Acylglycerol kinase augments JAK2/STAT3 signaling in esophageal squamous cells
Acylglycerol kinase augments JAK2/STAT3 signaling in esophageal squamous cells
复制标题
酰基甘油激酶增强食管鳞状细胞中的 JAK2/STAT3 信号传导
DOI：
10.1172/jci68143
复制
发表时间：
2013-06-01
影响因子：
15.9
通讯作者：
Song, Libing
中科院分区：
文献类型：
--
作者：
Chen, Xiuting;Ying, Zhe;Song, Libing
JAK2的活性通过其JAK同源结构域2(JH2)的自我抑制效应受到严格控制，JH2在生理条件下限制JAK2/STAT3信号的强度和持续时间。虽然在血液系统恶性肿瘤中广泛观察到JAK2内的多种突变，这些突变可以取消JH2的功能并维持JAK2的激活，但在实体肿瘤中尚未检测到类似的突变。实体瘤细胞如何超越JH2结构域的自身抑制效应来维持JAK2/STAT3信号的结构性激活仍然令人费解。在这里，我们证明了AGK直接与JH2结构域相互作用，解除了JAK2的抑制，激活了JAK2/STAT3信号。AGK的过表达维持了JAK2/STAT3的结构性激活，从而促进了食管鳞癌(ESCC)细胞的肿瘤干细胞群，增强了体内和体外的致瘤性。此外，AGK水平与原发性ESCC中STAT3磷酸化增加、无病生存期较差和总生存期较短显著相关。更重要的是，在ESCC、肺癌和乳腺癌中，AGK的表达与JAK2/STAT3的过度激活显著相关。这些发现揭示了实体瘤中JAK2/STAT3信号的结构性激活机制，并可能代表一个预后生物标志物和治疗靶点。
JAK2 activity is tightly controlled through a self-inhibitory effect via its JAK homology domain 2 (JH2), which restricts the strength and duration of JAK2/STAT3 signaling under physiological conditions. Although multiple mutations within JAK2, which abrogate the function of JH2 and sustain JAK2 activation, are widely observed in hematological malignancies, comparable mutations have not been detected in solid tumors. How solid tumor cells override the autoinhibitory effect of the JH2 domain to maintain constitutive activation of JAK2/STAT3 signaling remains puzzling. Herein, we demonstrate that AGK directly interacted with the JH2 domain to relieve inhibition of JAK2 and activate JAK2/STAT3 signaling. Overexpression of AGK sustained constitutive JAK2/STAT3 activation, consequently promoting the cancer stem cell population and augmenting the tumorigenicity of esophageal squamous cell carcinoma (ESCC) cells both in vivo and in vitro. Furthermore, AGK levels significantly correlated with increased STAT3 phosphorylation, poorer disease-free survival, and shorter overall survival in primary ESCC. More importantly, AGK expression was significantly correlated with JAK2/STAT3 hyperactivation in ESCC, as well as in lung and breast cancer. These findings uncover a mechanism for constitutive activation of JAK2/STAT3 signaling in solid tumors and may represent a prognostic biomarker and therapeutic target.