_list: D016227:Benzoquinones; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D016023:Integrins; D047029:Lactams, Macrocyclic; D016169:Lymphocyte Function-Associated Antigen-1; D011809:Quinones; D013267:Stilbenes; D010566:Virulence Factors, Bordetella; D018799:Intercellular Adhesion Molecule-1; D017828:Rifabutin; D019000:Phosphotyrosine; C041525:3,3',4,5'-tetrahydroxystilbene; C020754:herbimycin; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C497262:Zap70 protein, mouse