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PMID: 16788103 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Bruton tyrosine kinase is essential for botrocetin/VWF-induced signaling and GPIb-dependent thrombus formation in vivo.

Blood ·Vol. 108 ·No. 8 ·2006-10-15 ·Pages 2596-603

Liu J, Fitzgerald ME, Berndt MC, Jackson CW, Gartner TK

Abstract

Botrocetin (bt)-facilitated binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein (GP) Ib-IX-V complex on platelets in suspension initiates a signaling cascade that causes alphaIIbbeta3 activation and platelet aggregation. Previous work has demonstrated that bt/VWF-mediated agglutination activates alphaIIbbeta3 and elicits ATP secretion in a thromboxane A2 (TxA2)-dependent manner. The signaling that results in TxA2 production was shown to be initiated by Lyn, enhanced by Src, and propagated through Syk, SLP-76, PI3K, PLCgamma2, and PKC. Here, we demonstrate that the signaling elicited by GPIb-mediated agglutination that results in TxA2 production is dependent on Bruton tyrosine kinase (Btk). The results demonstrate that Btk is downstream of Lyn, Syk, SLP-76, and PI3K; upstream of ERK1/2, PLCgamma2, and PKC; and greatly enhances Akt phosphorylation. The relationship(s), if any, between ERK1/2, PLCgamma2, and PKC were not elucidated. The requirement for Btk and TxA2 receptor function in GPIb-dependent arterial thrombosis was confirmed in vivo by characterizing blood flow in ferric chloride-treated mouse carotid arteries. These results demonstrate that the Btk family kinase, Tec, cannot provide the function(s) missing because of the absence of Btk and that Btk is essential for both bt/VWF-mediated agglutination-induced TxA2 production and GPIb-dependent stable arterial thrombus formation in vivo.

MeSH Terms
Agammaglobulinaemia Tyrosine Kinase Animals Carotid Artery Thrombosis/blood,etiology Crotalid Venoms/metabolism MAP Kinase Signaling System Male Mice Mice, Inbred CBA Mice, Knockout Mice, Mutant Strains Phospholipase C gamma/blood Phosphorylation Platelet Aggregation/physiology Platelet Glycoprotein GPIb-IX Complex/metabolism Protein-Tyrosine Kinases/deficiency,genetics,metabolism Signal Transduction Thrombosis/blood,etiology Thromboxane A2/blood von Willebrand Factor/metabolism
Chemicals
Crotalid Venoms Platelet Glycoprotein GPIb-IX Complex von Willebrand Factor Thromboxane A2 botrocetin Protein-Tyrosine Kinases Agammaglobulinaemia Tyrosine Kinase Btk protein, mouse Phospholipase C gamma
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Liu Junling
Department of Biology, University of Memphis, Memphis, TN 38152, USA.
Fitzgerald Malinda E
Berndt Michael C
Jackson Carl W
Gartner T Kent
References (60)
60 references, click to expand
  1. Src family kinase-mediated and Erk-mediated thromboxane A2 generation are essential for VWF/GPIb-induced fibrinogen receptor activation in human platelets.
    Blood. 2005 Nov 15;106(10):3410-4 PMID: 16020504
  2. Botrocetin/VWF-induced signaling through GPIb-IX-V produces TxA2 in an alphaIIbbeta3- and aggregation-independent manner.
    Blood. 2005 Oct 15;106(8):2750-6 PMID: 15985541
  3. Glycoprotein VI-dependent and -independent pathways of thrombus formation in vivo.
    Blood. 2006 May 15;107(10):3902-6 PMID: 16455953
  4. Distinct antithrombotic consequences of platelet glycoprotein Ibalpha and VI deficiency in a mouse model of arterial thrombosis.
    J Thromb Haemost. 2006 Sep;4(9):2014-21 PMID: 16961609
  5. Rapid tyrosine phosphorylation and activation of Bruton's tyrosine/Tec kinases in platelets induced by collagen binding or CD32 cross-linking.
