The EDD E3 ubiquitin ligase ubiquitinates and up-regulates beta-catenin.
The EDD E3 ubiquitin ligase ubiquitinates and up-regulates beta-catenin.
复制标题
DOI：
10.1091/mbc.e10-05-0440
复制
发表时间：
2011-02-01
影响因子：
3.3
通讯作者：
Rosin-Arbesfeld R
中科院分区：
文献类型：
--
作者：
Hay-Koren A;Caspi M;Zilberberg A;Rosin-Arbesfeld R
经典Wnt途径的效应蛋白是β-连环蛋白，其受泛素系统调节。这项研究表明，E3泛素连接酶EDD泛素化β-catenin，导致β-catenin的表达水平和活性的上调。因此，结果证明了泛素系统在上调Wnt途径中的作用。Wnt/β-catenin信号传导在发育中起核心作用，并且还参与多种疾病。β-连环蛋白活性通过包括激酶糖原合成酶激酶-3 β（GSK-3β）在内的多蛋白复合物进行严格调节。GSK-3β磷酸化β-连环蛋白，标记其通过蛋白酶体进行泛素化和降解。因此，在Wnt途径的调节中，已知泛素系统主要参与介导β-连环蛋白的周转，导致Wnt信号传导水平降低。在这里，我们报告了泛素系统的一个臂增加β-连环蛋白的蛋白质水平。我们发现GSK-3β直接与E3泛素连接酶相互作用，该酶通过差异显示（EDD）鉴定，也与β-连环蛋白结合。EDD的表达导致GSK-3β和β-catenin的核积累增强，并导致β-catenin表达水平和活性的上调。重要的是，EDD通过Lys 29-或Lys 11-连接的泛素链泛素化β-连环蛋白，导致β-连环蛋白的稳定性增强。我们的研究结果表明泛素系统在Wnt信号通路的上调中的作用，表明EDD可以作为结直肠癌基因发挥作用。
The effector protein of the canonical Wnt pathway is β-catenin, which is regulated by the ubiquitin system. This study shows that the E3 ubiquitin ligase EDD ubiquitinates β-catenin, leading to up-regulation of β-catenin's expression levels and activity. Thus the results demonstrate a role for the ubiquitin system in up-regulation of the Wnt pathway. Wnt/β-catenin signaling plays a central role in development and is also involved in a diverse array of diseases. β-Catenin activity is tightly regulated via a multiprotein complex that includes the kinase glycogen synthase kinase-3β (GSK-3β). GSK-3β phosphorylates β-catenin, marking it for ubiquitination and degradation via the proteasome. Thus in regulation of the Wnt pathway, the ubiquitin system is known to be involved mostly in mediating the turnover of β-catenin, resulting in reduced Wnt signaling levels. Here we report that an arm of the ubiquitin system increases β-catenin protein levels. We show that GSK-3β directly interacts with the E3 ubiquitin ligase identified by differential display (EDD) that also binds β-catenin. Expression of EDD leads to enhanced nuclear accumulation of both GSK-3β and β-catenin and results in up-regulation of β-catenin expression levels and activity. Importantly, EDD ubiquitinates β-catenin through Lys29- or Lys11-linked ubiquitin chains, leading to enhanced stability of β-catenin. Our results demonstrate a role for the ubiquitin system in up-regulation of the Wnt signaling pathway, suggesting that EDD could function as a colorectal oncogene.