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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.
FIG 6. RNF220 acts as a canonical Wnt signaling amplifier. (A) Effects of RNF220 and its truncates on the stimulation of Wnt reporter expression by β-catenin in 293 cells. Plasmids of RNF220 constructs were transfected with three different doses to evaluate their effects. WT, wild type. (B) The δNδR truncate of RNF220 reversed the stimulation effect of wild-type RNF220 on β-catenin activity in 293 cells. RNF220 plasmids were cotransfected with β-catenin as indicated, and then luciferase reporter assays were performed. (C) RNF220 wild type but not the δNδR truncate cooperated with β-catenin to induce secondary axes in Xenopus embryos. The numbers of embryos in each group are indicated above the bars, and representative embryos are shown in the right panel. (D and E) Real-time PCR analysis of the expression of Siamois and Xnr3 in Xenopus animal caps injected with β-catenin with or without RNF220 mRNA. ns, not significant; **, P < 0.001.
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