USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds

Babita Madana, Matthew P. Walkerb, Robert Young, Laura Quick, Kelly A. Orgel, Meagan Ryan, Priti Gupta, Ian C. Henrichc, Marc Ferrer, Shane Marine, Brian S. Roberts, William T. Arthur, Jason D. Berndt, Andre M. Oliveira, Randall T. Moon, David M. Virshup, Margaret M. Chou, Michael B. Major

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

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.

Original languageEnglish
Pages (from-to)E2945-E2954
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number21
DOIs
StatePublished - May 24 2016

Keywords

  • Frizzled
  • USP6
  • Ubiquitin
  • Ubiquitin-specific protease
  • Wnt signaling

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