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USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds
- Source :
- Proceedings of the National Academy of Sciences. 113
- Publication Year :
- 2016
- Publisher :
- Proceedings of the National Academy of Sciences, 2016.
-
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.
- Subjects :
- 0301 basic medicine
Small interfering RNA
Frizzled
Ubiquitin-Protein Ligases
Biology
Mice
03 medical and health sciences
0302 clinical medicine
Proto-Oncogene Proteins
Ring finger
medicine
Animals
Humans
Wnt Signaling Pathway
Oncogene Proteins
Multidisciplinary
Oncogene
Ubiquitination
Wnt signaling pathway
LRP6
LRP5
Neoplasms, Experimental
Frizzled Receptors
DNA-Binding Proteins
HEK293 Cells
030104 developmental biology
medicine.anatomical_structure
PNAS Plus
DKK1
Low Density Lipoprotein Receptor-Related Protein-6
030220 oncology & carcinogenesis
Cancer research
Intercellular Signaling Peptides and Proteins
Ubiquitin Thiolesterase
HeLa Cells
Subjects
Details
- ISSN :
- 10916490 and 00278424
- Volume :
- 113
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences
- Accession number :
- edsair.doi.dedup.....f2151b965f6e2d65ae89cd825dbed0b4