학술논문
USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds.
Document Type
Article
Author
Madan, Babita; Walker, Matthew P.; Young, Robert; Quick, Laura; Orgel, Kelly A.; Ryan, Meagan; Gupta, Priti; Henrich, Ian C.; Ferrer, Marc; Marine, Shane; Roberts, Brian S.; Arthur, William T.; Berndt, Jason D.; Oliveira, Andre M.; Moon, Randall T.; Virshup, David M.; Chou, Margaret M.; Major, Michael B.
Source
Subject
*ONCOGENES
*WNT proteins
*SMALL interfering RNA
*ENDOCYTOSIS
*CELL membranes
*PROTEASE inhibitors
*
*
*
*
*
Language
ISSN
0027-8424
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. [ABSTRACT FROM AUTHOR]