Tyrosine-phosphorylated SOCS3 negatively regulates cellular transformation mediated by the myeloproliferative neoplasm-associated JAK2 V617F mutant.
Tyrosine-phosphorylated SOCS3 negatively regulates cellular transformation mediated by the myeloproliferative neoplasm-associated JAK2 V617F mutant.
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DOI：
10.1016/j.cyto.2019.154753
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发表时间：
2019-11
期刊：
影响因子：
3.8
通讯作者：
M. Funakoshi-Tago;Rina Tsuruya;Fumihito Ueda;Aki Ishihara;T. Kasahara;H. Tamura;K. Tago
中科院分区：
文献类型：
--
作者：
M. Funakoshi-Tago;Rina Tsuruya;Fumihito Ueda;Aki Ishihara;T. Kasahara;H. Tamura;K. Tago
在大多数骨髓增生性肿瘤（mpn）患者中，发现JAK2基因中存在点突变V617F，这种JAK2突变引起异常信号通路。在目前的研究中，我们发现细胞因子信号蛋白3的抑制因子（SOCS3）对JAK2 V617F突变引起的细胞转化具有肿瘤抑制活性。SOCS3的敲低提高了JAK2 V617F突变体的表达水平，增强了信号传导介质的激活，包括转录3和转录激活因子3 （STAT3, STAT5）和细胞外信号调节激酶（ERK），也增加了表达JAK2 V617F突变体和促红细胞生成素受体（EpoR）的Ba/F3细胞的增殖率和肿瘤发生活性。相反，强制表达SOCS3通过下调JAK2 V617F突变体的表达水平，显著抑制JAK2 V617F突变体诱导的下游信号分子激活、细胞增殖和肿瘤发生。SOCS3通过其SH2结构域与JAK2V617F突变体相互作用，并被JAK2V617F突变体磷酸化其SOCS盒中的tyr204和tyr221位点。携带SH2结构域突变（R71E）和tyr1 -221突变（Y221F）的SOCS3突变体未能对JAK2V617F突变体诱导的细胞转化和肿瘤发生发挥抑制作用。综上所述，这些结果表明SOCS3通过其SH2结构域和其SOCS盒中tyr1 -221的磷酸化，在JAK2 V617F突变诱导的致癌信号通路中起负作用。
In the majority of myeloproliferative neoplasms (MPNs) patients, a point mutation, V617F has been found in Janus kinase 2 (JAK2) gene, and this JAK2 mutant provoked aberrant signaling pathway. In the current study, we found that suppressor of cytokine signaling proteins 3 (SOCS3) possessed the tumor suppressive activity against the JAK2 V617F mutant-provoked cellular transformation. The knockdown of SOCS3 increased the expression level of the JAK2 V617F mutant, which enhanced the activation of signaling mediators, including signal transducer and activator of transcription 3 and 5 (STAT3, STAT5) and extracellular signal-regulated kinase (ERK), and also increased of the proliferation rate and tumorigenesis activity of Ba/F3 cells expressing the JAK2 V617F mutant and erythropoietin receptor (EpoR). In contrast, the enforced expression of SOCS3 significantly inhibited the JAK2 V617F mutant-induced activation of downstream signaling molecules, cell proliferation, and tumorigenesis by down-regulating the expression level of the JAK2 V617F mutant. SOCS3 interacted with the JAK2V617F mutant through its SH2 domain and was phosphorylated at Tyr-204 and Tyr-221 in its SOCS box by the JAK2V617F mutant. SOCS3 mutants carrying a mutation in the SH2 domain (R71E) and a substitution at Tyr-221 (Y221F) failed to exert inhibitory effects on JAK2V617F mutant-induced cellular transformation and tumorigenesis. Collectively, these results imply that SOCS3 plays a negative role in the JAK2 V617F mutant-induced oncogenic signaling pathway through its SH2 domain and the phosphorylation of Tyr-221 in its SOCS box.