Affinage

RNF43

E3 ubiquitin-protein ligase RNF43 · UniProt Q68DV7

Length
783 aa
Mass
85.7 kDa
Annotated
2026-06-10
100 papers in source corpus 39 papers cited in narrative 39 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RNF43 is a transmembrane RING-type E3 ubiquitin ligase that operates as a negative-feedback brake on Wnt signaling, limiting the abundance of Wnt receptors at the cell surface (PMID:22895187, PMID:23847203). It ubiquitinates Frizzled receptors and targets them for lysosomal degradation, with member-selective preference for FZD1/5/7 dictated by its transmembrane domain (PMID:22895187, PMID:38969364); receptor engagement is mediated by Dishevelled, which acts as an adaptor recruiting RNF43 to Frizzled/LRP6 and is required for receptor downregulation (PMID:25891077, PMID:25825523). Catalytic activity is gated by phosphorylation of a conserved serine triplet, and cancer mutations that abolish this phospho-switch eliminate Wnt-inhibitory function while sparing other activities (PMID:32934222). RNF43 is itself a direct transcriptional target of the TCF4/β-catenin complex, closing a negative feedback loop (PMID:24466159). This braking activity is neutralized when R-spondin ligands clamp into a groove on the RNF43 ectodomain and bridge it to LGR4 in a ternary complex, with LGR4 (not LGR5) supplying high-affinity RSPO recruitment; the protease-associated (PA) domain mediates this R-spondin sensitivity but is dispensable for Wnt suppression itself (PMID:24225776, PMID:23756651, PMID:32527265, PMID:37402772). The RSPO–LGR–RNF43/ZNRF3 module governs stem-cell Wnt responsiveness and tissue homeostasis: loss of RNF43 (with ZNRF3) expands Wnt signaling to drive intestinal and hepatic tumorigenesis and metabolic reprogramming, and RNF43 controls oligodendrocyte progenitor differentiation through Fzd1 (PMID:26023187, PMID:34129813, PMID:34390652, PMID:35039505). Inactivating RNF43 mutations raise surface Frizzled and render tumors dependent on paracrine Wnt, conferring sensitivity to Porcupine inhibitors and an acquired requirement for FZD5 (PMID:23847203, PMID:26023187, PMID:27869803, PMID:33067269). Distinct truncating mutations are not simple null alleles: certain C-terminal truncations retain receptor downregulation but trap Casein kinase 1 at the membrane to block β-catenin turnover, while RING-domain and some extracellular missense mutants hyperactivate Wnt by forming inactive dimers with endogenous RNF43/ZNRF3 (PMID:32965059, PMID:33067269). Beyond canonical Wnt, RNF43 suppresses noncanonical WNT5A signaling by ubiquitinating VANGL2 and internalizing ROR1/ROR2 (PMID:34702444), and additional substrates including B-RAF have been reported (PMID:38225722).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2008 Medium

    Before its Wnt role was known, RNF43 was established as a bona fide E3 ligase capable of autoubiquitylation, fixing its biochemical identity as a RING enzyme.

    Evidence Cell-free autoubiquitylation assay plus fractionation and yeast two-hybrid interaction screening

    PMID:18313049

    Open questions at the time
    • No physiological substrate identified at this stage
    • Reported ER/nuclear-envelope localization later challenged as antibody artifact
  2. 2012 High

    Defined RNF43's core function: it ubiquitinates surface Frizzled receptors to route them to lysosomes and dampen Wnt signaling, with reconstitution in mutant cells restoring Wnt sensitivity.

    Evidence Overexpression/reconstitution in HEK293T and HCT116, ubiquitination and lysosomal trafficking assays, conditional mouse intestinal knockout

    PMID:22895187

    Open questions at the time
    • Did not resolve receptor selectivity among FZD members
    • Adaptor and recruitment mechanism unknown
  3. 2013 High

    Connected RNF43 loss to cancer dependency, showing inactivating mutations raise surface Frizzled and create selective addiction to upstream Wnt that is druggable with Porcupine inhibitors.

    Evidence Loss-of-function and reconstitution in pancreatic cancer lines, surface-Frizzled measurement, xenografts, LGK974 sensitivity

    PMID:23847203

    Open questions at the time
    • Mechanism distinguishing mutant classes not addressed
    • Did not identify the specific FZD required
  4. 2013 High

    Structurally defined how R-spondin inhibits RNF43, showing R-spondin clamps the RNF43 ectodomain and bridges it to LGR4/5 in a ternary complex.

    Evidence X-ray crystallography of RNF43 ectodomain with R-spondin and of the ternary RSPO1-LGR5-RNF43 complex, with disease-mutation mapping

    PMID:23756651 PMID:24225776

    Open questions at the time
    • Did not establish how complex formation translates to reduced ligase activity in cells
    • LGR4 vs LGR5 functional asymmetry not yet quantified
  5. 2014 Medium

    Established the regulatory architecture: RNF43 is itself a Wnt/β-catenin transcriptional target, defining a self-limiting negative feedback loop neutralized by RSPO/LGR.

    Evidence Reporter assays with WRE mutagenesis, β-catenin knockdown and ChIP; review synthesis of epistasis and binding data

    PMID:24466159 PMID:24532711

    Open questions at the time
    • Feedback kinetics in vivo not quantified
    • Cell-type specificity of WRE usage unexplored
  6. 2015 High

    Identified Dishevelled as the obligate adaptor recruiting RNF43 to Wnt receptors, and dissected separable extracellular/RING and cytoplasmic determinants for canonical versus noncanonical suppression.

    Evidence DVL knockout, reciprocal co-IP, domain mapping and rescue; domain-deletion/localization and Wnt reporter assays

    PMID:25825523 PMID:25891077

    Open questions at the time
    • How DVL DEP/PDZ engagement is regulated remains open
    • Relative contribution of canonical vs noncanonical arms in vivo unresolved
  7. 2015 High

    In vivo genetics tied RNF43/ZNRF3 loss to paracrine-Wnt-driven tumor growth, demonstrating Paneth-cell Wnt3 and Porcupine activity as the actionable dependency.

    Evidence Math1 and Wnt3 deletions in Rnf43/Znrf3 DKO mice, Porcupine inhibitor C59 treatment

    PMID:26023187

    Open questions at the time
    • Source-cell dependency may differ in other tissues
    • Did not address mutant-specific signaling outputs
  8. 2016 High

    Pinpointed FZD5 as the specific receptor required by RNF43-mutant pancreatic cancer, nominating a precise antibody target.

    Evidence Genome-wide CRISPR screen, anti-FZD5/8 antibodies, in vitro growth, xenografts, patient-derived organoids

    PMID:27869803

    Open questions at the time
    • Molecular basis of FZD5 selectivity not yet defined
    • Generality across other RNF43-mutant tissues untested
  9. 2016 High

    Extended the receptor module to physiology, showing the RSPO-LGR-ZNRF3/RNF43 axis sets the hepatic Wnt gradient controlling metabolic liver zonation and regeneration.

    Evidence Liver-specific conditional knockouts, recombinant RSPO1, LGR4/5 loss-of-function, size and regeneration readouts

    PMID:27088858

    Open questions at the time
    • Did not separate RNF43 from ZNRF3 contributions
    • Downstream metabolic effectors not defined
  10. 2020 High

    Resolved that distinct mutation classes act through different mechanisms: a phospho-switch licenses ligase activity, C-terminal truncations trap CK1 to drive ligand-independent Wnt, and systematic profiling separated dominant-negative dimerizing mutants from loss-of-function truncations.

    Evidence Serine-triplet mutagenesis with zebrafish/organoid models; CRISPR knock-in of patient truncations with CK1 co-IP and organoid assays; systematic functional assay of 164 patient mutations

    PMID:32527265 PMID:32934222 PMID:32965059 PMID:33067269

    Open questions at the time
    • Reports conflict on whether specific C-terminal truncations are loss-of-function or retain activity (contrast with PMID 32103169)
    • Kinase responsible for the serine-triplet phospho-switch not identified
  11. 2021 High

    Broadened the substrate and regulatory landscape: USP42 stabilizes RNF43/ZNRF3 at the membrane, RNF43/ZNRF3 cooperate to restrain hepatic Wnt and lipid metabolism, RNF43 suppresses noncanonical WNT5A signaling via VANGL2/ROR ubiquitination and internalization, and it tunes OPC differentiation through Fzd1.

    Evidence Co-IP/deubiquitination assays; hepatocyte conditional double-KO with scRNA-seq; BioID, ubiquitination and internalization assays in melanoma; conditional Rnf43 KO in OPCs with injury models

    PMID:33786993 PMID:34129813 PMID:34390652 PMID:34702444

    Open questions at the time
    • Tissue-specific balance between canonical and noncanonical roles unclear
    • Whether noncanonical substrates are targeted in non-melanoma contexts untested
  12. 2024 Medium

    Defined the molecular determinant of receptor selectivity and Wnt-stimulated targeting, and added new substrates linking RNF43 to RAS-MAPK signaling.

