Affinage

ZNRF3

E3 ubiquitin-protein ligase ZNRF3 · UniProt Q9ULT6

Length
936 aa
Mass
100.6 kDa
Annotated
2026-06-11
64 papers in source corpus 24 papers cited in narrative 23 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZNRF3 is a cell-surface transmembrane RING-domain E3 ubiquitin ligase that acts as a negative-feedback regulator of Wnt/β-catenin signaling by ubiquitinating Frizzled (FZD) and LRP6 Wnt receptors and driving their membrane clearance and degradation (PMID:22575959). Receptor targeting is selective rather than constitutive: ZNRF3 degrades Wnt-engaged FZD, with Wnt stimulation enhancing the FZD–DVL association and DVL serving as the adaptor that recruits ZNRF3 to FZD; fusing the DVL DEP domain to ZNRF3 bypasses this dependency (PMID:25891077, PMID:41086253, PMID:41070826). Substrate preference is encoded in part by the transmembrane domain, which directs ZNRF3 toward particular FZD subtypes (PMID:38969364), and the ligase additionally engages EGFR through its extracellular domain to drive EGFR ubiquitination and degradation (PMID:41960900). ZNRF3 is itself the effector arm of the R-spondin/LGR axis: R-spondin binds the ZNRF3 ectodomain via its Fu1 domain and, together with LGR4 (bound through Fu2), cross-links the receptors into a 2:2:2 ternary complex centered on a ZNRF3 dimer, sequestering and auto-inactivating ZNRF3 through forced dimerization and membrane clearance (PMID:22575959, PMID:24225776, PMID:24165923, PMID:41034211). ZNRF3 abundance and surface activity are further tuned post-translationally—phosphorylation of a '4Y' endocytic motif by MET inhibits internalization while PTPRK dephosphorylation promotes it (PMID:31934854, PMID:34590584), the deubiquitinase USP42 stabilizes ZNRF3 against R-spondin-induced clearance (PMID:33786993), and SCFβ-TRCP ubiquitinates ZNRF3 in a phospho-degron-dependent manner to control its stability (PMID:29497989). In vivo, this regulatory output sets Wnt/β-catenin gradients that govern adrenal cortex homeostasis (PMID:30692207), hepatocyte proliferation and metabolic zonation (PMID:34129813), and mammalian testis sex determination (PMID:29735715). Germline ZNRF3 variants cause human disease: RING-domain and RSPO-binding-domain variants produce neurodevelopmental disorders with macrocephaly or microcephaly respectively (PMID:39168120), and exon-2/RSPO-binding-domain lesions cause congenital adrenal hypoplasia (PMID:37878959), while 46,XY DSD-associated missense variants disrupt ZNRF3 activity (PMID:29735715).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 2012 High

    Established ZNRF3 as the molecular identity of a membrane E3 ligase that limits Wnt signaling and the target of R-spondin, answering how R-spondin potentiates Wnt at the receptor level.

    Evidence Co-IP, surface receptor turnover, and in vivo Wnt/PCP assays defining FZD/LRP6 turnover and R-spondin/LGR4-induced ZNRF3 clearance

    PMID:22575959

    Open questions at the time
    • Structural basis of R-spondin/LGR4/ZNRF3 assembly not resolved
    • Adaptor coupling ZNRF3 to FZD unknown
  2. 2013 High

    Resolved the structural logic of the dual-receptor model, showing R-spondin Fu1 clamps the ZNRF3 ectodomain while Fu2 engages LGR receptors and that binding enhances ZNRF3 ectodomain dimerization.

    Evidence X-ray crystallography of ZNRF3 ectodomain alone and bound to Rspo, SPR/binding measurements, Rspo chimera mutagenesis, and in vitro reconstitution of ternary complexes

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

    Open questions at the time
    • Stoichiometry of the full ternary complex not definitively established at this stage
    • How ectodomain dimerization translates to catalytic auto-inactivation unresolved
  3. 2015 High

    Identified DVL as the obligate adaptor recruiting ZNRF3 to FZD, explaining how a RING ligase reaches its receptor substrate.

