XB-ART-50450Mol Cell Biol December 1, 2014; 34 (23): 4355-66.
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The ubiquitin ligase RNF220 enhances canonical Wnt signaling through USP7-mediated deubiquitination of β-catenin.
Wnt/β-catenin signaling plays critical roles in embryonic development and disease. Here, we identify RNF220, a RING domain E3 ubiquitin ligase, as a new regulator of β-catenin. RNF220 physically interacts with β-catenin, but instead of promoting its ubiquitination and proteasomal degradation, it stabilizes β-catenin and promotes canonical Wnt signaling. Our analysis showed that RNF220 interacts with USP7, a ubiquitin-specific peptidase, which is required for RNF220 to stabilize β-catenin. The RNF220/USP7 complex deubiquitinates β-catenin and enhances canonical Wnt signaling. Interestingly, the stability of RNF220 itself is negatively regulated by Gsk3β, which is a key component of the β-catenin destruction complex and is inhibited upon Wnt stimulation. Accordingly, the RNF220/USP7 complex works as a positive feedback regulator of β-catenin signaling. In colon cancer cells with stimulated Wnt signaling, knockdown of RNF220 or USP7 impairs Wnt signaling and expression of Wnt target genes, suggesting a potentially novel role of RNF220 in Wnt-related tumorigenesis.
PubMed ID: 25266658
PMC ID: PMC4248747
Article link: Mol Cell Biol
Species referenced: Xenopus laevis
Genes referenced: axin2 ccnd1 ctnnb1 gapdh gsk3b nodal3.1 rnf220.1 rnf220.2 sia1 usp7
Phenotypes: Xla Wt + ctnnb1 (fig.6.c)
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References [+] :
Canning, A RING finger ubiquitin ligase is protected from autocatalyzed ubiquitination and degradation by binding to ubiquitin-specific protease USP7. 2004, Pubmed