title: PSGL-1 engagement by E-selectin signals through Src kinase Fgr and ITAM adapters DAP12 and FcR gamma to induce slow leukocyte rolling.
abstract: E-selectin binding to P-selectin glycoprotein ligand-1 (PSGL-1) can activate the beta(2) integrin lymphocyte function-associated antigen-1 by signaling through spleen tyrosine kinase (Syk). This signaling is independent of G alpha(i)-protein-coupled receptors, results in slow rolling, and promotes neutrophil recruitment to sites of inflammation. However, the signaling pathways linking E-selectin engagement of PSGL-1 to Syk activation are unknown. To test the role of Src family kinases and immunoreceptor tyrosine-based activating motif (ITAM)-containing adaptor proteins, we used different gene-deficient mice in flow chamber, intravital microscopy, and peritonitis studies. E-selectin-mediated phosphorylation of Syk and slow rolling was abolished in neutrophils from fgr(-/-) or hck(-/-) lyn(-/-) fgr(-/-) mice. Neutrophils from Tyrobp(-/-) Fcrg(-/-) mice lacking both DAP12 and FcRgamma were incapable of sustaining slow neutrophil rolling on E-selectin and intercellular adhesion molecule-1 and were unable to phosphorylate Syk and p38 MAPK. This defect was confirmed in vivo by using mixed chimeric mice. G alpha(i)-independent neutrophil recruitment into the inflamed peritoneal cavity was sharply suppressed in Tyrobp(-/-) Fcrg(-/-) mice. Our data demonstrate that an ITAM-dependent pathway involving the Src-family kinase Fgr and the ITAM-containing adaptor proteins DAP12 and FcRgamma is involved in the initial signaling events downstream of PSGL-1 that are required to initiate neutrophil slow rolling.
authors.affiliation: Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
authors.forename: Clare L
authors.initials: CL
authors.lastname: Abram
authors.forename: Matthias
authors.initials: M
authors.lastname: Hundt
authors.forename: Amnon
authors.initials: A
authors.lastname: Altman
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.forename: Klaus
authors.initials: K
authors.lastname: Ley
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D036904:Leukocyte Rolling / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051572:Proto-Oncogene Proteins c-hck / Q000235:genetics / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000072377:Syk Kinase; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019040:E-Selectin; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C084882:P-selectin ligand protein; D011518:Proto-Oncogene Proteins; D017452:Receptors, IgG; C484963:Tyrobp protein, mouse; D011505:Protein-Tyrosine Kinases; C496632:Hck protein, mouse; D051572:Proto-Oncogene Proteins c-hck; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C060902:lyn protein-tyrosine kinase; C053102:proto-oncogene proteins c-fgr; D019061:src-Family Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go
references.citation: Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7410-4
references.pmid: 1714601
references.citation: Immunity. 2003 Sep;19(3):391-402
references.pmid: 14499114
references.citation: Nat Rev Immunol. 2005 Jan;5(1):43-57
references.pmid: 15630428
references.citation: Circ Res. 1996 Dec;79(6):1196-204
references.pmid: 8943958
references.citation: Immunol Rev. 2005 Dec;208:50-65
references.pmid: 16313340
references.citation: Immunol Lett. 2006 Apr 15;104(1-2):29-37
references.pmid: 16332394
references.citation: J Exp Med. 1997 Aug 29;186(5):719-30
references.pmid: 9271587
references.citation: Cell. 1994 Feb 11;76(3):519-29
references.pmid: 8313472
references.citation: J Immunol. 2000 Jan 1;164(1):9-12
references.pmid: 10604985
