JAK1 and Tyk2 activation by the homologous polycythemia vera JAK2 V617F mutation - Cross-talk with IGF1 receptor
JAK1 and Tyk2 activation by the homologous polycythemia vera JAK2 V617F mutation - Cross-talk with IGF1 receptor
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DOI：
10.1074/jbc.c500358200
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发表时间：
2005-12-23
影响因子：
4.8
通讯作者：
Constantinescu, SN
中科院分区：
文献类型：
--
作者：
Staerk, J;Kallin, A;Constantinescu, SN
大多数真性红细胞增多症（PV）患者在JAK 2的假激酶结构域中具有独特的体细胞突变（V617 F），这导致组成性信号传导。在这里，我们表明JAK 1（V658 F）和Tyk 2（V678 F）中的同源突变导致这些激酶的组成性激活。它们的表达诱导了依赖于丝氨酸的细胞的自主生长以及Ba/F3细胞中STAT 5、STAT 3、促分裂原活化蛋白激酶和Akt信号传导的组成性激活。当在JAK蛋白缺陷的纤维肉瘤细胞中表达时，突变JAK也表现出组成型信号传导。JAK 2 V617 F突变体的表达使Ba/F3细胞对胰岛素样生长因子1（IGF 1）高度敏感，IGF 1是PV红系祖细胞的标志。在选择用于由JAK 2 V617 F突变体诱导的自主生长的Ba/F3细胞后，细胞通过在自主细胞的组成性激活特征之上激活STAT 5、STAT 3、Erk 1/2和Akt来响应IGF 1。对增殖和STAT活化的协同作用似乎特异于JAK 2 V617 F突变体。我们的研究结果表明，同源V617 F突变诱导JAK 1和Tyk 2的激活，这表明JAK 1，JAK 2和Tyk 2突变体的共同激活机制。JAK 3不被同源突变M592 F激活，尽管存在保守的GVC前导序列。我们认为JAK 1和Tyk 2基因的突变可能被鉴定为人类癌症和自身免疫性疾病的初始分子缺陷。
The majority of polycythemia vera (PV) patients harbor a unique somatic mutation (V617F) in the pseudokinase domain of JAK2, which leads to constitutive signaling. Here we show that the homologous mutations in JAK1 (V658F) and in Tyk2 (V678F) lead to constitutive activation of these kinases. Their expression induces autonomous growth of cytokine-dependent cells and constitutive activation of STAT5, STAT3, mitogen-activated protein kinase, and Akt signaling in Ba/F3 cells. The mutant JAKs exhibit constitutive signaling also when expressed in fibrosarcoma cells deficient in JAK proteins. Expression of the JAK2 V617F mutant renders Ba/F3 cells hypersensitive to insulin-like growth factor 1 (IGF1), which is a hallmark of PV erythroid progenitors. Upon selection of Ba/F3 cells for autonomous growth induced by the JAK2 V617F mutant, cells respond to IGF1 by activating STAT5, STAT3, Erk1/2, and Akt on top of the constitutive activation characteristic of autonomous cells. The synergic effect on proliferation and STAT activation appears specific to the JAK2 V617F mutant. Our results show that the homologous V617F mutation induces activation of JAK1 and Tyk2, suggesting a common mechanism of activation for the JAK1, JAK2, and Tyk2 mutants. JAK3 is not activated by the homologous mutation M592F, despite the presence of the conserved GVC preceding sequence. We suggest that mutations in the JAK1 and Tyk2 genes may be identified as initial molecular defects in human cancers and autoimmune diseases.