title: 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.
abstract: 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-1alpha (SDF-1alpha)-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-1alpha- 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.
authors: Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors: Haifa
authors: H
authors: Ghandour
authors: Xavier
authors: X
authors: Cullere
authors: Angeles
authors: A
authors: Alvarez
authors: Francis W
authors: FW
authors: Luscinskas
authors: Tanya N
authors: TN
authors: Mayadas
mesh_terms: D002448:Cell Adhesion; D002478:Cells, Cultured; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D006801:Humans; D039041:Integrin alpha4beta1 / Q000502:physiology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D008954:Models, Biological; D011493:Protein Kinase C / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D010738:Type C Phospholipases / Q000502:physiology; D020827:rap1 GTP-Binding Proteins / Q000502:physiology*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D039041:Integrin alpha4beta1; D016169:Lymphocyte Function-Associated Antigen-1; C115955:RAP1GDS1 protein, human; C415483:RASGRP2 protein, human; D011493:Protein Kinase C; D010738:Type C Phospholipases; D020827:rap1 GTP-Binding Proteins
references: J Immunol. 1992 Feb 15;148(4):1080-5
references: 1371129
references: J Exp Med. 2000 Aug 21;192(4):495-506
references: 10952719
references: J Biol Chem. 1997 Oct 31;272(44):28081-8
references: 9346962
references: Trends Biochem Sci. 1998 Jan;23(1):30-4
references: 9478133
references: Science. 1998 May 15;280(5366):1082-6
references: 9582122
references: Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13278-83
references: 9789079
references: J Immunol. 1999 Jan 15;162(2):1084-95
references: 9916737
references: J Exp Med. 1999 May 3;189(9):1467-78
references: 10224287
references: J Biol Chem. 1999 Jun 25;274(26):18463-9
references: 10373454
references: Blood. 2005 Mar 1;105(5):1950-5
references: 15374886
references: Curr Opin Cell Biol. 2005 Apr;17(2):123-8
references: 15780587
references: Nat Immunol. 2005 May;6(5):497-506
references: 15834409
references: J Immunol. 2005 Jul 1;175(1):350-7
references: 15972668
references: J Exp Med. 2001 May 21;193(10):1149-58
references: 11369786
references: J Leukoc Biol. 2001 Jun;69(6):860-6
references: 11404368
references: Nat Immunol. 2002 Mar;3(3):251-8
references: 11836528
references: J Biol Chem. 2002 Aug 16;277(33):29468-76
references: 12171996
references: J Biol Chem. 2002 Oct 25;277(43):40893-900
references: 12091396
references: Biochem Soc Trans. 2003 Feb;31(Pt 1):83-6
references: 12546659
references: J Cell Biol. 2003 Apr 28;161(2):417-27
references: 12707305
references: Peptides. 2003 Mar;24(3):487-501
references: 12732350
references: Nat Immunol. 2003 Aug;4(8):741-8
references: 12845325
references: Immunol Rev. 2003 Oct;195:58-71
references: 12969310
references: J Immunol. 2004 Mar 1;172(5):2731-8
references: 14978070
references: J Biol Chem. 2004 Mar 19;279(12):11875-81
references: 14702343
references: Nat Med. 2004 Sep;10(9):982-6
references: 15334074
references: J Cell Biol. 1992 Jan;116(1):219-26
references: 1346139
references: Trends Immunol. 2005 Jul;26(7):360-6
references: 15978522
references: Mol Biol Cell. 2005 Jul;16(7):3223-35
references: 15872091
references: J Cell Biol. 2005 Jul 4;170(1):141-51
references: 15983060
references: Nat Rev Immunol. 2005 Jul;5(7):546-59
references: 15965491
references: Immunology. 2005 Oct;116(2):164-71
references: 16162265
references: Nat Immunol. 2005 Dec;6(12):1182-90
references: 16369557
references: Mol Cell Biol. 2006 Jan;26(2):643-53
references: 16382154
references: Nat Immunol. 2006 Sep;7(9):919-28
references: 16892067
references: Curr Biol. 2006 Sep 19;16(18):1796-806
references: 16979556
references: Biochem Soc Trans. 2006 Nov;34(Pt 5):858-61
references: 17052215
references: J Immunol. 2006 Dec 1;177(11):7707-14
references: 17114441
references: Blood. 2007 Jan 1;109(1):176-84
references: 16960156
references: Blood. 2007 Apr 15;109(8):3529-37
references: 17185466
references: J Clin Invest. 2007 Jun;117(6):1699-707
references: 17492052
references: J Exp Med. 2007 Jul 9;204(7):1571-82
references: 17576779
references: EMBO J. 1999 Feb 1;18(3):501-11
references: 9927410
references: Blood. 2000 Jan 15;95(2):602-9
references: 10627469
references: Dev Immunol. 2000;7(2-4):279-91
references: 11097218
references: Cell. 1995 Feb 10;80(3):413-22
references: 7532110