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Molecular mechanism of thrombin receptor pathway that mediated apoptosis in neural cells

Research Project

Project/Area Number 10680605
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional biochemistry
Research InstitutionMie University

Principal Investigator

IDO Masaru  Mie University, Hospital, Associate Professor, 医学部・附属病院, 助教授 (90167263)

Co-Investigator(Kenkyū-buntansha) SUZUKI Koji  Mie University, Faculty of Medicine, Professor, 医学部, 教授 (70077808)
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 1999: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1998: ¥1,600,000 (Direct Cost: ¥1,600,000)
KeywordsThrombin receptor / Serine / threonin kinase / Platenet / PCR
Research Abstract

Thrombin is a multifunctional serine protease that plays an important role in hemostasis and wound healings. High concentrations of thrombin in the central nervous system is often associated with neural cell death. Protease-activated receptor 1 (PAR1/ thrombin receptor) is a member of the G protein-coupled receptor containing seven transmembrane domains. Thrombin cleaves the receptor at the Arg41/Ser42 peptide bond and unmasks a tethered amino-terminal sequence beginning with the Ser-Phe-Leu-Leu-Arg-Asn (thrombin receptor agonist peptide/TRAP) ; subsequent binding of this ligand sequence to the body of the receptor is coupled with a transmembrane signaling mediated by G proteins. Neural cell death by thrombin is mediated by the activation of PAR1. Thus, regulation is coupled with internalization and PAR1. Phosphorylation of Ser and/or Thr in this region by Ala residue or truncation of this region results in resistance to desensitization and internalization. However, protein kinase capable of phosphorylating PAR1 in human platelet is unknown. In the present study, we identified the 33-kDa Ser/Thr protein kinase, which was activated by thrombin, TRAP, but not by hirudin-treated thrombin or diisopropylfluoro- phosphate-inactivated thrombin, suggesting that it is activated through PAR1. Furthermore, treatment of cells with thromboxane AィイD22ィエD2 analog, STAィイD22ィエD2, led to an activation of this protein kinase and phosphorylation of PAR1. In conclusion, the present study provides evidence of homologous and heterologous activation of a novel 33-kDa Ser/Thr kinase that phosphorylates the cytoplasmic tail of PAR1.

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (15 results)

All Other

All Publications (15 results)

  • [Publications] Ido M, Hayashi T, Gabazza EC and Suzuki K: "Identification of a Novel 33-kDa Ser/Thr Kinase that Phosphorylates the Cytoplasmic Tail of Protease-Activated Receptor 1 (Thrombin Receptor) in Human Platelets"Thromb Haemost. 83・4(in press). (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ido M, Hayashi T and Suzuki K: "Ca^<2+>-Dependent Activation of th 33-kDa Thrombin Receptor-Associated Kinase in Human Platelets"Lipoprotein Metabolism and Atherogenesis (Springer Verlag). (in press). (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ido M, Hayashi T, Nishioka J, and Suzuki K.: "Hereditary Thrombophilia Caused by Abnormality of the Anticoagulant Protein C Pathway : Prenatal diagnosis of compound heterozygous protein C deficiency"In Pulmonary embolism (eds. Nakano, T. & Goldhaber, S. Z.) Springer-Verlag, Tokyo. 21-35 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Wakita T, Hayashi T, Yuasa H, Nishioka J. Kawamura J. and: "Molecular cloning, tissue distribution and androgen regulation of rat protein C inhibitor"FEBS Lett.. 429. 263-268 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Sano T, Gabazza EC, Hayashi T, Ido M, Uchida A, and Suzuki K.: "The zymogen prothrombin stimulates cell locomotion and calcium influx in murine osteosarcoma cells by different mechanism from thrombin"Int J Oncology 15 : 1197-1203. 15. 1197-1203 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Nishioka, J, Ning M, Hayashi T, and Suzuki K.: "Protein C inhibitor secreted from activated platelets efficiently inhibits activated protein C on phosphatidyl-ethanolamine of platelet membrane and microvesicles"J Biol Chem. 273. 11282-11287 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ido M, Hayashi T, Gabazza EC and Suzuki K: "Identification of a Novel 33-kDa Ser/Thr Kinase that Phosphorylates the Cytoplasmic Tail of Protease-Activated Receptor 1 (Thrombin Receptor) in Human Platelets"Thrombosis and Haemostasis. (in press). (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ido M, Hayashi T, and Suzuki K: "CaィイD12+ィエD1-Dependent Activation of the 33-kDa Thrombin Receptor-Associated kinase In Human Platelets"Lipoprotein Metabolism and Atherogenesis (Springer Verlag). (in press). (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ido M, Hayashi T, Nishioka J and Suzuki K: "Hereditary thrombophilia caused by abnormality of the anticoagulant protein C pathway : Prenatal diagnosis of compound heterozygous protein C deficiency by direct detection of mutaion sites"Pulmonary Embolism (eds. Nakano, T. & Goldhaber, S.Z.) Springer-Verlag, Tokyo. 21-35 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Wakita T, Hayashi T, Yuasa H, Nishioka J, Kawamura J, and Suzuki K.: "Molecular cloning tissue distribution and androgen regulation of rat protein C inhibitor"FEBS Lett.. 429. 263-268 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Sano T, Gabazza EC, Zhou H, Takeya H, Hayashi T, Ido M, Adachi Y, Uchida A, and Suzuki K.: "The zymogen prothrombin stimulates cell locomotion and calcium influx in murine osteosarcoma cells by different mechanism from thrombin"Int. J. Oncology. 15. 1197-1203 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Nishioka J, Ning M, Hayashi T, and Suzuki K.: "Protein C inhibitor secreted from activated platelets efficiently inhibits activated protein C on phosphatidyl-ethanolamine of platelet membrane and microvesicles"J. Biol. Chem.. 273. 11281-11287 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ido M,Hayashi T,and Suzuki K: "Ca^<2+>-Dependent Activation of the 33-kDa Thrombin Receptor-Associated Kinase In Human Platelets"Lipoprotein Metabolism and Atherogenesis(Springer Verlag). (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ido M,Hayashi T,Gabazza EC and Suzuki K: "Identification of a Novel 33-kDa Ser/Thr Kinase that Phosphorylates the Cytoplasmic Tail of Protease-Activated Receptor 1 (Thrombin Receptor) in"Thrombosis and Haemostasis. 83・4(in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Masaru Ido,Tatsuya Hayashi,and Koji Suzuki: "Ca^<2+>-Dependent Activation of the 33-kDa Thrombin Receptor-Associated Kinase in Human Platelets" Lipoprotein Metabolism and Atherogenesis(Springer Verlag). (in press). (1999)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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