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Beschreibung

E3 ubiquitin-protein ligase RNF43 (UniProt Q68DV7, also known as RING finger protein 43) is encoded by the RNF43 gene (Gene ID 54894) in human. RNF43 and the homologous ZNRF3 are cell-surface transmembrane E3 ubiquitin ligases upregulated upon Wnt/ -catenin signaling and act as potent Wnt signaling pathway negative feedback regulators by mediating ubiquitination of Frizzled (FZD) and LRP6 for lysosomal degradation. RNF43/ZNRF3 activity is counteracted by stem cell growth factor R-spondin that induces membrane ZNRF3/RNF43 clearance by binding ZNRF3/RNF43 and LGR4/LGR5. Physical interaction with Dishevelled (DVL) is essential for ZNRF3/RNF43 Wnt inhibitory activity, and DVL knockdown significantly increases cell surface levels of FZD and LRP6. In addition, RNF43 suppresses canonical and noncanonical Wnt signaling via distinct mechanisms. While interaction between the extracellular protease-associated (PA) domain and the cysteine-rich domain (CRD) of FZD and RNF43 intracellular RING finger domain is necessary for canonical Wnt/ -catenin signaling inhibition, interaction between FZD PDZ domain and RNF43 C-terminal cytoplasmic region is essential for suppressing noncanonical Wnt signaling. R-spondin overexpression through gene translocation and loss-of-function RNF43/ZNRF3 gene mutations are found in human cancers as means to escape from Wnt signaling negative feedback regulation. Human RNF43 is produced with a signal peptide (a.a. 1-23) sequence, which is posttranslationally removed to yiled the mature enzyme with an N-terminal extracellular domain (a.a. 24-197), a transmembrane domain (a.a. 198-218), and a large cytoplasmic region (a.a. 219-783) that contains an atypical RING-type zinc finger (a.a. 272-313) and a pro-rich (a.a. 569-760) region.