Affinage

ZNRF3

E3 ubiquitin-protein ligase ZNRF3 · UniProt Q9ULT6

Length
936 aa
Mass
100.6 kDa
Annotated
2026-04-28
62 papers in source corpus 24 papers cited in narrative 24 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZNRF3 is a cell-surface transmembrane RING-domain E3 ubiquitin ligase that functions as a central negative regulator of Wnt/β-catenin signaling by selectively ubiquitinating and promoting lysosomal degradation of Wnt-engaged Frizzled receptors and LRP6, with preferential substrate specificity for FZD5/8 and FZD6 (PMID:22575959, PMID:38969364, PMID:41086253, PMID:41070826). ZNRF3 is recruited to its Frizzled substrates through the adaptor protein Dishevelled (DVL), whose DEP domain bridges FZD–ZNRF3 interaction upon Wnt stimulation; ZNRF3 activity is negatively regulated when R-spondin ligands bridge it to LGR4 in a 2:2:2 ternary complex that sequesters and auto-inactivates ZNRF3, as resolved by crystallography and cryo-EM (PMID:25891077, PMID:41034211, PMID:24225776). ZNRF3 membrane abundance is controlled by a phosphorylation rheostat on its '4Y' endocytic motif—MET kinase phosphorylation retains ZNRF3 at the surface while PTPRK dephosphorylation promotes internalization—and by USP42-mediated deubiquitination that counteracts R-spondin–induced clearance (PMID:34590584, PMID:31934854, PMID:33786993). Germline ZNRF3 variants cause domain-dependent neurodevelopmental disorders (RING-domain variants producing dominant-negative Wnt hyperactivation and macrocephaly; RSPO-binding-domain variants causing attenuated Wnt signaling and microcephaly), loss of ZNRF3 causes XY gonadal sex reversal through ectopic Wnt/β-catenin activation, and ZNRF3 exon 2 deletions cause congenital adrenal hypoplasia (PMID:39168120, PMID:29735715, PMID:37878959).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2012 High

    The fundamental question of how Wnt receptor abundance is actively regulated was answered: ZNRF3 was identified as a transmembrane E3 ligase that ubiquitinates FZD and LRP6 to drive their turnover, and R-spondin was shown to inhibit ZNRF3 by bridging it to LGR4 for membrane clearance.

    Evidence Co-immunoprecipitation, receptor ubiquitination assays, cell-surface turnover assays, and Xenopus loss-of-function

    PMID:22575959

    Open questions at the time
    • Catalytic mechanism and substrate specificity among FZD family members unknown
    • How ZNRF3 is recruited to FZD substrates was not established
    • Whether ZNRF3 targets non-Wnt receptor substrates remained unexplored
  2. 2013 High

    The structural basis for R-spondin–mediated ZNRF3 inhibition was resolved: crystal structures showed that RSPO Fu1 domain inserts into a groove on the ZNRF3 ectodomain while Fu2 engages LGR4/5, assembling a ternary complex that sequesters ZNRF3.

    Evidence X-ray crystallography of ZNRF3 ectodomain alone and in complex with RSPO1/RSPO2, biophysical binding assays, in vitro reconstitution of ternary complex, and functional mutagenesis

    PMID:24050775 PMID:24165923 PMID:24225776 PMID:24349440

    Open questions at the time
    • Full-length ternary complex structure not available
    • Stoichiometry of the complex in a membrane context was unresolved
    • Role of ZNRF3 dimerization in its catalytic cycle unknown
  3. 2015 High

    The question of how ZNRF3 reaches its FZD substrate was resolved: Dishevelled (DVL) was identified as an essential adaptor whose DEP domain bridges FZD to ZNRF3, and a ternary LGR5–RSPO2–ZNRF3 crystal structure confirmed a 2:2:2 stoichiometry.

