Frizzled-4 is a seven-pass cell-surface receptor with an extracellular cysteine-rich ligand-binding domain and cytoplasmic regions that recruit signaling proteins. It responds to Wnt ligands through canonical beta-catenin and context-dependent noncanonical pathways. It also recognizes Norrin, a ligand unrelated to Wnts, and transduces Norrin signals with an LRP coreceptor. These receptor activities regulate vascular development, especially in the retina, and contribute to neuronal morphogenesis in experimental systems. Pathogenic FZD4 variants can disrupt receptor trafficking or signaling and cause familial exudative vitreoretinopathy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001540 amyloid-beta binding | IPI PMID:18234671 Amyloid-beta binds to the extracellular cysteine-rich domain... | KEEP AS NON CORE | Summary: CHEBI:64646 is beta40. Reason: CHEBI:64646 is beta40. Original 18234671 Fig. 1C names FZD4 binding to beta40. Retain this positive interaction outside the established receptor-signaling core; do not infer normal physiological ligand status. Supporting Evidence: |
| GO:0001540 amyloid-beta binding | IPI PMID:18234671 Amyloid-beta binds to the extracellular cysteine-rich domain... | UNDECIDED | Summary: APP PRO_0000000092 is beta42. Reason: APP PRO_0000000092 is beta42. Available 18234671 legends place the beta42 panel on FZD5. The unread full article may contain additional FZD4 experiments, so neither removal nor a definitive misattribution is justified. Supporting Evidence: |
| GO:0001540 amyloid-beta binding | IPI PMID:18234671 Amyloid-beta binds to the extracellular cysteine-rich domain... | KEEP AS NON CORE | Summary: The explicit FZD4 cysteine-rich-domain experiment supports the beta40 partner context. Reason: APP PRO_0000000093 is beta40, supported by the same explicit FZD4 Fig. 1C observation. Preserve this distinct original context. Supporting Evidence: |
| GO:0004888 transmembrane signaling receptor activity | IEA GO_REF:0000002 | TOO GENERAL | Summary: The broad transmembrane receptor assertion is correct but covered by retained Wnt receptor activity and cytokine receptor activity. Reason: The broad transmembrane receptor assertion is correct but covered by retained Wnt receptor activity and cytokine receptor activity. The Wnt receptor is_a ancestry was checked explicitly. |
| GO:0004896 cytokine receptor activity | IDA PMID:17955262 Moderate reduction of Norrin signaling activity associated w... | ACCEPT | Summary: 17955262 directly studies Norrin-dependent signaling and disease-associated receptor variants. Reason: 17955262 directly studies Norrin-dependent signaling and disease-associated receptor variants. Cytokine receptor activity captures the Norrin receptor role without incorrectly calling Norrin a Wnt. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:17955262 Moderate reduction of Norrin signaling activity associated w... | MODIFY | Summary: The Norrin partner supports the more informative cytokine-binding term. Reason: PMID:17955262 reports Norrin-dependent reporter signaling together with cell-surface binding assays and tests disease-associated Norrin substitutions. The original Q00604 partner is Norrin, the non-Wnt cytokine ligand recognized by FZD4. Refine the generic binding assertion to cytokine binding, preserving its IPI provenance and literal partner. This does not add a purified binary affinity or natural-product-specific claim; the original normal source is abstract-only. Proposed replacements: cytokine binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:19277043 Secreted Frizzled-related protein-1 is a negative regulator ... | KEEP AS NON CORE | Summary: Human SFRP1 associates with the expressed FZD4 extracellular domain in a construct-dependent co-immunoprecipitation assay. Reason: The original full-text Figure 6 and construct methods test the human FZD4 extracellular domain fused to Fc against Myc-tagged human SFRP1 in 293-cell co-immunoprecipitation. Wild-type SFRP1 and its first deletion associate, whereas loss of its cysteine-rich domain disrupts association. This supports the SFRP1 interaction in a domain-based expression assay, not a demonstrated FZD4-specific androgen-receptor mechanism or direct G-protein coupling. Retain generic binding as non-core. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:19837033 TSPAN12 regulates retinal vascular development by promoting ... | MODIFY | Summary: Norrin recognition in the TSPAN12 receptor system supports cytokine binding. Reason: The authentic PMID:19837033 abstract explicitly identifies Norrin binding to FZD4, and the retained IntAct co-immunoprecipitation context supports the literal NDP/Q00604 association in the TSPAN12 receptor system. Refine protein binding to cytokine binding because the ligand class is established. Preserve the receptor-complex and abstract-level access limits: this is not a new claim of isolated binary affinity or a demonstration that every co-associated protein contacts FZD4 directly. Proposed replacements: cytokine binding Supporting Evidence: PMID:19837033 Although Norrin is structurally unrelated to Wnts, it binds FZD4 |
| GO:0005515 protein binding | IPI PMID:20802536 Direct interaction between NHERF1 and Frizzled regulates Ξ²-c... | MODIFY | Summary: Terminal-motif and NHERF1-domain experiments support PDZ domain binding. Reason: PMID:20802536 Results and Figure 1 establish recognition of the human FZD4 terminal motif by NHERF1 PDZ2: the receptor V537A substitution strongly reduces association, scaffold PDZ2 mutants impair binding, and recombinant NHERF1 binds the receptor in an overlay assay. Refine generic protein binding to PDZ domain binding. Preserve the literal G3GTH2 hamster Slc9a3r1/NHERF1 accession without claiming the paper independently identifies that exact clone species; human receptor identity and hamster assay-host identity are separate. Proposed replacements: PDZ domain binding Supporting Evidence: PMID:20802536 NHERF1 binds Fzd4 via the receptorβs terminal PDZ ligand. |
| GO:0005515 protein binding | IPI PMID:20802536 Direct interaction between NHERF1 and Frizzled regulates Ξ²-c... | KEEP AS NON CORE | Summary: The Dvl2 association is positive, while this experiment does not localize its receptor-contacting domain. Reason: PMID:20802536 Figure 6 directly tests myc-Dvl2 association with FZD4, competition with NHERF1 and Wnt5a-dependent membrane recruitment. These are positive receptor/adaptor association experiments, but the PDZ2 mutagenesis and recombinant overlay in Figure 1 identify the NHERF1 interface, not the Dvl2 interface. Retain this literal mouse Q60838 Dvl2 context as non-core generic binding rather than assigning the neighboring NHERF1 domain result to it. The separate PMID:19388021 human DVL2 peptide/PDZ-domain assay remains represented by its own specific annotation. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Human FZD4 and the retained DMWD fragment interact in the Haenig yeast two-hybrid screen and pairwise retesting. Reason: The authentic Haenig Table S2 NN1.0 row 3664 matches human FZD4 and DMWD; retained expanded-network and IntAct records preserve the 316β649 fragment. These are human-protein yeast two-hybrid results with pairwise reporter retesting. The original Table S4 contains no FZD4 pair-specific DULIP validation. Retain the positive generic interaction as non-core without claiming an endogenous human-cell complex, full-length binding where a fragment was used. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: The Haenig screen supports the FZD4βA2M yeast two-hybrid interaction, without pair-specific mammalian validation. Reason: The authentic Haenig Table S2 NN1.0 row 3663 matches human FZD4 and A2M; retained expanded-network and IntAct records preserve the clone without an explicit fragment feature in the retained interaction records. These are human-protein yeast two-hybrid results with pairwise reporter retesting. The original Table S4 contains no FZD4 pair-specific DULIP validation. Retain the positive generic interaction as non-core without claiming an endogenous human-cell complex, full-length binding where a fragment was used. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: FZD4βHTT interaction is supported in the tested yeast two-hybrid constructs, with fragment and mutation-tagged records kept distinct. Reason: The authentic Haenig Table S2 NN1.0 row 3666 matches human FZD4 and HTT; retained expanded-network and IntAct records preserve the 1221β1939 fragment, alongside separately retained 1β511 and 1β88 mutation-tagged contexts. These are human-protein yeast two-hybrid results with pairwise reporter retesting. The original Table S4 contains no FZD4 pair-specific DULIP validation. Retain the positive generic interaction as non-core without claiming an endogenous human-cell complex, full-length binding where a fragment was used, or an exact polyglutamine state from the HTT feature label. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: The Haenig workbook supports FZD4βDNM2 interaction at gene level; the original P50570-2 partner suffix remains unchanged. Reason: The authentic Haenig Table S2 NN1.0 row 3665 matches human FZD4 and DNM2; retained expanded-network and IntAct records preserve the gene-level workbook match with the literal P50570-2 annotation suffix preserved. These are human-protein yeast two-hybrid results with pairwise reporter retesting. The original Table S4 contains no FZD4 pair-specific DULIP validation. Retain the positive generic interaction as non-core without claiming an endogenous human-cell complex, full-length binding where a fragment was used. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: SPRED1-bait/FZD4-prey yeast two-hybrid results support the generic interaction without an endogenous-complex claim. Reason: The authentic Haenig Table S2 NN1.0 row 10468 matches human FZD4 and SPRED1; retained expanded-network and IntAct records preserve the SPRED1-bait/FZD4-prey orientation. These are human-protein yeast two-hybrid results with pairwise reporter retesting. The original Table S4 contains no FZD4 pair-specific DULIP validation. Retain the positive generic interaction as non-core without claiming an endogenous human-cell complex, full-length binding where a fragment was used. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | UNDECIDED | Summary: The retained FZD4-peptide/GRID2IP measurements do not positively resolve the imported binding assertion. Reason: For A4D2P6 (GRID2IP, Glutamate receptor, ionotropic, delta 2-interacting protein 1), every matching FZD4 terminal-peptide/domain measurement retained from the original workbook is below the authorsβ assay threshold. The original pKd field is zero; IntAct retains a literal kd:1.0x10(molar) and negative=false. These values are preserved as source data, not interpreted as a measured 10-M affinity or proof of no interaction. The accessible measurements do not positively establish this pair; clarification of the imported positive assertion or another supporting assay is needed. Keep the curator assertion unresolved rather than remove it. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | UNDECIDED | Summary: MPDZ binding remains unresolved because the retained FZD4-peptide/domain measurements are below the authors' threshold. Reason: For O75970 (MPDZ, MUPP1), every matching FZD4 terminal-peptide/domain measurement retained from the original workbook is below the authorsβ assay threshold. The original pKd field is zero; IntAct retains a literal kd:1.0x10(molar) and negative=false. These values are preserved as source data, not interpreted as a measured 10-M affinity or proof of no interaction. The accessible measurements do not positively establish this pair; clarification of the imported positive assertion or another supporting assay is needed. Keep the curator assertion unresolved rather than remove it. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Positive original terminal-peptide/domain measurements support refinement to PDZ domain binding. Reason: The original PDZ interactome workbook has above-threshold measurements for FZD4βs terminal 528β537 peptide KPGKGSETVV against a domain of P78352 (DLG4, PSD95), at original data rows 2090, 2398, 12395. The experiment measures peptideβPDZ-domain recognition, not a full-length endogenous receptor complex or a partner-specific cellular signaling function. Refine this directly measured recognition to PDZ domain binding while preserving the original partner accession and peptide/domain scope. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | UNDECIDED | Summary: The retained FZD4-peptide/TJP1 measurements are insufficient to verify the imported positive binding context. Reason: For Q07157 (TJP1, Tight junction protein ZO-1), every matching FZD4 terminal-peptide/domain measurement retained from the original workbook is below the authorsβ assay threshold. The original pKd field is zero; IntAct retains a literal kd:1.0x10(molar) and negative=false. These values are preserved as source data, not interpreted as a measured 10-M affinity or proof of no interaction. The accessible measurements do not positively establish this pair; clarification of the imported positive assertion or another supporting assay is needed. Keep the curator assertion unresolved rather than remove it. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Positive original terminal-peptide/domain measurements support refinement to PDZ domain binding. Reason: The original PDZ interactome workbook has above-threshold measurements for FZD4βs terminal 528β537 peptide KPGKGSETVV against a domain of Q12959 (DLG1, Synapse-associated protein 97), at original data rows 1446, 3458. The experiment measures peptideβPDZ-domain recognition, not a full-length endogenous receptor complex or a partner-specific cellular signaling function. Refine this directly measured recognition to PDZ domain binding while preserving the original partner accession and peptide/domain scope. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Positive original terminal-peptide/domain measurements support refinement to PDZ domain binding. Reason: The original PDZ interactome workbook has above-threshold measurements for FZD4βs terminal 528β537 peptide KPGKGSETVV against a domain of Q14005 (IL16), at original data rows 15466. The experiment measures peptideβPDZ-domain recognition, not a full-length endogenous receptor complex or a partner-specific cellular signaling function. Positive original domain rows remain available even though the imported IntAct subset for this partner contains only the zero-valued cases. Refine this directly measured recognition to PDZ domain binding while preserving the original partner accession and peptide/domain scope. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Positive original terminal-peptide/domain measurements support refinement to PDZ domain binding. Reason: The original PDZ interactome workbook has above-threshold measurements for FZD4βs terminal 528β537 peptide KPGKGSETVV against a domain of Q14160 (CRIB1, KIAA0147), at original data rows 8979, 10194, 11806. The experiment measures peptideβPDZ-domain recognition, not a full-length endogenous receptor complex or a partner-specific cellular signaling function. Refine this directly measured recognition to PDZ domain binding while preserving the original partner accession and peptide/domain scope. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Positive original terminal-peptide/domain measurements support refinement to PDZ domain binding. Reason: The original PDZ interactome workbook has above-threshold measurements for FZD4βs terminal 528β537 peptide KPGKGSETVV against a domain of Q15700 (Channel-associated protein of synapse-110, DLG2), at original data rows 2333, 9368. The experiment measures peptideβPDZ-domain recognition, not a full-length endogenous receptor complex or a partner-specific cellular signaling function. Refine this directly measured recognition to PDZ domain binding while preserving the original partner accession and peptide/domain scope. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | UNDECIDED | Summary: The retained CAP70/Q5T2W1 measurements do not positively resolve the imported FZD4 peptide-binding assertion. Reason: For Q5T2W1 ("Na(+)/H(+) exchanger regulatory factor 3", CAP70), every matching FZD4 terminal-peptide/domain measurement retained from the original workbook is below the authorsβ assay threshold. The original pKd field is zero; IntAct retains a literal kd:1.0x10(molar) and negative=false. These values are preserved as source data, not interpreted as a measured 10-M affinity or proof of no interaction. The accessible measurements do not positively establish this pair; clarification of the imported positive assertion or another supporting assay is needed. Keep the curator assertion unresolved rather than remove it. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Positive original terminal-peptide/domain measurements support refinement to PDZ domain binding. Reason: The original PDZ interactome workbook has above-threshold measurements for FZD4βs terminal 528β537 peptide KPGKGSETVV against a domain of Q68DX3 (FRMPD2, PDZ domain-containing protein 4), at original data rows 16841. The experiment measures peptideβPDZ-domain recognition, not a full-length endogenous receptor complex or a partner-specific cellular signaling function. Positive original domain rows remain available even though the imported IntAct subset for this partner contains only the zero-valued cases. Refine this directly measured recognition to PDZ domain binding while preserving the original partner accession and peptide/domain scope. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Positive original terminal-peptide/domain measurements support refinement to PDZ domain binding. Reason: The original PDZ interactome workbook has above-threshold measurements for FZD4βs terminal 528β537 peptide KPGKGSETVV against a domain of Q86UL8 (ACVRINP1, AIP1), at original data rows 1198, 4583, 16567. The experiment measures peptideβPDZ-domain recognition, not a full-length endogenous receptor complex or a partner-specific cellular signaling function. Refine this directly measured recognition to PDZ domain binding while preserving the original partner accession and peptide/domain scope. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | UNDECIDED | Summary: The Q86UT5 FZD4-binding context remains unresolved; the separately retained IntAct participant suffix is not substituted into GOA. Reason: For Q86UT5 (IKEPP, Intestinal and kidney-enriched PDZ protein), every matching FZD4 terminal-peptide/domain measurement retained from the original workbook is below the authorsβ assay threshold. The original pKd field is zero; IntAct retains a literal kd:1.0x10(molar) and negative=false. These values are preserved as source data, not interpreted as a measured 10-M affinity or proof of no interaction. The accessible measurements do not positively establish this pair; clarification of the imported positive assertion or another supporting assay is needed. Keep the curator assertion unresolved rather than remove it. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Positive original terminal-peptide/domain measurements support refinement to PDZ domain binding. Reason: The original PDZ interactome workbook has above-threshold measurements for FZD4βs terminal 528β537 peptide KPGKGSETVV against a domain of Q8N448 (LNX2, Numb-binding protein 2), at original data rows 2118. The experiment measures peptideβPDZ-domain recognition, not a full-length endogenous receptor complex or a partner-specific cellular signaling function. Refine this directly measured recognition to PDZ domain binding while preserving the original partner accession and peptide/domain scope. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Positive original terminal-peptide/domain measurements support refinement to PDZ domain binding. Reason: The original PDZ interactome workbook has above-threshold measurements for FZD4βs terminal 528β537 peptide KPGKGSETVV against a domain of Q8NI35 (CIPP, Channel-interacting PDZ domain-containing protein), at original data rows 16381, 16528, 17984. The experiment measures peptideβPDZ-domain recognition, not a full-length endogenous receptor complex or a partner-specific cellular signaling function. Positive original domain rows remain available even though the imported IntAct subset for this partner contains only the zero-valued cases. Refine this directly measured recognition to PDZ domain binding while preserving the original partner accession and peptide/domain scope. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Positive original terminal-peptide/domain measurements support refinement to PDZ domain binding. Reason: The original PDZ interactome workbook has above-threshold measurements for FZD4βs terminal 528β537 peptide KPGKGSETVV against a domain of Q8TBB1 (LNX, LNX1), at original data rows 16329. The experiment measures peptideβPDZ-domain recognition, not a full-length endogenous receptor complex or a partner-specific cellular signaling function. Positive original domain rows remain available even though the imported IntAct subset for this partner contains only the zero-valued cases. Refine this directly measured recognition to PDZ domain binding while preserving the original partner accession and peptide/domain scope. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Positive original terminal-peptide/domain measurements support refinement to PDZ domain binding. Reason: The original PDZ interactome workbook has above-threshold measurements for FZD4βs terminal 528β537 peptide KPGKGSETVV against a domain of Q92796 (DLG3, KIAA1232), at original data rows 2815, 6249, 9167. The experiment measures peptideβPDZ-domain recognition, not a full-length endogenous receptor complex or a partner-specific cellular signaling function. Refine this directly measured recognition to PDZ domain binding while preserving the original partner accession and peptide/domain scope. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Positive original terminal-peptide/domain measurements support refinement to PDZ domain binding. Reason: The original PDZ interactome workbook has above-threshold measurements for FZD4βs terminal 528β537 peptide KPGKGSETVV against a domain of Q96QZ7 (AIP3, Atrophin-1-interacting protein 3), at original data rows 4603. The experiment measures peptideβPDZ-domain recognition, not a full-length endogenous receptor complex or a partner-specific cellular signaling function. Refine this directly measured recognition to PDZ domain binding while preserving the original partner accession and peptide/domain scope. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | UNDECIDED | Summary: APBA2 binding remains unresolved from the retained below-threshold FZD4 peptide/domain measurements. Reason: For Q99767 (APBA2, Adapter protein X11beta), every matching FZD4 terminal-peptide/domain measurement retained from the original workbook is below the authorsβ assay threshold. The original pKd field is zero; IntAct retains a literal kd:1.0x10(molar) and negative=false. These values are preserved as source data, not interpreted as a measured 10-M affinity or proof of no interaction. The accessible measurements do not positively establish this pair; clarification of the imported positive assertion or another supporting assay is needed. Keep the curator assertion unresolved rather than remove it. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | UNDECIDED | Summary: The retained GRIP2 measurements do not positively establish the imported FZD4 peptide-binding assertion. Reason: For Q9C0E4 (GRIP2, KIAA1719), every matching FZD4 terminal-peptide/domain measurement retained from the original workbook is below the authorsβ assay threshold. The original pKd field is zero; IntAct retains a literal kd:1.0x10(molar) and negative=false. These values are preserved as source data, not interpreted as a measured 10-M affinity or proof of no interaction. The accessible measurements do not positively establish this pair; clarification of the imported positive assertion or another supporting assay is needed. Keep the curator assertion unresolved rather than remove it. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MODIFY | Summary: Positive original terminal-peptide/domain measurements support refinement to PDZ domain binding. Reason: The original PDZ interactome workbook has above-threshold measurements for FZD4βs terminal 528β537 peptide KPGKGSETVV against a domain of Q9P202 (Autosomal recessive deafness type 31 protein, DFNB31), at original data rows 10684. The experiment measures peptideβPDZ-domain recognition, not a full-length endogenous receptor complex or a partner-specific cellular signaling function. Refine this directly measured recognition to PDZ domain binding while preserving the original partner accession and peptide/domain scope. Proposed replacements: PDZ domain binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | UNDECIDED | Summary: GRIP1 binding remains unresolved because the retained FZD4 peptide/domain measurements are below the authors' threshold. Reason: For Q9Y3R0 (GRIP1), every matching FZD4 terminal-peptide/domain measurement retained from the original workbook is below the authorsβ assay threshold. The original pKd field is zero; IntAct retains a literal kd:1.0x10(molar) and negative=false. These values are preserved as source data, not interpreted as a measured 10-M affinity or proof of no interaction. The accessible measurements do not positively establish this pair; clarification of the imported positive assertion or another supporting assay is needed. Keep the curator assertion unresolved rather than remove it. Supporting Evidence: |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: The actual FZD4 lineage inherits the plasma-membrane IBD, consistent with direct surface-localization experiments. Reason: The actual dated PTHR11309 tree places human FZD4 AN15/PTN002477899 beneath the GO:0005886 IBD at AN0/PTN000139394, with no retained loss node on its lineage and an exact 537-residue target alignment. Incoming and retained GAF donor sets differ by one added and one omitted donor, and both versions remain intact; neither donor count nor target self-membership is a defect. The ancestral membrane localization is consistent with direct human FZD4 surface experiments, so retain this core location. Supporting Evidence: GO_REF:0000033 |
| GO:0005886 plasma membrane | IC PMID:17955262 Moderate reduction of Norrin signaling activity associated w... | ACCEPT | Summary: Norrin binding to surface FZD4 supports the inferred plasma-membrane context without changing its IC provenance. Reason: The original Norrin study measures ligand association with cell-surface FZD4 and links binding to receptor signaling. Its IC location inference from the literal Wnt-receptor function is consistent with direct surface assays. Retain plasma membrane as a core receptor location; do not change the original inference code into an experimental one. Supporting Evidence: |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Supported HPA antibody-localization records corroborate FZD4 plasma-membrane residence in the sampled human cell lines. Reason: The authentic HPA method and current official FZD4 XML identify supported antibody-based plasma-membrane localization, including human U2OS and Hep-G2 cell-line observations. This is consistent with the directly demonstrated receptor surface location. Retain plasma membrane as core while keeping cell-line, antibody and method scope; the additional HPA locations are not manufactured as new annotations. Supporting Evidence: GO_REF:0000052 |
| GO:0005886 plasma membrane | IDA PMID:12172548 Mutant frizzled-4 disrupts retinal angiogenesis in familial ... | ACCEPT | Summary: Intact/permeabilized staining supports wild-type human FZD4 surface localization, distinct from the tested disease variants. Reason: The original Figure 4 of PMID12172548 compares HA-tagged wild-type human FZD4 with the M493_W494del and L501fsX533 variants by intact-versus-permeabilized COS-7 staining. This directly addresses receptor localization and is consistent with wild-type surface display. Retain the core plasma-membrane annotation; abnormal localization or abundance of the disease variants must not be assigned to the wild-type product. Supporting Evidence: |
| GO:0005886 plasma membrane | IDA PMID:14688793 Mutant Frizzled 4 associated with vitreoretinopathy traps wi... | ACCEPT | Summary: Wild-type FZD4 surface staining is distinguished from mutant-dependent endoplasmic-reticulum trapping. Reason: Original Figure 4bβg and Supplementary Figure S4 compare intact and permeabilized cells expressing wild-type HA-FZD4, the retained mutant, and their coexpression. Wild-type surface staining is distinguished from mutant-dependent ER trapping. This supports the normal plasma-membrane location and does not make the ER-retained mutant a natural isoform or the default localization. Supporting Evidence: |
| GO:0005886 plasma membrane | IDA PMID:15035989 Vascular development in the retina and inner ear: control by... | ACCEPT | Summary: The Norrin receptor framework and independent direct experiments support FZD4 plasma-membrane localization despite limited access to this paper. Reason: The original abstract describes Norrin as a high-affinity FZD4 ligand and the FZD4/LRP receptor system; direct FZD4 surface localization is independently established by the other retained human receptor experiments. The normal cache remains abstract-only and the attempted original full-text recovery failed, so no unobserved figure or construct detail is claimed. Retain the well-established core plasma-membrane location while preserving the original IDA provenance. Supporting Evidence: |
| GO:0005886 plasma membrane | IDA PMID:30135577 Crystal structure of the Frizzled 4 receptor in a ligand-fre... | ACCEPT | Summary: Structural-study surface assays support membrane residence within their engineered-construct and control scope. Reason: The official original articleβs extended-data captions include FZD4 cellular-localization, surface-biotinylation and FACS analyses, with mutant and expression controls. The structural construct deletes residues 1β177 and 517β537 and contains stabilizing substitutions; it is not a natural isoform. These data support membrane display in the tested constructs together with direct wild-type evidence elsewhere. Retain plasma membrane without inferring physical G-protein coupling from a class-F structural label. Supporting Evidence: |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: The combined electronic plasma-membrane assertion agrees with independent human receptor-localization evidence. Reason: The combined electronic row preserves its literal mouse orthology and UniProt subcellular-location sources. It represents merged provenance rather than multiple independent experiments. Plasma-membrane localization is independently supported by human FZD4 surface assays and current HPA curation, so retain the core location without changing the incoming method or source identifiers. Supporting Evidence: GO_REF:0000120 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3965444 | ACCEPT | Summary: The modeled WNT receptor complex provides membrane context without proving FZD4-specific G-protein exchange chemistry. Reason: The event describes nucleotide exchange in a WNT:FZD:G-protein model. This CC annotation records the receptorβs membrane context; it does not establish a specific FZD4βG-protein physical pair or GEF chemistry from family membership. The retained event summary and incoming TAS location were inspected, not every transitive participant graph. Direct FZD4 surface biology independently supports plasma membrane as a core location. Supporting Evidence: Reactome:R-HSA-3965444 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-3965447 | ACCEPT | Summary: The G-protein dissociation model retains receptor membrane context without establishing every FZD4 coupling interaction. Reason: The event describes dissociation of G-protein subunits from a modeled WNT:FZD complex. Its membrane location is compatible with the receptor, but the event narrative is not independent proof of FZD4 coupling to every listed G-alpha subtype. The retained event summary and incoming TAS location were inspected, not every transitive participant graph. Direct FZD4 surface biology independently supports plasma membrane as a core location. Supporting Evidence: Reactome:R-HSA-3965447 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-4641236 | ACCEPT | Summary: FZD4 remains membrane receptor cargo in the USP8-dependent recycling model; deubiquitinase activity belongs to USP8. Reason: The event describes USP8-dependent