    Evidence TMD domain-swap endocytosis assays for multiple FZD members; Wnt-stimulated FZD5/8 degradation assays with KO validation; B-RAF co-IP, K499/T491 mutagenesis and combination drug studies

    PMID:38225722 PMID:38969364 PMID:41070826

    Open questions at the time
    • B-RAF as substrate from a single lab without independent confirmation
    • How Wnt ligand promotes the FZD5-RNF43 interaction mechanistically unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved which of RNF43's many reported non-Wnt substrates (p53, E-cadherin, PAR2, PD-L1, NDUFS1, EGFR, p85) represent core physiological functions versus context-restricted or unconfirmed activities, and what the validated subcellular localization is given antibody-artifact concerns.
  • E-cadherin substrate claim contradicted by an independent study
  • Prior nuclear localization shown to be antibody artifact
  • Several substrates rest on single Co-IP without reciprocal or in vivo validation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 4 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 2 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3 R-HSA-9609507 Protein localization 3 R-HSA-1266738 Developmental Biology 2
Partners
CSNK1DVLFZD5LGR4ROR1RSPO1USP42VANGL2
Complex memberships
RSPO-LGR4/5-RNF43/ZNRF3 ternary complex

Evidence

Reading pass · 39 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 (FZD) receptors on the cell surface, targeting them for lysosomal degradation and thereby reducing Wnt signaling. Expression of RNF43 in HEK293T cells blocks Wnt responses and targets surface-expressed frizzled receptors to lysosomes; reconstitution of RNF43 in RNF43-mutant HCT116 cells removes their response to exogenous Wnt. Overexpression and reconstitution in cell lines, ubiquitination assays, lysosomal trafficking assays, mouse intestinal epithelium conditional knockout Nature High 22895187
2013 RNF43 inhibits Wnt/β-catenin signaling by reducing the membrane level of Frizzled in pancreatic cancer cells, serving as a negative feedback mechanism. Inactivating mutations in RNF43 increase cell-surface Frizzled and render pancreatic cancer cells dependent on autocrine/paracrine Wnt signaling, demonstrated by sensitivity to the Porcupine inhibitor LGK974 selectively in RNF43-mutant lines. Loss-of-function cell culture assays, cell-surface Frizzled measurement, wild-type RNF43 reconstitution, xenograft models, pharmacological Wnt inhibition Proceedings of the National Academy of Sciences of the United States of America High 23847203
2013 Crystal structure of the RNF43 ectodomain in complex with R-spondin 2 (Rspo2 Fu1-Fu2 fragment) reveals that a prominent loop in the Fu1 domain of Rspo2 clamps into a groove on the RNF43 ectodomain surface, forming a ternary complex with LGR4/5. LGR5 does not directly contact RNF43 but increases RSPO1 affinity for RNF43, supporting LGR5 as an engagement receptor and RNF43 as an effector receptor. X-ray crystallography, biophysical binding assays, mutational analysis Nature communications High 24225776
2013 Crystal structure of RSPO1 bound simultaneously to both LGR5 and RNF43 ectodomains confirms physical linkage; RSPO1 is sandwiched by LGR5 and RNF43, with its CRD rod module contacting LGR5 and a hairpin inserted into the RNF43 ectodomain groove. Disease mutations map to the RSPO1-RNF43 interface. X-ray crystallography of ternary RSPO1-LGR5-RNF43 complex Genes & development High 23756651
2014 RNF43 (and ZNRF3) are encoded by Wnt target genes and constitute a negative Wnt feedback loop; the LGR5/R-spondin complex neutralizes RNF43/ZNRF3 activity, thereby amplifying Wnt signaling in stem cells. This module controls removal of Wnt receptors from the stem cell surface. Review integrating genetic epistasis and binding studies (mechanistic synthesis of prior experimental work) Genes & development Medium 24532711
2014 RNF43 expression is directly regulated by the canonical Wnt/β-catenin pathway via two Wnt-responsive elements (WREs) in intron 2 that associate with the TCF4/β-catenin complex, establishing RNF43 as a direct transcriptional target of TCF4/β-catenin and part of a negative feedback loop. Reporter gene assay with WRE mutagenesis, siRNA knockdown of β-catenin, chromatin immunoprecipitation (ChIP) PloS one Medium 24466159
2015 Dishevelled (DVL) acts as a dual-function adaptor that recruits RNF43/ZNRF3 to Wnt receptors. DVL knockout increases cell-surface FZD and LRP6; DVL is required for RNF43/ZNRF3-mediated ubiquitination and degradation of FZD. Physical interaction between DVL and ZNRF3/RNF43 is essential for their Wnt-inhibitory activity, and the DEP domain of DVL is required for FZD binding and downregulation. DVL knockout cells, co-immunoprecipitation, ubiquitination assays, domain fusion rescue experiments Molecular cell High 25891077
