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Proc Natl Acad Sci U S A. 2016 May 24;113(21):E2945-54. doi: 10.1073/pnas.1605691113. Epub 2016 May 9.

USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds.

Author information

1
Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore 169857;
2
Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295;
3
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104;
4
Department of Automated Biotechnology, Merck Research Laboratories, North Wales, PA 19454; National Center for Advancing Translation Sciences/NIH, Rockville, MD 20850;
5
Department of Screening and Protein Sciences, Merck Research Laboratories, North Wales, PA 19454;
6
Rosetta Inpharmatics, LLC, Merck & Co., Inc., Seattle, WA 98109; HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806;
7
Rosetta Inpharmatics, LLC, Merck & Co., Inc., Seattle, WA 98109; Seattle Genetics, Bothell, WA 98021;
8
Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, WA 98195; Department of Pharmacology, University of Washington School of Medicine, Seattle, WA 98195; Institute for Stem Cell and Regenerative Medicine at the University of Washington, Seattle, WA 98195;
9
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905.
10
Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, WA 98195; Department of Pharmacology, University of Washington School of Medicine, Seattle, WA 98195; Institute for Stem Cell and Regenerative Medicine at the University of Washington, Seattle, WA 98195; rtmoon@uw.edu david.virshup@duke-nus.edu.sg mmc@mail.med.upenn.edu ben_major@med.unc.edu.
11
Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore 169857; rtmoon@uw.edu david.virshup@duke-nus.edu.sg mmc@mail.med.upenn.edu ben_major@med.unc.edu.
12
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; rtmoon@uw.edu david.virshup@duke-nus.edu.sg mmc@mail.med.upenn.edu ben_major@med.unc.edu.
13
Department of Cell Biology and Physiology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295; rtmoon@uw.edu david.virshup@duke-nus.edu.sg mmc@mail.med.upenn.edu ben_major@med.unc.edu.

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.

KEYWORDS:

Frizzled; USP6; Wnt signaling; ubiquitin; ubiquitin-specific protease

PMID:
27162353
PMCID:
PMC4889410
DOI:
10.1073/pnas.1605691113
[Indexed for MEDLINE]
Free PMC Article

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