deubiquitination and receptor recycling. FZD4 is the membrane receptor cargo, not the deubiquitinase. The retained event summary and incoming TAS location were inspected, not every transitive participant graph. Direct FZD4 surface biology independently supports plasma membrane as a core location. Supporting Evidence: Reactome:R-HSA-4641236 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-4641249 | ACCEPT | Summary: The ligase-association model supports membrane context while leaving the exact FZD4βZNRF3 contact unresolved. Reason: The event groups receptor-complex association with ZNRF3/RNF43. The cited summary explicitly mentions endogenous FZD6 co-immunoprecipitation; this CC assertion does not resolve the separate FZD4-specific ligase-binding question. The retained event summary and incoming TAS location were inspected, not every transitive participant graph. Direct FZD4 surface biology independently supports plasma membrane as a core location. Supporting Evidence: Reactome:R-HSA-4641249 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-4641253 | ACCEPT | Summary: The FZD4 ubiquitination event supports membrane-localized receptor substrate, not receptor ubiquitin-ligase activity. Reason: The summary explicitly describes FZD4 ubiquitination and receptor downregulation. FZD4 is the membrane-localized substrate; ZNRF3 performs the ubiquitination. The retained event summary and incoming TAS location were inspected, not every transitive participant graph. Direct FZD4 surface biology independently supports plasma membrane as a core location. Supporting Evidence: Reactome:R-HSA-4641253 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5099899 | ACCEPT | Summary: The explicit WNT5A:FZD4 event supports plasma-membrane receptor context before internalization. Reason: The retained official event names WNT5A:FZD4 at the plasma membrane, with a FZD4 input and receptor-complex output. Internalization after WNT5A stimulation supplies context; it is not a purified ligand-affinity measurement. The retained event summary and incoming TAS location were inspected, not every transitive participant graph. Direct FZD4 surface biology independently supports plasma membrane as a core location. Supporting Evidence: Reactome:R-HSA-5099899 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5138432 | ACCEPT | Summary: The DVL2 phosphorylation event places FZD4 at the membrane without assigning it PKC activity. Reason: The retained official event describes PKC phosphorylation of DVL2 in FZD4 internalization. The receptor remains membrane-associated in this model and is not itself assigned PKC catalytic activity. The retained event summary and incoming TAS location were inspected, not every transitive participant graph. Direct FZD4 surface biology independently supports plasma membrane as a core location. Supporting Evidence: Reactome:R-HSA-5138432 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5138433 | ACCEPT | Summary: The WNT5A/FZD4 recruitment model supports membrane context while preserving the unresolved arrestin requirement. Reason: The summary places the WNT5A/FZD4 complex in DVL2/AP-2-associated recruitment and explicitly records conflicting evidence on the requirement for arrestin. Membrane localization is retained without resolving that mechanistic controversy. The retained event summary and incoming TAS location were inspected, not every transitive participant graph. Direct FZD4 surface biology independently supports plasma membrane as a core location. Supporting Evidence: Reactome:R-HSA-5138433 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5138441 | ACCEPT | Summary: DVL2 recruitment to WNT5A:FZD4 supports the existing plasma-membrane location. Reason: The retained official event describes recruitment of DVL2 to WNT5A:FZD4 at the plasma membrane, supported by colocalization and co-immunoprecipitation. This is a location annotation, not a new adaptor function. The retained event summary and incoming TAS location were inspected, not every transitive participant graph. Direct FZD4 surface biology independently supports plasma membrane as a core location. Supporting Evidence: Reactome:R-HSA-5138441 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5138459 | ACCEPT | Summary: The WNT5A:FZD4 uptake event retains plasma-membrane residence before the coated-vesicle transition. Reason: The official event has the WNT5A:FZD4 coat-containing complex at the plasma membrane before uptake and a coated-vesicle output. Preserve the pre-internalization membrane context separately from the vesicle-location row. The retained event summary and incoming TAS location were inspected, not every transitive participant graph. Direct FZD4 surface biology independently supports plasma membrane as a core location. Supporting Evidence: Reactome:R-HSA-5138459 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5340587 | ACCEPT | Summary: The RNF43-loss model supports receptor membrane context without assigning the regulator's mutation phenotype to FZD4 function. Reason: The event concerns RNF43 loss-of-function and increased receptor abundance/signaling. The receptorβs membrane location remains valid; the RNF43 mutation and cancer proliferation outcomes are not assigned as FZD4 molecular functions. The retained event summary and incoming TAS location were inspected, not every transitive participant graph. Direct FZD4 surface biology independently supports plasma membrane as a core location. Supporting Evidence: Reactome:R-HSA-5340587 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8866269 | ACCEPT | Summary: Arrestin recruitment supplies a membrane-cargo context without proving a specific FZD4 coupling mechanism. Reason: The arrestin-recruitment event provides a membrane-cargo context in a general receptor-endocytosis model. It does not independently demonstrate every FZD4/arrestin contact or equate arrestin recruitment with G-protein coupling. The retained event summary and incoming TAS location were inspected, not every transitive participant graph. Direct FZD4 surface biology independently supports plasma membrane as a core location. Supporting Evidence: Reactome:R-HSA-8866269 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8866283 | ACCEPT | Summary: Recruitment of receptor cargo to coated pits is compatible with the established FZD4 plasma-membrane location. Reason: The event models receptor cargo recruitment to nascent clathrin-coated pits. The receptor occupies the membrane; the sorting activities belong to coat/adaptor machinery. The retained event summary and incoming TAS location were inspected, not every transitive participant graph. Direct FZD4 surface biology independently supports plasma membrane as a core location. Supporting Evidence: Reactome:R-HSA-8866283 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8867754 | ACCEPT | Summary: The BAR-protein recruitment model retains membrane receptor cargo without assigning curvature-generating activity to FZD4. Reason: The event describes recruitment of BAR-domain proteins to membrane curvature. FZD4 is receptor cargo in the modeled membrane, not a BAR-domain curvature-generating protein. The retained event summary and incoming TAS location were inspected, not every transitive participant graph. Direct FZD4 surface biology independently supports plasma membrane as a core location. Supporting Evidence: Reactome:R-HSA-8867754 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8867756 | ACCEPT | Summary: The cargo-recruitment event supports membrane context without making FZD4 a cargo-sorting adaptor. Reason: The event recruits CLASP proteins and cargo into the nascent coated pit. Its membrane context is compatible with FZD4 receptor uptake and does not establish a new cargo-sorting function for FZD4. The retained event summary and incoming TAS location were inspected, not every transitive participant graph. Direct FZD4 surface biology independently supports plasma membrane as a core location. Supporting Evidence: Reactome:R-HSA-8867756 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868071 | ACCEPT | Summary: PIK3C2A recruitment supplies membrane context; its kinase function is not assigned to FZD4. Reason: The event describes clathrin recruitment of PIK3C2A. The kinase is a separate protein; the FZD4 CC assertion records membrane-associated receptor cargo. The retained event summary and incoming TAS location were inspected, not every transitive participant graph. Direct FZD4 surface biology independently supports plasma membrane as a core location. Supporting Evidence: Reactome:R-HSA-8868071 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868072 | ACCEPT | Summary: The phosphoinositide-phosphorylation event supports membrane location without assigning that catalytic step to FZD4. Reason: The event describes PIK3C2A phosphoinositide phosphorylation at the membrane. Retain receptor location without assigning this catalytic step to FZD4. The retained event summary and incoming TAS location were inspected, not every transitive participant graph. Direct FZD4 surface biology independently supports plasma membrane as a core location. Supporting Evidence: Reactome:R-HSA-8868072 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868230 | ACCEPT | Summary: The SNX9/actin-recruitment model supports membrane receptor context without making FZD4 an actin nucleator. Reason: The event describes SNX9-associated recruitment of actin machinery and its membrane-tension context. It does not make FZD4 an actin nucleator; receptor cargo remains membrane-localized. The retained event summary and incoming TAS location were inspected, not every transitive participant graph. Direct FZD4 surface biology independently supports plasma membrane as a core location. Supporting Evidence: Reactome:R-HSA-8868230 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868236 | ACCEPT | Summary: Dynamin recruitment to the coated-pit neck retains FZD4 as membrane receptor cargo. Reason: The event describes BAR-protein recruitment of dynamin to the coated-pit neck. FZD4 is receptor cargo and not the scission GTPase. The retained event summary and incoming TAS location were inspected, not every transitive participant graph. Direct FZD4 surface biology independently supports plasma membrane as a core location. Supporting Evidence: Reactome:R-HSA-8868236 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868648 | ACCEPT | Summary: The phosphoinositide-hydrolysis event supports membrane context while preserving the distinct phosphatase actors. Reason: The event describes SYNJ/OCRL phosphoinositide hydrolysis during pit maturation and uncoating. The phosphatase chemistry belongs to those enzymes, not the membrane receptor. The retained event summary and incoming TAS location were inspected, not every transitive participant graph. Direct FZD4 surface biology independently supports plasma membrane as a core location. Supporting Evidence: Reactome:R-HSA-8868648 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868651 | ACCEPT | Summary: Synaptojanin recruitment supplies coated-pit membrane context without establishing a direct FZD4/endophilin pair. Reason: The event describes endophilin-mediated synaptojanin recruitment. This supplies a coated-pit membrane context, not a direct FZD4/endophilin interaction claim. The retained event summary and incoming TAS location were inspected, not every transitive participant graph. Direct FZD4 surface biology independently supports plasma membrane as a core location. Supporting Evidence: Reactome:R-HSA-8868651 |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8868661 | ACCEPT | Summary: The scission event retains FZD4's pre-scission plasma-membrane context; dynamin performs GTP hydrolysis. Reason: The event describes dynamin-driven scission of the nascent vesicle from the plasma membrane. Retain the pre-scission receptor membrane context separately from the vesicle annotation; dynamin performs GTP hydrolysis. The retained event summary and incoming TAS location were inspected, not every transitive participant graph. Direct FZD4 surface biology independently supports plasma membrane as a core location. Supporting Evidence: Reactome:R-HSA-8868661 |
