Chemokine-induced Zap70 kinase-mediated dissociation of the Vav1-talin complex activates alpha4beta1 integrin for T cell adhesion.
Lymphocyte integrins mediate cell arrest on endothelium during immune surveillance after activation by chemokine-stimulated inside-out signals. Here we show that a Vav1-talin complex in T cells is a key target for chemokine-triggered inside-out signaling leading to integrin alpha4beta1 activation. Thus, Vav1 dissociation from talin was required to generate high-affinity alpha4beta1 conformations. Assembly of the Vav1-talin complex required PtdIns(4,5)P(2), which was provided by talin-bound phosphatidylinositol phosphate kinase Igamma. Chemokine-promoted Vav1 dissociation from talin followed an initial increase in talin binding to alpha4beta1. This process was dependent on ZAP-70, which binds to and phosphorylates Vav1 in the complex, leading to further alpha4beta1 activation and cell adhesion strengthening. Moreover, Vav1-talin dissociation was needed for Rac1 activation, thus indicating that alpha4beta1 and Rac1 activation can be coupled by chemokine-stimulated ZAP-70 function. Our data suggest that Vav1 might function as a repressive adaptor of talin that must dissociate from alpha4beta1-talin complexes for efficient integrin activation.
García-Bernal
David
D
Cellular and Molecular Medicine Program, Centro de Investigaciones Biológicas (CSIC), 28040 Madrid, Spain.
Parmo-Cabañas
Marisa
M
Dios-Esponera
Ana
A
Samaniego
Rafael
R
Hernán-P de la Ossa
Dolores
D
Teixidó
Joaquin
J
D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000494:pharmacology; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D010770:Phosphotransferases / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000187:drug effects / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D016608:Talin / Q000187:drug effects / Q000378:metabolism*; D014162:Transfection; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D054377:Chemokine CXCL12; D039041:Integrin alpha4beta1; D051567:Proto-Oncogene Proteins c-vav; D016608:Talin; C496618:VAV1 protein, human; D019010:Vascular Cell Adhesion Molecule-1; D010770:Phosphotransferases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D020830:rac1 GTP-Binding Protein