E3 ubiquitin-protein ligase that acts as a negative regulator of the Wnt signaling pathway by mediating the ubiquitination, endocytosis and subsequent degradation of Wnt receptor complex components Frizzled. Acts on both canonical and non-canonical Wnt signaling pathway (PubMed:22895187). Along with RSPO2 and ZNRF3, constitutes a master switch that governs limb specification (By similarity). S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine. Protein modification; protein ubiquitination. Interacts with AKAP8L, NONO and SFPQ. Interacts with FZD5 (By similarity). Identified in a complex composed of RNF43, LGR5 and RSPO1 (By similarity). Interacts with RSPO2 (By similarity). Interacts with LMBR1L (PubMed:31073040). May be secreted. Expressed in crypt base columnar cells of small intestinal epithelium. Crypt base columnar cells are small cycling cells residing between the terminally differentiated Paneth cells at crypt bottoms. Colocalizes with Lgr5-positive stem cells. At 14.5 dpc, in the developing limb, expressed only in the ectoderm and, in developing lungs, detected in the epithelium. Autoubiquitinated. Conditional knockout mice lacking both Rnf43 and Znrf3 in intestine show a marked expansion of the proliferative compartment, resembling the effects of acute deletion of Apc. Belongs to the ZNRF3 family.