    Evidence DVL knockout cells, reciprocal Co-IP, ubiquitination assays, and DEP-domain fusion rescue

    PMID:25891077

    Open questions at the time
    • Whether DVL recruitment selects specific FZD subtypes not addressed
    • Dependence on Wnt ligand engagement not yet defined
  4. 2015 Medium

    Confirmed that R-spondin cross-links LGR and ZNRF3 into a 2:2:2 assembly (versus 1:1:1 with RNF43), distinguishing the architectures of the two paralogs.

    Evidence Low-resolution X-ray crystallography of the ternary hLGR5–Rspo2–ZNRF3 complex

    PMID:26123262

    Open questions at the time
    • Low resolution limits interface detail
    • Functional consequence of differing stoichiometry untested
  5. 2018 Medium

    Showed ZNRF3 stability is itself regulated by a phospho-degron, placing ZNRF3 protein levels under SCFβ-TRCP control analogous to β-catenin.

    Evidence Co-IP, ubiquitination assays, proteasome inhibition, and CKI-phosphorylation/degron analysis

    PMID:29497989

    Open questions at the time
    • Single lab
    • Physiological/in vivo relevance of β-TRCP-mediated turnover not established
  6. 2018 High

    Demonstrated ZNRF3 is required for mammalian testis sex determination and linked human ZNRF3 variants to 46,XY DSD via ectopic Wnt/β-catenin activity.

    Evidence Conditional KO mice with pathway epistasis, exome sequencing, and variant functional testing in human cells and zebrafish

    PMID:29735715

    Open questions at the time
    • Cell-type-specific substrates in the gonad not defined
    • Mechanism connecting ZNRF3 loss to Sox9 repression incompletely mapped
  7. 2019 High

    Defined an in vivo, dosage-sensitive role for ZNRF3 in adrenal cortex homeostasis dependent on Porcupine-secreted Wnt and β-catenin.

    Evidence Adrenocortical conditional KO, Porcupine inhibitor treatment, and genetic β-catenin dosage reduction

    PMID:30692207

    Open questions at the time
    • Why ZNRF3 loss expands only the inner cortex unexplained
    • Non-redundancy with RNF43 in adrenal context not mechanistically resolved
  8. 2020 High

    Identified a '4Y' endocytic motif and its phosphatase PTPRK, revealing post-translational control of ZNRF3 internalization independent of R-spondin.

    Evidence Endocytic-signal mutagenesis, Xenopus loss-of-function, Wnt reporter and internalization assays

    PMID:31934854

    Open questions at the time
    • Kinase phosphorylating the motif not yet identified at this stage
    • In vivo relevance in mammals untested
  9. 2021 High

    Completed the 4Y-motif regulatory circuit by identifying MET as the kinase opposing PTPRK, linking HGF/MET signaling to Wnt receptor stability.

    Evidence MET–ZNRF3 Co-IP, phosphorylation assays, pharmacological MET inhibition, internalization and Wnt reporter assays

    PMID:34590584

    Open questions at the time
    • Whether MET–ZNRF3 crosstalk operates in tumors in vivo not shown
    • Quantitative balance of MET vs PTPRK control across tissues unknown
  10. 2021 High

    Showed USP42 deubiquitinates and stabilizes ZNRF3 at the membrane, adding a deubiquitinase layer that counters R-spondin-induced clearance.

    Evidence Co-IP, in vitro deubiquitination, membrane clearance, Wnt reporter, and organoid assays

    PMID:33786993

    Open questions at the time
    • Regulation of USP42 activity itself not defined
    • In vivo consequences of USP42–ZNRF3 axis untested
  11. 2021 High

    Established that ZNRF3 and RNF43 cooperatively restrain Wnt to maintain liver metabolic zonation and limit hepatocyte proliferation and tumorigenesis.

