Deubiquitinase USP47/UBP64E Regulates β-Catenin Ubiquitination and Degradation and Plays a Positive Role in Wnt Signaling

• Published in: Molecular and cellular biology 2015-10, Vol.35 (19), p.3301-3311
• Main Authors: Shi, Jiandang, Liu, Yajuan, Xu, Xuehe, Zhang, Wen, Yu, Tianxin, Jia, Jianhang, Liu, Chunming
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; beta Catenin - metabolism; beta-Transducin Repeat-Containing Proteins - metabolism; Binding Sites; Drosophila melanogaster; Drosophila Proteins - physiology; HEK293 Cells; Humans; Molecular Sequence Data; Proteolysis; Ubiquitin Thiolesterase - physiology; Ubiquitin-Specific Proteases - physiology; Ubiquitination; Wings, Animal - enzymology; Wnt Signaling Pathway
• ISSN: 1098-5549; 0270-7306; 1098-5549
• DOI: 10.1128/MCB.00373-15

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.