Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 35, Issue 19, Pages 3301-3311Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00373-15
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Funding
- National Institutes of Health [R01CA172379]
- [R01GM079684]
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Wnt signaling plays important roles in development and tumorigenesis. A central question about the Wnt pathway is the regulation of beta-catenin. Phosphorylation of beta-catenin by CK1 alpha and GSK3 promotes beta-catenin binding to beta-TrCP, leading to beta-c atenin degradation through the proteasome. The phosphorylation and ubiquitination of beta-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 beta-catenin ubiquitination. Inactivation of USP47 by RNAi increased beta-catenin ubiquitination, attenuated Wnt signaling, and repressed cancer cell growth. Furthermore, USP47 deubiquitinates itself, whereas beta-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.
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