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Background  RNF43 and its homolog ZNRF3 are transmembrane E3 ubiquitin ligases frequently mutated in many human cancer types. Their main role relays on the inhibition of canonical Wnt signaling by the negative regulation of frizzled receptors and LRP5/6 co-receptors levels at the plasma membrane. Intracellular RING domains of RNF43/ZNRF3 mediate the key enzymatic activity of these proteins, but the function of the extracellular Protease Associated (PA) fold in the inhibition of Wnt/β-catenin pathway is controversial up-to date, apart from the interaction with secreted antagonists R-spondin family proteins shown by the crystallographic studies.    Methods  In our research we utilised cell-based approaches to study the role of RNF43 lacking PA domain in the canonical Wnt signalling pathway transduction. We developed controlled overexpression (TetON) and CRISPR/Cas9 mediated knock-out models in human cells.    Results  RNF43ΔPA mutant activity impedes canonical Wnt pathway, as manifested by the reduced phosphorylation of LRP6, DVL2 and DVL3 and by the decreased β-catenin-dependent gene expression. Finally, rescue experiments in the CRISPR/Cas9 derived  RNF43 / ZNRF3  double knock-out cell lines showed that RNFΔPA overexpression is enough to inhibit activation of LRP6 and β-catenin activity as shown by the Western blot and Top flash dual luciferase assays. Moreover, RNF43 variant without PA domain was not sensitive to the R-spondin1 treatment.    Conclusion  Taken together, our results help to understand better the mode of RNF43 tumor suppressor action and solve some discrepancies present in the field.Video AbstractGraphical Abstract

Protease associated domain of RNF43 is not necessary for the suppression of Wnt/β-catenin signaling in human cells