references.citation: Cell. 1993 Jul 16;74(1):143-56
references.pmid: 8334701
references.citation: Nat Rev Immunol. 2007 Sep;7(9):678-89
references.pmid: 17717539
references.citation: J Clin Invest. 2006 Dec;116(12):3211-9
references.pmid: 17143330
references.citation: Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7580-4
references.pmid: 9636192
references.citation: J Exp Med. 2004 Oct 4;200(7):935-9
references.pmid: 15466624
references.citation: Blood. 2002 Jan 1;99(1):336-41
references.pmid: 11756189
references.citation: Annu Rev Cell Dev Biol. 1997;13:513-609
references.pmid: 9442882
references.citation: J Leukoc Biol. 2006 Dec;80(6):1491-9
references.pmid: 16997858
references.citation: J Immunol. 2000 May 15;164(10):4991-5
references.pmid: 10799849
references.citation: Immunity. 1998 Jun;8(6):693-701
references.pmid: 9655483
references.citation: Nat Immunol. 2006 Dec;7(12):1326-33
references.pmid: 17086186
references.citation: J Cell Biol. 1996 May;133(4):895-910
references.pmid: 8666673
references.citation: Immunity. 2007 Jun;26(6):773-83
references.pmid: 17543554
references.citation: Cell. 1994 Jan 28;76(2):301-14
references.pmid: 7507411
references.citation: J Exp Med. 1997 May 5;185(9):1661-70
references.pmid: 9151903
references.citation: J Exp Med. 1995 Feb 1;181(2):669-75
references.pmid: 7530761
references.citation: Immunity. 2005 Mar;22(3):285-94
references.pmid: 15780986
references.citation: Nat Immunol. 2007 Aug;8(8):882-92
references.pmid: 17632516
references.citation: Blood. 2000 Apr 1;95(7):2413-9
references.pmid: 10733515
references.citation: Immunity. 2004 Feb;20(2):181-91
references.pmid: 14975240
references.citation: Immunol Today. 2000 Dec;21(12):611-4
references.pmid: 11114420
references.citation: Trends Immunol. 2004 Oct;25(10):529-35
references.pmid: 15364055
references.citation: J Clin Invest. 2002 Feb;109(3):301-9
references.pmid: 11827988
references.citation: Microcirculation. 2006 Mar;13(2):99-109
references.pmid: 16459323
references.citation: Immunity. 2002 Apr;16(4):547-58
references.pmid: 11970878
references.citation: Blood. 2006 Nov 15;108(10):3352-9
references.pmid: 16849645
references.citation: Exp Hematol. 1997 Dec;25(13):1367-77
references.pmid: 9406996
references.citation: Proc Natl Acad Sci U S A. 1999 Aug 17;96(17):9792-6
references.pmid: 10449773
references.citation: Blood. 2001 Jul 1;98(1):108-16
references.pmid: 11418469
references.citation: Immunity. 2002 Oct;17(4):401-12
references.pmid: 12387735
references.citation: J Leukoc Biol. 1999 Mar;65(3):313-20
references.pmid: 10080533
references.citation: Immunol Rev. 2007 Aug;218:29-44
references.pmid: 17624942
references.citation: Genes Dev. 1994 Feb 15;8(4):387-98
references.pmid: 8125254
references.citation: Immunity. 2004 Apr;20(4):393-406
references.pmid: 15084269
references.citation: Immunity. 2000 Sep;13(3):345-53
references.pmid: 11021532
references.citation: Ann Biomed Eng. 2002 Sep;30(8):987-1001
references.pmid: 12449760
references.citation: Cell. 1991 Dec 20;67(6):1033-6
references.pmid: 1760836
references.citation: Immunity. 1997 Jul;7(1):69-81
references.pmid: 9252121
references.citation: Cell. 2000 Sep 1;102(5):635-46
references.pmid: 11007482
references.citation: Curr Opin Cell Biol. 1997 Apr;9(2):187-92
references.pmid: 9069259
references.citation: J Immunol. 2000 Apr 15;164(8):4348-58
references.pmid: 10754335
references.citation: Immunol Rev. 2007 Aug;218:9-28
references.pmid: 17624941
references.citation: Am J Physiol. 1996 Dec;271(6 Pt 2):H2740-7
references.pmid: 8997339
references.citation: Blood. 2000 Jul 15;96(2):719-26
references.pmid: 10887140