    Evidence DVL triple-knockout cells, Co-IP, DEP-ZNRF3 fusion rescue experiments; X-ray crystallography of LGR5-Rspo2-ZNRF3 complex

    PMID:25891077 PMID:26123262

    Open questions at the time
    • Whether DVL requirement is universal across all FZD subtypes was untested
    • Structural basis of DVL–ZNRF3 interaction not determined
  4. 2018 High

    Two upstream regulatory layers of ZNRF3 were established: SCFβ-TRCP ubiquitinates and degrades ZNRF3 via the proteasome, and ZNRF3 loss in developing gonads causes XY sex reversal through ectopic Wnt/β-catenin signaling.

    Evidence Co-IP and ubiquitination assays with degron mutagenesis for β-TRCP; conditional knockout mouse with gonadal phenotyping and zebrafish functional assays for sex determination

    PMID:29497989 PMID:29735715

    Open questions at the time
    • Physiological contexts where β-TRCP–mediated ZNRF3 degradation is rate-limiting remain undefined
    • Whether ZNRF3 loss alone is sufficient for human DSD requires larger genetic studies
  5. 2019 High

    ZNRF3 was shown to be the dominant Wnt-restraining E3 ligase in the adrenal cortex: its loss caused Wnt-dependent adrenal hyperplasia that was reversed by reducing β-catenin dosage.

    Evidence Adrenocortical-specific conditional knockout, Porcupine inhibitor treatment, genetic β-catenin dosage reduction

    PMID:30692207

    Open questions at the time
    • Whether ZNRF3 and RNF43 have non-overlapping tissue-specific roles beyond adrenal cortex not systematically addressed
    • ZNRF3 substrates beyond FZD in adrenal cells not identified
  6. 2020 High

    A phosphorylation-based endocytic switch controlling ZNRF3 membrane residence was discovered: PTPRK dephosphorylates a '4Y' motif in ZNRF3 to promote its internalization, establishing that ZNRF3 activity is tuned by tyrosine phosphorylation state.

    Evidence Xenopus loss-of-function, phosphorylation site mutagenesis, endocytosis assays

    PMID:31934854

    Open questions at the time
    • The kinase responsible for 4Y phosphorylation was not yet identified
    • Whether the 4Y motif is regulated in all tissues or context-specific was unknown
  7. 2021 High

    A MET–PTPRK rheostat controlling ZNRF3 surface levels was defined, USP42 was identified as a deubiquitinase stabilizing ZNRF3 against R-spondin–induced clearance, and cooperative tumor suppression by ZNRF3 and RNF43 in the liver was demonstrated.

    Evidence MET kinase assays and pharmacological inhibition for MET-4Y axis; Co-IP and DUB assays in intestinal organoids for USP42; liver-specific double-knockout with scRNA-seq for tumor suppression

    PMID:33786993 PMID:34129813 PMID:34590584

    Open questions at the time
    • How MET–HGF signaling is integrated with R-spondin–LGR4 regulation of ZNRF3 in vivo is unresolved
    • USP42 regulation and whether other DUBs act on ZNRF3 are unknown
    • Mechanistic basis for RNF43 compensatory upregulation upon ZNRF3 loss is not defined
  8. 2023 Medium

    LGR4 was distinguished from LGR5 as the functional co-receptor for bivalent RSPO binding to ZNRF3, and synthetic peptides targeting the ZNRF3 ectodomain were shown to phenocopy R-spondin by inducing ZNRF3 clearance and organoid expansion.

    Evidence Whole-cell binding affinity assays comparing LGR4 vs LGR5; disulfide-constrained peptide binding assays with organoid growth readout

    PMID:37402772 PMID:38056465

    Open questions at the time
    • LGR4–ZNRF3 complex specificity mechanism at atomic level was not fully defined
    • In vivo efficacy and selectivity of synthetic ZNRF3-targeting peptides untested
  9. 2024 High

    Substrate specificity determinants were mapped—ZNRF3 preferentially targets FZD6 while RNF43 targets FZD1/5/7, governed by the transmembrane domain—and ZNRF3 was shown to ubiquitinate EGFR via its ectodomain, expanding its substrate repertoire beyond Wnt receptors.

