RNF43 is an enzyme frequently mutated in many forms of cancer. Under normal circumstances, the protein is known to inhibit canonical Wnt signaling, which regulates various aspects of cell development and disease. What remains controversial, however, is the function of a part of the protein known as the “protease-associated” (PA) domain. To find out, researchers recorded the effects of RNF43 without this domain in human cells. They discovered that the PA domain is not essential for RNF43 to block Wnt signaling. Rather, the PA domain’s job is to regulate levels of RNF43 on the cell surface, which is achieved through the pro-Wnt protein RSPO1. Understanding how RSPO1 behaves when RNF43 lacks its PA domain could be informative, as it could refine the perceived role of RNF43 mutations in human disease.