Mechanistic Insights into Regulation of JAK2 Tyrosine Kinase.
Mechanistic Insights into Regulation of JAK2 Tyrosine Kinase.
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DOI：
10.3389/fendo.2017.00361
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发表时间：
2017
影响因子：
5.2
通讯作者：
Hubbard SR
中科院分区：
文献类型：
--
作者：
Hubbard SR
JAK2是Janus激酶(JAKs)非受体蛋白酪氨酸激酶家族的成员，包括JAK1-3和TYK2。JAK作为细胞因子受体的胞质信号成分，通过细胞因子介导的反式磷酸化被激活，从而导致受体的磷酸化以及信号转导和转录激活因子(STAT)蛋白的募集和磷酸化。JAK在酪氨酸激酶中是独一无二的，因为它们拥有一个假激活域，该结构域正好位于C末端酪氨酸激酶结构域的上游。大量的生化和临床数据表明，JAKs的假激活区对于维持低基础水平(缺乏细胞因子)的酪氨酸激酶活性至关重要。特别是，JAK基因的功能获得突变，最常见的是JAK2假激酶域的V617F，已经在包括骨髓增生性肿瘤和白血病在内的血液疾病患者中被定位。最近的结构和生化研究已经开始破译维持JAK的基础低活性状态以及通过突变导致结构性活动和疾病的分子机制。这篇综述将检查这些机制，并描述这些知识如何潜在地为旨在获得JAK2突变(V617F)选择性抑制剂的药物开发工作提供信息。
JAK2 is a member of the Janus kinase (JAKs) family of non-receptor protein tyrosine kinases, which includes JAK1–3 and TYK2. JAKs serve as the cytoplasmic signaling components of cytokine receptors and are activated through cytokine-mediated trans-phosphorylation, which leads to receptor phosphorylation and recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins. JAKs are unique among tyrosine kinases in that they possess a pseudokinase domain, which is just upstream of the C-terminal tyrosine kinase domain. A wealth of biochemical and clinical data have established that the pseudokinase domain of JAKs is crucial for maintaining a low basal (absence of cytokine) level of tyrosine kinase activity. In particular, gain-of-function mutations in the JAK genes, most frequently, V617F in the pseudokinase domain of JAK2, have been mapped in patients with blood disorders, including myeloproliferative neoplasms and leukemias. Recent structural and biochemical studies have begun to decipher the molecular mechanisms that maintain the basal, low-activity state of JAKs and that, via mutation, lead to constitutive activity and disease. This review will examine these mechanisms and describe how this knowledge could potentially inform drug development efforts aimed at obtaining a mutant (V617F)-selective inhibitor of JAK2.
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DOI：
10.1042/bcj20160085
发表时间：
2016-06-01
期刊：
The Biochemical journal
影响因子：
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作者：
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DOI：
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发表时间：
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影响因子：
11.1
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DOI：
10.1073/pnas.1401180111
发表时间：
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影响因子：
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作者：
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