2015 RNF43 suppresses both Wnt/β-catenin (canonical) and noncanonical Wnt signaling by distinct mechanisms. Canonical suppression requires interaction between the extracellular PA domain of RNF43 and the CRD of Frizzled, plus the intracellular RING domain. Noncanonical suppression requires the C-terminal cytoplasmic region of RNF43 interacting with the PDZ domain of Dishevelled. Missense mutations in the extracellular domain change RNF43 localization from endosome to ER, abolishing canonical but not noncanonical Wnt suppression. Domain deletion/mutation analysis, co-immunoprecipitation, immunofluorescence localization, Wnt reporter assays Molecular and cellular biology High 25825523
2015 RNF43 physically interacts with TCF4 in the nucleus and tethers TCF4 to the nuclear membrane, silencing TCF4 transcriptional activity even in the presence of constitutively active β-catenin mutants. This nuclear inhibitory mechanism is disrupted by tumor-associated RNF43 mutations, and RING domain mutation of RNF43 transactivates Wnt target genes in cells and Xenopus embryos. Co-immunoprecipitation, immunofluorescence (nuclear localization), TCF4 transcriptional reporter assays, Xenopus embryo functional assays, RNF43 RING domain mutagenesis Science signaling Medium 26350900
2015 Paracrine Wnt3 secretion from Paneth cells is an essential driver of Rnf43/Znrf3-double-knockout intestinal tumor growth; removal of Paneth cells by Math1 mutation or deletion of Wnt3 inhibits tumor formation. Treatment with the Porcupine inhibitor C59 strongly inhibits RZ−/− neoplasia growth while sparing adjacent normal crypts. Genetic epistasis (Math1 KO, Wnt3 KO in Rnf43/Znrf3 DKO mice), pharmacological Porcupine inhibitor treatment in vivo Proceedings of the National Academy of Sciences of the United States of America High 26023187
2008 RNF43 protein resides in the endoplasmic reticulum and at least partially in the nuclear envelope/inner nuclear membrane. Recombinant RNF43 has autoubiquitylation activity in a cell-free system. RNF43 interacts with HAP95 (a chromatin-associated nuclear envelope protein) by yeast two-hybrid and co-immunoprecipitation, but HAP95 is not a ubiquitination substrate of RNF43. Immunofluorescence, biochemical fractionation, sucrose density gradient, cell-free autoubiquitylation assay, yeast two-hybrid, co-immunoprecipitation Experimental cell research Medium 18313049
2008 RNF43 physically interacts with the PSF/p54nrb heterodimer (nuclear RNA-binding proteins); co-expression of PSF relocates RNF43 from the nuclear periphery to the nucleoplasm. Pull-down assay with mass spectrometry identification, co-immunoprecipitation, immunofluorescence Proteomics Low 18655028
2010 RNF43 interacts with NEDL1 (a p53-activating E3 ligase) and with p53 itself; RNF43 suppresses p53 transcriptional activity in H1299 cells and attenuates UV-induced apoptosis. Yeast two-hybrid screening, co-immunoprecipitation, p53 transcriptional reporter assay, apoptosis assay after UV irradiation Biochemical and biophysical research communications Medium 21108931
2015 RNF43 promotes growth of colorectal cancer cells in an autocrine manner; the RNF43 protein is secreted and conditioned medium from RNF43-transfected cells enhances NIH3T3 cell growth. Exogenous RNF43 expression confers growth-promoting effects; suppression by siRNA retards colon cancer cell growth. Overexpression in COS7 and NIH3T3 cells, conditioned medium assay, siRNA knockdown, growth assays International journal of oncology Low 15492824
2015 The nucleoprotein (NP) of influenza A virus (IAV) interacts with RNF43 (identified by yeast two-hybrid). IAV infection attenuates RNF43 transcript and protein levels; RNF43-depleted cells show escalated viral replication. RNF43 polyubiquitinates p53, leading to p53 destabilization. NP of IAV targets RNF43 to prevent p53 ubiquitination, causing p53 stabilization and enhanced apoptosis. Yeast two-hybrid, RNF43 depletion (viral replication assay), ubiquitination assay of p53, viral infection models Cell death & disease Low 25996295
2016 The RSPO-LGR4/5-ZNRF3/RNF43 module controls Wnt/β-catenin-mediated metabolic liver zonation and hepatic growth. Liver-specific ZNRF3/RNF43 loss-of-function expands the hepatic Wnt/β-catenin signaling gradient; RSPO1 increases liver size and improves regeneration in an LGR4/5-dependent manner. Liver-specific conditional knockout mice, recombinant RSPO1 treatment, LGR4/5 LOF, liver size and regeneration readouts Nature cell biology High 27088858
2016 Genome-wide CRISPR-Cas9 screens in RNF43-mutant pancreatic cancer cells identify a specific requirement for the Wnt receptor FZD5 for proliferation. Antibodies against FZD5 (and FZD8) inhibit growth of RNF43-mutant PDAC in vitro and as xenografts. This specificity could not be explained by FZD5 expression patterns alone. Genome-wide CRISPR-Cas9 screen, recombinant anti-FZD antibodies, in vitro growth assays, xenograft models, patient-derived organoids Nature medicine High 27869803
