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2006 Fiscal Year Final Research Report Summary

Molecular analysis of autonomous activating mutation of c-mpl responsible for familial essential thrombocythemia

Research Project

Project/Area Number 17591004
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionNagoya City University

Principal Investigator

KOMATSU Hirokazu  Nagoya City University, Graduate School of Medical Sciences, Lecturer (60336675)

Co-Investigator(Kenkyū-buntansha) UEDA Ryuzo  Nagoya City University, Graduate School of Medical Sciences, Professor (20142169)
IIDA Shinsuke  Nagoya City University, Graduate School of Medical Sciences, Lecturer (50295614)
Project Period (FY) 2005 – 2006
KeywordsFamilial essential thrombocythemia / Activating mutation / c-mpl / transmembrane domain / dimerization / polarity
Research Abstract

We previously reported that a dominant-positive activating mutation (Asn505) in the transmembrane domain (TMD) of c-MPL, which encodes the thrombopoietin receptor, caused familial essential thrombocythemia. Here, we show that the Asn505 mutation induces both autonomous dimerization of c-Mpl and signal activation in the absence of its ligand. Signal activation was preserved in a truncated mutant of Asn505 that lacked the extracellular domain of c-Mpl. We also found that the substitution of the amino acid (AA) residue at position 505 with others of strong polarity (Glu, Asp or Gln) also resulted in activated dimerization without ligand stimulation. Overall, these data show that the Asn505 mutation transduced the signal through the autonomous dimerization of the c-Mpl protein due to strong AA polarity. This finding provides a new insight into the mechanism of disease causation by mutations in the TMD of cytokine/hematopoietic receptors.

  • Research Products

    (5 results)

All 2009 2006

All Journal Article (4 results) Book (1 results)

  • [Journal Article] The Asn505 mutation of c-MPL gene, which causes familial essential thrombocythemia, induces autonomous homodimerization of the c-Mp1protein due to strong amino acid polarity.2009

    • Author(s)
      Jianmin Ding, Hirokazu Komatsu. Shinsuke Iida, Hiroki Yano, Shigeru Kusumoto, Atsushi Inagaki, Masaki Ri, Asahi Ito, Atsushi Wakita, Takashi Ishida, Masakazu Nitta, Ryuzo Ueda.
    • Journal Title

      Blood (in press)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] The CCR4 as a novel-specific molecular target for immunotherapy in Hodgkin lymphoma.2006

    • Author(s)
      Ishida T, Ishii T, Inagaki A, Yano H, Kusumoto S, Ri M, Komatsu H, Iida S, Inagaki H, Ueda R.
    • Journal Title

      Leukemia 20 (12)

      Pages: 2162-2168

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Specific recruitment of CC chemokine receptor 4-positive regulatory T cells in Hodgkin lymphoma fosters immune privilege2006

    • Author(s)
      Ishida T, Ishii T, Inagaki A, Yano H, Komatsu H, Iida S, Inagaki H, Ueda R
    • Journal Title

      Cancer Res. 66 (11)

      Pages: 5716-5722

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Clinical significance of serum Thl-Th2-and regulatory Tcells-associated cytokines in adult T-cell leukemia/lymphoma : high interleukin-5 and-10 levels are significant unfavorable prognostic factors.2006

    • Author(s)
      Inagaki A, Ishida T, Ishii T, Komatsu H, Iida S, Ding J, Yonekura K, Takeuchi S, Takatsuka Y, Utsunomiya A, Ueda R.
    • Journal Title

      Int J Cancer 118 (12)

      Pages: 3054-3061

    • Description
      「研究成果報告書概要(和文)」より
  • [Book] Annual Review 血液2006

    • Author(s)
      小松弘和, 丁建民, 飯田真介, 上田龍三
    • Total Pages
      9
    • Publisher
      血小板系トロンボポエチン受容体c-MPL遺伝子の活性型変異による家族性血小板血症
    • Description
      「研究成果報告書概要(和文)」より

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Published: 2010-06-09  

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