| GO:0005911 cell-cell junction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The mouse donor's epithelial-contact experiments support a specialized junctional location without claiming direct human localization. Reason: The literal mouse Q61088 donor has a cell-cell-junction IDA from PMID15195140. The original abstract and official Figure 4 describe mouse Fzd4/MAGI3/Ltap localization at epithelial contact sites in an expression-cell system. This supports the orthology-derived junctional context as non-core, without claiming a direct human junction assay or universal localization. |
| GO:0007166 cell surface receptor signaling pathway | IEA GO_REF:0000002 | TOO GENERAL | Summary: Broad cell-surface signaling is entailed by the retained Wnt and Norrin pathways. Reason: Broad cell-surface signaling is entailed by the retained Wnt and Norrin pathways. Both relevant is_a ancestries were checked. |
| GO:0007223 Wnt signaling pathway, calcium modulating pathway | IDA PMID:12172548 Mutant frizzled-4 disrupts retinal angiogenesis in familial ... | ACCEPT | Summary: 12172548 explicitly reports wild-type human FZD4 activating CAMKII/PKC when expressed in Xenopus embryos, unlike disease variants. Reason: 12172548 explicitly reports wild-type human FZD4 activating CAMKII/PKC when expressed in Xenopus embryos, unlike disease variants. This supports calcium-branch signaling without establishing a specific heterotrimeric G-protein coupling mechanism. Supporting Evidence: |
| GO:0009986 cell surface | IDA PMID:19643732 A coated vesicle-associated kinase of 104 kDa (CVAK104) indu... | ACCEPT | Summary: The original Fzd4-GFP comparator supports cell-surface localization independently of the paper's Fzd5-focused internalization findings. Reason: The original PMID19643732 Figure 2A visibly includes Fzd4-GFP at the cell periphery in transfected 293 cells, alongside Fzd1 and Fzd5. Figure 2B distinguishes the strong CVAK104-dependent Fzd5 internalization from the Fzd4 control. Thus the paperβs focus on Fzd5 does not invalidate the FZD4 cell-surface observation. Retain the core surface location without assigning Fzd5-specific CVAK104 binding to FZD4. Supporting Evidence: |
| GO:0009986 cell surface | IEA GO_REF:0000117 | ACCEPT | Summary: The ARBA cell-surface prediction agrees with independent direct FZD4 localization, without elevating its electronic provenance. Reason: The actual ARBA00027349 record predicts GO:0009986 cell surface through automated rule conditions. The rule is not itself an experiment, and its complete FZD4 rule-condition match was not independently reconstructed. The predicted location is nevertheless supported by direct human FZD4 intact-cell staining and ligand/surface assays, so retain it as core without elevating the IEA provenance. Supporting Evidence: GO_REF:0000117 PMID:19643732 each Fzd-GFP localized predominantly at the cell surface |
| GO:0010812 negative regulation of cell-substrate adhesion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mouse Fzd4 knockdown supports a context-dependent negative regulation of cell-substrate adhesion. Reason: The mouse donor's 18156211 experiment and original Fig. 2 support increased spreading after Fzd4 knockdown. Retain a context-dependent adhesion phenotype, separate from receptor molecular function. Supporting Evidence: |
| GO:0010812 negative regulation of cell-substrate adhesion | IMP PMID:18156211 Regulation of endothelial cell cytoskeletal reorganization b... | KEEP AS NON CORE | Summary: Preserve the human experimental annotation. Reason: Preserve the human experimental annotation. Read the article's original Fig. 2 and cross-system legends: the negative-regulation direction is supported, but not every assay is an endogenous human experiment. Do not infer a wrong-gene or wrong-species defect from incomplete full text. Supporting Evidence: |
| GO:0016020 membrane | IEA GO_REF:0000002 | TOO GENERAL | Summary: The broad membrane assignment is represented more precisely by the supported plasma-membrane term. Reason: The InterPro signature mapping supports a membrane protein, consistent with the seven-pass receptor architecture. Current GO identifies plasma membrane GO:0005886 as a direct is_a child of membrane GO:0016020, and multiple retained human observations establish that more specific location. Mark the broad membrane term too general while preserving the original IPR000539/IPR017981 sources. Supporting Evidence: GO_REF:0000002 |
| GO:0016055 Wnt signaling pathway | IEA GO_REF:0000120 | TOO GENERAL | Summary: Broad electronic Wnt signaling is covered by retained specific Wnt branches; this does not substitute Norrin for a Wnt ligand. Reason: Broad electronic Wnt signaling is covered by retained specific Wnt branches; this does not substitute Norrin for a Wnt ligand. |
| GO:0016055 Wnt signaling pathway | ISS GO_REF:0000024 | TOO GENERAL | Summary: Wnt signaling is a correct broad pathway covered by retained canonical/noncanonical Wnt functions. Reason: Wnt signaling is a correct broad pathway covered by retained canonical/noncanonical Wnt functions. Preserve the hippocampal-neuron extension and its original mouse transfer evidence. |
| GO:0017147 Wnt-protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: The actual target lineage passes through the experimentally grounded family-root IBD at PANTHER:PTN000139394. Reason: The actual target lineage passes through the experimentally grounded family-root IBD at PANTHER:PTN000139394. Target cysteine-rich ligand-binding and receptor motifs are retained, with no target-lineage loss assertion. Human receptor evidence independently supports Wnt recognition. The current GOA donor alternatives and older retained PAINT source list are preserved separately; donor-count differences do not invalidate this phylogenetic assertion. Supporting Evidence: |
| GO:0017147 Wnt-protein binding | IEA GO_REF:0000120 | ACCEPT | Summary: Mouse/rat Fzd4 orthology supports conserved Wnt recognition; independent human receptor assays support the function. Reason: Mouse/rat Fzd4 orthology supports conserved Wnt recognition; independent human receptor assays support the function. Do not describe the combined electronic transfer as a new direct human binding experiment. |
| GO:0017147 Wnt-protein binding | TAS PMID:18234671 Amyloid-beta binds to the extracellular cysteine-rich domain... | ACCEPT | Summary: Retain the established Wnt-binding function. Reason: Retain the established Wnt-binding function. 18234671 concerns interference with Frizzled/Wnt interactions; the available FZD4 beta40 experiment does not by itself establish every Wnt ligand specificity. Supporting Evidence: |
| GO:0017147 Wnt-protein binding | TAS PMID:25424568 A novel Wnt5a-Frizzled4 signaling pathway mediates activity-... | ACCEPT | Summary: Preserve the Wnt5a has_input extension. Reason: Preserve the Wnt5a has_input extension. 25424568 supports a functional Wnt5aβFzd4 relationship in neuronal cultures; distinguish that signaling evidence from a purified affinity determination. Supporting Evidence: |
| GO:0019221 cytokine-mediated signaling pathway | IEA GO_REF:0000108 | KEEP AS NON CORE | Summary: Cytokine-mediated signaling is coherent with Norrin recognition; the checked ontology does not make Norrin signaling its is_a descendant. Reason: The GO:0004896 cytokine-receptor mapping agrees with the Norrin/FZD4 receptor mechanism: Norrin binding initiates a signaling cascade with downstream cellular regulation. An explicit current is_a-only lookup for GO:0110135 does not include GO:0019221 among its ancestors, so a formal ancestry-based TOO_GENERAL judgment is not supported by that lookup. Retain this independently coherent broad signaling context as non-core while the more informative Norrin pathway remains in the core. No unverified ontology edge is asserted. Supporting Evidence: |
| GO:0019955 cytokine binding | IEA GO_REF:0000107 | ACCEPT | Summary: The mouse cytokine-binding donor chain includes experimental Norrin binding in 15035989, and the human target has independent binding/signaling evidence. Reason: The mouse cytokine-binding donor chain includes experimental Norrin binding in 15035989, and the human target has independent binding/signaling evidence. Retain as a conserved ligand-recognition role. |
| GO:0019955 cytokine binding | IPI PMID:17955262 Moderate reduction of Norrin signaling activity associated w... | ACCEPT | Summary: The original Norrin partner is Q00604. Reason: The original Norrin partner is Q00604. 17955262 reports cell-surface binding alongside Norrin-dependent signaling; retain the specific ligand context. Supporting Evidence: |
| GO:0030165 PDZ domain binding | IDA PMID:20802536 Direct interaction between NHERF1 and Frizzled regulates Ξ²-c... | KEEP AS NON CORE | Summary: FZD4 terminal-motif recognition by NHERF1 PDZ2 is supported by mutagenesis, association and overlay assays. Reason: The original NHERF1 full text establishes binding through the terminal FZD4 motif and NHERF1 PDZ2 using co-immunoprecipitation, receptor and scaffold mutants, and recombinant-protein overlay. This is specific PDZ-domain recognition that regulates receptor trafficking in the tested cells. It supports the annotation but is an interaction mechanism supporting the receptor role, rather than an additional core signaling-receptor activity. Supporting Evidence: |
