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Blood, 15 November 2007, Vol. 110, No. 10, pp. 3682-3690. Prepublished online as a Blood First Edition Paper on September 12, 2007; DOI 10.1182/blood-2007-03-077628. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-03-077628v1 blood-2007-03-077628v2 110/10/3682    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ghandour, H. Articles by Mayadas, T. N. Search for Related Content PubMed PubMed Citation Articles by Ghandour, H. Articles by Mayadas, T. N. Related Collections Immunobiology Cell Adhesion and Motility Signal Transduction Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Essential role for Rap1 GTPase and its guanine exchange factor CalDAG-GEFI in LFA-1 but not VLA-4 integrin–mediated human T-cell adhesion Haifa Ghandour1, Xavier Cullere1, Angeles Alvarez1, Francis W. Luscinskas1, and Tanya N. Mayadas1 1 Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA Regulated adhesion of T cells by the integrins LFA-1 (lymphocyte function-associated antigen-1) and VLA-4 (very late antigen-4) is essential for T-cell trafficking. The small GTPase Rap1 is a critical activator of both integrins in murine lymphocytes and T-cell lines. Here we examined the contribution of the Rap1 regulatory pathway in integrin activation in primary CD3+ human T cells. We demonstrate that inactivation of Rap1 GTPase in human T cells by expression of SPA1 or Rap1GAP blocked stromal cell-derived factor-1 (SDF-1)–stimulated LFA-1–ICAM-1 (intercellular adhesion molecule-1) interactions and LFA-1 affinity modulation but unexpectedly did not significantly affect binding of VLA-4 to its ligand VCAM-1 (vascular cell adhesion molecule 1). Importantly, silencing of the Rap1 guanine exchange factor CalDAG-GEFI inhibited SDF-1- and phorbol 12-myristate 13-acetate (PMA)–induced adhesion to ICAM-1 while having no effect on adhesion to VCAM-1. Pharmacologic inhibition of Phospholipase C (PLC) blocked Rap1 activation and inhibited cell adhesion and polarization on ICAM-1 and VCAM-1. Protein kinase C (PKC) inhibition led to enhanced levels of active Rap1 concomitantly with increased T-cell binding to ICAM-1, whereas adhesion to VCAM-1 was reduced. Thus, PLC/CalDAG-GEFI regulation of Rap1 is selectively required for chemokine- and PMA-induced LFA-1 activation in human T cells, whereas alternate PLC- and PKC-dependent mechanisms are involved in the regulation of VLA-4. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Rap1: selective activator of ß2 integrins? Philip J. S. Stork Blood 2007 110: 3496-3497. [Full Text] [PDF] This article has been cited by other articles: R. Evans, I. Patzak, L. Svensson, K. De Filippo, K. Jones, A. McDowall, and N. Hogg Integrins in immunity J. Cell Sci., January 15, 2009; 122(2): 215 - 225. [Abstract] [Full Text] [PDF]

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