    Evidence TMD-swap chimeras with FZD endocytosis assays; Co-IP and ubiquitination assays for EGFR interaction; knockout-based EGFR upregulation

    PMID:38969364 PMID:41960900

    Open questions at the time
    • Full FZD-family specificity map for ZNRF3 is incomplete
    • EGFR as ZNRF3 substrate requires independent replication and in vivo confirmation
    • Whether ZNRF3 targets additional RTKs is unexplored
  10. 2024 Medium

    Disease-associated ZNRF3 variants were functionally stratified: RING-domain missense variants cause dominant-negative Wnt hyperactivation and macrocephaly; RSPO-binding-domain variants cause attenuated Wnt signaling and microcephaly; and exon 2 deletions impair RSPO1 binding causing congenital adrenal hypoplasia. Endogenous knock-in studies showed that missense variants at physiological levels exhibit partial loss-of-function rather than true dominant-negative effects, with RSPO-domain variants undergoing ER-associated degradation.

    Evidence Wnt/β-catenin reporter assays with domain-specific variants, endogenous knock-in and protein stability assays, RT-PCR and cell-based TCF-LEF reporter for exon 2 deletion

    PMID:37878959 PMID:39168120 PMID:39674817

    Open questions at the time
    • In vivo neurodevelopmental phenotypes of specific variants not modeled in animals
    • Whether dominant-negative effects manifest at endogenous expression levels remains contested between studies
    • Genotype–phenotype correlations require larger patient cohorts
  11. 2025 High

    The longstanding model that ZNRF3 constitutively degrades FZD was revised: ZNRF3 selectively targets Wnt-engaged FZD, with Wnt stimulation enhancing FZD–DVL association to recruit ZNRF3, establishing ZNRF3 as a signal-dependent negative feedback mechanism rather than a constitutive turnover factor.

    Evidence Endogenous Wnt-dependent FZD degradation assays, Co-IP for WNT-enhanced FZD-DVL-ZNRF3 complex, DVL perturbation

    PMID:41070826 PMID:41086253

    Open questions at the time
    • Whether DVL-independent Wnt-induced FZD5/8 degradation pathway is ZNRF3-specific or shared with RNF43 needs clarification
    • How Wnt-engaged vs unengaged FZD are discriminated at the molecular level is unresolved
  12. 2025 High

    Cryo-EM resolved the full 2:2:2 LGR4–RSPO2–ZNRF3 ternary complex, showing ZNRF3 enclosed as a central dimer, providing the structural basis for how RSPO-mediated sequestration and forced dimerization auto-inactivate ZNRF3.

    Evidence Cryo-electron microscopy structure determination of human LGR4–RSPO2–ZNRF3 complex

    PMID:41034211

    Open questions at the time
    • Catalytic RING domain and intracellular region not resolved in the cryo-EM structure
    • How forced dimerization mechanistically inactivates E3 ligase activity is not demonstrated biochemically

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions remain: the structural basis of ZNRF3–DVL–FZD ternary recruitment, the complete FZD-family specificity map, the physiological significance of ZNRF3-mediated EGFR degradation, and how MET/PTPRK phosphorylation integrates with R-spondin–LGR4 regulation in tissue-specific stem cell niches.
  • No structure of ZNRF3 intracellular domain or ZNRF3–DVL complex
  • EGFR as ZNRF3 substrate not independently replicated
  • Tissue-specific integration of multiple ZNRF3 regulatory inputs not modeled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016874 ligase activity 3
Localization
GO:0005886 plasma membrane 5
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-392499 Metabolism of proteins 4 R-HSA-1266738 Developmental Biology 3
Partners
DVLEGFRLGR4METPTPRKRSPO1RSPO2USP42
Complex memberships
LGR4-RSPO-ZNRF3 ternary complex