| GO:0030165 PDZ domain binding | IPI PMID:19388021 Sequence requirement and subtype specificity in the high-aff... | KEEP AS NON CORE | Summary: A competition assay supports binding of the FZD4 internal peptide to human DVL1 PDZ, with IC50 distinguished from affinity. Reason: The retained indexed original Table II tests the FZD4 internal Dishevelled-binding-region peptide against the human DVL1 PDZ domain in a competition assay, reporting an IC50 of 2.2 micromolar. This is a directly measured PDZ-domain interaction; IC50 is not a dissociation constant, and the peptide/domain assay does not by itself establish a full-length endogenous binary complex. Retain this supporting molecular interaction as non-core alongside the receptor activities. Supporting Evidence: |
| GO:0030165 PDZ domain binding | IPI PMID:19388021 Sequence requirement and subtype specificity in the high-aff... | KEEP AS NON CORE | Summary: A competition assay supports binding of the FZD4 internal peptide to human DVL2 PDZ, without a whole-receptor affinity claim. Reason: The retained indexed original Table II tests the FZD4 internal Dishevelled-binding-region peptide against the human DVL2 PDZ domain in a competition assay, reporting an IC50 of 0.9 micromolar. This is a directly measured PDZ-domain interaction; IC50 is not a dissociation constant, and the peptide/domain assay does not by itself establish a full-length endogenous binary complex. Retain this supporting molecular interaction as non-core alongside the receptor activities. Supporting Evidence: |
| GO:0030165 PDZ domain binding | IPI PMID:19388021 Sequence requirement and subtype specificity in the high-aff... | KEEP AS NON CORE | Summary: The FZD4 internal peptide binds human DVL3 PDZ in the reported competition assay. Reason: The retained indexed original Table II tests the FZD4 internal Dishevelled-binding-region peptide against the human DVL3 PDZ domain in a competition assay, reporting an IC50 of 1.8 micromolar. This is a directly measured PDZ-domain interaction; IC50 is not a dissociation constant, and the peptide/domain assay does not by itself establish a full-length endogenous binary complex. Retain this supporting molecular interaction as non-core alongside the receptor activities. Supporting Evidence: |
| GO:0030182 neuron differentiation | ISS GO_REF:0000024 | UNDECIDED | Summary: The WNT7B similarity source needs checking, and the FZD4 differentiation role remains unresolved. Reason: The literal ISS source P56706 is WNT7B, not a Frizzled ortholog, so its similarity-transfer provenance requires an upstream check. PMID:12429992 reports FZD4 expression changes during retinoic-acid-induced differentiation of human NT2 cells, but does not establish that FZD4 itself executes neuronal differentiation. The review article retains a positive FZD4 transcript response to retinoic acid, but that observation does not resolve this particular ISS/product annotation or establish neuronal differentiation. Preserve the original row as UNDECIDED and retain the exact questionable source identifier. Supporting Evidence: |
| GO:0030335 positive regulation of cell migration | IMP PMID:22057916 Tumor suppressor microRNA-493 decreases cell motility and mi... | KEEP AS NON CORE | Summary: Original 22057916 Methods/Results show direct FZD4 siRNA reduces T24/J82 migration. Reason: Original 22057916 Methods/Results show direct FZD4 siRNA reduces T24/J82 migration. Retain this context-dependent cancer-cell phenotype, without promoting it to receptor core function or relying only on miR-493 effects. Supporting Evidence: |
| GO:0030425 dendrite | IEA GO_REF:0000107 | UNDECIDED | Summary: The automated mouse dendrite-location transfer remains unresolved without the original localization experiment. Reason: The complete mouse donor response links this automated dendrite transfer to the same PMID25424568 experimental source. The original abstract supports a neuronal morphogenesis role but does not expose the localization assay; the failed full-text retrieval is not evidence that the curator was wrong. Keep the dendrite location unresolved rather than infer localization solely from the phenotype, preserving both literal donor identifiers. |
| GO:0030425 dendrite | ISS GO_REF:0000024 | UNDECIDED | Summary: The mouse dendrite-localization transfer remains unresolved because the accessible morphogenesis abstract does not expose its localization assay. Reason: The literal mouse Q61088 donor has a dendrite IMP from PMID25424568 with the same part_of CL:0002608 context. The accessible original abstract supports Wnt5a/Fzd4-dependent dendrite branching and growth in primary hippocampal cultures, but the full localization experiment and its controls were not recovered. A morphogenesis phenotype alone is not sufficient to verify located_in dendrite. Preserve the ISS and cell-type extension as unresolved pending the original localization evidence. |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-5138459 | KEEP AS NON CORE | Summary: The explicit WNT5A:FZD4 uptake event supports transient coated-vesicle membrane residence. Reason: WNT5A:FZD4 uptake explicitly yields a clathrin-coated-vesicle complex in the retained official event; this is transient receptor trafficking. Retain the existing clathrin-coated endocytic-vesicle membrane location as a non-core trafficking context. The individual event summary and incoming TAS assertion were inspected without claiming a complete transitive-participant audit; direct FZD4 internalization and the specific WNT5A:FZD4 event support the broader trafficking interpretation. Supporting Evidence: Reactome:R-HSA-5138459 |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868658 | KEEP AS NON CORE | Summary: The HSPA8 uncoating model places receptor cargo in vesicular membrane without assigning ATPase activity to FZD4. Reason: The event describes HSPA8-driven coat removal; FZD4 is modeled vesicular cargo, not an ATPase. Retain the existing clathrin-coated endocytic-vesicle membrane location as a non-core trafficking context. The individual event summary and incoming TAS assertion were inspected without claiming a complete transitive-participant audit; direct FZD4 internalization and the specific WNT5A:FZD4 event support the broader trafficking interpretation. Supporting Evidence: Reactome:R-HSA-8868658 |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868659 | KEEP AS NON CORE | Summary: Auxilin recruitment supplies a transient coated-vesicle context for the receptor cargo. Reason: The event describes recruitment of auxilins to clathrin-coated vesicles; the receptor is cargo, not an auxilin cochaperone. Retain the existing clathrin-coated endocytic-vesicle membrane location as a non-core trafficking context. The individual event summary and incoming TAS assertion were inspected without claiming a complete transitive-participant audit; direct FZD4 internalization and the specific WNT5A:FZD4 event support the broader trafficking interpretation. Supporting Evidence: Reactome:R-HSA-8868659 |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868660 | KEEP AS NON CORE | Summary: HSPA8 recruitment supplies vesicular membrane context without making FZD4 an ATP-dependent uncoating factor. Reason: The event describes auxilin recruitment of HSPA8:ATP; it supplies vesicle context rather than an ATP-dependent activity of FZD4. Retain the existing clathrin-coated endocytic-vesicle membrane location as a non-core trafficking context. The individual event summary and incoming TAS assertion were inspected without claiming a complete transitive-participant audit; direct FZD4 internalization and the specific WNT5A:FZD4 event support the broader trafficking interpretation. Supporting Evidence: Reactome:R-HSA-8868660 |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8868661 | KEEP AS NON CORE | Summary: Dynamin-mediated scission supports receptor cargo in vesicular membrane without assigning GTP hydrolysis to FZD4. Reason: The dynamin scission event produces vesicular membrane cargo; FZD4 does not perform the GTP hydrolysis. Retain the existing clathrin-coated endocytic-vesicle membrane location as a non-core trafficking context. The individual event summary and incoming TAS assertion were inspected without claiming a complete transitive-participant audit; direct FZD4 internalization and the specific WNT5A:FZD4 event support the broader trafficking interpretation. Supporting Evidence: Reactome:R-HSA-8868661 |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8869438 | KEEP AS NON CORE | Summary: Coat disassembly supplies a transient vesicular receptor context while retaining the model's timing uncertainty. Reason: The event describes loss of coat-associated proteins, with timing and mechanism explicitly uncertain in the summary; it is not direct evidence that FZD4 disassembles the coat. Retain the existing clathrin-coated endocytic-vesicle membrane location as a non-core trafficking context. The individual event summary and incoming TAS assertion were inspected without claiming a complete transitive-participant audit; direct FZD4 internalization and the specific WNT5A:FZD4 event support the broader trafficking interpretation. Supporting Evidence: Reactome:R-HSA-8869438 |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8871193 | KEEP AS NON CORE | Summary: The AP-2 uncoating model supports vesicular cargo context without assigning its catalytic or exchange steps to FZD4. Reason: The event describes AAK1 displacement and AP-2 dephosphorylation during uncoating; FZD4 is receptor cargo, not the catalyst or exchange factor. Retain the existing clathrin-coated endocytic-vesicle membrane location as a non-core trafficking context. The individual event summary and incoming TAS assertion were inspected without claiming a complete transitive-participant audit; direct FZD4 internalization and the specific WNT5A:FZD4 event support the broader trafficking interpretation. Supporting Evidence: Reactome:R-HSA-8871193 |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-8871194 | KEEP AS NON CORE | Summary: The RAB5/GAPVD1 trafficking model supports vesicular receptor context without asserting a direct FZD4βRAB5 pair. Reason: The event describes RAB5/GAPVD1 association with AP-2 during receptor-cargo trafficking, not a demonstrated direct FZD4βRAB5 binding pair. Retain the existing clathrin-coated endocytic-vesicle membrane location as a non-core trafficking context. The individual event summary and incoming TAS assertion were inspected without claiming a complete transitive-participant audit; direct FZD4 internalization and the specific WNT5A:FZD4 event support the broader trafficking interpretation. Supporting Evidence: Reactome:R-HSA-8871194 |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:22575959 ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensiti... | UNDECIDED | Summary: FZD4 ubiquitination and surface regulation are established, but the exact FZD4βZNRF3 physical-binding assertion remains unresolved. Reason: The original abstract establishes ZNRF3 association with the Wnt-receptor complex. Accessible original Figure 3 and Supplementary Figure 5 directly show effects on FZD4 ubiquitination and surface abundance, but the displayed co-immunoprecipitation panels identify FZD8 or FZD6, not an independently resolved FZD4βZNRF3 pair. Receptor ubiquitination does not alone prove the specific physical binding asserted here. Preserve the literal Q9ULT6 IPI context as unresolved pending the exact FZD4 interaction experiment; this is not a claim of curator misattribution or a contradiction of FZD4 turnover. Supporting Evidence: |