    Blood. 2000 Mar 1;95(5):1663-70 PMID: 10688822
  6. Phosphoinositide 3-kinase forms a complex with platelet membrane glycoprotein Ib-IX-V complex and 14-3-3zeta.
    Blood. 2000 Jul 15;96(2):577-84 PMID: 10887121
  7. Phospholipase Cgamma2 is essential in the functions of B cell and several Fc receptors.
    Immunity. 2000 Jul;13(1):25-35 PMID: 10933392
  8. Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen.
    J Clin Invest. 2000 Aug;106(3):385-92 PMID: 10930441
  9. Synergistic adhesive interactions and signaling mechanisms operating between platelet glycoprotein Ib/IX and integrin alpha IIbbeta 3. Studies in human platelets ans transfected Chinese hamster ovary cells.
    J Biol Chem. 2000 Dec 29;275(52):41377-88 PMID: 10967111
  10. Interaction between the Btk PH domain and phosphatidylinositol-3,4,5-trisphosphate directly regulates Btk.
    J Biol Chem. 2001 May 11;276(19):16201-6 PMID: 11279148
  11. A mitogen-activated protein kinase-dependent signaling pathway in the activation of platelet integrin alpha IIbbeta3.
    J Biol Chem. 2001 Nov 9;276(45):42226-32 PMID: 11522789
  12. Blockade of adenosine diphosphate receptors P2Y(12) and P2Y(1) is required to inhibit platelet aggregation in whole blood under flow.
    Blood. 2001 Dec 1;98(12):3340-5 PMID: 11719372
  13. Essential role for phosphoinositide 3-kinase in shear-dependent signaling between platelet glycoprotein Ib/V/IX and integrin alpha(IIb)beta(3).
    Blood. 2002 Jan 1;99(1):151-8 PMID: 11756165
  14. Functional significance of adenosine 5'-diphosphate receptor (P2Y(12)) in platelet activation initiated by binding of von Willebrand factor to platelet GP Ibalpha induced by conditions of high shear rate.
    Circulation. 2002 May 28;105(21):2531-6 PMID: 12034661
  15. A crucial role of glycoprotein VI for platelet recruitment to the injured arterial wall in vivo.
    J Exp Med. 2003 Jan 6;197(1):41-9 PMID: 12515812
  16. PI3K and Btk differentially regulate B cell antigen receptor-mediated signal transduction.
    Nat Immunol. 2003 Mar;4(3):280-6 PMID: 12563258
  17. Intercellular calcium communication regulates platelet aggregation and thrombus growth.
    J Cell Biol. 2003 Mar 31;160(7):1151-61 PMID: 12668663
  18. Chemotactic factor-induced recruitment and activation of Tec family kinases in human neutrophils. II. Effects of LFM-A13, a specific Btk inhibitor.
    J Immunol. 2003 May 15;170(10):5235-43 PMID: 12734372
  19. AlphaIIbbeta3-mediated outside-in signaling induced by the agonist peptide LSARLAF utilizes ADP and thromboxane A2 receptors to cause alpha-granule secretion by platelets.
    J Thromb Haemost. 2003 Feb;1(2):363-73 PMID: 12871512
  20. Signaling role for phospholipase C gamma 2 in platelet glycoprotein Ib alpha calcium flux and cytoskeletal reorganization. Involvement of a pathway distinct from FcR gamma chain and Fc gamma RIIA.
    J Biol Chem. 2003 Aug 29;278(35):32880-91 PMID: 12813055
  21. The anti-leukemic Bruton's tyrosine kinase inhibitor alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl) propenamide (LFM-A13) prevents fatal thromboembolism.