    Evidence Liver-specific conditional single and double KO mice, scRNA-seq, chromatin accessibility, and proliferation/histology readouts

    PMID:34129813

    Open questions at the time
    • Molecular basis of RNF43 compensatory upregulation unknown
    • Direct receptor substrates driving zonation not pinpointed
  12. 2023 Medium

    Refined the receptor cooperativity model, showing LGR4 (but not LGR5) forms a 2:2 complex with ZNRF3/RNF43 to confer high-affinity bivalent R-spondin binding.

    Evidence Whole-cell binding affinity measurements with monovalent and bivalent RSPO ligands and co-expression studies

    PMID:37402772

    Open questions at the time
    • Single lab whole-cell assays
    • Structural basis of LGR4-specific cooperativity not resolved here
  13. 2023 Medium

    Provided pharmacological proof-of-concept that engineered ZNRF3-binding peptides can clear ZNRF3 from the surface to activate Wnt, validating ZNRF3 as a druggable node.

    Evidence Disulfide-constrained peptide surface-clearance, ubiquitination, Wnt reporter, organoid, and valency-comparison assays

    PMID:38056465

    Open questions at the time
    • Mechanism of valency-dependent clearance not structurally defined
    • In vivo efficacy/specificity untested
  14. 2024 High

    Mapped substrate selectivity to the transmembrane domain, showing ZNRF3 and RNF43 prefer distinct FZD subtypes and that TMD swaps redirect specificity.

    Evidence FZD endocytosis assays, TMD-swap mutagenesis, flow cytometry, surface receptor quantification

    PMID:38969364

    Open questions at the time
    • Molecular features within the TMD dictating preference not defined
    • Physiological significance of subtype preference untested in vivo
  15. 2024 Medium

    Extended ZNRF3 substrate range beyond Wnt receptors by identifying EGFR as an ectodomain-engaged target for ubiquitination and degradation.

    Evidence ZNRF3–EGFR Co-IP, ubiquitination assays, overexpression/KO cell growth assays, and proteogenomic correlation

    PMID:41960900

    Open questions at the time
    • Single lab
    • Relative contribution of EGFR vs Wnt-receptor targeting to phenotypes unresolved
  16. 2024 Medium

    Linked domain-specific germline ZNRF3 variants to opposite-direction Wnt dysregulation and human neurodevelopmental and adrenal phenotypes.

    Evidence Structural modeling and TCF/LEF reporter assays of RING- and RSPO-binding-domain variants; RT-PCR and reporter assays of ΔEx2-ZNRF3

    PMID:37878959 PMID:39168120

    Open questions at the time
    • Dominant-negative mechanism inferred from overexpression assays
    • In vivo validation of variant effects lacking
  17. 2024 High

    Reassessed disease-variant mechanism at endogenous levels, showing tumor-associated truncating and RSPO-domain variants act as loss-of-function (via ERAD/misfolding) rather than dominant-negative.

    Evidence Endogenous knock-in of variants, β-catenin signaling and protein stability assays, and 27°C temperature rescue

    PMID:39674817

    Open questions at the time
    • Reconciliation with dominant-negative claims from overexpression studies incomplete
    • Tissue-context dependence of variant behavior not addressed
  18. 2025 High

    Provided a high-resolution structural mechanism for ZNRF3 inactivation, showing R-spondin/LGR4 assemble a 2:2:2 complex with a central ZNRF3 dimer whose forced dimerization underlies sequestration and auto-inactivation.

    Evidence Cryo-EM structures of LGR4, LGR4–RSPO2, and LGR4–RSPO2–ZNRF3 complexes

    PMID:41034211

    Open questions at the time
    • Catalytic consequence of dimerization on RING activity not directly demonstrated
    • Dynamics of complex assembly/disassembly not captured
  19. 2025 High

    Clarified that ZNRF3 targets Wnt-engaged FZD selectively, with Wnt enhancing FZD–DVL association and DVL recruiting ZNRF3, integrating substrate selection with ligand sensing.

