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* Department of Immunology, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, Madrid, Spain;
Theodor Kocher Institute, University of Bern, Bern, Switzerland;
Unidad de Microscopía Confocal, Hospital Universitario Gregorio Marañón, Madrid, Spain; and
Department of Immunobiology, Division of Immunogenetics, and Neuroscience Medical Institute of. Bioregulation, Kyushu University, Japan
The 
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1 integrin is an essential adhesion molecule for recruitment of circulating lymphocytes into lymphoid organs and peripheral sites of inflammation. Chemokines stimulate 41 adhesive activity allowing lymphocyte arrest on endothelium and subsequent diapedesis. Activation of the GTPase Rac by the guanine-nucleotide exchange factor Vav1 promoted by CXCL12 controls T lymphocyte adhesion mediated by 41. In this study, we investigated the role of DOCK2, a lymphocyte guanine-nucleotide exchange factor also involved in Rac activation, in CXCL12-stimulated human T lymphocyte adhesion mediated by 41. Using T cells transfected with DOCK2 mutant forms defective in Rac activation or with DOCK2 small interfering RNA, we demonstrate that DOCK2 is needed for efficient chemokine-stimulated lymphocyte attachment to VCAM-1 under shear stress. Flow chamber, soluble binding, and cell spreading assays identified the strengthening of 41-VCAM-1 interaction, involving high affinity 41 conformations, as the adhesion step mainly controlled by DOCK2 activity. The comparison of DOCK2 and Vav1 involvement in CXCL12-promoted Rac activation and 41-dependent human T cell adhesion indicated a more prominent role of Vav1 than DOCK2. These results suggest that DOCK2-mediated signaling regulates chemokine-stimulated human T lymphocyte 41 adhesive activity, and that cooperation with Vav1 might be required to induce sufficient Rac activation for efficient adhesion. In contrast, flow chamber experiments using lymph node and spleen T cells from DOCK2–/– mice revealed no significant alterations in CXCL12-promoted adhesion mediated by 41, indicating that DOCK2 activity is dispensable for triggering of this adhesion in mouse T cells, and suggesting that Rac activation plays minor roles in this process.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants SAF2005-02119 from Ministerio de Educación y Ciencia (to J.T.), Swiss National Foundation Grant SNF3100A0-107510 (to J.V.S.), and grants from the Ministry of Education, Culture, Sports, Science and Technology, Japan and Japan Science and Technology Agency (to Y.F.).
2 Address correspondence and reprint requests to Dr. Joaquin Teixidó, Department of Immunology, Centro de Investigaciones Biológicas, Ramiro de Maeztu 9, 28040 Madrid, Spain. E-mail address: joaquint{at}cib.csic.es
3 Abbreviations used in this paper. GEF, guanine-nucleotide exchange factor; siRNA, small interfering RNA; WT, wild type; sVCAM, recombinant human VCAM-1; BCECF-AM, 2',7'-bis(carboxyethyl)-5(6')-carboxyfluorescein-acetoxymethyl ester; PBL-T, PBL T lymphocytes; SH, Src homology; CD62L, CD62 ligand.
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  M. A. Kwofie and J. Skowronski Specific Recognition of Rac2 and Cdc42 by DOCK2 and DOCK9 Guanine Nucleotide Exchange Factors J. Biol. Chem., February 8, 2008; 283(6): 3088 - 3096. [Abstract] [Full Text] [PDF]
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