The EDD E3 ubiquitin ligase ubiquitinates and up-regulates β-catenin

Wnt/beta-catenin signaling plays a central role in development and is also involved in a diverse array of diseases. beta-Catenin activity is tightly regulated via a multiprotein complex that includes the kinase glycogen synthase kinase-3 beta (GSK-3 beta). GSK-3 beta phosphorylates beta-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 beta-catenin, resulting in reduced Wnt signaling levels. Here we report that an arm of the ubiquitin system increases beta-catenin protein levels. We show that GSK-3 beta directly interacts with the E3 ubiquitin ligase identified by differential display (EDD) that also binds beta-catenin. Expression of EDD leads to enhanced nuclear accumulation of both GSK-3 beta and beta-catenin and results in up-regulation of beta-catenin expression levels and activity. Importantly, EDD ubiquitinates beta-catenin through Lys29- or Lys11-linked ubiquitin chains, leading to enhanced stability of beta-catenin. Our results demonstrate a role for the ubiquitin system in upregulation of the Wnt signaling pathway, suggesting that EDD could function as a colorectal oncogene.