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