Affinage

RNF43

E3 ubiquitin-protein ligase RNF43 · UniProt Q68DV7

Length
783 aa
Mass
85.7 kDa
Annotated
2026-04-28
100 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RNF43 is a transmembrane RING-type E3 ubiquitin ligase that functions as a central negative-feedback regulator of Wnt signaling by ubiquitinating Frizzled receptors—preferentially FZD1, FZD5, and FZD7—for lysosomal degradation, a process requiring Dishevelled (DVL) as a substrate adaptor and phosphorylation at a conserved serine triplet (PMID:22895187, PMID:25891077, PMID:32934222, PMID:38969364). R-spondin ligands antagonize RNF43 by forming a ternary complex with LGR4 and the RNF43 ectodomain, neutralizing its Frizzled-clearing activity and potentiating Wnt signaling; this interaction is counteracted by the deubiquitinase USP42 (PMID:23756651, PMID:24225776, PMID:33786993, PMID:37402772). Beyond Frizzled, RNF43 ubiquitinates additional substrates including B-RAF at K499, EGFR, and VANGL2, and suppresses noncanonical WNT5A signaling through interactions with ROR1/ROR2/VANGL1/VANGL2 (PMID:34702444, PMID:38225722, PMID:41960900). Cancer-associated C-terminal truncating mutations can retain Frizzled regulation yet trap CK1 at the plasma membrane, driving ligand-independent β-catenin activation and resistance to anti-Wnt therapies (PMID:32965059).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2008 Medium

    Initial biochemical characterization established that RNF43 possesses intrinsic E3 ubiquitin ligase (autoubiquitylation) activity and localizes to the ER/nuclear envelope, but its physiological substrates were unknown.

    Evidence Cell-free autoubiquitylation assay with recombinant MBP-RNF43, immunofluorescence, and yeast two-hybrid identification of HAP95 interaction

    PMID:18313049

    Open questions at the time
    • HAP95 interaction confirmed by single Co-IP without reciprocal validation
    • Physiological substrates not identified
    • ER/nuclear envelope localization later challenged by antibody concerns
  2. 2012 High

    The breakthrough discovery that RNF43 ubiquitinates Frizzled receptors for lysosomal degradation established its role as a Wnt negative-feedback regulator, and double knockout with ZNRF3 in mouse intestine caused Wnt-dependent adenomas.

    Evidence In vitro ubiquitination assays, HEK293T overexpression, conditional mouse knockout, organoid culture

    PMID:22895187

    Open questions at the time
    • Mechanism of substrate recognition (how RNF43 engages Frizzled) not yet defined
    • Relative contribution of RNF43 vs ZNRF3 unclear
    • Adaptor requirements unknown
  3. 2013 High

    Structural and functional studies defined the R-spondin/LGR/RNF43 ternary complex architecture, revealing how R-spondins bridge LGR receptors and RNF43 to neutralize Frizzled degradation, and showed that cancer-associated RNF43 mutations create Wnt ligand dependency.

    Evidence Crystal structures of RNF43 ectodomain with RSPO2 and ternary RSPO1–LGR5–RNF43 complex; binding assays; RNF43 reconstitution in pancreatic cancer cells with porcupine inhibitor sensitivity

    PMID:23756651 PMID:23847203 PMID:24225776

    Open questions at the time
    • Whether all R-spondin family members use identical binding mode unresolved
    • Mechanism of R-spondin-induced RNF43 membrane clearance not determined
    • Intracellular signaling consequences of ternary complex formation undefined
  4. 2014 Medium

    RNF43 was shown to be a direct Wnt/β-catenin target gene regulated by TCF4/β-catenin occupancy at intronic Wnt-responsive elements, completing the negative-feedback loop architecture.

    Evidence Luciferase reporter assay with WRE mutants, ChIP for TCF4/β-catenin at intronic elements

    PMID:24466159

    Open questions at the time
    • Regulation in non-intestinal tissues not addressed
    • Kinetics of feedback induction not measured
  5. 2015 High

    DVL was identified as an essential adaptor bridging RNF43 to Frizzled substrates, with domain dissection revealing that the PA domain mediates Frizzled CRD interaction for canonical signaling while the C-terminal cytoplasmic region suppresses noncanonical Wnt signaling independently of RING-dependent ubiquitination.

    Evidence DVL knockout cells, Co-IP, DEP-ZNRF3 fusion rescue, domain deletion/mutation analysis, Wnt reporter assays

    PMID:25825523 PMID:25891077

    Open questions at the time
    • Identity of the kinase phosphorylating RNF43 to activate it not yet known
    • Structural basis of DVL–RNF43 interaction unresolved
    • Mechanism of RING-independent noncanonical suppression unclear
  6. 2015 High

    Genetic epistasis demonstrated that paracrine Wnt3 from Paneth cells is the essential proliferative signal in RNF43/ZNRF3-null intestinal tumors, validating porcupine inhibition as a therapeutic strategy.

    Evidence Genetic crosses of Rnf43/Znrf3 KO with Math1 KO and Wnt3 KO mice; porcupine inhibitor C59 treatment in vivo

    PMID:26023187

    Open questions at the time
    • Applicability to human RNF43-mutant cancers not directly demonstrated
    • Whether all RNF43 mutation classes are equally porcupine-sensitive unknown
  7. 2019 Medium

    RNF43 substrate scope was expanded beyond Frizzled to include PAR2 and phospho-E-cadherin, suggesting broader membrane protein quality control functions.

    Evidence Co-IP and ubiquitination assays for PAR2 (with R-spondin/LGR5 rescue) and E-cadherin (K816 site mutagenesis), xenograft models

    PMID:31286874 PMID:36468684

    Open questions at the time
    • PAR2 as substrate not independently replicated
    • E-cadherin ubiquitination requirement for FZD8 is unusual and unexplained mechanistically
    • Relative importance of non-Frizzled substrates in physiology unknown
  8. 2020 High

    The critical regulatory mechanism of RNF43 phosphorylation at a conserved serine triplet was defined: phosphorylation is required for Frizzled ubiquitination, and cancer mutations that abolish it selectively lose tumor-suppressive but not p53-inhibitory function. Separately, C-terminal truncating mutations were shown to trap CK1 at the plasma membrane, driving ligand-independent β-catenin activation.

    Evidence Phosphomutant/phosphomimetic constructs in zebrafish and organoids; gene-edited human colon stem cells with CK1 Co-IP and β-catenin phosphorylation assays

    PMID:32934222 PMID:32965059

    Open questions at the time
    • Identity of the kinase(s) phosphorylating the serine triplet unknown
    • CK1 trapping mechanism (direct binding vs indirect) not structurally resolved
    • Whether phosphorylation and CK1-trapping mutations co-occur in tumors not examined
  9. 2021 High

    USP42 was identified as the deubiquitinase counteracting R-spondin-induced RNF43/ZNRF3 membrane clearance, and RNF43 was shown to suppress noncanonical WNT5A signaling by ubiquitinating VANGL2 and internalizing ROR1, establishing dual canonical/noncanonical tumor-suppressive functions.

    Evidence Co-IP and deubiquitination assays for USP42–ZNRF3; BioID proximity labeling plus Co-IP and degradation assays for ROR1/ROR2/VANGL interactions; invasion and xenograft models

    PMID:33786993 PMID:34702444

    Open questions at the time
    • Whether USP42 acts on RNF43 directly (in addition to ZNRF3) not established
    • Structural basis of RNF43–ROR/VANGL interaction unknown
    • In vivo relevance of noncanonical suppression in normal tissue homeostasis not tested
  10. 2021 High

    A non-redundant role for RNF43 (distinct from ZNRF3) in oligodendrocyte progenitor differentiation was demonstrated: RNF43 is Wnt-induced specifically after injury and promotes remyelination by clearing Fzd1.

    Evidence Conditional Rnf43 KO in OPCs, neonatal hypoxic injury model, adult demyelination model, Fzd1 pharmacological inhibition rescue

    PMID:34390652

    Open questions at the time
    • Whether other Frizzled subtypes contribute to OPC phenotype not resolved
    • Human translational relevance limited to expression data
  11. 2024 High

    RNF43 and ZNRF3 were shown to have distinct Frizzled substrate preferences dictated by the transmembrane domain, and RNF43 was found to ubiquitinate B-RAF at K499 and EGFR, broadening its tumor-suppressive reach beyond Wnt receptors.

    Evidence TMD swap domain mutants with quantitative FZD endocytosis assays; K499R B-RAF mutagenesis with Co-IP; EGFR Co-IP and ubiquitination assays in KO/OE systems

    PMID:38225722 PMID:38969364 PMID:41960900

    Open questions at the time
    • Structural basis of TMD-mediated Frizzled selectivity unknown
    • Physiological contexts where B-RAF and EGFR ubiquitination by RNF43 are rate-limiting undefined
    • Whether all non-Frizzled substrates require DVL adaptor function untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the identity of the kinase(s) phosphorylating the RNF43 serine triplet, the structural basis of TMD-determined Frizzled selectivity, whether non-Frizzled substrates (B-RAF, EGFR, VANGL2) use the same DVL-dependent adaptor mechanism, and the in vivo tissue-specific hierarchy among RNF43's multiple substrates.
  • Kinase for serine triplet phosphorylation unidentified
  • No structural model of full-length RNF43 in complex with any Frizzled
  • Relative in vivo importance of Wnt-dependent vs Wnt-independent substrates unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016874 ligase activity 4
Localization
GO:0005886 plasma membrane 4 GO:0005768 endosome 2 GO:0005783 endoplasmic reticulum 2 GO:0005635 nuclear envelope 1
Pathway
R-HSA-162582 Signal Transduction 10 R-HSA-392499 Metabolism of proteins 7 R-HSA-1643685 Disease 5
Partners
BRAFCSNK1A1DVL2EGFRFZD5LGR4ROR1VANGL2
Complex memberships
RSPO-LGR4-RNF43 ternary complex

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 RNF43 is a transmembrane E3 ubiquitin ligase that selectively ubiquitinates Frizzled receptors at the cell surface, targeting them for lysosomal degradation, thereby reducing Wnt signaling. Deletion of RNF43 (with ZNRF3) in mouse intestinal epithelium induces adenoma formation dependent on paracrine Wnt. In vitro ubiquitination assays, HEK293T overexpression, RNF43 reconstitution in HCT116 cells, conditional mouse knockout, organoid culture Nature High 22895187
2013 Crystal structures of the RNF43 ectodomain in complex with the Fu1-Fu2 fragment of R-spondin 2 (Rspo2) revealed that a prominent loop in Rspo2 Fu1 clamps into a groove in the RNF43 ectodomain surface, establishing the structural basis of R-spondin-mediated inhibition of RNF43 E3 ligase activity. X-ray crystallography of ZNRF3 ectodomain, RNF43 ectodomain, and Rspo2(Fu1-Fu2) complexes; biophysical binding assays; cellular Wnt reporter assays Nature Communications High 24225776
2013 Crystal structure of RSPO1 bound simultaneously to LGR5 and RNF43 ectodomains showed that RSPO1 is sandwiched between LGR5 and RNF43, with its CRD rod module contacting LGR5 and a hairpin inserted into RNF43. LGR5 does not contact RNF43 but increases RSPO1 affinity for RNF43, establishing LGR5 as an engagement receptor and RNF43 as an effector receptor. X-ray crystallography of ternary RSPO1-LGR5-RNF43 ectodomain complex; binding affinity measurements Genes & Development High 23756651
2013 RNF43 inhibits Wnt/β-catenin signaling by reducing membrane-level Frizzled in pancreatic cancer cells. Inactivating RNF43 mutations increase cell-surface Frizzled and confer dependency on Wnt ligand secretion (Porcupine-dependent) for proliferation. RNF43 reconstitution in RNF43-mutant pancreatic cancer cell lines, cell-surface Frizzled quantification, Wnt inhibitor (LGK974) sensitivity assays, siRNA knockdown, xenograft models Proceedings of the National Academy of Sciences High 23847203
2015 Dishevelled (DVL) acts as a dual-function adaptor required for ZNRF3/RNF43-mediated ubiquitination and degradation of Frizzled (FZD) and LRP6. Physical interaction between ZNRF3/RNF43 and DVL is essential for their Wnt inhibitory activity; the DEP domain of DVL binds FZD, and fusion of DEP to ZNRF3/RNF43 overcomes their DVL dependency. DVL knockout cells, Co-IP, cell surface FZD/LRP6 quantification, ubiquitination assays, domain-swap experiments (DEP-ZNRF3 fusion) Molecular Cell High 25891077
2015 RNF43 suppresses canonical Wnt/β-catenin signaling through its extracellular PA domain interaction with the Frizzled CRD, requiring the intracellular RING finger domain for ubiquitination. RNF43 also suppresses noncanonical Wnt signaling through its C-terminal cytoplasmic region binding the PDZ domain of Dishevelled, independently of the PA and RING domains. Missense mutations in the extracellular portion of RNF43 redirect its localization from endosome to ER, abrogating canonical but not noncanonical Wnt suppression. Domain deletion/mutation analysis, co-IP, localization studies (immunofluorescence), Wnt reporter assays in HEK293T and cancer cells Molecular and Cellular Biology High 25825523
2015 RNF43 was detected in the nucleus of human intestinal crypt and colon cancer cells where it physically interacts with TCF4 and tethers it to the nuclear membrane, silencing TCF4 transcriptional activity even in the presence of constitutively active β-catenin. Tumor-associated RING domain mutations disrupt this inhibitory mechanism. Co-IP of endogenous RNF43 and TCF4, nuclear fractionation, immunofluorescence, Wnt reporter assays, Xenopus embryo overexpression, mutant RNF43 analysis Science Signaling Medium 26350900
2015 Paracrine Wnt secretion from Paneth cells (Wnt3) is the essential driver of Rnf43/Znrf3-null intestinal tumor growth; removal of Paneth cells by Math1 mutation or deletion of Wnt3 inhibits tumorigenesis. Treatment with porcupine inhibitor C59 strongly inhibited RZ-null neoplasia growth while sparing normal crypts. Genetic epistasis (Math1 KO, Wnt3 KO crossed to Rnf43/Znrf3 KO mice), pharmacological porcupine inhibitor (C59) treatment in vivo Proceedings of the National Academy of Sciences High 26023187
