title: Deubiquitinase USP47/UBP64E Regulates β-Catenin Ubiquitination and Degradation and Plays a Positive Role in Wnt Signaling.
abstract: Wnt signaling plays important roles in development and tumorigenesis. A central question about the Wnt pathway is the regulation of β-catenin. Phosphorylation of β-catenin by CK1α and GSK3 promotes β-catenin binding to β-TrCP, leading to β-catenin degradation through the proteasome. The phosphorylation and ubiquitination of β-catenin have been well characterized; however, it is unknown whether and how a deubiquitinase is involved. In this study, by screening RNA interference (RNAi) libraries, we identified USP47 as a deubiquitinase that prevents β-catenin ubiquitination. Inactivation of USP47 by RNAi increased β-catenin ubiquitination, attenuated Wnt signaling, and repressed cancer cell growth. Furthermore, USP47 deubiquitinates itself, whereas β-TrCP promotes USP47 ubiquitination through interaction with an atypical motif in USP47. Finally, in vivo studies in the Drosophila wing suggest that UBP64E, the USP47 counterpart in Drosophila, is required for Armadillo stabilization and plays a positive role in regulating Wnt target gene expression.
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Jiandang
authors.initials: J
authors.lastname: Shi
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Xuehe
authors.initials: X
authors.lastname: Xu
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA.
authors.forename: Tianxin
authors.initials: T
authors.lastname: Yu
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA jianhang.jia@uky.edu chunming.liu@uky.edu.
authors.forename: Jianhang
authors.initials: J
authors.lastname: Jia
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA Markey Cancer Center, University of Kentucky, Lexington, Kentucky, USA jianhang.jia@uky.edu chunming.liu@uky.edu.
authors.forename: Chunming
authors.initials: C
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D029721:Drosophila Proteins / Q000502:physiology*; D004331:Drosophila melanogaster; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D059748:Proteolysis; D043222:Ubiquitin Thiolesterase / Q000502:physiology*; D064570:Ubiquitin-Specific Proteases / Q000502:physiology*; D054875:Ubiquitination; D014921:Wings, Animal / Q000201:enzymology; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*; D044844:beta-Transducin Repeat-Containing Proteins / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; D029721:Drosophila Proteins; C557800:USP47 protein, human; D051176:beta Catenin; D044844:beta-Transducin Repeat-Containing Proteins; C000603177:USP47 protein, Drosophila; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases