The ubiquitin ligase RNF220 enhances canonical Wnt signaling through USP7-mediated deubiquitination of β-catenin

  • Mol Cell Biol. 2014 Dec 1;34(23):4355-66. doi: 10.1128/MCB.00731-14.
Pengcheng Ma  1 ,  Xiangcai Yang  2 ,  Qinghua Kong  1 ,  Chaocui Li  1 ,  Shuangjuan Yang  3 ,  Yan Li  4 ,  Bingyu Mao  5
Affiliations
  • 1. State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Kumming, China.
  • 2. State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Kumming, China Kunming College of Life Science, University of Chinese Academy of Sciences, Kumming, China.
  • 3. Kunming Biological Diversity Regional Center of Large Apparatus and Equipments, Kunming Institute of Zoology, Kumming, China.
  • 4. State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China.
  • 5. State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Kumming, China [email protected].
PMID: 25266658 DOI: 10.1128/MCB.00731-14
Abstract

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.