2008 RNF43 localizes to the endoplasmic reticulum and nuclear envelope, exhibits autoubiquitylation activity in a cell-free system with purified recombinant protein, and interacts with HAP95 (a chromatin-associated nuclear envelope protein) as identified by yeast two-hybrid and confirmed by Co-IP. Indirect immunofluorescence, biochemical fractionation, sucrose density gradient, cell-free autoubiquitylation assay with recombinant MBP-RNF43, yeast two-hybrid, Co-IP Experimental Cell Research Medium 18313049
2010 RNF43 interacts with NEDL1 (a p53-enhancing E3 ligase) and with p53 itself, and suppresses p53-mediated transcriptional activity and UV-induced apoptosis in H1299 cells. Yeast two-hybrid screening, Co-IP, transcriptional reporter assays, UV apoptosis assay Biochemical and Biophysical Research Communications Medium 21108931
2014 RNF43 expression is directly regulated as a Wnt target gene through two Wnt-responsive elements (WREs) in intron 2 that bind the TCF4/β-catenin complex, as demonstrated by reporter assays with WRE mutations and ChIP showing TCF4/β-catenin occupancy at both elements. Luciferase reporter assay with WRE mutants, siRNA knockdown of β-catenin, ChIP assay PloS One Medium 24466159
2020 RNF43 E3 ligase activity toward Frizzled requires phosphorylation at a conserved triplet of serine residues. Cancer-associated mutations abrogating this phosphorylation abolish Frizzled degradation and Wnt inhibition while retaining p53 inhibitory function. Phosphomimetic substitutions (Ser→Asp) restored tumor suppressive activity of extracellular oncogenic mutants. Phosphomutant and phosphomimetic RNF43 constructs, zebrafish development assay, mouse intestinal organoids, co-expression with active Ras for tumorigenesis, Wnt reporter assays Nature Communications High 32934222
2020 A subset of RNF43 C-terminal truncating cancer mutations retains Wnt receptor downregulation but traps Casein kinase 1 (CK1) at the plasma membrane via the cytosolic tail, preventing cytoplasmic β-catenin turnover and driving ligand-independent β-catenin-mediated transcription. These mutations confer decreased sensitivity to anti-Wnt therapy. Gene editing of human colon stem cells, Co-IP of CK1 with truncated RNF43 variants, β-catenin phosphorylation assays, Wnt reporter assays, organoid growth in absence of niche factors The EMBO Journal High 32965059
2021 The deubiquitinase USP42 antagonizes R-spondin-induced clearance of RNF43/ZNRF3 by binding the Dishevelled-interacting region (DIR) of ZNRF3 and deubiquitinating ZNRF3, thereby stalling the R-spondin-LGR4-ZNRF3 ternary complex at the membrane and maintaining Frizzled/LRP6 turnover. Co-IP of USP42 with ZNRF3, deubiquitination assays, LRP6/FZD cell surface quantification, Wnt reporter assays, siRNA knockdown in colon cancer cells and mouse intestinal organoids EMBO Reports High 33786993
2021 RNF43 inhibits noncanonical WNT5A signaling in human cells by interacting with ROR1, ROR2, VANGL1, and VANGL2 receptor complex components. RNF43 triggers ubiquitination and proteasomal degradation of VANGL2 and clathrin-dependent internalization of ROR1, and inhibits ROR2 activation, suppressing WNT5A-driven melanoma invasion and resistance to BRAF/MEK inhibitors. BioID proximity labeling, Co-IP, ubiquitination assays, VANGL2 degradation assays, ROR1 internalization (clathrin inhibitor), in vitro invasion assays, in vivo xenograft experiments eLife High 34702444
2021 Rnf43 (but not Znrf3) is potently activated by Wnt signaling in oligodendrocyte progenitor cells (OPCs), marks activated OPCs in human MS and HIE, and promotes OPC differentiation/remyelination specifically after injury by negatively regulating Fzd1 receptor presentation at the cell surface. Conditional Rnf43 KO in OPCs, neonatal hypoxic injury model, adult demyelination model, ex vivo and in vivo remyelination assays, Fzd1 inhibition (UM206) Neuron High 34390652
2024 RNF43 and ZNRF3 preferentially downregulate distinct subsets of Frizzled receptors: RNF43 preferentially targets FZD1/FZD5/FZD7 for endocytosis whereas ZNRF3 preferentially targets FZD6. The transmembrane domain (TMD) of RNF43 is a key molecular determinant for FZD5 endocytosis; swapping TMDs between RNF43 and ZNRF3 redirects their FZD preferences. FZD endocytosis assays (flow cytometry and imaging), TMD swap domain mutants, cell surface receptor quantification Life Science Alliance High 38969364
2024 RNF43 ubiquitinates B-RAF at lysine K499 to promote proteasome-dependent degradation of B-RAF, reducing MEK activity. Phosphorylation of B-RAF at T491 suppresses this ubiquitination by decreasing RNF43–B-RAF interaction. Loss of RNF43 elevates B-RAF/MEK signaling, and MEK plus Wnt inhibitors synergistically suppress RNF43-mutant pancreatic cancer growth. Co-IP, ubiquitination assay with specific lysine mutants (K499R), phosphorylation site mutagenesis (T491), proteasome inhibitor assays, MEK inhibitor sensitivity in cell lines and in vivo Advanced Science High 38225722
2024 ZNRF3/RNF43 interact with EGFR via their extracellular domains, leading to EGFR ubiquitination and degradation dependent on the RING domain E3 ligase activity. ZNRF3/RNF43 knockout elevates EGFR signaling and promotes tumorigenesis. Co-IP of ZNRF3/RNF43 with EGFR, ubiquitination assays, ZNRF3/RNF43 overexpression and KO in cancer cells, in vivo tumor growth assays, proteogenomic correlation analysis eLife High 41960900
2022 RNF43 G659fs mutant binds the p85 regulatory subunit of PI3K, leading to p85 ubiquitination and degradation, which increases PI3K/mTOR signaling. RNF43 G659fs cells are selectively killed by PI3K/mTOR inhibitors in vitro, in isogenic xenografts, and in patient-derived organoids. Co-IP of RNF43-G659fs with p85, ubiquitination assay, drug library screen, isogenic cell line and organoid drug sensitivity assays, xenograft experiments Nature Communications High 35676246
2019 RNF43 ubiquitinates c-Src-phosphorylated E-cadherin (phospho-Tyr797) at Lys816, promoting its degradation and enabling nuclear β-catenin translocation, thereby facilitating EMT in lung adenocarcinoma. This ubiquitination requires Frizzled 8 (FZD8). Protein antibody microarray, E3 ligase profiling, Co-IP, ubiquitination site mutagenesis (Y797, K816), immunofluorescence, xenograft models, shRNA knockdown BMC Cancer Medium 31286874
2019 RNF43 co-associates with PAR2 (protease-activated receptor 2), promotes its membrane elimination and polyubiquitination, and PAR2 degradation is rescued by R-spondin2 in the presence of LGR5, establishing RNF43 as a negative feedback regulator of PAR2 in colon cancer. Co-IP, cell surface biotinylation assay for PAR2, polyubiquitination assay, R-spondin/LGR5 rescue experiment, β-catenin reporter assay, AOM/DSS mouse model FASEB Journal Medium 36468684
2023 RNF43 interacts with PD-L1 and augments both K48- and K63-linked ubiquitination of PD-L1 in gastric cancer cell lines, reducing PD-L1 surface expression and enhancing T-cell anti-tumor activity. Co-IP of RNF43 and PD-L1, ubiquitination linkage-specific assays (K48, K63), T-cell killing assays Scandinavian Journal of Immunology Low 39007965
2024 RNF43 reinforces ubiquitination and proteasomal degradation of NDUFS1 (NADH dehydrogenase Fe-S protein 1) by direct interaction with it, suppressing oxidative phosphorylation and inhibiting endometrial stromal cell viability and migration. RNF43 mRNA stability and expression are regulated by METTL3/IGF2BP2-mediated m6A modification. Co-IP of RNF43 and NDUFS1, ubiquitination assay, m6A methylation assays (METTL3 overexpression/inhibition, IGF2BP2 RIP), cell viability and migration assays, knockdown/overexpression Journal of Cellular Physiology Low 38988031
2008 RNF43 interacts with the heterodimer PSF/p54nrb as identified by pull-down and confirmed by Co-IP; co-expression of PSF relocates RNF43 from the nuclear periphery to the nucleoplasm. Pull-down assay with MS identification, Co-IP, immunofluorescence Proteomics Low 18655028
2020 The RNF43 protease-associated (PA) extracellular domain is dispensable for inhibition of canonical Wnt/β-catenin signaling in human cells; RNF43 lacking the PA domain still reduces LRP6/DVL phosphorylation and β-catenin-dependent transcription, and is insensitive to R-spondin1. TetON-controlled RNF43ΔPA overexpression, CRISPR/Cas9 RNF43/ZNRF3 double KO rescue experiments, Western blot (pLRP6, pDVL, β-catenin), TOPflash luciferase assay Cell Communication and Signaling Medium 32527265
2023 LGR4, but not LGR5, forms a complex with RNF43/ZNRF3 that provides high-affinity bivalent binding of R-spondin ligands. LGR5 forms homodimers that do not interact with the E3 ligases; co-expression of ZNRF3 with LGR4 dramatically increases monovalent RSPO affinity, whereas co-expression with LGR5 has no effect. Binding affinity measurements in whole cells, co-expression of LGR4/LGR5 with ZNRF3, bivalent vs monovalent RSPO2 furin domain binding assays Scientific Reports Medium 37402772

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature 784 22895187
2014 The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength. Genes & development 523 24532711
2013 Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proceedings of the National Academy of Sciences of the United States of America 355 23847203
2016 The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size. Nature cell biology 265 27088858
2016 Genome-wide CRISPR screens reveal a Wnt-FZD5 signaling circuit as a druggable vulnerability of RNF43-mutant pancreatic tumors. Nature medicine 230 27869803
2013 Structural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin. Nature communications 162 24225776
2015 Dishevelled promotes Wnt receptor degradation through recruitment of ZNRF3/RNF43 E3 ubiquitin ligases. Molecular cell 161 25891077
2016 RNF43 germline and somatic mutation in serrated neoplasia pathway and its association with BRAF mutation. Gut 159 27329244
2016 Control of Wnt Receptor Turnover by R-spondin-ZNRF3/RNF43 Signaling Module and Its Dysregulation in Cancer. Cancers 144 27338477
2015 Porcupine inhibitor suppresses paracrine Wnt-driven growth of Rnf43;Znrf3-mutant neoplasia. Proceedings of the National Academy of Sciences of the United States of America 140 26023187
2011 Ginger (Zingiber officinale) reduces acute chemotherapy-induced nausea: a URCC CCOP study of 576 patients. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer 135 21818642
2013 The structural basis of R-spondin recognition by LGR5 and RNF43. Genes & development 124 23756651
2016 Frequent PTPRK-RSPO3 fusions and RNF43 mutations in colorectal traditional serrated adenoma. The Journal of pathology 107 26924569
2013 RNF43 is a tumour suppressor gene mutated in mucinous tumours of the ovary. The Journal of pathology 100 23096461
2016 RNF43 and ZNRF3 are commonly altered in serrated pathway colorectal tumorigenesis. Oncotarget 91 27661107
2016 KRAS, GNAS, and RNF43 mutations in intraductal papillary mucinous neoplasm of the pancreas: a meta-analysis. SpringerPlus 82 27512631
2005 5-Hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. The Lancet. Oncology 79 16198982
2015 Molecular Role of RNF43 in Canonical and Noncanonical Wnt Signaling. Molecular and cellular biology 77 25825523
2015 The E3 ligase RNF43 inhibits Wnt signaling downstream of mutated β-catenin by sequestering TCF4 to the nuclear membrane. Science signaling 66 26350900
2021 ZNRF3 and RNF43 cooperate to safeguard metabolic liver zonation and hepatocyte proliferation. Cell stem cell 64 34129813
2014 Clinicopathological significance of somatic RNF43 mutation and aberrant expression of ring finger protein 43 in intraductal papillary mucinous neoplasms of the pancreas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 58 25081753
2019 The most common RNF43 mutant G659Vfs*41 is fully functional in inhibiting Wnt signaling and unlikely to play a role in tumorigenesis. Scientific reports 56 31811196
2015 The nucleoprotein of influenza A virus induces p53 signaling and apoptosis via attenuation of host ubiquitin ligase RNF43. Cell death & disease 55 25996295
2015 Brg-1 targeting of novel miR550a-5p/RNF43/Wnt signaling axis regulates colorectal cancer metastasis. Oncogene 54 25961913
2021 Loss of Rnf43 Accelerates Kras-Mediated Neoplasia and Remodels the Tumor Immune Microenvironment in Pancreatic Adenocarcinoma. Gastroenterology 52 34973294
2010 RNF43 interacts with NEDL1 and regulates p53-mediated transcription. Biochemical and biophysical research communications 52 21108931
2004 A novel oncoprotein RNF43 functions in an autocrine manner in colorectal cancer. International journal of oncology 52 15492824
2020 A phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis. Nature communications 51 32934222
2022 RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state. Nature communications 49 35039505
2016 Dysregulated Wnt signalling and recurrent mutations of the tumour suppressor RNF43 in early gastric carcinogenesis. The Journal of pathology 48 27514024
2015 A deleterious RNF43 germline mutation in a severely affected serrated polyposis kindred. Human genome variation 46 27081527
2008 A cancer-associated RING finger protein, RNF43, is a ubiquitin ligase that interacts with a nuclear protein, HAP95. Experimental cell research 46 18313049
2020 The Functional Landscape of Patient-Derived RNF43 Mutations Predicts Sensitivity to Wnt Inhibition. Cancer research 44 33067269
2015 ZNRF3/RNF43--A direct linkage of extracellular recognition and E3 ligase activity to modulate cell surface signalling. Progress in biophysics and molecular biology 44 25937466
2021 USP42 protects ZNRF3/RNF43 from R-spondin-dependent clearance and inhibits Wnt signalling. EMBO reports 43 33786993
2020 RNF43 truncations trap CK1 to drive niche-independent self-renewal in cancer. The EMBO journal 43 32965059
