College of Life Sciences, Capital Normal University, Beijing, China.
Cell Death Dis. 2018 May 1;9(5):456. doi: 10.1038/s41419-018-0451-y.
The canonical Wnt/β-Catenin signaling pathway is widely involved in regulating diverse biological processes. Dysregulation of the pathway results in severe consequences, such as developmental defects and malignant cancers. Here, we identified Ube2s as a novel activator of the Wnt/β-Catenin signaling pathway. It modified β-Catenin at K19 via K11-linked polyubiquitin chain. This modification resulted in an antagonistic effect against the destruction complex/β-TrCP cascade-orchestrated β-Catenin degradation. As a result, the stability of β-Catenin was enhanced, thus promoting its cellular accumulation. Importantly, Ube2s-promoted β-Catenin accumulation partially released the dependence on exogenous molecules for the process of embryonic stem (ES) cell differentiation into mesoendoderm lineages. Moreover, we demonstrated that UBE2S plays a critical role in determining the malignancy properties of human colorectal cancer (CRC) cells in vitro and in vivo. The findings in this study extend our mechanistic understanding of the mesoendodermal cell fate commitment, and provide UBE2S as a putative target for human CRC therapy.
经典的 Wnt/β-连环蛋白信号通路广泛参与调节多种生物学过程。该通路的失调会导致严重的后果，如发育缺陷和恶性癌症。在这里，我们鉴定出 Ube2s 是 Wnt/β-连环蛋白信号通路的一种新型激活剂。它通过 K11 连接的多泛素链修饰β-连环蛋白的 K19。这种修饰导致与破坏复合物/β-TrCP 级联协同作用的β-连环蛋白降解的拮抗作用。结果，β-连环蛋白的稳定性增强，从而促进其细胞积累。重要的是，Ube2s 促进的β-连环蛋白积累部分释放了对外源分子的依赖性，从而促进了胚胎干细胞（ES）细胞向中胚层谱系的分化过程。此外，我们证明 UBE2S 在体外和体内决定人类结直肠癌（CRC）细胞的恶性特性方面起着关键作用。本研究的结果扩展了我们对中胚层细胞命运决定的机制理解，并为人类 CRC 治疗提供了 UBE2S 作为潜在靶点。
