2006 Fiscal Year Final Research Report Summary
Molecular analysis of autonomous activating mutation of c-mpl responsible for familial essential thrombocythemia
| Project/Area Number |
17591004
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Nagoya City University |
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Principal Investigator |
KOMATSU Hirokazu Nagoya City University, Graduate School of Medical Sciences, Lecturer (60336675)
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| 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)
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| Project Period (FY) |
2005 – 2006
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| Keywords | Familial essential thrombocythemia / Activating mutation / c-mpl / transmembrane domain / dimerization / polarity |
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| 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.
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[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.
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Journal Title
Description
「研究成果報告書概要(欧文)」より
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[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.
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Journal Title
Int J Cancer 118 (12)
Pages: 3054-3061
Description
「研究成果報告書概要(和文)」より
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