EPH receptor A2 governs a feedback loop that activates Wnt/β-catenin signaling in gastric cancer.
EPH receptor A2 governs a feedback loop that activates Wnt/β-catenin signaling in gastric cancer.
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EPH 受体 A2 控制激活胃癌中 Wnt/β-catenin 信号传导的反馈回路
DOI：
10.1038/s41419-018-1164-y
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发表时间：
2018-11-19
影响因子：
9
通讯作者：
Ma J
中科院分区：
文献类型：
--
作者：
Peng Q;Chen L;Wu W;Wang J;Zheng X;Chen Z;Jiang Q;Han J;Wei L;Wang L;Huang J;Ma J
促红细胞生成素肝癌 (EPH) 受体 A2 (EphA2) 属于受体酪氨酸激酶 Eph 家族。 EphA2与许多实体瘤的形成高度相关，并且与促进肿瘤细胞增殖、迁移、侵袭以及血管生成的信号通路失调有关。 Wnt 信号传导失调与包括胃癌在内的多种人类疾病有关。我们之前报道过 EphA2 通过 Wnt/β-catenin 信号传导促进胃癌的上皮间质转化。在此，我们提出了 EphA2 调节 Wnt/β-catenin 信号传导的新机制。 EphA2 作为 Wnt 配体的受体，通过直接结合 Dvl2 将 Axin1 招募到质膜上。 Wnt3a 处理增强了 EphA2-Dvl2/Axin1 相互作用，表明 EphA2 作为 Wnt/β-catenin 通路的功能性受体，在下游信号传导中发挥着至关重要的作用。我们发现 Dvl2 通过与 EphA2 的酪氨酸激酶结构域结合来介导 EphA2-Axin1 相互作用。我们提出 EphA2/Dvl2/Axin1 形成复合物，使 β-catenin 破坏复合物不稳定，并允许 β-catenin 易位到细胞核并启动主要 Wnt 信号传导靶基因 c-MYC 的转录。有趣的是，c-MYC 可以直接结合 EphA2 和 Wnt1 启动子以增强其转录。整个过程形成了EphA2介导的前馈循环。 EphA2 的小分子抑制剂可在体外和体内有效抑制胃癌的增殖，包括来自胃癌患者的异种移植物。因此，我们的数据表明 EphA2 是胃癌治疗的优秀候选者。
The erythropoietin-producing hepatoma (EPH) receptor A2 (EphA2) belongs to the Eph family of receptor tyrosine kinases. EphA2 is highly correlated with the formation of many solid tumors and has been linked to the dysregulation of signaling pathways that promote tumor cell proliferation, migration, and invasion as well as angiogenesis. Deregulation of Wnt signaling is implicated in many forms of human disease including gastric cancer. We previously reported that EphA2 promotes the epithelial–mesenchymal transition through Wnt/β-catenin signaling in gastric cancer. Herein, we present a novel mechanism by which EphA2 regulates Wnt/β-catenin signaling. EphA2 acts as a receptor for Wnt ligands and recruits Axin1 to the plasma membrane by directly binding Dvl2. The EphA2-Dvl2/Axin1 interaction was enhanced by Wnt3a treatment, suggesting that EphA2 acts as a functional receptor for the Wnt/β-catenin pathway and plays a vital role in downstream signaling. We showed that Dvl2 mediates the EphA2-Axin1 interaction by binding to the tyrosine kinase domain of EphA2. We propose that EphA2/Dvl2/Axin1 forms a complex that destabilizes the β-catenin destruction complex and allows β-catenin to translocate to the nucleus and initiate the transcription of c-MYC, the primary Wnt signaling target gene. Intriguingly, c-MYC could bind directly to the EphA2 and Wnt1 promoter to enhance their transcription. The entire process formed an EphA2-mediated feed-forward loop. A small molecular inhibitor of EphA2 potently inhibited the proliferation of gastric cancer in vitro and in vivo, including gastric cancer patient–derived xenografts. Thus, our data identify EphA2 as an excellent candidate for gastric cancer therapy.
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影响因子：
50.3
作者：
Binda E;Visioli A;Giani F;Lamorte G;Copetti M;Pitter KL;Huse JT;Cajola L;Zanetti N;DiMeco F;De Filippis L;Mangiola A;Maira G;Anile C;De Bonis P;Reynolds BA;Pasquale EB;Vescovi AL
通讯作者：
Vescovi AL
影响因子：
7.2
作者：
MacDonald, Bryan T.;He, Xi
通讯作者：
He, Xi
影响因子：
7.3
作者：
Beauchamp, Amanda;Debinski, Waldemar
通讯作者：
Debinski, Waldemar
影响因子：
9.2
作者：
Cliffe, A;Hamada, F;Bienz, M
通讯作者：
Bienz, M
DOI：
10.1146/annurev-pharmtox-011112-140226
发表时间：
2015
影响因子：
12.5
作者：
Barquilla A;Pasquale EB
通讯作者：
Pasquale EB