A LAD-III syndrome is associated with defective expression of the Rap-1 activator CalDAG-GEFI in lymphocytes, neutrophils, and platelets

Ronit Pasvolsky, Sara W. Feigelson, Sara Sebnem Kilic, Amos J. Simon, Guy Tal-Lapidot, Valentin Grabovsky, Jill R. Crittenden, Ninette Amariglio, Michal Safran, Ann M. Graybiel, Gideon Rechavi, Shifra Ben-Dor, Amos Etzioni, Ronen Alon

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138 Scopus citations


Leukocyte and platelet integrins rapidly alter their affinity and adhesiveness in response to various activation (inside-out) signals. A rare leukocyte adhesion deficiency (LAD), LAD-III, is associated with severe defects in leukocyte and platelet integrin activation. We report two new LAD cases in which lymphocytes, neutrophils, and platelets share severe defects in β1, β2, and β3 integrin activation. Patients were both homozygous for a splice junction mutation in their CalDAG-GEFI gene, which is a key Rap-1/2 guanine exchange factor (GEF). Both mRNA and protein levels of the GEF were diminished in LAD lymphocytes, neutrophils, and platelets. Consequently, LAD-III platelets failed to aggregate because of an impaired αIIbβ3 activation by key agonists. β2 integrins on LAD-III neutrophils were unable to mediate leukocyte arrest on TNFα-stimulated endothelium, despite normal selectin-mediated rolling. In situ subsecond activation of neutrophil β2 integrin adhesiveness by surface-bound chemoattractants and of primary T lymphocyte LFA-1 by the CXCL12 chemokine was abolished. Chemokine inside-out signals also failed to stimulate lymphocyte LFA-1 extension and high affinity epitopes. Chemokine-triggered VLA-4 adhesiveness in T lymphocytes was partially defective as well. These studies identify CalDAG-GEFI as a critical regulator of inside-out integrin activation in human T lymphocytes, neutrophils, and platelets. JEM

Original languageEnglish
Pages (from-to)1571-1582
Number of pages12
JournalJournal of Experimental Medicine
Issue number7
StatePublished - 9 Jul 2007
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the Seoul National University Nobel Laureates Invitation Program, the Basic Science Research Programs of the National Research Foundation (NRF) funded by the Ministry of Science, Information & Communication Technology (ICT), and Future Planning (MSIP) (NRF-2016R1A2B3011389 to Y.T.K. and NRF-2015R1A6A3A01020301 to S.M.S.), Seoul National University Hospital (to Y.T.K.), Research Resettlement Fund for the new faculty of Seoul National University (to Y.T.K.), the R&D Convergence Program (CAP-16-03-KRIBB) of the National Research Council of Science and Technology (NST) of the Republic of Korea and Korea Research Institute of Bioscience & Biotechnology (KRIBB) Research Initiative Program. A.C. was supported by the Dr. Miriam and Sheldon Adelson Medical Research Foundation (AMRF) and the Bio and Medical Technology Development Program (project no. 2012M3A9B6055305) through the Korean Ministry of Education, Science and Technology, Korea. A.C. is an Israel Cancer Research Fund USA professor.


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