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

导致家族性原发性血小板增多症的 c-mpl 自主激活突变的分子分析

• 批准号: 17591004
• 负责人: KOMATSU Hirokazu
• 金额: $ 1.98万
• 依托单位: Nagoya City University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591004/
• 关键词: 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

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.

我们以前报道，一个显性阳性激活突变（Asn 505）的跨膜结构域（TMD）的c-MPL，它编码的血小板生成素受体，引起家族性原发性血小板增多症。在这里，我们表明，Asn 505突变诱导自主二聚化的c-Mpl和信号激活的情况下，其配体。信号激活被保留在一个截短的突变体Asn 505，缺乏c-Mpl的胞外结构域。我们还发现，取代的氨基酸（AA）残基在位置505与其他强极性（谷氨酸，天冬氨酸或谷氨酰胺）也导致激活的二聚化没有配体刺激。总之，这些数据表明Asn 505突变通过c-Mpl蛋白的自主二聚化转导信号，这是由于强AA极性。这一发现提供了一个新的见解疾病的致病机制，在TMD的细胞因子/造血受体的突变。

项目成果

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• 发表时间: 2005
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• DOI: 10.1182/blood.v104.11.1111.1111
• 发表时间: 2004-11
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• 影响因子: 20.3
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Annual Review 血液

年度审查血液

• 发表时间: 2015
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• 通讯作者: 朝倉英策（単著）

The CCR4 as a novel-specific molecular target for immunotherapy in Hodgkin lymphoma

• DOI: 10.1038/sj.leu.2404415
• 发表时间: 2006-12-01
• 期刊: LEUKEMIA
• 影响因子: 11.4
• 作者: Ishida, T.;Ishii, T.;Ueda, R.
• 通讯作者: Ueda, R.