2019 RNF43 ubiquitinates E-cadherin phosphorylated at tyrosine 797 by c-Src (at lysine 816), leading to E-cadherin degradation, nuclear β-catenin translocation and EMT in lung adenocarcinoma cells. This ubiquitination requires Frizzled 8 (FZD8) interaction with RNF43 but not the PA domain of RNF43. Protein antibody microarray, E3 ligase profiling, immunoprecipitation, immunoblotting, immunofluorescence, shRNA knockdown, xenograft models, site-directed mutagenesis of E-cadherin phosphorylation and ubiquitination sites BMC cancer Medium 31286874
2019 RNF43 C-terminal truncation mutants (including G659fs), when expressed at endogenous levels via CRISPR knock-in, retain the ability to suppress β-catenin signaling and Wnt-receptor turnover equivalently to wild-type RNF43, and retain DVL-binding. Only N-terminal RNF43 mutations convey Wnt-dependency onto cancer cells. (NOTE: this finding partially contradicts other studies that report C-terminal truncations as loss-of-function.) CRISPR-Cas9 endogenous knock-in/knockout in HEK293T and KM12 cells, β-catenin reporter assay, Wnt-receptor surface flow cytometry, co-immunoprecipitation Oncogene Medium 32103169
2020 RNF43 activity requires phosphorylation at a conserved triplet of serines (phospho-switch). This phospho-regulation is required for zebrafish development and mouse intestinal organoid growth. Cancer-associated mutations that abrogate RNF43 phosphorylation cooperate with active Ras to promote tumorigenesis by abolishing Wnt-inhibitory function of RNF43 while maintaining p53-inhibitory function. Phosphomimetic substitutions of the serine trio restore tumor-suppressive activity of extracellular oncogenic mutants. Site-directed mutagenesis of serine phosphosites, phosphomimetic substitutions, zebrafish developmental assays, mouse intestinal organoids, co-expression with active Ras, Wnt reporter assays Nature communications High 32934222
2020 A class of RNF43 truncating cancer mutations (C-terminal truncations) retains Wnt receptor downregulation activity but interferes with a ubiquitin-independent suppressor role of the RNF43 cytosolic tail involving Casein kinase 1 (CK1) binding and phosphorylation. Truncated RNF43 variants trap CK1 at the plasma membrane, preventing β-catenin turnover and driving ligand-independent Wnt/β-catenin transcription. Gene editing in human colon stem cells shows these truncations cooperate with p53 loss for niche-independent self-renewal. CRISPR gene editing of patient-derived mutations, CK1 co-immunoprecipitation, phosphorylation assays, β-catenin reporter assays, PORCN inhibitor sensitivity assays, human colon organoids The EMBO journal High 32965059
2020 Systematic functional assay of 119 missense and 45 truncating patient-derived RNF43 mutations reveals: RING domain missense mutations and a subset of extracellular domain mutations hyperactivate Wnt/β-catenin by forming inactive dimers with endogenous RNF43 or ZNRF3. C-terminal truncation mutants (including G659fs) are loss-of-function at endogenous levels, increase cell-surface Frizzled and Wnt/β-catenin signaling, and render xenografts responsive to PORCN inhibition. Cell-based reporter assays, genome editing, flow cytometry for surface Frizzled, immunofluorescence, patient-derived xenografts and cell lines Cancer research High 33067269
2021 USP42 deubiquitinase antagonizes R-spondin by protecting ZNRF3/RNF43 from ubiquitin-dependent membrane clearance. USP42 binds to the Dishevelled interacting region (DIR) of ZNRF3 and stalls the R-spondin-LGR4-ZNRF3 ternary complex by deubiquitinating ZNRF3, increasing LRP6 and FZD turnover and inhibiting Wnt signaling. Co-immunoprecipitation, ubiquitination assays, deubiquitination assays, Wnt reporter assays, colon cancer cells and mouse small intestinal organoids EMBO reports Medium 33786993
2021 ZNRF3 deletion alone promotes hepatocyte proliferation, which becomes limited by compensatory RNF43 upregulation. Concomitant deletion of both ZNRF3 and RNF43 in hepatocytes results in metabolic reprogramming of periportal hepatocytes, clonal expansion, and liver tumor development, demonstrating cooperative roles of the two ligases in restricting WNT/β-catenin activity to balance metabolic function and proliferation. Hepatocyte-specific conditional double knockout mice (ZNRF3 and RNF43), single-cell RNA sequencing, organoid culture, chromatin accessibility analysis Cell stem cell High 34129813
2021 RNF43 is a negative regulator of noncanonical WNT5A signaling. RNF43 interacts with noncanonical Wnt receptor complex components ROR1, ROR2, VANGL1, and VANGL2 (identified by BioID and immunoprecipitation). RNF43 triggers VANGL2 ubiquitination and proteasomal degradation and induces clathrin-dependent internalization of ROR1 receptor and inhibits ROR2 activation, thereby blocking pro-metastatic WNT5A signaling in melanoma. BioID proximity labeling, co-immunoprecipitation, ubiquitination assays, receptor internalization assays, in vitro and in vivo invasion assays, BRAF/MEK inhibitor resistance models eLife High 34702444
