JAK2V617F-mediated phosphorylation of PRMT5 downregulates its methyltransferase activity and promotes myeloproliferation.
JAK2V617F-mediated phosphorylation of PRMT5 downregulates its methyltransferase activity and promotes myeloproliferation.
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DOI：
10.1016/j.ccr.2010.12.020
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发表时间：
2011-02-15
期刊：
影响因子：
50.3
通讯作者：
Nimer SD
中科院分区：
文献类型：
--
作者：
Liu F;Zhao X;Perna F;Wang L;Koppikar P;Abdel-Wahab O;Harr MW;Levine RL;Xu H;Tefferi A;Deblasio A;Hatlen M;Menendez S;Nimer SD
JAK2V617F组成型激活酪氨酸激酶见于大多数骨髓增生性肿瘤患者。在研究JAK2和PRMT5（一种最初被鉴定为JAK2结合蛋白1的精氨酸甲基转移酶）之间的相互作用时，我们发现JAK2V617 F（和JAK2K539 L）比野生型JAK2更强地结合PRMT5。这些致癌激酶还获得了磷酸化PRMT5的能力，大大削弱了其甲基化组蛋白底物的能力，并代表了允许它们调节染色质修饰的特定功能获得性。我们很容易检测到JAK2V617F阳性患者样本中的PRMT5磷酸化，当我们使用shRNA敲低人CD34+细胞中的PRMT5时，我们观察到集落形成和红系分化增加。这些结果表明，PRMT5的磷酸化有助于突变体JAK2诱导的骨髓增殖表型。
The JAK2V617F constitutively activated tyrosine kinase is found in most patients with myeloproliferative neoplasms. While examining the interaction between JAK2 and PRMT5, an arginine methyltransferase originally identified as JAK2 binding protein 1, we found that JAK2V617F (and JAK2K539L) bound PRMT5 more strongly than did wild-type JAK2. These oncogenic kinases also acquired the ability to phosphorylate PRMT5, greatly impairing its ability to methylate its histone substrates, and representing a specific gain-of-function that allows them to regulate chromatin modifications. We readily detected PRMT5 phosphorylation in JAK2V617F-positive patient samples and when we knocked down PRMT5 in human CD34+ cells using shRNA, we observed increased colony formation and erythroid differentiation. These results indicate that phosphorylation of PRMT5 contributes to the mutant JAK2-induced myeloproliferative phenotype.