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JAK1 and Tyk2 activation by the homologous polycythemia vera JAK2 V617F mutation - Cross-talk with IGF1 receptor

机译:通过同源真性红细胞增多症JAK2 V617F突变激活JAK1和Tyk2-与IGF1受体的串扰

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摘要

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.
机译:大多数真性红细胞增多症(PV)患者在JAK2的假激酶结构域中都具有独特的体细胞突变(V617F),这会导致组成型信号传导。在这里,我们显示JAK1(V658F)和Tyk2(V678F)中的同源突变导致这些激酶的组成型激活。它们的表达诱导Ba / F3细胞中细胞因子依赖性细胞的自主生长以及STAT5,STAT3,有丝分裂原激活的蛋白激酶和Akt信号转导的组成性激活。当在缺乏JAK蛋白的纤维肉瘤细胞中表达时,突变JAK也会显示出组成型信号。 JAK2 V617F突变体的表达使Ba / F3细胞对胰岛素样生长因子1(IGF1)高度敏感,后者是PV红系祖细胞的标志。选择由JAK2 V617F突变体诱导的自主生长的Ba / F3细胞后,细胞通过激活STAT5,STAT3,Erk1 / 2和Akt来响应IGF1,这是自主细胞的组成型激活特征。对增殖和STAT激活的协同作用似乎是JAK2 V617F突变体特有的。我们的结果表明,同源的V617F突变诱导JAK1和Tyk2的激活,提示JAK1,JAK2和Tyk2突变体的激活的共同机制。尽管存在保守的GVC在先序列,但JAK3未被同源突变M592F激活。我们建议JAK1和Tyk2基因中的突变可能被确定为人类癌症和自身免疫性疾病的初始分子缺陷。

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