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 ZNRF3 is a cell-surface transmembrane E3 ubiquitin ligase that promotes the ubiquitination and turnover of Wnt receptors Frizzled (FZD) and LRP6, thereby inhibiting Wnt signaling. R-spondin inhibits ZNRF3 by directly binding its extracellular domain and inducing association between ZNRF3 and LGR4, resulting in membrane clearance of ZNRF3. Co-immunoprecipitation, cell-surface receptor turnover assays, in vivo loss-of-function (Xenopus), receptor ubiquitination assays Nature High 22575959
2013 Crystal structures of the ZNRF3 ectodomain (ZNRF3ecto) alone and in complex with the Fu1-Fu2 fragment of Rspo2 reveal that a prominent loop in Rspo2 Fu1 clamps into a groove on the ZNRF3 ectodomain surface. Rspo binding enhances dimerization of ZNRF3ecto. Signaling potency of Rspo proteins depends on their ability to recruit ZNRF3 via Fu1 into a ternary complex with LGR receptors (which interact with Rspo via Fu2). X-ray crystallography, biophysical binding assays, cellular signaling assays, mutagenesis Nature communications High 24225776
2013 Crystal structure of the ZNRF3 ectodomain and its complex with R-spondin 1 shows ZNRF3 binds RSPO1 and LGR5-RSPO1 with micromolar affinity via the RSPO1 furin-like 1 (Fu1) domain. The ZNRF3-binding site overlaps with trans-interactions in 2:2 LGR5-RSPO1 complexes, suggesting ZNRF3/RNF43 compete for binding. X-ray crystallography, surface plasmon resonance/binding affinity measurements PloS one High 24349440
2013 Interaction of R-spondin with both ZNRF3 and LGR4 through distinct motifs is required for R-spondin-induced LGR4/ZNRF3 complex formation, ZNRF3 membrane clearance, and Wnt signaling activation. A ZNRF3 mutant with reduced R-spondin affinity is resistant to R-spondin-mediated inhibition, supporting a dual-receptor model where LGR4/5 are engagement receptors and ZNRF3/RNF43 are effector receptors. Mutagenesis, Co-immunoprecipitation, cell-surface clearance assays, Wnt signaling reporter assays EMBO reports High 24165923
2013 Recombinant RSPO:LGR4:ZNRF3 ternary complexes can be reconstituted in vitro with bacterially produced proteins. RSPOs weakly bind ZNRF3 ECD, and RSPO2/3 form detectable ternary complexes with LGR4 and ZNRF3. The LGR4 ECD and ZNRF3 ECD inhibit RSPO-enhanced Wnt signaling in cell-based assays. In vitro reconstitution, TR-FRET binding assay, native gel electrophoretic mobility shift assay, cell-based signaling assay Biochemistry High 24050775
2015 Dishevelled (DVL) acts as a dual-function adaptor that recruits ZNRF3/RNF43 to Wnt receptors: DVL knockout cells show increased cell-surface FZD and LRP6; DVL is required for ZNRF3/RNF43-mediated ubiquitination and degradation of FZD; physical interaction with DVL (via the DEP domain binding FZD) is essential for Wnt-inhibitory activity of ZNRF3/RNF43; fusing the DEP domain to ZNRF3 overcomes DVL dependency. DVL knockout, Co-immunoprecipitation, ubiquitination assays, domain fusion experiments, cell-surface receptor assays Molecular cell High 25891077
2015 Crystal structure of human LGR5 ectodomain complexed with mouse Rspo2 Fu1-Fu2, and a low-resolution ternary LGR5-Rspo2-ZNRF3 ectodomain complex structure, confirms that Rspo proteins cross-link LGR4/5 and ZNRF3 into a 2:2:2 complex (versus 1:1:1 with RNF43). X-ray crystallography, ternary complex structure determination Journal of structural biology High 26123262
2018 SCFβ-TRCP E3 ubiquitin ligase directly interacts with and ubiquitinates ZNRF3, promoting its proteasomal degradation in a CKI-phosphorylation- and degron-dependent manner (analogous to β-catenin degradation by β-TRCP), thereby positively regulating Wnt signaling by removing the negative regulator ZNRF3. Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, degron mutagenesis Protein & cell Medium 29497989