2022 RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition. Nature communications 41 35676246
2020 Commonly observed RNF43 mutations retain functionality in attenuating Wnt/β-catenin signaling and unlikely confer Wnt-dependency onto colorectal cancers. Oncogene 39 32103169
2018 Impact of loss-of-function mutations at the RNF43 locus on colorectal cancer development and progression. The Journal of pathology 39 29756208
2022 The RSPO-LGR4/5-ZNRF3/RNF43 module in liver homeostasis, regeneration, and disease. Hepatology (Baltimore, Md.) 38 35006616
2016 RNF43 Is an Early and Specific Mutated Gene in the Serrated Pathway, With Increased Frequency in Traditional Serrated Adenoma and Its Associated Malignancy. The American journal of surgical pathology 38 27305845
2021 RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy. eLife 36 34702444
2022 Characterization of RNF43 frameshift mutations that drive Wnt ligand- and R-spondin-dependent colon cancer. The Journal of pathology 34 35040131
2021 Oligodendroglial ring finger protein Rnf43 is an essential injury-specific regulator of oligodendrocyte maturation. Neuron 34 34390652
2020 Loss of RNF43 Function Contributes to Gastric Carcinogenesis by Impairing DNA Damage Response. Cellular and molecular gastroenterology and hepatology 31 33188943
2020 RNF43 mutation is associated with aggressive tumor biology along with BRAF V600E mutation in right-sided colorectal cancer. Oncology reports 29 32236609
2019 Loss of endogenous RNF43 function enhances proliferation and tumour growth of intestinal and gastric cells. Carcinogenesis 29 30380024
2023 RNF43 and ZNRF3 in Wnt Signaling - A Master Regulator at the Membrane. International journal of stem cells 28 37643759
2022 Comprehensive Analysis of R-Spondin Fusions and RNF43 Mutations Implicate Novel Therapeutic Options in Colorectal Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 28 35254413
2017 RNF43 mutation frequently occurs with GNAS mutation and mucin hypersecretion in intraductal papillary neoplasms of the bile duct. Histopathology 28 27864998
2019 RNF43 ubiquitinates and degrades phosphorylated E-cadherin by c-Src to facilitate epithelial-mesenchymal transition in lung adenocarcinoma. BMC cancer 26 31286874
2014 Identification of two Wnt-responsive elements in the intron of RING finger protein 43 (RNF43) gene. PloS one 26 24466159
2015 Frequent frameshift mutations in 2 mononucleotide repeats of RNF43 gene and its regional heterogeneity in gastric and colorectal cancers. Human pathology 22 26297255
2013 RNF43 mutations are recurrent in Chinese patients with mucinous ovarian carcinoma but absent in other subtypes of ovarian cancer. Gene 22 24001777
2020 Protease associated domain of RNF43 is not necessary for the suppression of Wnt/β-catenin signaling in human cells. Cell communication and signaling : CCS 20 32527265
2017 Rnf43. Journal of clinical pathology 20 29018044
2007 A Phase II/III Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Ginger (Zingiber officinale) for Nausea Caused by Chemotherapy for Cancer: A Currently Accruing URCC CCOP Cancer Control Study. Supportive cancer therapy 20 18632524
2021 Ub and Dub of RNF43/ZNRF3 in the WNT signalling pathway. EMBO reports 17 33938624
2021 Post-translational Wnt receptor regulation: Is the fog slowly clearing?: The molecular mechanism of RNF43/ZNRF3 ubiquitin ligases is not yet fully elucidated and still controversial. BioEssays : news and reviews in molecular, cellular and developmental biology 16 33569855
2020 RNF43 mutation analysis in serrated polyposis, sporadic serrated polyps and Lynch syndrome polyps. Histopathology 16 33098683
2023 The tumor biological significance of RNF43 and LRP1B in gastric cancer is complex and context-dependent. Scientific reports 15 36823311
2023 LGR4 and LGR5 form distinct homodimers that only LGR4 complexes with RNF43/ZNRF3 to provide high affinity binding of R-spondin ligands. Scientific reports 15 37402772
2018 RNF43 is mutated less frequently in Lynch Syndrome compared with sporadic microsatellite unstable colorectal cancers. Familial cancer 15 28573495
2021 CircRNA-IGLL1/miR-15a/RNF43 axis mediates ammonia-induced autophagy in broilers jejunum via Wnt/β-catenin pathway. Environmental pollution (Barking, Essex : 1987) 14 34637826
2018 A phase I clinical trial of RNF43 peptide-related immune cell therapy combined with low-dose cyclophosphamide in patients with advanced solid tumors. PloS one 14 29293510
2024 E3 ligases RNF43 and ZNRF3 display differential specificity for endocytosis of Frizzled receptors. Life science alliance 13 38969364
2022 RNF43/ZNRF3 negatively regulates taste tissue homeostasis and positively regulates dorsal lingual epithelial tissue homeostasis. Stem cell reports 13 34995498