    Evidence FZD endocytosis assays, Co-IP, ZNRF3/RNF43 KO cells, and Wnt stimulation experiments (two concurrent studies)

    PMID:41070826 PMID:41086253

    Open questions at the time
    • How Wnt biochemically licenses the FZD–DVL–ZNRF3 handoff not fully resolved
    • Whether all FZD subtypes follow this Wnt-dependent rule untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple regulatory inputs (R-spondin/LGR sequestration, 4Y phosphorylation, USP42/β-TRCP ubiquitin turnover, DVL recruitment, TMD-encoded substrate choice) are integrated to set tissue-specific Wnt gradients in vivo remains unresolved.
  • No unified quantitative model coupling surface ZNRF3 dynamics to β-catenin output across tissues
  • Catalytic mechanism by which forced dimerization inactivates the RING ligase not directly tested
  • Relative physiological weight of EGFR versus Wnt-receptor targeting unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 3 GO:0140096 catalytic activity, acting on a protein 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-392499 Metabolism of proteins 3
Partners
DVLEGFRLGR4METPTPRKRSPO1RSPO2USP42
Complex memberships
RSPO–LGR4–ZNRF3 ternary (2:2:2) complex

Evidence

Reading pass · 23 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 turnover of Frizzled and LRP6 Wnt receptors, thereby inhibiting Wnt signaling. R-spondin inhibits ZNRF3 by directly binding to its extracellular domain and inducing association between ZNRF3 and LGR4, which results in membrane clearance of ZNRF3. Co-immunoprecipitation, cell surface receptor turnover assays, in vivo Wnt/PCP signaling assays, functional epistasis Nature High 22575959
2013 Crystal structures of the ZNRF3 ectodomain alone and in complex with R-spondin 2 (Rspo2 Fu1-Fu2) and with RNF43 ectodomain reveal that a prominent loop in Rspo Fu1 clamps into a groove on the ZNRF3 ectodomain surface. Rspo binding enhances dimerization of ZNRF3 ectodomain. Signaling potency of Rspo depends on ability to recruit ZNRF3 or RNF43 via Fu1 into a complex with LGR receptors (which bind Rspo via Fu2). X-ray crystallography, biophysical binding assays, cell-based signaling assays, mutagenesis of Rspo chimeras Nature communications High 24225776
2013 Crystal structures of the ZNRF3 ectodomain and its complex with R-spondin 1 (RSPO1) show that ZNRF3 binds RSPO1 via the RSPO1 furin-like 1 (Fu1) domain with micromolar affinity. The ZNRF3-binding site overlaps with trans-interactions seen in 2:2 LGR5-RSPO1 complexes, suggesting that ZNRF3/RNF43 binding disrupts such arrangements. X-ray crystallography, SPR/binding affinity measurements PloS one High 24349440
2013 Both LGR4 and ZNRF3 binding motifs of R-spondin are required for R-spondin-induced LGR4/ZNRF3 interaction, membrane clearance of ZNRF3, and activation of Wnt signaling. A ZNRF3 mutant with reduced affinity to R-spondin cannot be suppressed by R-spondin, supporting a dual receptor model where LGR4/5 is the engagement receptor and ZNRF3/RNF43 is the effector receptor. Mutagenesis of R-spondin binding interfaces, co-immunoprecipitation, membrane clearance assays, Wnt signaling reporter assays EMBO reports High 24165923
2013 Recombinant ZNRF3 ectodomain and LGR4 LRR1-14 fragment can be reconstituted in vitro from bacterially expressed proteins. ZNRF3 ECD inhibits RSPO-enhanced Wnt3a signaling, and ternary RSPO:LGR4:ZNRF3 complexes were detected for RSPO2 and RSPO3. RSPO proteins bind ZNRF3 weakly compared to LGR4. Bacterial protein reconstitution, TR-FRET binding assay, native gel electrophoretic mobility shift assay, cell-based signaling assay Biochemistry High 24050775
2015 Dishevelled (DVL) is required for ZNRF3/RNF43-mediated ubiquitination and degradation of Frizzled. DVL physically interacts with ZNRF3, and this interaction is essential for ZNRF3 Wnt-inhibitory activity. Binding of Frizzled through the DEP domain of DVL is required for DVL-mediated FZD downregulation. Fusion of the DEP domain to ZNRF3 overcomes DVL dependency for FZD downregulation. DVL knockout cells, co-immunoprecipitation, ubiquitination assay, domain fusion rescue experiments, cell surface receptor quantification Molecular cell High 25891077
