ZNRF3 (zinc/RING finger protein 3), also called RNF203, is a 101 kDa (predicted) type I transmembrane protein that is a member of the ZNRF3 family of ubiquitin ligases (1). Human ZNRF3 is synthesized as a 936 amino acid (aa) protein that contains a putative 55 aa signal sequence, a 164 aa extracellular domain (ECD), a transmembrane domain, and a cytoplasmic domain with an atypical RING (really interesting new gene) -type zinc finger (1). The mature human ZNRF3 ECD shares 98% aa sequence identity with mouse ZNRF3. An alternative start site at Met101 creates a 90 kDa (predicted) form; the shorter ECD of this human isoform shares 100% aa sequence identity with canine, feline and equine, 99% with porcine, and 98% with rat ZNRF3 (1). In the plasma membrane, ZNRF3 is co‑expressed with the related protein RNF43, and both serve as E3 ubiquitin ligases that promote turnover of Frizzled Wnt receptors and LRP6 to antagonize Wnts (2‑4). Interaction with the R‑Spondin Wnt‑regulating proteins antagonizes ZNRF3, thus stabilizing Frizzleds and LRP6, allowing their accumulation, and promoting Wnt signaling (2, 3). ZNRF3 is expressed in stem cells at the bottom of colon crypts, where it limits the ability of Wnts to induce proliferation (4). It is also expressed in normal gastric tissues, but is down‑regulated in gastric adenocarcinomas (5).