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Blood, 10 September 2009, Vol. 114, No. 11, pp. 2344-2353. Prepublished online as a Blood First Edition Paper on July 17, 2009; DOI 10.1182/blood-2009-04-218636. This Article Full Text Full Text (PDF) Supplemental Methods and Figures All Versions of this Article: blood-2009-04-218636v1 114/11/2344    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 CrossRef Google Scholar Articles by Manevich-Mendelson, E. Articles by Alon, R. PubMed PubMed Citation Articles by Manevich-Mendelson, E. Articles by Alon, R. Related Collections Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  VASCULAR BIOLOGY Loss of Kindlin-3 in LAD-III eliminates LFA-1 but not VLA-4 adhesiveness developed under shear flow conditions Eugenia Manevich-Mendelson1,*, Sara W. Feigelson1,*, Ronit Pasvolsky1, Memet Aker2, Valentin Grabovsky1, Ziv Shulman1, Sara Sebnem Kilic3, Maria Alessandra Rosenthal-Allieri46, Shifra Ben-Dor7, Adi Mory8, Alain Bernard46, Markus Moser9, Amos Etzioni8, and Ronen Alon1 1 Department of Immunology, Weizmann Institute of Science, Rehovot, Israel; 2 Division of Pediatric Hemato-Oncology, Hadassah Medical Center, Jerusalem, Israel; 3 Department of Pediatric Immunology, Uludag University School of Medicine, Bursa, Turkey; 4 Inserm Unité Mixte de Recherche 576, Nice, France; 5 Université Nice-Sophia, Antipolis, France; 6 Centre Hospitalier Universitaire de Nice, Laboratoire d'Immunologie, Hôpital de l'Archet, Nice, France; 7 Department of Biologic Services, Weizmann Institute of Science, Rehovot, Israel; 8 Department of Pediatrics, Meyer Children's Hospital, Rambam Medical Center and B. Rappaport School of Medicine, Technion, Haifa, Israel; and 9 Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany Leukocyte adhesion deficiency (LAD)–III is associated with homozygous stop codon mutations in Kindlin-3, the hematopoietic member of the Kindlin family of integrin coactivators. In addition, a subgroup of LAD-III patients has a homozygous splice junction mutation in and reduced expression of the Rap-1 guanine nucleotide exchange factor, CalDAG-GEFI (CDGI). In this study, we compared the adhesive properties of the leukocyte function-associated antigen-1 (LFA-1) and very late activation antigen-4 (VLA-4) integrins in both primary and activated leukocytes derived from these 2 LAD-III subgroups. Primary lymphocytes lacking both Kindlin-3 and CDGI lost all firm T-cell receptor–stimulated LFA-1 adhesiveness, in contrast to LAD-III lymphocytes deficient in Kindlin-3 alone. Effector T cells expanded from all tested LAD-III variants expressed normal CDGI, but lacked Kindlin-3. These Kindlin-3–null effector T cells exhibited total loss of inside-out LFA-1 activation by chemokine signals as well as abrogated intrinsic LFA-1 adhesiveness. Surprisingly, VLA-4 in Kindlin-3–null resting or effector lymphocytes retained intrinsic rolling adhesions to vascular cell adhesion molecule-1 and exhibited only partial defects in chemokine-stimulated adhesiveness to vascular cell adhesion molecule-1. Deletion of the putative β1 Kindlin-3 binding site also retained VLA-4 adhesiveness. Thus, our study provides the first evidence that Kindlin-3 is more critical to LFA-1 than to VLA-4–adhesive functions in human lymphocytes. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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