2015 Crystal structure of the ternary hLGR5-mRspo2Fu1-Fu2-mZNRF3ecto complex at low resolution confirms that Rspo proteins cross-link LGRs and ZNRF3 into a 2:2:2 complex (vs. 1:1:1 complex with RNF43). X-ray crystallography Journal of structural biology Medium 26123262
2018 SCFβ-TRCP E3 ubiquitin ligase directly interacts with and ubiquitinates ZNRF3, regulating its protein stability via proteasomal degradation. ZNRF3 ubiquitination by β-TRCP is both CKI-phosphorylation- and degron-dependent, analogous to β-catenin degradation. Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, phosphorylation-dependent degron analysis Protein & cell Medium 29497989
2020 PTPRK (protein tyrosine phosphatase receptor-type kappa) promotes ZNRF3 internalization and Wnt receptor degradation by dephosphorylating a '4Y' endocytic tyrosine motif in ZNRF3. Phosphorylation of this motif inhibits ZNRF3 internalization and reduces Wnt receptor turnover; dephosphorylation by PTPRK promotes ZNRF3 internalization. Xenopus Ptprk deficiency increases Wnt signaling with organizer defects. Identification of 4Y endocytic signal by mutagenesis, Xenopus loss-of-function, cell-based Wnt reporter assays, ZNRF3 internalization assays eLife High 31934854
2021 MET proto-oncogene phosphorylates the '4Y' endocytic motif of ZNRF3 in response to HGF stimulation, thereby inhibiting ZNRF3 internalization and reducing Wnt receptor degradation, thus enhancing Wnt/β-catenin signaling. PTPRK dephosphorylates the same motif to promote ZNRF3 internalization. MET inhibition promotes ZNRF3 internalization and Wnt receptor degradation. Co-immunoprecipitation of MET-ZNRF3, phosphorylation assays, pharmacological MET inhibition, ZNRF3 internalization assays, Wnt reporter assays eLife High 34590584
2021 USP42 deubiquitinase binds to the Dishevelled-interacting region (DIR) of ZNRF3 and deubiquitinates ZNRF3, protecting it from R-spondin-induced ubiquitin-dependent membrane clearance. USP42 thereby stabilizes ZNRF3 at the plasma membrane, increases FZD/LRP6 turnover, and inhibits Wnt signaling. Co-immunoprecipitation, deubiquitination assay, membrane clearance assay, Wnt signaling reporter, organoid assays EMBO reports High 33786993
2021 ZNRF3 deletion in hepatocytes promotes hepatocyte proliferation; RNF43 is upregulated as a compensatory response. Concomitant deletion of both RNF43 and ZNRF3 results in metabolic reprogramming of periportal hepatocytes, clonal expansion, and liver tumor formation, showing that ZNRF3 and RNF43 cooperate to restrict WNT/β-catenin activity and balance metabolic function and proliferation in the liver. Conditional knockout mice (liver-specific), scRNA-seq, chromatin accessibility assays, histology, proliferation assays Cell stem cell High 34129813
2018 ZNRF3 is required for mammalian testis sex determination. XY mice lacking ZNRF3 show gonadal sex reversal associated with ectopic WNT/β-catenin activity and reduced Sox9 expression. Two human ZNRF3 missense variants identified in 46,XY DSD patients disrupt ZNRF3 activity in cell lines and zebrafish embryo assays. Conditional KO mice, exome sequencing, functional assays in human cell lines and zebrafish embryos Proceedings of the National Academy of Sciences of the United States of America High 29735715
2019 Adrenocortical-specific loss of ZNRF3 (but not RNF43) results in adrenal hyperplasia dependent on Porcupine-mediated Wnt ligand secretion. ZNRF3 loss triggers moderate-level Wnt/β-catenin activation expanding only the inner cortex, and genetic reduction of β-catenin dosage reverses the ZNRF3-deficient phenotype. Conditional KO mice, Porcupine inhibitor treatment, genetic β-catenin dosage reduction, histology, signaling analysis Genes & development High 30692207
2023 LGR4 (but not LGR5) forms a 2:2 complex with RNF43/ZNRF3 that provides high-affinity bivalent binding of R-spondin. Co-expression of ZNRF3 with LGR4 dramatically increases binding affinity of monovalent RSPO2 furin domain, whereas co-expression of ZNRF3 with LGR5 has no effect, indicating LGR4 and RNF43/ZNRF3 cooperate for high-affinity R-spondin engagement. Whole-cell binding affinity measurements with monovalent and bivalent RSPO ligands, co-expression studies Scientific reports Medium 37402772
