title: Platelet-associated IgAs and impaired GPVI responses in platelets lacking WIP.
abstract: The role of the Wiskott-Aldrich syndrome protein (WASp) in platelet function is unclear because platelets that lack WASp function normally. WASp constitutively associates with WASp-interacting protein (WIP) in resting and activated platelets. The role of WIP in platelet function was investigated using mice that lack WIP or WASp. WIP knockout (KO) platelets lack WASp and thus are double deficient. WIP KO mice have a thrombocytopenia, similar to WASp KO mice, resulting in part from enhanced platelet clearance. Most WIP KO, but not WASp KO, mice evolved platelet-associated immunoglobulins (Ig) of the IgA class, which normalize their platelet survival but diminish their glycoprotein VI (GPVI) responses. Protein tyrosine phosphorylation, including that of phospholipase C-gamma2, and calcium mobilization are impaired in IgA-presenting WIP KO platelets stimulated through GPVI, resulting in defects in alpha-granule secretion, integrin alphaIIbbeta3 activation, and actin assembly. The anti-GPVI antibody JAQ1 induces the irreversible loss of GPVI from circulating platelets in wild-type mice, but not in WIP KO mice that bear high levels of platelet-associated IgAs. Together, the data indicate that platelet-associated IgAs negatively modulate GPVI signaling and function in WIP KO mice.
authors.affiliation: Division of Translational Medicine, Brigham and Women's Hospital, One Blackfan Cir, Karp 6, Boston, MA02115, USA. hfalet@rics.bwh.harvard.edu
authors.forename: Hervé
authors.initials: H
authors.lastname: Falet
authors.forename: Michael P
authors.initials: MP
authors.lastname: Marchetti
authors.forename: Karin M
authors.initials: KM
authors.lastname: Hoffmeister
authors.forename: Michel J
authors.initials: MJ
authors.lastname: Massaad
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
authors.forename: John H
authors.initials: JH
authors.lastname: Hartwig
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000276:immunology / Q000378:metabolism*; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007070:Immunoglobulin A / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013921:Thrombocytopenia / Q000235:genetics / Q000378:metabolism; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D007070:Immunoglobulin A; D010980:Platelet Membrane Glycoproteins; C491671:Waspip protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; C098341:platelet membrane glycoprotein VI
references.citation: Cell. 2003 Jan 10;112(1):87-97
references.pmid: 12526796
references.citation: J Pathol. 2006 Jan;208(2):270-82
references.pmid: 16362985
references.citation: Exp Hematol. 2003 Feb;31(2):150-8
references.pmid: 12591280
references.citation: Blood. 1985 Jun;65(6):1439-43
references.pmid: 3995178
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):926-31
references.pmid: 17213309
references.citation: J Exp Med. 2004 Feb 2;199(3):357-68
references.pmid: 14757742
references.citation: J Exp Med. 2004 Jan 5;199(1):99-112
references.pmid: 14707117
references.citation: Cell. 1994 Aug 26;78(4):635-44
references.pmid: 8069912
references.citation: J Thromb Haemost. 2006 Mar;4(3):648-55
references.pmid: 16460447
references.citation: Blood. 1993 Nov 15;82(10):2961-6
references.pmid: 8219187
references.citation: Nat Cell Biol. 2001 May;3(5):484-91
references.pmid: 11331876
references.citation: J Exp Med. 2001 Feb 19;193(4):459-69
references.pmid: 11181698
references.citation: Blood. 2003 Dec 1;102(12):4229-35
references.pmid: 12907434
references.citation: Br J Haematol. 1997 Jun;97(4):747-54
references.pmid: 9217172
references.citation: Mol Cell. 2002 Dec;10(6):1269-81
references.pmid: 12504004
references.citation: J Immunol. 1999 Apr 15;162(8):5019-24
references.pmid: 10202051
references.citation: Immunity. 2002 Feb;16(2):193-204
references.pmid: 11869681
references.citation: Nat Cell Biol. 2000 Jul;2(7):441-8
references.pmid: 10878810
references.citation: Br J Haematol. 1999 Sep;106(4):875-83
references.pmid: 10519987
references.citation: Blood. 2004 Sep 1;104(5):1350-5
references.pmid: 15150079
references.citation: Blood. 2001 May 1;97(9):2633-9
references.pmid: 11313252
references.citation: Blood. 2002 Sep 15;100(6):2113-22
references.pmid: 12200375
references.citation: J Thromb Haemost. 2005 Aug;3(8):1752-62
references.pmid: 16102042
references.citation: J Biol Chem. 2001 Feb 23;276(8):5916-23
references.pmid: 11113155
references.citation: Blood. 1999 Dec 15;94(12):4166-76
references.pmid: 10590061
references.citation: Cell. 2002 Nov 15;111(4):565-76
references.pmid: 12437929
references.citation: J Cell Biol. 2000 Apr 3;149(1):181-94
references.pmid: 10747096
references.citation: Am J Kidney Dis. 2004 Mar;43(3):e7-12
references.pmid: 14981635
references.citation: Child Nephrol Urol. 1988-1989;9(1-2):118-20
references.pmid: 3251617
references.citation: N Engl J Med. 1972 Mar 9;286(10):499-504
references.pmid: 5062078
references.citation: Immunity. 1998 Jul;9(1):81-91
references.pmid: 9697838
references.citation: J Allergy Clin Immunol. 2006 Apr;117(4):725-38; quiz 739
references.pmid: 16630926
references.citation: Proc Natl Acad Sci U S A. 1995 May 9;92(10):4706-10
references.pmid: 7753869
references.citation: Blood. 2006 Jul 1;108(1):134-40
references.pmid: 16522820
references.citation: Blood. 1998 Sep 15;92(6):1852-8
references.pmid: 9731041
references.citation: J Immunol. 2005 Jul 15;175(2):1329-36
references.pmid: 16002738
references.citation: Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14671-6
references.pmid: 9405671
references.citation: Immunity. 2000 Jul;13(1):25-35
references.pmid: 10933392
references.citation: Int Immunol. 2007 Feb;19(2):185-92
references.pmid: 17205972
references.citation: Curr Biol. 2003 Mar 4;13(5):384-93
references.pmid: 12620186
references.citation: J Cell Biol. 2000 Sep 18;150(6):1311-20
references.pmid: 10995437
references.citation: J Pathol. 2007 Jan;211(1):67-75
references.pmid: 17086554
references.citation: Biochem J. 1995 Mar 1;306 ( Pt 2):337-44
references.pmid: 7534064
references.citation: J Exp Med. 2003 Jan 6;197(1):41-9
references.pmid: 12515812
references.citation: Curr Biol. 1999 May 20;9(10):555-8
references.pmid: 10339430
references.citation: Mol Cell Biol. 2004 Jun;24(12):5269-80
references.pmid: 15169891
references.citation: Blood. 1999 Jul 15;94(2):509-18
references.pmid: 10397718
references.citation: J Exp Med. 1999 Nov 1;190(9):1329-42
references.pmid: 10544204
references.citation: J Cell Biol. 2006 Apr 10;173(1):121-32
references.pmid: 16606694
references.citation: Biochem Biophys Res Commun. 2007 Feb 23;353(4):875-81
references.pmid: 17207458
references.citation: Cell. 1996 Mar 8;84(5):723-34
references.pmid: 8625410