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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Henrich, Ian C. Walker, Matthew P. Roberts, Brian S. Ryan, Meagan Young, Robert Madan, Babita Oliveira, Andre M. Ferrer, Marc Marine, Shane Virshup, David M. Arthur, William T. Gupta, Priti Chou, Margaret M. Moon, Randall T. Major, Michael B. Quick, Laura Berndt, Jason D. Orgel, Kelly A. |
| Description | Author Affiliation: Madan B ( Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore 169857); Walker MP ( Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295); Young R ( Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104); Quick L ( Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104); Orgel KA ( Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295); Ryan M ( Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295); Gupta P ( Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore 169857); Henrich IC ( Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104); Ferrer M ( Department of Automated Biotechnology, Merck Research Laboratories, North Wales, PA 19454); Marine S ( Department of Screening and Protein Sciences, Merck Research Laboratories, North Wales, PA 19454); Roberts BS ( Rosetta Inpharmatics, LLC, Merck & Co., Inc., Seattle, WA 98109); Arthur WT ( Rosetta Inpharmatics, LLC, Merck & Co., Inc., Seattle, WA 98109); Berndt JD ( Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, WA 98195); Oliveira AM ( Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905.); Moon RT ( Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, WA 98195); Virshup DM ( Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore 169857); Chou MM ( Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104); Major MB ( Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295); |
| Abstract | The Wnt signaling pathways play pivotal roles in carcinogenesis. Modulation of the cell-surface abundance of Wnt receptors is emerging as an important mechanism for regulating sensitivity to Wnt ligands. Endocytosis and degradation of the Wnt receptors Frizzled (Fzd) and lipoprotein-related protein 6 (LRP6) are regulated by the E3 ubiquitin ligases zinc and ring finger 3 (ZNRF3) and ring finger protein 43 (RNF43), which are disrupted in cancer. In a genome-wide small interfering RNA screen, we identified the deubiquitylase ubiquitin-specific protease 6 (USP6) as a potent activator of Wnt signaling. USP6 enhances Wnt signaling by deubiquitylating Fzds, thereby increasing their cell-surface abundance. Chromosomal translocations in nodular fasciitis result in USP6 overexpression, leading to transcriptional activation of the Wnt/β-catenin pathway. Inhibition of Wnt signaling using Dickkopf-1 (DKK1) or a Porcupine (PORCN) inhibitor significantly decreased the growth of USP6-driven xenograft tumors, indicating that Wnt signaling is a key target of USP6 during tumorigenesis. Our study defines an additional route to ectopic Wnt pathway activation in human disease, and identifies a potential approach to modulate Wnt signaling for therapeutic benefit. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 21 |
| Volume Number | 113 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2016-05-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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