The ubiquitin ligase RNF220 enhances canonical Wnt signaling through USP7-mediated deubiquitination of beta-catenin.
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Ma P, Yang X, Kong Q, Li C, Yang S, Li Y, Mao B
The ubiquitin ligase RNF220 enhances canonical Wnt signaling through USP7-mediated deubiquitination of beta-catenin.
Mol Cell Biol. 2014 Dec 1;34(23):4355-66. doi: 10.1128/MCB.00731-14. Epub 2014 Sep 29.
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- 25266658 [ View in PubMed]
- Abstract
Wnt/beta-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 beta-catenin. RNF220 physically interacts with beta-catenin, but instead of promoting its ubiquitination and proteasomal degradation, it stabilizes beta-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 beta-catenin. The RNF220/USP7 complex deubiquitinates beta-catenin and enhances canonical Wnt signaling. Interestingly, the stability of RNF220 itself is negatively regulated by Gsk3beta, which is a key component of the beta-catenin destruction complex and is inhibited upon Wnt stimulation. Accordingly, the RNF220/USP7 complex works as a positive feedback regulator of beta-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.