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

Zinc and ring finger protein 3 (ZNRF3) and Ring finger protein 43 (RNF43) are closely related transmembrane E3 ubiquitin ligases that serve as critical negative regulators of the Wnt/beta-catenin signaling pathway [1, 17]. They function by targeting Wnt receptors, such as Frizzled (FZD) and LRP6, for ubiquitination and subsequent lysosomal degradation, thereby controlling the sensitivity of cells to Wnt ligands [7, 13]. These proteins are essential for maintaining stem cell homeostasis and proper tissue architecture, particularly in the intestinal epithelium and liver [1, 9, 22]. Mutations or deletions in ZNRF3 and RNF43 are frequently observed in various malignancies, including colorectal, pancreatic, and endometrial cancers, where their loss leads to the stabilization of Wnt receptors and constitutive pathway activation [2, 4, 6]. In the context of drug development, tumors harboring RNF43 mutations exhibit a specific dependency on Wnt ligands, making them highly sensitive to Porcupine inhibitors and other upstream Wnt signaling antagonists [14, 17]. Beyond Wnt signaling, recent evidence suggests these ligases also regulate other key growth factor receptors like EGFR, further expanding their role as tumor suppressors and therapeutic targets [5, 10, 19]. Therapeutic approaches also include the development of R-spondin mimetics that bind to ZNRF3/RNF43 to stabilize Wnt receptors for regenerative medicine applications [21, 23]. Overall, ZNRF3 and RNF43 represent a major regulatory hub at the plasma membrane that balances cell proliferation and differentiation across multiple tissues [1, 8].

Other names

ZNRF3RNF43RNF203BK747E2.1Zinc/RING finger protein 3RING finger protein 43

ZNRF3 and RNF43 are transmembrane E3 ubiquitin ligases that negatively regulate the Wnt signaling pathway by ubiquitinating Frizzled (FZD) receptors and LRP6 co-receptors, leading to their endocytosis and lysosomal degradation [1, 7]. This process reduces the availability of receptors on the cell surface, thereby inhibiting Wnt signal transduction [13, 17]. Therapeutic strategies include using Porcupine inhibitors to block Wnt ligand production in RNF43-mutant tumors, which are ligand-dependent, or using R-spondin mimetics to stabilize Wnt receptors for regenerative purposes [14, 21]. Additionally, these ligases regulate other substrates like EGFR and PAR2, providing further avenues for therapeutic intervention in cancer [5, 16].