Liu Lixian, Xing Liying, Chen Rongyuan, Zhang Jianing, Huang Yuye, Huang Lijuan, Xie Bingbing, Ren Xiangrong, Wang Shasha, Kuang Haiqing, Lin Xianchai, Kumar Anil, Kim Jong Kyong, Lee Chunsik, Li Xuri
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
Front Cell Dev Biol. 2021 Feb 22;9:634242. doi: 10.3389/fcell.2021.634242. eCollection 2021.
The mitogen-inducible gene 6 (MIG6) is an adaptor protein widely expressed in vascular endothelial cells. However, it remains unknown thus far whether it plays a role in angiogenesis. Here, using comprehensive and model systems, we unveil a potent anti-angiogenic effect of MIG6 in retinal development and neovascularization and the underlying molecular and cellular mechanisms. Loss of function assays using genetic deletion of or siRNA knockdown increased angiogenesis and , while MIG6 overexpression suppressed pathological angiogenesis. Moreover, we identified the cellular target of MIG6 by revealing its direct inhibitory effect on vascular endothelial cells (ECs). Mechanistically, we found that the anti-angiogenic effect of MIG6 is fulfilled by binding to SHC1 and inhibiting its phosphorylation. Indeed, SHC1 knockdown markedly diminished the effect of MIG6 on ECs. Thus, our findings show that MIG6 is a potent endogenous inhibitor of angiogenesis that may have therapeutic value in anti-angiogenic therapy.
丝裂原诱导基因6（MIG6）是一种在血管内皮细胞中广泛表达的衔接蛋白。然而，迄今为止，它是否在血管生成中发挥作用仍不清楚。在这里，我们使用全面的模型系统，揭示了MIG6在视网膜发育和新生血管形成中的强大抗血管生成作用以及潜在的分子和细胞机制。使用基因敲除或siRNA敲低进行的功能丧失实验增加了血管生成，而MIG6过表达则抑制了病理性血管生成。此外，我们通过揭示其对血管内皮细胞（ECs）的直接抑制作用，确定了MIG6的细胞靶点。从机制上讲，我们发现MIG6的抗血管生成作用是通过与SHC1结合并抑制其磷酸化来实现的。事实上，SHC1敲低显著减弱了MIG6对内皮细胞的作用。因此，我们的研究结果表明，MIG6是一种强大的内源性血管生成抑制剂，可能在抗血管生成治疗中具有治疗价值。