2019 Mutated Rnf43 Aggravates Helicobacter Pylori-Induced Gastric Pathology. Cancers 13 30884828
2019 RNF43 frameshift mutations contribute to tumourigenesis in right-sided colon cancer. Pathology, research and practice 13 31122752
2008 Proteomic identification of a PSF/p54nrb heterodimer as RNF43 oncoprotein-interacting proteins. Proteomics 13 18655028
2023 RNF43 induces the turnover of protease-activated receptor 2 in colon cancer. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 12 36468684
2022 Deficient Rnf43 potentiates hyperactive Kras-mediated pancreatic preneoplasia initiation and malignant transformation. Animal models and experimental medicine 10 35229994
2021 RNF43 overexpression attenuates the Wnt/β-catenin signalling pathway to suppress tumour progression in cholangiocarcinoma. Oncology letters 10 34733364
2021 RNF43 pathogenic Germline variant in a family with colorectal cancer. Clinical genetics 9 34541672
2017 RT-qPCR analysis of the tumor antigens TOMM34 and RNF43 in samples extracted from paraffin-embedded specimens of colorectal cancer. Oncology letters 9 28789449
2024 m6A methylation of RNF43 inhibits the progression of endometriosis through regulating oxidative phosphorylation via NDUFS1. Journal of cellular physiology 8 38988031
2023 RNF43 mutation as a predictor of immunotherapeutic efficacy in colorectal cancer. American journal of cancer research 8 38058823
2022 RNF43 as a predictor of malignant transformation of pancreatic mucinous cystic neoplasm. Virchows Archiv : an international journal of pathology 8 35066614
2022 RNF43 R117fs mutant positively regulates Wnt/β-catenin signaling by failing to internalize FZD expressed on the cell surface. Scientific reports 8 35487932
2015 Association of RNF43 with cell cycle proteins involved in p53 pathway. International journal of clinical and experimental pathology 8 26823834
2023 Inherited BRCA1 and RNF43 pathogenic variants in a familial colorectal cancer type X family. Familial cancer 7 38063999
2023 Predictive Impact of RNF43 Mutations in Patients With Proficient Mismatch Repair/Microsatellite Stable BRAFV600E-Mutated Metastatic Colorectal Cancer Treated With Target Therapy or Chemotherapy. JCO precision oncology 6 37797285
2025 Structure-Guided Development of Chemically Tailored Peptide Binders of RNF43/ZNRF3 to Enable Versatile Design of Membrane Protein-Targeting PROTACs. Angewandte Chemie (International ed. in English) 5 40000409
2024 RNF43 Inactivation Enhances the B-RAF/MEK Signaling and Creates a Combinatory Therapeutic Target in Cancer Cells. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 5 38225722
2024 Association of RNF43 Genetic Alterations With BRAFV600E and MSIhigh in Colorectal Cancer. JCO precision oncology 5 38394466
2024 New Target(s) for RNF43 Regulation: Implications for Therapeutic Strategies. International journal of molecular sciences 5 39125653
2024 RNF43 and ZNRF3: Versatile regulators at the membrane and their role in cancer. Biochimica et biophysica acta. Reviews on cancer 5 39551397
2023 Issues with RNF43 antibodies to reliably detect intracellular location. PloS one 5 37023034
2024 Loss of ZNRF3/RNF43 Unleashes EGFR in Cancer. bioRxiv : the preprint server for biology 4 38260423
2024 Germline pathogenic variants in RNF43 in patients with and without serrated polyposis syndrome. Familial cancer 4 39546056
2023 RNF43 Suppressed Triple-Negative Breast Cancer Progression by Inhibiting Wnt/beta-Catenin Pathway. Annals of clinical and laboratory science 4 36889779
2023 RNF43 is associated with genomic features and clinical outcome in BRAF mutant colorectal cancer. Frontiers in oncology 4 37409251
2015 The ubiquitin ligase RNF43 downregulation increases membrane expression of frizzled receptor in pancreatic ductal adenocarcinoma. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 4 26240024
2024 RNF43 in cancer: Molecular understanding and clinical significance in immunotherapy. The journal of gene medicine 3 39146560
2022 Exome sequencing revealed comparable frequencies of RNF43 and BRAF mutations in Middle Eastern colorectal cancer. Scientific reports 3 35907983
2025 STT3A is essential for Wnt signaling and represents a target for cancers driven by RNF43 deficiency. Cell chemical biology 2 41130209
2024 Selective epigenetic alterations in RNF43 in pancreatic exocrine cells from high-fat-diet-induced obese mice; implications for pancreatic cancer. BMC research notes 2 38622664
2023 PD-L1 expression downregulation by RNF43 in gastric carcinoma enhances antitumour activity of T cells. Scandinavian journal of immunology 2 39007965
2026 Loss of ZNRF3/RNF43 unleashes EGFR in cancer. eLife 1 41960900
2023 The fusion gene hsf5-rnf43 in Nile tilapia: A potential regulator in the maintenance of testis function and sexual differentiation. iScience 1 38026183