title: CBAP functions as a novel component in chemokine-induced ZAP70-mediated T-cell adhesion and migration.
abstract: Activated chemokine receptor initiates inside-out signaling to transiently trigger activation of integrins, a process involving multiple components that have not been fully characterized. Here we report that GM-CSF/IL-3/IL-5 receptor common beta-chain-associated protein (CBAP) is required to optimize this inside-out signaling and activation of integrins. First, knockdown of CBAP expression in human Jurkat T cells caused attenuated CXC chemokine ligand-12 (CXCL12)-induced cell migration and integrin α4β1- and αLβ2-mediated cell adhesion in vitro, which could be rescued sufficiently upon expression of murine CBAP proteins. Freshly isolated CBAP-deficient primary T cells also exhibited diminution of chemotaxis toward CC chemokine ligand-21 (CCL21) and CXCL12, and these chemokines-induced T-cell adhesions in vitro. Adoptive transfer of isolated naive T cells demonstrated that CBAP deficiency significantly reduced lymph node homing ability in vivo. Finally, migration of T cell-receptor-activated T cells induced by inflammatory chemokines was also attenuated in CBAP-deficient cells. Further analyses revealed that CBAP constitutively associated with both integrin β1 and ZAP70 and that CBAP is required for chemokine-induced initial binding of the talin-Vav1 complex to integrin β1 and to facilitate subsequent ZAP70-mediated dissociation of the talin-Vav1 complex and Vav1 phosphorylation. Within such an integrin signaling complex, CBAP likely functions as an adaptor and ultimately leads to activation of both integrin α4β1 and Rac1. Taken together, our data suggest that CBAP indeed can function as a novel signaling component within the ZAP70/Vav1/talin complex and plays an important role in regulating chemokine-promoted T-cell trafficking.
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yun-Jung
authors.initials: YJ
authors.lastname: Chiang
authors.forename: Kun-Chin
authors.initials: KC
authors.lastname: Ho
authors.forename: Chien-Tsang
authors.initials: CT
authors.lastname: Sun
authors.forename: Jeng-Jiann
authors.initials: JJ
authors.lastname: Chiu
authors.forename: Fang-Jen
authors.initials: FJ
authors.lastname: Lee
authors.forename: Fang
authors.initials: F
authors.lastname: Liao
authors.forename: Hsin-Fang
authors.initials: HF
authors.lastname: Yang-Yen
authors.forename: Jeffrey Jong-Young
authors.initials: JJ
authors.lastname: Yen
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D018925:Chemokines / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D019169:Jurkat Cells; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D051567:Proto-Oncogene Proteins c-vav; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D016608:Talin / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D018925:Chemokines; D019012:Integrin beta1; D008565:Membrane Proteins; D051567:Proto-Oncogene Proteins c-vav; C584197:TMEM102 protein, human; C584198:TMEM102 protein, mouse; D016608:Talin; C496618:VAV1 protein, human; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D020830:rac1 GTP-Binding Protein