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USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds.

Publication ,  Journal Article
Madan, B; Walker, MP; Young, R; Quick, L; Orgel, KA; Ryan, M; Gupta, P; Henrich, IC; Ferrer, M; Marine, S; Roberts, BS; Arthur, WT; Moon, RT ...
Published in: Proc Natl Acad Sci U S A
May 24, 2016

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.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

May 24, 2016

Volume

113

Issue

21

Start / End Page

E2945 / E2954

Location

United States

Related Subject Headings

  • Wnt Signaling Pathway
  • Ubiquitination
  • Ubiquitin-Protein Ligases
  • Ubiquitin Thiolesterase
  • Proto-Oncogene Proteins
  • Oncogene Proteins
  • Neoplasms, Experimental
  • Mice
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Intercellular Signaling Peptides and Proteins
 

Citation

APA
Chicago
ICMJE
MLA
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Madan, B., Walker, M. P., Young, R., Quick, L., Orgel, K. A., Ryan, M., … Major, M. B. (2016). USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds. Proc Natl Acad Sci U S A, 113(21), E2945–E2954. https://doi.org/10.1073/pnas.1605691113
Madan, Babita, Matthew P. Walker, Robert Young, Laura Quick, Kelly A. Orgel, Meagan Ryan, Priti Gupta, et al. “USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds.Proc Natl Acad Sci U S A 113, no. 21 (May 24, 2016): E2945–54. https://doi.org/10.1073/pnas.1605691113.
Madan B, Walker MP, Young R, Quick L, Orgel KA, Ryan M, et al. USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds. Proc Natl Acad Sci U S A. 2016 May 24;113(21):E2945–54.
Madan, Babita, et al. “USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds.Proc Natl Acad Sci U S A, vol. 113, no. 21, May 2016, pp. E2945–54. Pubmed, doi:10.1073/pnas.1605691113.
Madan B, Walker MP, Young R, Quick L, Orgel KA, Ryan M, Gupta P, Henrich IC, Ferrer M, Marine S, Roberts BS, Arthur WT, Berndt JD, Oliveira AM, Moon RT, Virshup DM, Chou MM, Major MB. USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds. Proc Natl Acad Sci U S A. 2016 May 24;113(21):E2945–E2954.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

May 24, 2016

Volume

113

Issue

21

Start / End Page

E2945 / E2954

Location

United States

Related Subject Headings

  • Wnt Signaling Pathway
  • Ubiquitination
  • Ubiquitin-Protein Ligases
  • Ubiquitin Thiolesterase
  • Proto-Oncogene Proteins
  • Oncogene Proteins
  • Neoplasms, Experimental
  • Mice
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Intercellular Signaling Peptides and Proteins