Jung, HKim, B-GHan, W HLee, J HCho, J-YPark, W SMaurice, M MHan, J-KLee, M JFinley, DJho, E-h2014-03-102013Jung, H., B. Kim, W. H. Han, J. H. Lee, J. Cho, W. S. Park, M. M. Maurice, et al. 2013. “Deubiquitination of Dishevelled by Usp14 is required for Wnt signaling.” Oncogenesis 2 (8): e64. doi:10.1038/oncsis.2013.28. http://dx.doi.org/10.1038/oncsis.2013.28.2157-9024http://nrs.harvard.edu/urn-3:HUL.InstRepos:11877122Dishevelled (Dvl) is a key regulator of Wnt signaling both in the canonical and non-canonical pathways. Here we report the identification of a regulatory domain of ubiquitination (RDU) in the C-terminus of Dvl. Mutations in the RDU resulted in accumulation of polyubiquitinated forms of Dvl, which were mainly K63 linked. Small interfering RNA-based screening identified Usp14 as a mediator of Dvl deubiquitination. Genetic and chemical suppression of Usp14 activity caused an increase in Dvl polyubiquitination and significantly impaired downstream Wnt signaling. These data suggest that Usp14 functions as a positive regulator of the Wnt signaling pathway. Consistently, tissue microarray analysis of colon cancer revealed a strong correlation between the levels of Usp14 and β-catenin, which suggests an oncogenic role for Usp14 via enhancement of Wnt/β-catenin signaling.en-USWntdishevelleddeubiquitinaseUsp14ubiquitinationJournal Article2014-03-1010.1038/oncsis.2013.28