2018 ZNRF3 is required for mammalian sex determination: XY mice lacking ZNRF3 exhibit complete or partial gonadal sex reversal associated with ectopic WNT/β-catenin activity and reduced Sox9 expression during fetal sex determination. Human ZNRF3 missense variants disrupt ZNRF3 activity in cell lines and zebrafish assays. Conditional knockout mouse, Wnt reporter assays, zebrafish functional assay, exome sequencing of DSD patients Proceedings of the National Academy of Sciences of the United States of America High 29735715
2019 Adrenocortical-specific loss of ZNRF3 (but not RNF43) causes adrenal hyperplasia dependent on Porcupine-mediated Wnt ligand secretion, and disrupts a Wnt/β-catenin signaling gradient in the adrenal cortex. ZNRF3 loss triggers moderate-level β-catenin activation that drives proliferative expansion of the inner cortex. Genetically reducing β-catenin dosage significantly reverses this phenotype. Tissue-specific conditional knockout, Porcupine inhibitor, genetic epistasis (β-catenin dosage reduction), Wnt reporter assays Genes & development High 30692207
2020 The tumor suppressor PTPRK (protein tyrosine phosphatase receptor-type kappa) dephosphorylates a '4Y' endocytic tyrosine motif in ZNRF3, keeping it unphosphorylated and thereby promoting ZNRF3 internalization and Wnt receptor degradation. PTPRK deficiency in Xenopus increases Wnt signaling and causes head/axial defects. Xenopus loss-of-function, phosphorylation site mutagenesis (4Y motif), endocytosis assays, Wnt reporter assays, identification of endocytic signal eLife High 31934854
2021 MET proto-oncogene (receptor tyrosine kinase) binds to ZNRF3 and phosphorylates its '4Y' endocytic motif in response to HGF stimulation, thereby reducing ZNRF3 internalization and ZNRF3-dependent Wnt receptor degradation, and enhancing Wnt/β-catenin signaling. PTPRK dephosphorylates this same motif, establishing a MET-PTPRK rheostat controlling ZNRF3 activity. Co-immunoprecipitation, kinase assay (MET phosphorylation of 4Y motif), pharmacological MET inhibition, ZNRF3 internalization assay, Wnt reporter assay eLife High 34590584
2021 The deubiquitinase USP42 binds to the Dishevelled-interacting region (DIR) of ZNRF3 and deubiquitinates ZNRF3, protecting it from R-spondin-LGR4-induced ubiquitin-dependent membrane clearance. USP42 thereby maintains ZNRF3 at the plasma membrane, promotes FZD and LRP6 turnover, and inhibits Wnt signaling. Co-immunoprecipitation, deubiquitination assay, cell-surface clearance assay, Wnt reporter assay, intestinal organoids EMBO reports High 33786993
2021 ZNRF3 deletion promotes hepatocyte proliferation; subsequent RNF43 upregulation limits this proliferation. Concomitant deletion of both ZNRF3 and RNF43 results in metabolic reprogramming of periportal hepatocytes, clonal expansion, and liver tumor formation, demonstrating cooperative roles of ZNRF3 and RNF43 in spatially and temporally restricting WNT/β-catenin activity in the liver. Liver-specific conditional knockout (ZNRF3 alone and ZNRF3/RNF43 double KO), scRNA-seq, chromatin accessibility, organoid studies Cell stem cell High 34129813
2023 LGR4 (but not LGR5) forms a complex with RNF43/ZNRF3 to provide high-affinity bivalent binding of R-spondin ligands. LGR4 and ZNRF3 form a 2:2 dimer accommodating bivalent RSPO binding, whereas LGR5 forms a homodimer incompatible with ZNRF3 co-complex formation. Whole-cell binding affinity assays (monovalent vs bivalent RSPO), co-expression of receptors, LGR4/LGR5 comparison Scientific reports Medium 37402772
2024 RNF43 and ZNRF3 display differential substrate specificity for Frizzled receptors: RNF43 preferentially down-regulates FZD1/FZD5/FZD7 whereas ZNRF3 preferentially targets FZD6. The transmembrane domain (TMD) of RNF43 is a key molecular determinant for FZD5 endocytosis; swapping the TMD between RNF43 and ZNRF3 redirects their FZD substrate preference. Endocytosis assays, TMD swap domain chimeras, knockdown/knockout, receptor surface level measurement Life science alliance High 38969364
