RNF43 (RING finger protein 43) is an E3 ubiquitin ligase that may be expressed on the plasma membrane or intracellularly. It can associate with the nuclear matrix protein HAP95/AKAP8L, the ubiquitin ligase NEDL1, and p53. It also interacts with the cell surface ubiquitin ligase ZNRF3, and both RNF43 and ZNRF3 antagonize Wnt signaling by promoting the turnover of Frizzled receptors. Interaction with the R-Spondin Wnt-regulating proteins can also antagonize ZNRF3. RNF43 is frequently overexpressed in cancers, correlating with growth-promoting activity and colorectal and hepatocellular cancer pathogenesis. It is expressed in intestinal epithelial stem cells in colon crypts, where it limits the ability of Wnts to induce proliferation.