E3 ubiquitin-protein ligase that acts as a negative regulator of the Wnt signaling pathway by mediating the ubiquitination and subsequent degradation of Wnt receptor complex components Frizzled and LRP6. Acts on both canonical and non-canonical Wnt signaling pathway. Acts as a tumor suppressor in the intestinal stem cell zone by inhibiting the Wnt signaling pathway, thereby resticting the size of the intestinal stem cell zone (PubMed:22575959, PubMed:22895187). Along with RSPO2 and RNF43, 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. Negatively regulated by R-spondin proteins such as RSPO1: interaction with RSPO1 induces the indirect association between ZNRF3 and LGR4, promoting membrane clearance of ZNRF3. Protein modification; protein ubiquitination. Interacts with LRP6, FZD4, FZD5, FZD6 and FZD8 (By similarity). Interacts with RSPO1; interaction promotes indirect interaction with LGR4 and membrane clearance of ZNRF3 (By similarity). Interacts with LMBR1L (PubMed:31073040). During limb development, at 14.5 dpc, ubiquitously expressed in the limb bud. In developing lungs, at 14.5 dpc, ubiquitously expressed. Embryos die around birth due to activation of Wnt signaling pathway. Embryos display a lack of lens formation due to Wnt activation. 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. Truncated N-terminus. Truncated N-terminus.