2024 ZNRF3 and RNF43 interact with EGFR via their extracellular domains, leading to EGFR ubiquitination and lysosomal degradation mediated by the intracellular RING domain. Overexpression of ZNRF3 reduces EGFR levels; knockout of ZNRF3/RNF43 upregulates EGFR signaling and promotes tumorigenesis. Co-immunoprecipitation, ubiquitination assay, overexpression/knockout, in vitro and in vivo tumor growth assays eLife Medium 41960900
2023 Disulfide-constrained peptides (DCPs) that bind the ZNRF3 ectodomain induce ZNRF3 ubiquitination and membrane clearance, leading to FZD stabilization and Wnt signaling activation. Multimeric DCPs induce expansive growth of human intestinal organoids in a valency-dependent manner. Peptide binding assay, cell-surface ZNRF3 clearance assay, FZD stabilization assay, Wnt reporter, intestinal organoid growth assay Cell chemical biology Medium 38056465
2025 Cryo-EM structures of human LGR4 alone, LGR4-RSPO2, and LGR4-RSPO2-ZNRF3 complexes show that LGR4, RSPO2, and ZNRF3 assemble into a 2:2:2 complex with the ZNRF3 dimer enclosed at the center. Upon RSPO2 binding, LGR4 undergoes no significant conformational changes. This forced ZNRF3 dimerization likely underlies how the complex sequesters ZNRF3 from Wnt receptors and facilitates ZNRF3 auto-inactivation. Cryo-electron microscopy structure determination Nature communications High 41034211
2025 ZNRF3-induced FZD degradation depends on endogenous WNT stimulation rather than being constitutive; ZNRF3 selectively degrades WNT-engaged FZD. WNT enhances FZD-DVL association, and DVL subsequently recruits ZNRF3 to WNT-engaged FZD to promote its degradation. R-spondin enhances WNT signaling by prolonging the action of the WNT-engaged FZD complex rather than simply increasing total FZD abundance. Endogenous WNT-dependent assays, Co-immunoprecipitation, FZD degradation assays, DVL dependency experiments Science signaling High 41086253
2025 Wnt induces selective endocytosis and degradation of FZD5/8 in a ZNRF3/RNF43-dependent manner; ZNRF3/RNF43 selectively target FZD5/8 upon Wnt stimulation; Wnt promotes the interaction between FZD5 and RNF43; DVL promotes ligand-independent FZD endocytosis but is dispensable for Wnt-induced FZD5/8 endocytosis and degradation. FZD endocytosis assays, ZNRF3/RNF43 knockout, Co-immunoprecipitation, DVL perturbation experiments eLife High 41070826
2024 ZNRF3 germline missense variants in the RING ligase domain cause macrocephalic neurodevelopmental disorder via dominant-negative enhancement of Wnt/β-catenin signaling (compromising Wnt receptor turnover), while a missense variant in the RSPO-binding domain causes microcephalic NDD via attenuated Wnt/β-catenin signaling. These domain-specific effects were validated in transcriptional reporter assays. Structural modeling, in vitro Wnt/β-catenin transcriptional reporter assays with Wnt3a and RSPO, comparison of RING vs RSPO-binding domain variants American journal of human genetics Medium 39168120
2024 ZNRF3 exon 2 deletions produce a 42-amino acid deleted protein (ΔEx2-ZNRF3) that is impaired in RSPO1 binding and fails to support RSPO1-dependent activation of Wnt/β-catenin signaling, causing congenital adrenal hypoplasia. RT-PCR, 3D structural modeling, cell-based TCF-LEF reporter assay comparing ΔEx2-ZNRF3 vs wild-type The Journal of clinical endocrinology and metabolism Medium 37878959
2024 Truncating ZNRF3 mutations at endogenous levels exhibit loss-of-function; missense mutations in RING and R-Spondin domains cause partial loss-of-function or hyperactivation but do NOT exhibit dominant-negative activity when heterozygously introduced at endogenous levels. R-Spondin domain variants undergo ER-associated degradation due to protein misfolding, reducing membrane levels. Endogenous knock-in of variants, β-catenin signaling assays, protein stability assays, low-temperature rescue Oncogene Medium 39674817

