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Blood, 1 February 2004, Vol. 103, No. 3, pp. 1033-1036. Prepublished online as a Blood First Edition Paper on October 9, 2003; DOI 10.1182/blood-2003-07-2499. This Article Full Text (PDF) All Versions of this Article: 2003-07-2499v1 103/3/1033    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kinashi, T. Articles by Alon, R. Search for Related Content PubMed PubMed Citation Articles by Kinashi, T. Articles by Alon, R. Social Bookmarking                   What's this? Submitted July 24, 2003 Accepted September 25, 2003 LAD-III, a leukocyte adhesion deficiency syndrome associated with defective Rap1 activation and impaired stabilization of integrin bonds Tatsuo Kinashi, Memet Aker, Maya Sokolovsky-Eisenberg, Valentin Grabovsky, Chisato Tanaka, Revital Shamri, Sara Feigelson, Amos Etzioni, and Ronen Alon* Bayer-chair Department of Molecular Immunology and Allergy, Kyoto University Graduate School of Medicine, Kyoto, Japan Division of Pediatric Hemato- Oncology, Hadassah Medical Center, Jerusalem, Israel Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel Department of Pediatrics, Meyer Children Hospital, Rambam Medical Center and the B. Rappaport School of Medicine, Technion, Israel * Corresponding author; email: ronalon{at}wicc.weizmann.ac.il. Recently, we reported a rare leukocyte adhesion deficiency (LAD) associated with severe defects in integrin activation by chemokine signals, despite normal ligand binding of leukocyte integrins. We now report that the small GTPase, Rap-1, a key regulator of inside-out integrin activation is abnormally regulated in LAD EBV lymphocyte cells. Both constitutive and chemokine-triggered activation of Rap-1 were abolished in LAD lymphocytes despite normal chemokine signaling. Nevertheless, Rap1 expression and activation by phorbol esters were intact, ruling out a LAD defect in Rap1 GTP loading. The VLA-4 integrin abnormally tethered LAD EBV lymphocytes to its ligand VCAM-1 under shear flow due to impaired generation of high avidity contacts despite normal ligand binding and intact avidity to surface-bound anti-VLA-4 mAb. Thus, a defect in constitutive Rap1 activation results in an inability of ligand-occupied integrins to generate high avidity binding to ligand under shear flow. This is a first report of an inherited Rap1 activation defect associated with a pathological disorder in leukocyte integrin function, we herein term LAD-III. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. Molteni, C. L. Crespo, S. Feigelson, C. Moser, M. Fabbri, V. Grabovsky, F. Krombach, C. Laudanna, R. Alon, and R. Pardi {beta}-Arrestin 2 is required for the induction and strengthening of integrin-mediated leukocyte adhesion during CXCR2-driven extravasation Blood, July 30, 2009; 114(5): 1073 - 1082. [Abstract] [Full Text] [PDF] A. Mor, J. P. Wynne, I. M. Ahearn, M. L. Dustin, G. Du, and M. R. Philips Phospholipase D1 Regulates Lymphocyte Adhesion via Upregulation of Rap1 at the Plasma Membrane Mol. Cell. Biol., June 15, 2009; 29(12): 3297 - 3306. [Abstract] [Full Text] [PDF] T. W. Kuijpers, E. van de Vijver, M. A. J. Weterman, M. de Boer, A. T. J. Tool, T. K. van den Berg, M. Moser, M. E. 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