E3 ubiquitin-protein ligase RNF43 (RNF43)

E3 ubiquitin-protein ligase RNF43 is a transmembrane RING-type E3 ubiquitin ligase that acts as a critical negative regulator of the Wnt signaling pathway. It functions by ubiquitinating Frizzled receptors at the cell surface, which triggers their endocytosis and subsequent lysosomal degradation, thereby dampening both canonical and non-canonical Wnt signaling. In many cancers, particularly colorectal and pancreatic ductal adenocarcinomas, RNF43 undergoes loss-of-function mutations that lead to an accumulation of Frizzled receptors and constitutive Wnt pathway activation. This genetic alteration renders tumors highly dependent on Wnt ligands for growth, a phenomenon known as Wnt addiction. Consequently, RNF43 mutation status serves as a key predictive biomarker for sensitivity to Wnt-targeted therapies, such as Porcupine (PORCN) inhibitors, which are currently being investigated in clinical trials to treat patients with RNF43-mutant malignancies.

Other names

Ring finger protein 43RNF124URCCSSPCSRING-type E3 ubiquitin transferase RNF43

Therapeutic strategies for RNF43-deficient cancers primarily involve the use of Porcupine (PORCN) inhibitors, which block the palmitoylation and secretion of Wnt ligands. By preventing Wnt secretion, these drugs mitigate the hyperactivation of the Wnt pathway caused by the loss of RNF43-mediated degradation of Frizzled receptors, thereby inhibiting the growth of Wnt-addicted tumors.