2024 RNF43 preferentially down-regulates FZD1/FZD5/FZD7 while ZNRF3 preferentially targets FZD6 for endocytosis. The transmembrane domain (TMD) of RNF43 is a key molecular determinant for inducing FZD5 endocytosis; TMD swap between RNF43 and ZNRF3 redirects their FZD substrate preference. FZD endocytosis assays, TMD swap mutagenesis, flow cytometry, cell surface receptor quantification Life science alliance High 38969364
2024 ZNRF3 and RNF43 interact with EGFR via their extracellular domains, leading to EGFR ubiquitination and subsequent degradation facilitated by the E3 ligase RING domain. ZNRF3 overexpression reduces EGFR levels; ZNRF3/RNF43 knockout increases EGFR signaling and promotes cancer cell growth. Co-immunoprecipitation of ZNRF3-EGFR, ubiquitination assays, ZNRF3 overexpression/KO cell growth assays, proteogenomics correlation eLife Medium 41960900
2024 Deletions of ZNRF3 exon 2 produce a 42-amino-acid deleted protein (ΔEx2-ZNRF3) that impairs R-spondin (RSPO1) binding and attenuates RSPO1-dependent activation of Wnt/β-catenin signaling in cell-based TCF-LEF reporter assays, causing congenital adrenal hypoplasia. RT-PCR, 3D structural modeling, cell-based TCF-LEF reporter assay with RSPO1 stimulation The Journal of clinical endocrinology and metabolism Medium 37878959
2024 ZNRF3 germline missense variants in the RING ligase domain cause macrocephalic NDD through dominant-negative hyperactivation of Wnt/β-catenin signaling (disrupting ubiquitin ligase function/Wnt receptor turnover), while a missense variant in the RSPO-binding domain causes microcephalic NDD by attenuating Wnt/β-catenin signaling through disrupted RSPO binding. Structural modeling, in vitro TCF/LEF transcriptional reporter assays with and without Wnt3a and RSPO stimulation, variant functional testing American journal of human genetics Medium 39168120
2024 Tumor-associated ZNRF3 truncating mutations show loss-of-function at endogenous expression levels. Defective R-Spondin domain missense variants undergo ER-associated degradation due to protein misfolding, reducing protein levels and preventing correct membrane localization (partially restorable at 27°C). When representative RING and R-Spondin domain variants are heterozygously introduced at endogenous levels, their effect on β-catenin signaling mirrors heterozygous knockout, with no dominant-negative activity detected. Endogenous knock-in of variants, β-catenin signaling assays, protein stability assays, temperature rescue experiments Oncogene High 39674817
2025 Cryo-EM structures of human LGR4, LGR4-RSPO2, and LGR4-RSPO2-ZNRF3 ternary complexes show that LGR4, RSPO2, and ZNRF3 assemble into a 2:2:2 complex with the ZNRF3 dimer at the center. Upon RSPO2 binding, LGR4 undergoes no significant conformational change. Forced ZNRF3 dimerization by the ternary complex likely underpins sequestration of 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; ZNRF3 selectively degrades Wnt-engaged FZD rather than constitutively degrading all FZD. Wnt enhances FZD-DVL association, and DVL then recruits ZNRF3 to FZD to promote its degradation. ZNRF3/RNF43 selectively target FZD5/8 for degradation upon Wnt stimulation, while DVL promotes ligand-independent FZD endocytosis but is dispensable for Wnt-induced FZD5/8 endocytosis. FZD endocytosis assays, co-immunoprecipitation, ZNRF3/RNF43 knockout cells, Wnt stimulation experiments Science signaling High 41070826 41086253
2023 Disulfide-constrained peptides (DCPs) that bind ZNRF3 induce ZNRF3 ubiquitination and cell surface clearance, leading to FZD stabilization and Wnt pathway activation. Multimeric DCPs were more effective than monomeric forms at inducing ZNRF3 clearance. Cell surface ZNRF3 clearance assay, ubiquitination assay, Wnt reporter assay, organoid growth assay, peptide valency comparison Cell chemical biology Medium 38056465

