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 Gsk3 beta, 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.
1.Kunming Inst Zool, State Key Lab Genet Resources & Evolut, Kunming, Peoples R China 2.Univ Chinese Acad Sci, Kunming Coll Life Sci, Kunming, Peoples R China 3.Kunming Inst Zool, Kunming Biol Divers Reg Ctr Large Apparat & Equip, Kunming, Peoples R China 4.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming, Peoples R China
Ma,Pengcheng;Yang,Xiangcai;Kong,Qinghua;Li,Chaocui;Yang,Shuangjuan;Li,Yan;Mao,Bingyu.The Ubiquitin Ligase RNF220 Enhances Canonical Wnt Signaling through USP7-Mediated Deubiquitination of beta-Catenin,MOLECULAR AND CELLULAR BIOLOGY,2014,97(11):1481-1486