Ring finger protein 43 and Zinc and ring finger protein 3 (RNF43 and ZNRF3)

Ring finger protein 43 (RNF43) and zinc and ring finger protein 3 (ZNRF3) are closely related, single-pass transmembrane E3 ubiquitin ligases that negatively regulate Wnt signaling by ubiquitinating Frizzled family Wnt receptors, marking them for endocytosis and lysosomal degradation, thereby controlling cell-surface receptor levels and moderating Wnt pathway output. These proteins are critical tumor suppressors involved in embryonic development, tissue regeneration, and maintenance of homeostasis. Loss-of-function mutations in either protein, common in various cancers (e.g., colorectal, gastric, pancreatic), result in hyperactivation of the Wnt pathway and promote malignancy. RNF43 and ZNRF3 are controlled by R-spondins, which bind and induce their clearance from the membrane, thus relieving their suppression of the Wnt pathway. Targeted modulation of RNF43/ZNRF3 represents a potential anticancer strategy, but clinically approved drugs are not yet available. Note: While these two are usually studied together due to shared function and redundancy, they are distinct proteins encoded by separate genes. Their roles as E3 ligases place them in the enzyme molecular class, specifically regulating receptor abundance, and they are not ligand-gated receptors, GPCRs, or typical cell-surface signaling receptors.

Other names

RNF43ZNRF3Zinc and ring finger protein 3Ring finger protein 43

Negative regulation of Wnt signaling by ubiquitinating and promoting degradation of Wnt receptor Frizzled. Some drugs/peptides aim to modulate E3 ligase activity or disrupt RNF43/ZNRF3 interactions.