| GO:0035426 extracellular matrix-cell signaling | IEA GO_REF:0000107 | UNDECIDED | Summary: The mouse donor row traces to PMID:15035989, whose accessible abstract does not settle the precise extracellular-matrix signaling relationship. Reason: The mouse donor row traces to PMID:15035989, whose accessible abstract does not settle the precise extracellular-matrix signaling relationship. Selected original PMID:19837032 Results show retinal endothelial network formation on Matrigel and ECM transcript outputs, but these do not identify matrix-origin signaling as the Fzd4 input. Preserve the annotation as unresolved without treating Norrin secretion alone as sufficient evidence. |
| GO:0035567 non-canonical Wnt signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: The actual tree places human FZD4 below the noncanonical-pathway IBD at PANTHER:PTN000139394, with no target-path loss assertion. Reason: The actual tree places human FZD4 below the noncanonical-pathway IBD at PANTHER:PTN000139394, with no target-path loss assertion. Human FZD4 calcium-branch evidence in PMID:12172548 and the rodent neuronal Wnt5a/Fzd4 pathway in PMID:25424568 independently support signaling competence. Preserve the literal current donor set and its separate older-PAINT comparison. |
| GO:0035567 non-canonical Wnt signaling pathway | TAS PMID:25424568 A novel Wnt5a-Frizzled4 signaling pathway mediates activity-... | ACCEPT | Summary: 25424568 supports a Wnt5aβFzd4 dendritic signaling route involving the distal PDZ motif, with Dvl acting in parallel. Reason: 25424568 supports a Wnt5aβFzd4 dendritic signaling route involving the distal PDZ motif, with Dvl acting in parallel. Retain the noncanonical pathway while preserving rodent/culture scope. Supporting Evidence: |
| GO:0038023 signaling receptor activity | IEA GO_REF:0000120 | TOO GENERAL | Summary: Combined electronic sources support a signaling receptor, but retained specific Wnt and cytokine receptor functions are more informative. Reason: Combined electronic sources support a signaling receptor, but retained specific Wnt and cytokine receptor functions are more informative. |
| GO:0038023 signaling receptor activity | ISS GO_REF:0000024 | TOO GENERAL | Summary: Broad receptor activity is covered by retained Wnt receptor activity. Reason: Broad receptor activity is covered by retained Wnt receptor activity. Preserve the conjunctive neuron/Wnt extension; this is a term-precision judgment, not deletion of the neuronal context. |
| GO:0042803 protein homodimerization activity | IPI PMID:14688793 Mutant Frizzled 4 associated with vitreoretinopathy traps wi... | KEEP AS NON CORE | Summary: Receptor complementation supports FZD4 self-association in expressed constructs, without fixing endogenous dimer stoichiometry. Reason: Original Figure 4a directly tests FZD4 self-association by beta-galactosidase complementation in transfected 293T cells. Supplementary Figure S3 also reports FZD4/FZD4 complementation. This supports the existing homotypic association annotation as non-core. The assay demonstrates receptor proximity/oligomer association, not a fixed physiological dimer stoichiometry; mutant trapping and wild-type surface localization are distinct observations. Supporting Evidence: |
| GO:0042813 Wnt receptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: The actual target lineage passes through the receptor-activity IBD at PANTHER:PTN000139394. Reason: The actual target lineage passes through the receptor-activity IBD at PANTHER:PTN000139394. Human FZD4 has direct functional Wnt-receptor evidence in PMID:28733458, and target self-inclusion is expected experimental grounding rather than circularity. Target motifs are retained, with no loss assertion on the examined path. Supporting Evidence: |
| GO:0042813 Wnt receptor activity | IDA PMID:28733458 Mapping of Wnt-Frizzled interactions by multiplex CRISPR tar... | ACCEPT | Summary: 28733458's human-receptor functional screen directly supports FZD4-mediated Wnt signaling. Reason: 28733458's human-receptor functional screen directly supports FZD4-mediated Wnt signaling. Keep the distinction between signaling competence and isolated binding measurements. Supporting Evidence: |
| GO:0042813 Wnt receptor activity | IEA GO_REF:0000120 | ACCEPT | Summary: Orthology/domain support agrees with the experimentally established human Wnt receptor role. Reason: Orthology/domain support agrees with the experimentally established human Wnt receptor role. Supporting Evidence: |
| GO:0044877 protein-containing complex binding | IPI PMID:18234671 Amyloid-beta binds to the extracellular cysteine-rich domain... | UNDECIDED | Summary: The official ComplexPortal record identifies CPX-1134 as the amyloid-beta protein42 oligomeric complex. Reason: The official ComplexPortal record identifies CPX-1134 as the amyloid-beta protein42 oligomeric complex. PMID:18234671 Figure1C explicitly includes FZD4 with beta40, whereas the accessible beta42/aggregate panels in Figure2 name FZD5. The complete target-specific experiment remains unverified because full text was unavailable. Preserve this complex-specific assertion as unresolved; neither an absent experiment nor curator error is inferred. Supporting Evidence: |
| GO:0045202 synapse | IEA GO_REF:0000107 | TOO GENERAL | Summary: The donor-supported synaptic location is retained through the more specific glutamatergic-synapse term. Reason: The literal mouse Q61088 donor has same-term experimental annotations, and the retained indexed original PMID16501258 Results/Figure 1 reports Fzd4 puncta colocalizing with PSD-95 in mouse hippocampal synaptic regions. This supports the synaptic context. The same donor evidence also supports the more specific glutamatergic-synapse row retained here; current GO defines GO:0098978 as a direct is_a child of GO:0045202. Mark the broad synapse term too general without rejecting its provenance or turning mouse localization into a human experiment. |
| GO:0045893 positive regulation of DNA-templated transcription | IDA PMID:17955262 Moderate reduction of Norrin signaling activity associated w... | KEEP AS NON CORE | Summary: FZD4-dependent reporter activation supports non-core positive regulation of transcription. Reason: PMID:17955262 directly measures Norrin-dependent Topflash reporter activation and its reduction by FZD4 disease variants. GO:0045893 describes processes increasing DNA-templated transcription; it does not require the annotated protein to bind DNA. FZD4 contributes the upstream receptor-signaling step that regulates this transcriptional output. Retain the experimental positive-regulation assertion as a non-core signaling outcome, without assigning transcription-factor molecular activity or a nuclear location to the receptor. Supporting Evidence: PMID:17955262 utilizing the Norrin dependent Topflash reporter assay |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:14688793 Mutant Frizzled 4 associated with vitreoretinopathy traps wi... | KEEP AS NON CORE | Summary: The original SuperTOPflash experiment supports a receptor-dependent transcriptional-regulation context. Reason: The authentic PMID:14688793 abstract reports that ER-trapped mutant FZD4 inhibits wild-type receptor signaling. The retained original Figure 4h caption specifically identifies a SuperTOPflash reporter assay, while the complete article remains unavailable. GO:0045944 includes processes increasing transcription from RNA polymerase II promoters and is not restricted to DNA-binding factors. Together with independently established FZD4/beta-catenin reporter signaling, this supports retaining the curated IDA assertion as non-core transcriptional regulation. Preserve the mutant-versus-wild-type experiment and its access limit rather than relabeling receptor signaling as direct nuclear catalysis. Supporting Evidence: |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IDA PMID:15035989 Vascular development in the retina and inner ear: control by... | KEEP AS NON CORE | Summary: Norrin/FZD4 pathway activation supports transcriptional regulation with the original assay-access limit retained. Reason: The authentic PMID:15035989 abstract directly supports Norrin/FZD4/LRP-dependent activation of the classical Wnt pathway. Its complete transcriptional assay was not recovered, so the original curated IDA attribution remains source-qualified. Independent human FZD4 Topflash experiments in PMID:17955262 and TOP/FOP assays in PMID:20802536 support receptor-dependent transcriptional regulation at gene level. Because GO:0045944 denotes regulation rather than direct transcription-factor molecular activity, retain this downstream regulatory context as non-core without claiming that the unavailable original experiment was independently re-read. |
| GO:0045944 positive regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The conserved reporter-regulation outcome is supported independently in human FZD4 assays. Reason: The original mouse Q61088 and Ensembl donor identifiers support an orthology-derived transcriptional-regulation assertion. Independent human FZD4 reporter experiments in PMID:17955262 and PMID:20802536 establish the same gene-level outcome. GO:0045944 permits regulation through a signaling cascade; the receptor need not itself bind a promoter. Retain this non-core regulatory output while preserving electronic provenance and avoiding an unsupported nuclear or DNA-binding molecular function. |
| GO:0046982 protein heterodimerization activity | IPI PMID:14688793 Mutant Frizzled 4 associated with vitreoretinopathy traps wi... | KEEP AS NON CORE | Summary: FZD4βFZD9 complementation supports heterotypic association in the tested expression system, not an obligatory endogenous heterodimer. Reason: The original Supplementary Figure S3b explicitly includes human FZD4 and FZD9 in the receptor complementation matrix; the FZD4/FZD9 cell is 7.3-fold relative to the FZD1/Smoothened comparator, in a representative experiment of three. This supports the literal O00144/FZD9 heterotypic association as non-core. It does not establish a constitutive endogenous heterodimer or the stoichiometry of a physiological signaling complex. Supporting Evidence: |
| GO:0050775 positive regulation of dendrite morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The rat donor has experimental support in 25424568 for Fzd4-dependent dendrite growth. Reason: The rat donor has experimental support in 25424568 for Fzd4-dependent dendrite growth. Retain the developmental outcome with explicit transfer scope. Supporting Evidence: |
