The EDD E3 ubiquitin ligase ubiquitinates and up-regulates beta-catenin.
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.
Department of Anatomy and Anthropology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Avital
A
Hay-Koren
Michal
M
Caspi
Alona
A
Zilberberg
Rina
R
Rosin-Arbesfeld
D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D020868:Gene Silencing; D038362:Glycogen Synthase Kinase 3 / Q000032:analysis / Q000378:metabolism / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000737:chemistry; D055550:Protein Stability; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D054875:Ubiquitination; D015854:Up-Regulation; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
D051153:Wnt Proteins; D051176:beta Catenin; C117617:UBR5 protein, human; D044767:Ubiquitin-Protein Ligases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D008239:Lysine