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首页> 外文期刊>Oncogene >SOCS-mediated downregulation of mutant Jak2 (V617F, T875N and K539L) counteracts cytokine-independent signaling
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SOCS-mediated downregulation of mutant Jak2 (V617F, T875N and K539L) counteracts cytokine-independent signaling

机译：SOCS介导的突变Jak2（V617F，T875N和K539L）的下调抵消了细胞因子非依赖性信号传导

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Recently, mutations in the gene of Janus kinase 2 (Jak2) were discovered in patients suffering from chronic myeloproliferative disorders (MPD) and leukemia. As suppressors of cytokine signaling (SOCS) proteins are potent feedback inhibitors of Jak-mediated signaling, we investigated their role in signal transduction through constitutively active Jak2 mutants. We selected two mutants, Jak2-V617F and Jak2-K539L, found in patients with MPDs and Jak2-T875N identified in acute megakaryoblastic leukemia. We found SOCS family members to be induced through Jak2-V617F in human leukemia cell lines expressing the mutant allele and in stable HEK transfectants inducibly expressing constitutively active Jak2 mutants. SOCS proteins were recruited to the membrane and bound to the constitutively active Jaks. In contrast to wild-type Jak2, the mutant proteins were constitutively ubiquitinated and degraded through the proteasome. Taken together, we show a SOCS-mediated downregulation of the constitutively active, disease-associated mutant Jak2 proteins. Furthermore, a threshold level of mutant Jak expression has to be overcome to allow full cytokine-independent constitutive activation of signaling proteins, which may explain progression to homozygocity in MPDs as well as gene amplification in severe phenotypes and leukemia.
机译：最近，在患有慢性骨髓增生性疾病（MPD）和白血病的患者中发现了Janus激酶2（Jak2）基因的突变。由于细胞因子信号传导（SOCS）蛋白的抑制剂是Jak介导的信号传导的有效反馈抑制剂，因此我们研究了它们在通过组成型活性Jak2突变体进行信号传导中的作用。我们选择了在急性巨核细胞白血病中鉴定出的MPD和Jak2-T875N患者中发现的两个突变体Jak2-V617F和Jak2-K539L。我们发现SOCS家族成员是通过Jak2-V617F在表达突变体等位基因的人白血病细胞系中和在稳定表达表达组成性活性Jak2突变体的稳定HEK转染子中诱导的。 SOCS蛋白被募集到膜上并与组成型活性Jaks结合。与野生型Jak2相反，突变蛋白组成型泛素化并通过蛋白酶体降解。综上所述，我们显示了组成成分活跃的，疾病相关的突变Jak2蛋白的SOCS介导的下调。此外，必须克服突变型Jak表达的阈值水平，以允许信号蛋白完全独立于细胞因子的组成型活化，这可能解释了MPD中纯合性的进展以及严重表型和白血病中的基因扩增。

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