| GO:0060070 canonical Wnt signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Human functional receptor evidence in PMID:28733458 and PMID:20802536 supports canonical Wnt signaling. Reason: Human functional receptor evidence in PMID:28733458 and PMID:20802536 supports canonical Wnt signaling. The actual phylogeny additionally places FZD4 below PANTHER:PTN000139394 with the corresponding IBD and no target-path loss assertion. The target being among descendant experimental sources is expected, not circular. |
| GO:0060070 canonical Wnt signaling pathway | IDA PMID:14688793 Mutant Frizzled 4 associated with vitreoretinopathy traps wi... | ACCEPT | Summary: The established canonical receptor function is consistent with the 14688793 signaling/trafficking study and independent human assays. Reason: The established canonical receptor function is consistent with the 14688793 signaling/trafficking study and independent human assays. Do not reject its experimental annotation merely because the abstract emphasizes oligomerization. Supporting Evidence: |
| GO:0060070 canonical Wnt signaling pathway | IDA PMID:20802536 Direct interaction between NHERF1 and Frizzled regulates Ξ²-c... | ACCEPT | Summary: Original 20802536 experiments use human FZD4 in CHO cells and Wnt5a-responsive beta-catenin reporter signaling. Reason: Original 20802536 experiments use human FZD4 in CHO cells and Wnt5a-responsive beta-catenin reporter signaling. Preserve receptor species versus host species. Supporting Evidence: |
| GO:0060070 canonical Wnt signaling pathway | IDA PMID:28733458 Mapping of Wnt-Frizzled interactions by multiplex CRISPR tar... | ACCEPT | Summary: 28733458 directly tests human FZD4 in a Wnt-receptor functional screen, supporting canonical signaling. Reason: 28733458 directly tests human FZD4 in a Wnt-receptor functional screen, supporting canonical signaling. Supporting Evidence: |
| GO:0060070 canonical Wnt signaling pathway | TAS PMID:25424568 A novel Wnt5a-Frizzled4 signaling pathway mediates activity-... | ACCEPT | Summary: Canonical Wnt signaling is independently established for FZD4. Reason: Canonical Wnt signaling is independently established for FZD4. The 25424568 abstract emphasizes another signaling branch; that focus alone does not refute the curator's TAS assertion. Avoid claiming this abstract itself documents the canonical assay. Supporting Evidence: |
| GO:0061299 retina vasculature morphogenesis in camera-type eye | IBA GO_REF:0000033 | ACCEPT | Summary: Retinal vascular morphogenesis is an established physiological role of FZD4 receptor signaling. Reason: The actual retinal-development IBD at PANTHER:PTN002601720 is ancestral to the human FZD4 target, with the literal descendant evidence preserved. Human FEVR variants and Norrin-dependent receptor signaling are supported by PMID:12172548 and PMID:15035989. Independently, PMID:19837032 localizes the mouse retinal vascular defect to Fz4-expressing endothelial cells and directly tests Norrin-dependent signaling in those cells. FZD4 therefore performs the signal-reception step of the vascular-development program; this is a core physiological process rather than disease association alone. The inference preserves the distinction between human disease evidence and mouse cell-specific experiments. |
| GO:0061299 retina vasculature morphogenesis in camera-type eye | IMP PMID:12172548 Mutant frizzled-4 disrupts retinal angiogenesis in familial ... | ACCEPT | Summary: Human FZD4 variants and experimentally defective receptor signaling support a core role in retinal vascular development. Reason: The authentic PMID:12172548 abstract reports FZD4 variants segregating with impaired peripheral retinal vascularization and defective signaling of the human mutant receptors in Xenopus embryos. That access scope does not establish every human developmental mechanism. Together with the Norrin receptor evidence in PMID:15035989 and endothelial-specific mouse experiments in PMID:19837032, it supports FZD4 participation in retinal vascular morphogenesis through its receptor function. Retain the original IMP attribution and classify the established physiological role as core, without treating FZD4 as a vascular structural protein. |
| GO:0061299 retina vasculature morphogenesis in camera-type eye | IMP PMID:15024691 Mutations in LRP5 or FZD4 underlie the common familial exuda... | ACCEPT | Summary: The FZD4-associated retinal vascular phenotype belongs to the receptorβs established core developmental role. Reason: PMID:15024691 studies FEVR families at the LRP5/FZD4 locus; its authentic abstract discusses the FZD4 mutation screen but focuses on discovery of the second locus. That emphasis does not invalidate the original FZD4 IMP annotation. Independent human FZD4 evidence in PMID:12172548 and the direct endothelial Norrin/Fz4 signaling experiments in PMID:19837032 establish receptor participation in this developmental process. Accept the role while preserving the abstract-only access limitation for the original paper. |
| GO:0061301 cerebellum vasculature morphogenesis | IEA GO_REF:0000107 | UNDECIDED | Summary: The mouse donor annotation traces to PMID:15035989, whose full cerebellar experiment was not accessible. Reason: The mouse donor annotation traces to PMID:15035989, whose full cerebellar experiment was not accessible. Selected original PMID:19837032 Results directly establish endothelial Fz4-dependent cerebellar barrier integrity and vascular-origin granule-cell apoptosis in mice. Those positive maintenance results do not independently settle the generation-and-organization process specified by GO:0061301. Preserve the morphogenesis assertion as unresolved, without implying that the cerebellar vascular role is absent. |
| GO:0061304 retinal blood vessel morphogenesis | IEA GO_REF:0000107 | ACCEPT | Summary: FZD4 signaling participates directly in the development and organization of retinal blood vessels. Reason: This orthology inference uses mouse Fzd4 Q61088. PMID:19837032 directly compares postnatal retinal vascular growth and patterning in mouse Fz4 mutants and endothelial-specific knockouts, identifies defective endothelialβmural-cell interactions, and tests the receptor-dependent Norrin response in retinal endothelial cells. These experiments support the blood-vessel morphogenesis claim beyond a generic loss-of-function phenotype. Human FEVR and Norrin-receptor evidence independently support conservation of the physiological role. Keep the original electronic provenance and distinguish the mouse experiments from direct human vessel assays. |
| GO:0071300 cellular response to retinoic acid | ISS GO_REF:0000024 | UNDECIDED | Summary: The original ISS transfer is unresolved, and reported FZD4 transcript induction does not adjudicate the product-level retinoic-acid response annotation. Reason: The original ISS annotation cites GO_REF:0000024 and UniProtKB:P56706, which identifies WNT7B rather than a Frizzled ortholog. The intended donor and transfer cannot be reconstructed from the accessible records. The authentic PMID:12429992 review abstract reports increased FZD4 expression after all-trans-retinoic acid treatment of human NT2 cells. Although GO:0071300 includes changes in gene expression among cellular responses, this observation alone does not resolve whether the FZD4 protein participates in the response asserted by this particular annotation. The underlying product-level evidence remains unadjudicated. Use UNDECIDED pending recovery of the original transfer rationale or direct functional evidence, while preserving the positive expression observation, the literal ISS provenance and its source-defect CHECK. Supporting Evidence: PMID:12429992 FZD4 and FZD10 are up-regulated in NT2 cells after ATRA treatment. |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Mouse hippocampal donor evidence supports a specialized glutamatergic-synapse location without making it ubiquitous in humans. Reason: The complete current mouse Q61088 donor response retains glutamatergic-synapse IDA contexts from PMID16501258. The successfully retained indexed original Results/Figure 1 describes Fzd4 colocalization with PSD-95 in hippocampal synaptic regions, with nonspecific-IgG controls. This supports the orthology-derived synaptic location in its neuronal scope, but does not establish a ubiquitous human location or direct receptor contribution to every LTP outcome in that paper. Keep this specialized neuronal context non-core. |
| GO:0110135 Norrin signaling pathway | IDA PMID:15035989 Vascular development in the retina and inner ear: control by... | ACCEPT | Summary: 15035989 establishes the NorrinβFZD4 ligand/receptor system with LRP-dependent signaling and disease-related loss of function. Reason: 15035989 establishes the NorrinβFZD4 ligand/receptor system with LRP-dependent signaling and disease-related loss of function. Supporting Evidence: |
| GO:0110135 Norrin signaling pathway | IDA PMID:17955262 Moderate reduction of Norrin signaling activity associated w... | ACCEPT | Summary: 17955262 directly measures Norrin-dependent signaling of FZD4 variants and supports this pathway. Reason: 17955262 directly measures Norrin-dependent signaling of FZD4 variants and supports this pathway. Supporting Evidence: |
| GO:0110135 Norrin signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: Mouse-to-human transfer agrees with direct human Norrin/FZD4 evidence. Reason: Mouse-to-human transfer agrees with direct human Norrin/FZD4 evidence. Retain the dedicated Norrin pathway rather than mislabeling Norrin as a Wnt. |
| GO:0150012 positive regulation of neuron projection arborization | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Combined mouse/rat transfer agrees with the same neuronal-culture evidence. Reason: Combined mouse/rat transfer agrees with the same neuronal-culture evidence. Keep the original combined sources and distinguish them from direct human experimentation. Supporting Evidence: |
| GO:0150012 positive regulation of neuron projection arborization | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The mouse/rat experimental chain in 25424568 supports neuronal branching. Reason: The mouse/rat experimental chain in 25424568 supports neuronal branching. Preserve the hippocampal-neuron extension and treat arborization as a developmental output. Supporting Evidence: |
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Download this section (compressed HTML)Q: Which FZD4-specific experiments establish recognition of amyloid-beta42 or its oligomeric complex? Available original figure legends establish beta40 binding by FZD4 but name FZD5 in the beta42/aggregate panels; full-text target evidence remains unresolved.
Q: How do ligand and cellular context determine whether FZD4 signals through canonical or noncanonical pathways? Norrin, functional Wnt-receptor assays, calcium signaling and neuronal morphogenesis are supported in distinct experimental systems; a particular G-protein mechanism is not established here.
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