    Leuk Lymphoma. 2003 Sep;44(9):1569-77 PMID: 14565661
  22. Tec regulates platelet activation by GPVI in the absence of Btk.
    Blood. 2003 Nov 15;102(10):3592-9 PMID: 12842985
  23. BTK regulates PtdIns-4,5-P2 synthesis: importance for calcium signaling and PI3K activity.
    Immunity. 2003 Nov;19(5):669-78 PMID: 14614854
  24. GPIb-dependent platelet activation is dependent on Src kinases but not MAP kinase or cGMP-dependent kinase.
    Blood. 2004 Apr 1;103(7):2601-9 PMID: 14684423
  25. Signaling through GP Ib-IX-V activates alpha IIb beta 3 independently of other receptors.
    Blood. 2004 May 1;103(9):3403-11 PMID: 14726383
  26. In vivo toxicity and antithrombotic profile of the oral formulation of the antileukemic agent, LFM-A13-F.
    Arzneimittelforschung. 2004;54(6):330-9 PMID: 15281619
  27. Phospholipase Cgamma2 contributes to stable thrombus formation on VWF.
    FEBS Lett. 2004 Aug 27;573(1-3):26-30 PMID: 15327970
  28. Tec kinases mediate sustained calcium influx via site-specific tyrosine phosphorylation of the phospholipase Cgamma Src homology 2-Src homology 3 linker.
    J Biol Chem. 2004 Sep 3;279(36):37651-61 PMID: 15184383
  29. The genetics of the immune response to a synthetic double-stranded RNA in a mutant CBA mouse strain.
    J Immunol. 1973 May;110(5):1396-401 PMID: 4121424
  30. The role of platelet membrane glycoproteins Ib and IIb-IIIa in platelet adherence to human artery subendothelium.
    Br J Haematol. 1986 Aug;63(4):681-91 PMID: 2942171
  31. Shear-induced platelet aggregation can be mediated by vWF released from platelets, as well as by exogenous large or unusually large vWF multimers, requires adenosine diphosphate, and is resistant to aspirin.
    Blood. 1988 May;71(5):1366-74 PMID: 3258770
  32. Purification of botrocetin from Bothrops jararaca venom. Analysis of the botrocetin-mediated interaction between von Willebrand factor and the human platelet membrane glycoprotein Ib-IX complex.
    Biochemistry. 1989 Oct 17;28(21):8317-26 PMID: 2557900
  33. Rat model of arterial thrombosis induced by ferric chloride.
    Thromb Res. 1990 Nov 15;60(4):269-80 PMID: 2087688
  34. Shear stress-induced von Willebrand factor binding to platelet glycoprotein Ib initiates calcium influx associated with aggregation.
    Blood. 1992 Jul 1;80(1):113-20 PMID: 1611079
  35. A monomeric von Willebrand factor fragment, Leu-504--Lys-728, inhibits von Willebrand factor interaction with glycoprotein Ib-IX [corrected].
    Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):7880-4 PMID: 1518808
  36. Protein kinase C alpha activates RAF-1 by direct phosphorylation.
    Nature. 1993 Jul 15;364(6434):249-52 PMID: 8321321
  37. Mutation of unique region of Bruton's tyrosine kinase in immunodeficient XID mice.
    Science. 1993 Jul 16;261(5119):358-61 PMID: 8332901
  38. Protein kinase C-mediated serine phosphorylation directly activates Raf-1 in murine hematopoietic cells.
    J Biol Chem. 1994 Jan 14;269(2):1249-56 PMID: 8288587
  39. Adhesion receptor activation of phosphatidylinositol 3-kinase. von Willebrand factor stimulates the cytoskeletal association and activation of phosphatidylinositol 3-kinase and pp60c-src in human platelets.
    J Biol Chem. 1994 Oct 28;269(43):27093-9 PMID: 7523416
  40. Abolition of cyclic flow variations in stenosed, endothelium-injured coronary arteries in nonhuman primates with a peptide fragment (VCL) derived from human plasma von Willebrand factor-glycoprotein Ib binding domain.
    Circulation. 1994 Dec;90(6):2976-81 PMID: 7994845
  41. Platelet size distribution measurements as indicators of shear stress-induced platelet aggregation.
    Ann Biomed Eng. 1994 Nov-Dec;22(6):653-9 PMID: 7532923
  42. VCL, an antagonist of the platelet GP1b receptor, markedly inhibits platelet adhesion and intimal thickening after balloon injury in the rat.
