Amino acid residue E543 in JAK2 C618R is a potential therapeutic target for myeloproliferative disorders caused by JAK2 C618R mutation.
Amino acid residue E543 in JAK2 C618R is a potential therapeutic target for myeloproliferative disorders caused by JAK2 C618R mutation.
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JAK2 C618R 中的氨基酸残基 E543 是 JAK2 C618R 突变引起的骨髓增殖性疾病的潜在治疗靶点。
DOI：
10.1016/j.abb.2012.08.010
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发表时间：
2012-12
影响因子：
3.9
通讯作者：
Wu QY, Li F, Guo HY, Cao J(曹江), Chen C, Chen W
中科院分区：
文献类型：
--
作者：
Wu QY, Li F, Guo HY, Cao J(曹江), Chen C, Chen W
Janus kinase2(JAK2)是一种重要的细胞因子受体信号转导因子，在造血和免疫反应中起着关键作用。在部分骨髓增生性疾病(MPDS)患者中检测到获得性JAK2 C618R体细胞突变，并推测该突变是MPDS的生物标志物。然而，JAK2 C618R突变是如何导致MPDS的仍不清楚。我们的结果表明，JAK2C618R中的氨基酸残基E543是其结构性激活所必需的。当JAK2 C618R中该位置的谷氨酸突变为丙氨酸(E543A)时，其活性显著下降。但当谷氨酸突变为酸性氨基酸时，天冬氨酸、JAK2C618R活性变化不大。这些结果表明，氨基酸残基R618和E543之间存在相互作用，这种相互作用是维持JAK2 C618R结构性激活的关键。更重要的是，E543单突变对野生型JAK2(WT JAK2)的功能没有影响。这项研究表明，氨基酸残基E543可能是治疗JAK2 C618R突变引起的MPD的特异性抑制剂的潜在靶点。
Janus kinase 2 (JAK2) is an important mediator of cytokine receptor signaling and plays a key role in the hematopoietic and immune responses. The acquired JAK2 C618R somatic mutation is detected in a subset of myeloproliferative disorders (MPDs) patients and presumed to be a biomarker for MPDs. However, how JAK2 C618R mutation causes MPDs is still unclear. Our results indicate that the amino acid residue E543 in JAK2 C618R is indispensable for its constitutive activation. When the glutamic acid at this position was mutated to alanine (E543A) in the JAK2 C618R, its activity significantly decreased. However when the glutamic acid was mutated to the acidic amino acid, aspartic acid, JAK2 C618R activity changed little. These results suggest that there is an interaction between the amino acid residue R618 and E543, and that this interaction is crucial to sustain the constitutive activation of JAK2 C618R. More importantly, the E543 single mutation had no effects on the function of wild type JAK2 (WT JAK2). This study suggests that the amino acid residue E543 might be a potential target for specific inhibitors to treat MPDs caused by the JAK2 C618R mutation.
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影响因子：
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作者：
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DOI：
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