Source papers

Stage 0 corpus · 64 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature 791 22575959
2016 The RSPO-LGR4/5-ZNRF3/RNF43 module controls liver zonation and size. Nature cell biology 269 27088858
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 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
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 93 27661107
2013 Interaction with both ZNRF3 and LGR4 is required for the signalling activity of R-spondin. EMBO reports 89 24165923
2019 A ZNRF3-dependent Wnt/β-catenin signaling gradient is required for adrenal homeostasis. Genes & development 79 30692207
2021 ZNRF3 and RNF43 cooperate to safeguard metabolic liver zonation and hepatocyte proliferation. Cell stem cell 67 34129813
2013 Structures of Wnt-antagonist ZNRF3 and its complex with R-spondin 1 and implications for signaling. PloS one 67 24349440
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 65 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
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
2015 Crystal structure of R-spondin 2 in complex with the ectodomains of its receptors LGR5 and ZNRF3. Journal of structural biology 44 26123262
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
2013 ZNRF3 acts as a tumour suppressor by the Wnt signalling pathway in human gastric adenocarcinoma. Journal of molecular histology 42 23504200
2022 The RSPO-LGR4/5-ZNRF3/RNF43 module in liver homeostasis, regeneration, and disease. Hepatology (Baltimore, Md.) 39 35006616
2020 The tumor suppressor PTPRK promotes ZNRF3 internalization and is required for Wnt inhibition in the Spemann organizer. eLife 33 31934854
2023 RNF43 and ZNRF3 in Wnt Signaling - A Master Regulator at the Membrane. International journal of stem cells 30 37643759
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
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 23 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 20 29088784
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 19 27448298
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
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
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
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 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
2021 RSPO2 silence inhibits tumorigenesis of nasopharyngeal carcinoma by ZNRF3/Hedgehog-Gli1 signal pathway. Life sciences 7 34273374
2023 Potent and selective binders of the E3 ubiquitin ligase ZNRF3 stimulate Wnt signaling and intestinal organoid growth. Cell chemical biology 6 38056465
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
2025 Structural insights into Wnt/β-catenin signaling regulation by LGR4, R-spondin, and ZNRF3. Nature communications 1 41034211
2025 Wnt induces FZD5/8 endocytosis and degradation and the involvement of RSPO-ZNRF3/RNF43 and DVL. eLife 1 41070826
2025 The E3 ubiquitin ligase ZNRF3 restricts WNT receptor complex activity by stimulating the selective degradation of WNT-engaged FZD. Science signaling 1 41086253
2026 Site-Specific Immobilization of ZNRF3 Reveals the Importance of Target Structural Integrity on Macrocyclic Peptide Selections. ACS chemical biology 0 42042695
2026 Aloe-emodin ameliorates non-alcoholic fatty liver disease by regulating the ZNRF3/Wnt/β-catenin axis and suppressing hepatic lipogenesis. Biochemical and biophysical research communications 0 42214922
2026 Glucose restriction reprograms lipid metabolism and enhances immunotherapy through ZNRF3-Wnt-SCD signaling axis. Journal for immunotherapy of cancer 0 42236114
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 ZNRF3 in neurodevelopmental disorders: insights into Wnt signaling and therapeutic potential. Neurogenetics 0 41037104
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

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