    Circulation. 1995 Sep 1;92(5):1269-73 PMID: 7648675
  43. Defective B cell development and function in Btk-deficient mice.
    Immunity. 1995 Sep;3(3):283-99 PMID: 7552994
  44. Impaired expansion of mouse B cell progenitors lacking Btk.
    Immunity. 1995 Sep;3(3):301-12 PMID: 7552995
  45. Adhesion of blood platelets is inhibited by VCL, a recombinant fragment (leucine504 to lysine728) of von Willebrand factor.
    Arterioscler Thromb Vasc Biol. 1996 Jan;16(1):64-71 PMID: 8548428
  46. A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2.
    J Exp Med. 1996 Jul 1;184(1):31-40 PMID: 8691147
  47. Distinct specificity in the recognition of phosphoinositides by the pleckstrin homology domains of dynamin and Bruton's tyrosine kinase.
    EMBO J. 1996 Nov 15;15(22):6241-50 PMID: 8947047
  48. The Fc receptor gamma-chain and the tyrosine kinase Syk are essential for activation of mouse platelets by collagen.
    EMBO J. 1997 May 1;16(9):2333-41 PMID: 9171347
  49. Characterization of the B lymphocyte populations in Lyn-deficient mice and the role of Lyn in signal initiation and down-regulation.
    Immunity. 1997 Jul;7(1):69-81 PMID: 9252121
  50. Phosphatidylinositol 3-kinase-gamma activates Bruton's tyrosine kinase in concert with Src family kinases.
    Proc Natl Acad Sci U S A. 1997 Dec 9;94(25):13820-5 PMID: 9391111
  51. Regulation of arterial thrombolysis by plasminogen activator inhibitor-1 in mice.
    Circulation. 1998 Mar 17;97(10):1002-8 PMID: 9529269
  52. Btk/Tec kinases regulate sustained increases in intracellular Ca2+ following B-cell receptor activation.
    EMBO J. 1998 Apr 1;17(7):1973-85 PMID: 9524120
  53. A mouse model of severe von Willebrand disease: defects in hemostasis and thrombosis.
    Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9524-9 PMID: 9689113
  54. Impaired viability and profound block in thymocyte development in mice lacking the adaptor protein SLP-76.
    Cell. 1998 Jul 24;94(2):229-38 PMID: 9695951
  55. A role for Bruton's tyrosine kinase (Btk) in platelet activation by collagen.
    Curr Biol. 1998 Oct 8;8(20):1137-40 PMID: 9778529
  56. Coagulation defects and altered hemodynamic responses in mice lacking receptors for thromboxane A2.
    J Clin Invest. 1998 Dec 1;102(11):1994-2001 PMID: 9835625
  57. Preparation of monoclonal antibodies to murine platelet glycoprotein IIb/IIIa (alphaIIbbeta3) and other proteins from hamster-mouse interspecies hybridomas.
    Biochem Biophys Res Commun. 1999 Aug 19;262(1):167-73 PMID: 10448087
  58. Distinct roles of ADP receptors in von Willebrand factor-mediated platelet signaling and activation under high flow.
    Blood. 2004 Nov 15;104(10):3221-7 PMID: 15284110
  59. The roles of ADP and TXA in botrocetin/VWF-induced aggregation of washed platelets.
    J Thromb Haemost. 2004 Dec;2(12):2213-22 PMID: 15613029
  60. Protein kinase C can inhibit TRPC3 channels indirectly via stimulating protein kinase G.
    J Cell Physiol. 2006 May;207(2):315-21 PMID: 16331690
Article Info
Journal
Blood
Abbr.
Blood
ISSN
0006-4971
DOI
10.1182/blood-2006-01-011817
Published
2006-10-15
Epub
2006-00-20
Pages
2596-603
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC1895591
Subset
IM
Grants
NHLBI NIH HHS · HL 079990 · United States
NCI NIH HHS · P01 CA 20180 · United States
NCI NIH HHS · P30 CA 21765 · United States
External Links
PubMed source DOI: 10.1182/blood-2006-01-011817 PMC Full Text View journal details
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