RING finger, H2 subclass, found in RING finger proteins RNF43, ZNRF3, and similar proteins
RNF43 and ZNRF3 (also known as RNF203) are transmembrane E3 ubiquitin-protein ligases that belong to the PA-TM-RING ubiquitin ligases family, which has been characterized by containing an N-terminal signal peptide, a protease-associated (PA) domain, a transmembrane (TM) domain and a C3H2C3-type RING-H2 finger domain followed by a long C-terminal region. Both RNF43 and RNF203 function as tumor suppressors involved in the regulation of Wnt/beta-catenin signaling. They negatively regulate Wnt signaling through interacting with complexes of frizzled receptors (FZD) and low-density lipoprotein receptor-related protein (LRP) 5/6, which leads to ubiquitination of Frizzled receptors (FZD) and endocytosis of the Wnt receptor. Dishevelled (DVL), a positive Wnt regulator, is required for ZNRF3/RNF43-mediated ubiquitination and degradation of FZD. They also associate with R-spondin 1 (RSPO1). This interaction may block Frizzled ubiquitination and enhances Wnt signaling.