| 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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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | Familial essential thrombocythemia / Activating mutation / c-mpl / transmembrane domain / dimerization / polarity / 家族性血小板血症 / 活性型変異 / c-mp1 / stat5 / mek1 / 2 |
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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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