Source papers

Stage 0 corpus · 62 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature 783 22575959
2016 The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size. Nature cell biology 265 27088858
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 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
2015 MiR-146b-5p promotes metastasis and induces epithelial-mesenchymal transition in thyroid cancer by targeting ZNRF3. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 131 25547151
2016 RNF43 and ZNRF3 are commonly altered in serrated pathway colorectal tumorigenesis. Oncotarget 91 27661107
2013 Interaction with both ZNRF3 and LGR4 is required for the signalling activity of R-spondin. EMBO reports 87 24165923
2019 A ZNRF3-dependent Wnt/β-catenin signaling gradient is required for adrenal homeostasis. Genes & development 77 30692207
2013 Structures of Wnt-antagonist ZNRF3 and its complex with R-spondin 1 and implications for signaling. PloS one 65 24349440
2021 ZNRF3 and RNF43 cooperate to safeguard metabolic liver zonation and hepatocyte proliferation. Cell stem cell 64 34129813
2018 ZNRF3 functions in mammalian sex determination by inhibiting canonical WNT signaling. Proceedings of the National Academy of Sciences of the United States of America 63 29735715
2022 RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state. Nature communications 49 35039505
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
2021 A positive feedback loop of lncRNA-RMRP/ZNRF3 axis and Wnt/β-catenin signaling regulates the progression and temozolomide resistance in glioma. Cell death & disease 42 34657141
2015 Crystal structure of R-spondin 2 in complex with the ectodomains of its receptors LGR5 and ZNRF3. Journal of structural biology 41 26123262
2013 ZNRF3 acts as a tumour suppressor by the Wnt signalling pathway in human gastric adenocarcinoma. Journal of molecular histology 41 23504200
2022 The RSPO-LGR4/5-ZNRF3/RNF43 module in liver homeostasis, regeneration, and disease. Hepatology (Baltimore, Md.) 38 35006616
2020 The tumor suppressor PTPRK promotes ZNRF3 internalization and is required for Wnt inhibition in the Spemann organizer. eLife 33 31934854
2019 Effects of miR‑106b‑3p on cell proliferation and epithelial‑mesenchymal transition, and targeting of ZNRF3 in esophageal squamous cell carcinoma. International journal of molecular medicine 30 30816445
2023 RNF43 and ZNRF3 in Wnt Signaling - A Master Regulator at the Membrane. International journal of stem cells 28 37643759
2013 Reconstitution of R-spondin:LGR4:ZNRF3 adult stem cell growth factor signaling complexes with recombinant proteins produced in Escherichia coli. Biochemistry 26 24050775
2021 Somatic driver mutation prevalence in 1844 prostate cancers identifies ZNRF3 loss as a predictor of metastatic relapse. Nature communications 22 34716314
2022 Circ_0000190 sponges miR-382-5p to suppress cell proliferation and motility and promote cell death by targeting ZNRF3 in gastric cancer. Journal of biochemistry 21 35037032
2017 miR-146a promotes growth of osteosarcoma cells by targeting ZNRF3/GSK-3β/β-catenin signaling pathway. Oncotarget 19 29088784
2016 ZNRF3 Inhibits the Invasion and Tumorigenesis in Nasopharyngeal Carcinoma Cells by Inactivating the Wnt/β-Catenin Pathway. Oncology research 19 27733215
2015 ZNRF3 contributes to the growth of lung carcinoma via inhibiting Wnt/β-catenin pathway and is regulated by miR-93. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 19 26423400
2020 ZNRF3 Regulates Collagen-Induced Arthritis Through NF-kB and Wnt Pathways. Inflammation 18 32125593
2018 SCFβ-TRCP E3 ubiquitin ligase targets the tumor suppressor ZNRF3 for ubiquitination and degradation. Protein & cell 18 29497989