2021 Rnf43 (but not Znrf3) is potently activated by Wnt signaling in oligodendrocyte progenitor cells (OPCs) and promotes OPC differentiation specifically in injury contexts by negatively regulating Wnt signal strength at the level of Fzd1 receptor presentation on the OPC cell surface. Inhibition of Fzd1 using UM206 promotes remyelination following demyelinating injury. Conditional Rnf43 knockout in OPCs, neonatal hypoxic injury and adult demyelination models, Fzd1 inhibition, in vivo and ex vivo remyelination assays Neuron High 34390652
2022 RNF43_p.G659fs promotes cancer cell growth independent of Wnt signaling. RNF43-G659fs mutant binds the PI3K regulatory subunit p85, leading to increased PI3K signaling through p85 ubiquitination and degradation. PI3K/mTOR inhibitors selectively kill RNF43-G659fs cells in isogenic lines and xenografts, and reduce interferon response gene expression which is reversed by PI3K/mTOR inhibition. Drug repurposing library screen, isogenic cell lines, co-immunoprecipitation (G659fs:p85 interaction), ubiquitination assay, xenograft models, patient-derived organoids, RNA-seq Nature communications Medium 35676246
2022 RNF43/ZNRF3 hepatocyte-specific double knockout results in steatohepatitis, accumulation of unsaturated lipids, defective hepatocyte regeneration upon injury, and liver cancer development. Differentiation defects and lipid alterations are, in part, cell-autonomous, demonstrated by hepatocyte-, hepatoblast-, and ductal cell-derived organoids. Hepatocyte-specific conditional Rnf43/Znrf3 double KO mice, organoid cultures from multiple liver cell types, lipidomic analysis Nature communications High 35039505
2023 RNF43 is a negative feedback regulator of PAR2 (protease-activated receptor 2, a GPCR): RNF43 co-associates with PAR2 and promotes its membrane elimination and polyubiquitination, reducing PAR2-induced β-catenin signaling. This degradation is rescued by R-spondin2 in the presence of LGR5. Co-immunoprecipitation, cell-surface biotinylation assay, polyubiquitination assay, β-catenin reporter assays, mouse AOM/DSS colon cancer model with Par2 KO FASEB journal Medium 36468684
2023 RNF43 directly interacts with γH2AX (phosphorylated H2AX) and its loss impairs DNA damage response (DDR) activation in gastric cells, conferring resistance to γ-radiation and chemotherapy by dampening DDR and preventing apoptosis. Co-immunoprecipitation (RNF43:γH2AX), RNF43 depletion, γ-radiation and chemotherapy sensitivity assays, Helicobacter pylori infection in Rnf43ΔEx8 mice Cellular and molecular gastroenterology and hepatology Medium 33188943
2024 RNF43 preferentially targets FZD1, FZD5, and FZD7 for endocytosis, while the related ZNRF3 preferentially targets FZD6. The RNF43 transmembrane domain (TMD) is a key molecular determinant for FZD5 endocytosis specificity; swapping the TMD between RNF43 and ZNRF3 redirects their FZD preferences. Endocytosis assays comparing RNF43 vs. ZNRF3 for each FZD, TMD domain-swap mutagenesis, flow cytometry for surface FZD levels Life science alliance High 38969364
2024 RNF43 ubiquitinates B-RAF at K499 to promote proteasome-dependent B-RAF degradation, reducing MEK activity and proliferative ability in cancer cells. Phosphorylation of B-RAF at T491 suppresses this ubiquitination by decreasing the RNF43:B-RAF interaction. MEK and Wnt inhibitors synergistically suppress growth of RNF43-mutated pancreatic cancer cells in vitro and in vivo. Co-immunoprecipitation (RNF43:B-RAF), ubiquitination assay, site-directed mutagenesis (K499, T491), MEK activity assays, xenograft models, combination drug studies Advanced science Medium 38225722
2024 ZNRF3 and RNF43 interact with EGFR via their extracellular domains, leading to EGFR ubiquitination and subsequent degradation via the RING E3 ligase domain. Overexpression of ZNRF3 reduces EGFR levels and suppresses cancer cell growth; knockout of ZNRF3/RNF43 upregulates EGFR signaling and promotes tumorigenesis. Biochemical co-immunoprecipitation (extracellular domain interaction), ubiquitination assay, ZNRF3 overexpression, ZNRF3/RNF43 double knockout, in vitro and in vivo tumor growth assays, proteogenomic correlation bioRxivpreprint Medium 38260423
2023 RNF43 interacts with PD-L1 in gastric cancer cells and augments both K48- and K63-linked ubiquitination of PD-L1, reducing PD-L1 surface expression and enhancing T cell antitumor activity. Co-immunoprecipitation (RNF43:PD-L1), ubiquitination assay (K48/K63 linkage-specific), flow cytometry for PD-L1 surface levels, T cell co-culture killing assay Scandinavian journal of immunology Low 39007965
