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2004 Fiscal Year Final Research Report Summary

Characterization of regulatory proteins for β3 integrins.

Research Project

Project/Area Number 15390299
Research Category

Grant-in-Aid for Scientific Research (B)

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

Principal Investigator

TOMIYAMA Yoshiaki  Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (80252667)

Co-Investigator(Kenkyū-buntansha) ORITANI Kenji  Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (70324762)
SHIRAGA Masamichi  Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手
Project Period (FY) 2003 – 2004
Keywordsintegrin / CMK / inside-out signaling / ligand-binding sites / PKC / WAVE
Research Abstract

β3 integrins, which contain αIIbβ3 and αvβ3, play critical roles in atherosclerosis as well as thrombosis.
Therefore, the elucidation of the regulatory mechanisms for integrin function is a critical issue to control these vascular events. In this research project, we have tried to establish a new experimental model other than platelets to examine the regulation of β3 integrin function and their ligand-binding sites.
We examined ligand-binding sites within the αvβ-propeller domain employing alanine-scanning mutagenesis within W3 and W4 loops. We demonstrated that 178Tyr and Asp128 are the critical residues for ligand-binding.. In addition Ala215Tyr αv increased the integrin affinity.
We next demonstrated that in a megakaryocytic cell line, CMK,CD42b(GPIb)-positive cells could activate αIIbβ3 after PMA stimulation. We then searched molecules responsible for integrin activation employing differential display method and/or cDNA micrarray During CMK maturation expression levels of 306 genes increased. Among them we were interested in β1-tublin, CKIP-1, cortactin, PKCδ, PKCβ1, WAVE-1, Rab27B etc. Employing bryostatin-1 we suggested that PKCα and β play a role in integrin activation. Employing primary megakaryocytic cells derived from cord blood, we confirmed that WAVE-1 expression, but not WAVE-2 or -3, increased during megakaryocytic differentiation. In adhered platelets both WAVE-1 and WAVE-2 were localized at the edge of the lamellipodia, suggesting that these molecules may regulate actin reorganization during platelet spreading.

  • Research Products

    (9 results)

All 2005 2004 2003

All Journal Article (9 results)

  • [Journal Article] Expression and subcellular localization of WAVE isoforms in the megakaryocyte/platelet lineage.2005

    • Author(s)
      Kashiwagi H, et al.
    • Journal Title

      Journal of Thrombosis Haemostasis 3

      Pages: 361-368

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] SHPS-1 negatively regulates integrin α_<IIb>β_3 function through CD47 without disturbing FAK phosphorylation.2005

    • Author(s)
      Kato H, et al.
    • Journal Title

      Journal of Thrombosis Haemostasis 3

      Pages: 763-774

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Expression and subcellular localization of WAVE isoforms in the megakaryocyte/platelet lineage.2005

    • Author(s)
      Kashiwagi H, et al.
    • Journal Title

      Journal of Thrombosis and Haemostasis 3

      Pages: 361-368

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] SHPS-1 negatively regulates integrin α_<IIb>β_3 function through CD47 without disturbing FAK phosphorylation.2005

    • Author(s)
      Kato H, et al.
    • Journal Title

      Journal of Thrombosis and Haemostasis 3

      Pages: 763-774

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Activation of integrin αIIbβ3 in the glycoprotein Ib-high population of a megakaryocytic cell line, CMK, by inside-out signaling.2004

    • Author(s)
      Kashiwagi H, et al.
    • Journal Title

      Journal of Thrombosis and Haemostasis 2

      Pages: 177-186

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Amino acid mutagenesis within ligand-binding loops in αv confers loss-of-function or gain-of-function phenotype on integrin αvβ3.2004

    • Author(s)
      Honda S, et al.
    • Journal Title

      Thrombosis and Haemostasis 92

      Pages: 1092-1098

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] The pituitary adenylate cyclase-activating polypeptide is a physiological inhibitor of platelet activation.2004

    • Author(s)
      Freson K, et al.
    • Journal Title

      Journal of Clinical Investigation 113

      Pages: 905-912

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] A naturally-occurring Tyr143HisαIIb mutation abolishes αIIbβ3 function for soluble ligands but retains its ability for mediating cell adhesion and clot retraction : comparison with other mutations causing ligand-binding defects.2003

    • Author(s)
      Kiyoi T, et al.
    • Journal Title

      Blood 101

      Pages: 3485-3491

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] A naturally-occurring Tyr143HisαIIb mutation abolishes αIIbβ3 function for soluble ligands but retains its ability for mediating cell adhesion and clot retraction : comparison with other mutations causing ligand-binding defects.2003

    • Author(s)
      Kiyoi T, et al.
    • Journal Title

      Blood 102

      Pages: 3485-3491

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2006-07-11  

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