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Signaling through integrin alpha IIb beta3

Research Project

Project/Area Number 09671112
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionOsaka University

Principal Investigator

TOMIYAMA Yoshiaki  Osaka University Medical School, Assistant Professor, 医学部, 助手 (80252667)

Co-Investigator(Kenkyū-buntansha) HONDA Shigenori  Osaka University Medical School, Assistant Professor, 医学部, 助手 (00303959)
KANAKURA Yuzuru  Osaka University Medical School, Professor, 医学部, 教授 (20177489)
KURATA Yoshiyuki  Osaka University Hospital, Instructor, 医学部・附属病院, 講師 (80127224)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 1998: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1997: ¥2,300,000 (Direct Cost: ¥2,300,000)
Keywordsalpha IIb beta3 / integrin / platelets / NCX / signal transduction
Research Abstract

In this research project, we have investigated both inside-out and outside-in signaling through the integrin alphaIIbbeta3.
Concerning alphaIIbbeta3 activation via inside-out signaling, we have further investigated our hypothesis that Na^+/Ca^<2+> exchanger (NCX) may be involved as a common inside-out signaling.We cloned platelet NCX cDNA and showed that platelet NCX is BD type, while cardiac NCX is BCDEF.Next, employing two unrelated NCX inhibitors, DCB and bepridil, we investigated the role of NCX in platelet activation in detail.Both inhibitors abolished platelet alphaIIbbeta3 activation induced by all agonists examined.However, these inhibitors did not inhibit protein phosphorylation or increase in intracellular calcium concentration.These findings further support our hypothesis that NCX is involves in the common steps of inside-out signaling through alphaIIbbeta3.
We characterized a Japanese variant of Glanzmann thrombasthenia whose platelets express normal amounts of alphaIIbbeta3 and newly showed that a two-amino acid insertion in the Cysl46-Cysl67 loop of the alphaIIb subunit is responsible for this phenotype.In addition, Asp163 is a critical residue for ligand binding function.Concerning outside-in signaling, we showed alphaIIbbeta3 antagonists can be divided into two groups.In group I, antagonists can induce LIBS (ligand-induced binding site) on both alphaIIb and beta3, while in group II, antagonists can induce LIBS on alphaIIb, but not on beta3.Interestingly, only group I antagonists can initiate alphaIIbbeta3-mediated intracellular Ca^<2+> signaling.Our findings strongly sugget the association between beta3 LIBS expression and alphaIIbbeta3-mediated intracellular Ca^<2+> signaling.

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (21 results)

All Other

All Publications (21 results)

  • [Publications] Matsumura I,Tomiyama Y,et al: "Thrombopoietin-induced differentiation of a human megakaryoblastic leukemia cell line,CMK,involves transcriptional activation of p21 WAF1/Cip1 by STAT5." Molecular and Cellular Biology. 17(5). 2933-2943 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Honda S,Tomiyama Y,et al: "A two-amino acid insertion in the Cys146-Cys167 loop of the aIIb subunit is associated with a variant of Glanzmann thrombasthenia : critical role of Asp163 in ligand binding." Journal of Clinical Investigation. 102(6). 1183-1192 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tadokoro S,Tomiyama Y,et al: "A Gln747→Pro substitution in the αIIb subunit is responsible for a moderate αIIbβ3 deficiency in Glanzmann thrombasthenia." Blood. 92(8). 2750-2758 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tomiyama Y,Shiraga M,et al: "A Glanzmann thrombasthenia-like phenotype caused by a defect in inside-out signaling through the integrin αIIbβ3." Thrombosis and Haemostasis. 80(5). 735-742 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Honda S,Tomiyama Y,et al: "Association between ligand-induced conformational changes of integrin αIIbβ3 and αIIbβ3 mediated intracellular Ca2+ signaling." Blood. 92(10). 3675-3683 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Shiraga M,Tomiyama Y,et al: "Involvement of Na^+/Ca^<2+> exchanger in inside out signaling through the platelet integrin αIIbβ3." Blood. 92(10). 3710-3720 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Matsumura I,Tomiyama Y et al: "Thrombopoietin-induced differentiation of a human megakaryoblastic leukemia cell line, CMK,involves transcriptional activation of p21 WAF1/Cip1 by STAT5." Mol Cell Biol. 17(5). 2933-2943 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Honda S,Tomiyama Y et al: "A two-amino acid insertion in the Cys146-Cys167 loop of the alpha IIb subunit is associated with a variant of Glanzmann thrombasthenia : critical role of Asp163 in ligand binding." J Clin Invest. 102(6). 1183-1192 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tadokoro S,Tomiyama Y et al: "A Gln747*Pro substitution in the alpha IIb subunit is responsible for a moderate alpha IIb beta3 deficiency in Glanzmann thrombasthenia." Blood. 92(8). 2750-2758 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tomiyama Y,Shiraga M et al: "A Glanzmann thrombasthenia-like phenotype caused by defect in inside-out sibhaling through the integrin alpha IIb beta3." Thromb Haemost. 80(5). 735-742 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Honda S,Tomiyama Y et al: "Association between ligand-induced conformational changes of integrin alpha IIb beta3 and alpha IIb beta3 mediated intracellular Ca2+signaling." Blood. 92(10). 3675-3683 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Shiraga M,Tomiyama Y et al: "Involvement of Na+Ca_2+ exchanger in inside-out signaling through the platelet integrin alpha IIb beta3." Blood. 92(10). 3710-3720 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Honda S,Tomiyama Y,et al: "A two-amino acid insertion in the Cys146-Cys167 loop of the aIIb subunit is associated with a variant of Glanzmann thrombasthenia: critical role of Asp163 in ligand binding." Journal of Clinical Investigation. 102(6). 1183-1192 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tadokoro S,Tomiyama Y,et al: "A Gin747→Pro substitution in the αIIb subunit is responsible for a moderate αIIbβ3 deficiency in Glanzmann thrombasthenia." Blood. 92(8). 2750-2758 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tomiyama Y,Shiraga M,et al: "A Glanzmann thrombasthenia-like phenotype caused by a defect in inside-out signaling through the integrin αIIbβ3." Thrombosis and Haemostasis. 80(5). 735-742 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Honda S,Tomiyama Y,et al: "Association between ligand-induced conformational change of integrin αIIbβ3 and αIIbβ3 mediated intracellular Ca2_+ signaling." Blood. 92(10). 3675-3683 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Shiraga M,Tomiyama Y,et al: "Involvement of Na^+/Ca^<2+> exchanger in inside-out signaling through the platelet integrin αIIbβ3." Blood. 92(10). 3710-3720 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Matsumura I, et al: "Thrombopoletin-induced differentiation of a human megakaryoblastic leukemia cell line,CMK,involves transcriptional activation of p21 WAF1/Cip1 by STAT5." Molecular and Cellular Biology. 17(5). 2933-2943 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Oritani K, et al: "Matrix glycoprotein SC1/ECM2 augments B lymphopoiesis." Blood. 90(9). 3404-3413 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Horikawa Y, et al: "Marked reduced expression of platelet c-mpl receptor in essential thrombocytemia." Blood. 90(10). 4031-4038 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yokota T, et al: "Growth-supporting and death-preventing activities of fibronectin on hematopoletic stem/progenitor cells in and in vivo : structural requirement for fibronectin activites of CS1 and cell-binding domains." Blood. (in press). (1998)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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