2024 m6A methylation (mediated by METTL3/IGF2BP2 axis) regulates RNF43 mRNA stability. RNF43 protein directly interacts with and ubiquitinates NDUFS1 (NADH dehydrogenase Fe-S protein 1), promoting its proteasomal degradation and suppressing oxidative phosphorylation in endometrial stromal cells. m6A modification assay, METTL3/IGF2BP2 knockdown, co-immunoprecipitation (RNF43:NDUFS1), ubiquitination assay, NDUFS1 siRNA knockdown, cell viability/migration assays, rat endometriosis model Journal of cellular physiology Low 38988031
2020 The extracellular Protease Associated (PA) domain of RNF43 is not necessary for suppression of Wnt/β-catenin signaling. RNF43ΔPA mutant still inhibits LRP6 phosphorylation, DVL2/DVL3 phosphorylation, and β-catenin-dependent gene expression. RNF43ΔPA is not sensitive to R-spondin1 treatment, confirming that R-spondin inhibits RNF43 function through the PA domain. TetON controlled overexpression, CRISPR/Cas9 RNF43/ZNRF3 double KO rescue, Western blot, TOPflash dual luciferase assay Cell communication and signaling Medium 32527265
2023 Commercial RNF43 antibodies targeting exons 8-9 epitopes yield non-specific signals in immunoblotting, immunofluorescence, and immunohistochemistry; nuclear staining patterns attributed to RNF43 are antibody artifacts. Endogenous RNF43 localization to the nucleus (as reported in earlier studies) is not supported by validated antibody data. CRISPR deletion of RNF43 exons 8-9, immunoblotting, immunofluorescence, immunohistochemistry with knockout-validated negative controls for four commercial antibodies PloS one Medium 37023034
2025 Wnt ligands specifically induce FZD5/8 endocytosis and degradation in a ZNRF3/RNF43-dependent manner; ZNRF3/RNF43 selectively target FZD5/8 for Wnt-stimulated degradation. DVL proteins promote ligand-independent FZD endocytosis but are dispensable for Wnt-induced FZD5/8 degradation. Wnt promotes the interaction between FZD5 and RNF43. FZD endocytosis assays with Wnt stimulation, ZNRF3/RNF43 knockdown/knockout, DVL knockout, co-immunoprecipitation (FZD5:RNF43), receptor internalization fluorescence assays eLife Medium 41070826
2023 LGR4 (but not LGR5) forms a 2:2 complex with RNF43/ZNRF3 that accommodates bivalent RSPO binding, providing high-affinity RSPO recruitment. Co-expression of ZNRF3 with LGR4 dramatically increases monovalent RSPO2 binding affinity, whereas co-expression of ZNRF3 with LGR5 has no effect, explaining why only LGR4 mediates the RSPO-RNF43/ZNRF3 inhibitory complex. Whole-cell binding affinity measurements with monovalent and bivalent RSPO2 furin domains, co-expression of LGR4/5 with ZNRF3 in cells, structural modeling 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 793 22895187
2014 The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength. Genes & development 526 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 358 23847203
2016 The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size. Nature cell biology 269 27088858
2016 Genome-wide CRISPR screens reveal a Wnt-FZD5 signaling circuit as a druggable vulnerability of RNF43-mutant pancreatic tumors. Nature medicine 231 27869803
2013 Structural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin. Nature communications 166 24225776
2015 Dishevelled promotes Wnt receptor degradation through recruitment of ZNRF3/RNF43 E3 ubiquitin ligases. Molecular cell 165 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 146 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 141 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 136 21818642
2013 The structural basis of R-spondin recognition by LGR5 and RNF43. Genes & development 126 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 93 27661107
2016 KRAS, GNAS, and RNF43 mutations in intraductal papillary mucinous neoplasm of the pancreas: a meta-analysis. SpringerPlus 83 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 78 25825523
2015 The E3 ligase RNF43 inhibits Wnt signaling downstream of mutated β-catenin by sequestering TCF4 to the nuclear membrane. Science signaling 68 26350900
2021 ZNRF3 and RNF43 cooperate to safeguard metabolic liver zonation and hepatocyte proliferation. Cell stem cell 67 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 57 31811196
2015 The nucleoprotein of influenza A virus induces p53 signaling and apoptosis via attenuation of host ubiquitin ligase RNF43. Cell death & disease 56 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 53 34973294
2010 RNF43 interacts with NEDL1 and regulates p53-mediated transcription. Biochemical and biophysical research communications 53 21108931
2020 A phospho-switch controls RNF43-mediated degradation of Wnt receptors to suppress tumorigenesis. Nature communications 52 32934222
2004 A novel oncoprotein RNF43 functions in an autocrine manner in colorectal cancer. International journal of oncology 52 15492824
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 49 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 45 33067269