2016 ZNRF3 is downregulated in papillary thyroid carcinoma and suppresses the proliferation and invasion of papillary thyroid cancer cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 18 27448298
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
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
2020 MicroRNA‑301a/ZNRF3/wnt/β‑catenin signal regulatory crosstalk mediates glioma progression. International journal of oncology 15 33367931
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
2015 ZnRF3 Induces Apoptosis of Gastric Cancer Cells by Antagonizing Wnt and Hedgehog Signaling. Cell biochemistry and biophysics 11 27352324
2021 A MET-PTPRK kinase-phosphatase rheostat controls ZNRF3 and Wnt signaling. eLife 10 34590584
2023 Additional evidence for the role of chromosomal imbalances and SOX8, ZNRF3 and HHAT gene variants in early human testis development. Reproductive biology and endocrinology : RB&E 9 36631813
2015 ZnRF3 induces apoptosis of gastric cancer cells by antagonizing Wnt and Hedgehog signaling. Panminerva medica 9 25923840
2024 Single-Exon Deletions of ZNRF3 Exon 2 Cause Congenital Adrenal Hypoplasia. The Journal of clinical endocrinology and metabolism 8 37878959
2023 Potent and selective binders of the E3 ubiquitin ligase ZNRF3 stimulate Wnt signaling and intestinal organoid growth. Cell chemical biology 6 38056465
2021 RSPO2 silence inhibits tumorigenesis of nasopharyngeal carcinoma by ZNRF3/Hedgehog-Gli1 signal pathway. Life sciences 6 34273374
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 and ZNRF3: Versatile regulators at the membrane and their role in cancer. Biochimica et biophysica acta. Reviews on cancer 5 39551397
2024 Loss of ZNRF3/RNF43 Unleashes EGFR in Cancer. bioRxiv : the preprint server for biology 4 38260423
2024 Deleterious ZNRF3 germline variants cause neurodevelopmental disorders with mirror brain phenotypes via domain-specific effects on Wnt/β-catenin signaling. American journal of human genetics 4 39168120
2024 Lack of dominant-negative activity for tumor-related ZNRF3 missense mutations at endogenous levels. Oncogene 3 39674817
2024 Gonadal sex reversal at single-cell resolution in Znrf3-deficient mice. Development (Cambridge, England) 2 39629665
2026 Loss of ZNRF3/RNF43 unleashes EGFR in cancer. eLife 1 41960900
2025 Wnt induces FZD5/8 endocytosis and degradation and the involvement of RSPO-ZNRF3/RNF43 and DVL. bioRxiv : the preprint server for biology 1 39463927
2026 Site-Specific Immobilization of ZNRF3 Reveals the Importance of Target Structural Integrity on Macrocyclic Peptide Selections. ACS chemical biology 0 42042695
2025 The impact of an RNA-binding protein group on regulating the RSPO-LGR4/5-ZNRF3/RNF43 module and the immune microenvironment in hepatocellular carcinoma. BMC cancer 0 40264052
2025 Structural insights into Wnt/β-catenin signaling regulation by LGR4, R-spondin, and ZNRF3. Nature communications 0 41034211
2025 ZNRF3 in neurodevelopmental disorders: insights into Wnt signaling and therapeutic potential. Neurogenetics 0 41037104
2025 Wnt induces FZD5/8 endocytosis and degradation and the involvement of RSPO-ZNRF3/RNF43 and DVL. eLife 0 41070826
2025 The E3 ubiquitin ligase ZNRF3 restricts WNT receptor complex activity by stimulating the selective degradation of WNT-engaged FZD. Science signaling 0 41086253
2025 [Retracted] Effects of miR‑106b‑3p on cell proliferation and epithelial‑mesenchymal transition, and targeting of ZNRF3 in esophageal squamous cell carcinoma. International journal of molecular medicine 0 41170749
2025 MiR-668-5p targets ZNRF3, an E3 ubiquitin ligase to enhance osteoblast function and alleviate senescence in doxorubicin-induced age-related bone loss. Frontiers in endocrinology 0 41220584
2024 Znrf3 exon 2 deletion mice do not recapitulate congenital adrenal hypoplasia. Journal of molecular endocrinology 0 39235352