2021 USP42 protects ZNRF3/RNF43 from R-spondin-dependent clearance and inhibits Wnt signalling. EMBO reports 44 33786993
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
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 42 35676246
2020 Commonly observed RNF43 mutations retain functionality in attenuating Wnt/β-catenin signaling and unlikely confer Wnt-dependency onto colorectal cancers. Oncogene 40 32103169
2018 Impact of loss-of-function mutations at the RNF43 locus on colorectal cancer development and progression. The Journal of pathology 40 29756208
2022 The RSPO-LGR4/5-ZNRF3/RNF43 module in liver homeostasis, regeneration, and disease. Hepatology (Baltimore, Md.) 39 35006616
2021 Oligodendroglial ring finger protein Rnf43 is an essential injury-specific regulator of oligodendrocyte maturation. Neuron 39 34390652
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 39 27305845
2021 RNF43 inhibits WNT5A-driven signaling and suppresses melanoma invasion and resistance to the targeted therapy. eLife 37 34702444
2022 Characterization of RNF43 frameshift mutations that drive Wnt ligand- and R-spondin-dependent colon cancer. The Journal of pathology 34 35040131
2020 Loss of RNF43 Function Contributes to Gastric Carcinogenesis by Impairing DNA Damage Response. Cellular and molecular gastroenterology and hepatology 32 33188943
2023 RNF43 and ZNRF3 in Wnt Signaling - A Master Regulator at the Membrane. International journal of stem cells 30 37643759
2019 Loss of endogenous RNF43 function enhances proliferation and tumour growth of intestinal and gastric cells. Carcinogenesis 30 30380024
2020 RNF43 mutation is associated with aggressive tumor biology along with BRAF V600E mutation in right-sided colorectal cancer. Oncology reports 29 32236609
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 27 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 21 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
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 18 37402772
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 17 33569855
2021 Ub and Dub of RNF43/ZNRF3 in the WNT signalling pathway. EMBO reports 17 33938624
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
2018 RNF43 is mutated less frequently in Lynch Syndrome compared with sporadic microsatellite unstable colorectal cancers. Familial cancer 15 28573495
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 15 29293510
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
2024 E3 ligases RNF43 and ZNRF3 display differential specificity for endocytosis of Frizzled receptors. Life science alliance 13 38969364
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 13 36468684
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
2021 RNF43 overexpression attenuates the Wnt/β-catenin signalling pathway to suppress tumour progression in cholangiocarcinoma. Oncology letters 11 34733364
2024 m6A methylation of RNF43 inhibits the progression of endometriosis through regulating oxidative phosphorylation via NDUFS1. Journal of cellular physiology 10 38988031
2022 Deficient Rnf43 potentiates hyperactive Kras-mediated pancreatic preneoplasia initiation and malignant transformation. Animal models and experimental medicine 10 35229994
2022 RNF43 as a predictor of malignant transformation of pancreatic mucinous cystic neoplasm. Virchows Archiv : an international journal of pathology 9 35066614
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
2023 RNF43 mutation as a predictor of immunotherapeutic efficacy in colorectal cancer. American journal of cancer research 8 38058823
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
2024 New Target(s) for RNF43 Regulation: Implications for Therapeutic Strategies. International journal of molecular sciences 7 39125653
2023 Inherited BRCA1 and RNF43 pathogenic variants in a familial colorectal cancer type X family. Familial cancer 7 38063999
2023 RNF43 Suppressed Triple-Negative Breast Cancer Progression by Inhibiting Wnt/beta-Catenin Pathway. Annals of clinical and laboratory science 6 36889779
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 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 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
2025 STT3A is essential for Wnt signaling and represents a target for cancers driven by RNF43 deficiency. Cell chemical biology 3 41130209
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
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 The fusion gene hsf5-rnf43 in Nile tilapia: A potential regulator in the maintenance of testis function and sexual differentiation. iScience 2 38026183
2023 PD-L1 expression downregulation by RNF43 in gastric carcinoma enhances antitumour activity of T cells. Scandinavian journal of immunology 2 39007965
2025 Wnt induces FZD5/8 endocytosis and degradation and the involvement of RSPO-ZNRF3/RNF43 and DVL. eLife 1 41070826

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