{"gene":"FZD6","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2004,"finding":"HFz6 acts as a negative regulator of canonical Wnt/β-catenin signaling: it does not activate the canonical pathway in response to Wnt-1 or Wnt-5a group ligands, and represses Wnt-3a-induced canonical signaling when co-expressed with HFz1. The repression operates downstream of the β-catenin destruction complex (does not affect β-catenin stabilization or TCF4 nuclear levels or β-catenin·TCF4 complex formation), but inhibits TCF/LEF binding to target DNA as shown by EMSA. HFz6 activates the TAK1-NLK pathway, which blocks TCF/LEF binding to target promoters. N'- and C'-terminal sequences of HFz6 are required for its repressive activity.","method":"Reporter assays (canonical Wnt luciferase), co-expression with HFz1/Dvl1/stabilized β-catenin(S33Y)/LiCl, EMSA for TCF/LEF-DNA binding, deletion mutagenesis of HFz6 termini, Western blotting for β-catenin and TCF4 levels","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal functional assays (reporter, EMSA, mutagenesis, epistasis with downstream mediators) in a single rigorous study, replicated across several Wnt pathway stimuli","pmids":["14747478"],"is_preprint":false},{"year":2016,"finding":"FZD6 activates CaMKII-TAK1-NLK signaling downstream, which attenuates canonical Wnt pathway activity while promoting STAT3 and NF-κB signaling, thereby driving a mesenchymal GBM phenotype. This places FZD6 in a regulatory circuit with TCF4-miR-125b/miR-20b.","method":"Pathway inhibition/activation assays, gene expression analysis in PN vs MES GBM subtypes, functional validation targeting differentially enriched pathways","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pathway readouts in GBM cell models, single lab, mechanistic pathway placement confirmed experimentally","pmids":["27698350"],"is_preprint":false},{"year":2016,"finding":"FZD6 represses gastric cancer cell proliferation and migration via activation of the non-canonical Wnt pathway, and activation of non-canonical Wnt by FZD6 in turn ameliorates (reduces) canonical Wnt pathway activity. FZD6 is a direct target of miR-21, which suppresses FZD6 expression.","method":"Gain/loss-of-function experiments in gastric cancer cells, proliferation and migration assays, pathway reporter assays, miR-21 target validation","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD/OE with specific cellular phenotype readouts and pathway placement, single lab","pmids":["27347343"],"is_preprint":false},{"year":2019,"finding":"NPTX2 physically interacts with FZD6 to promote β-catenin nuclear translocation in colorectal cancer cells, resulting in increased MYC, cyclin D1, snail, and N-cadherin and decreased E-cadherin. siRNA knockdown of FZD6 almost completely reversed NPTX2-induced proliferative effects.","method":"Co-immunoprecipitation (physical interaction between NPTX2 and FZD6), siRNA knockdown of FZD6, β-catenin nuclear translocation assay, in vitro and in vivo proliferation/metastasis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP for physical interaction plus functional rescue by FZD6 siRNA, single lab, two orthogonal methods","pmids":["30833544"],"is_preprint":false},{"year":2019,"finding":"lncRNA PCAT-1 directly interacts with FZD6 protein to regulate its stability; PCAT-1 activates the Wnt/β-catenin signaling pathway in an FZD6-dependent manner in AML cells. Overexpression of FZD6 partially abolishes the effects of PCAT-1 silencing on AML cell proliferation and apoptosis.","method":"RNA-protein interaction assay, gain/loss-of-function experiments, cell proliferation and apoptosis assays, Wnt/β-catenin pathway readouts","journal":"American journal of translational research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — RNA-protein interaction plus functional rescue experiments, single lab, multiple orthogonal approaches","pmids":["31814913"],"is_preprint":false},{"year":2021,"finding":"In T-ALL, WNT10B drives Wnt pathway activation primarily through the FZD6 receptor complex via ligand binding. shRNA-mediated silencing of FZD6 or pharmacological inhibition of WNT secretion (LGK974 PORCN inhibitor) reduces WNT10B/FZD6 protein complex formation, impairs intracellular effectors, and reduces leukemic cell expansion.","method":"Co-immunoprecipitation (WNT10B/FZD6 protein complex), shRNA gene silencing, small molecule (LGK974) inhibition, Wnt pathway effector analysis, cell proliferation assays","journal":"Hematological oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal protein complex detection, ligand-receptor interaction validated by both genetic and pharmacological perturbation, single lab","pmids":["33497493"],"is_preprint":false},{"year":2022,"finding":"FZD6 knockout in melanoma does not affect cell proliferation but significantly reduces invasive ability in vitro and dramatically reduces lung metastasis in the Pten/BRaf mouse model. The invasive phenotype is mechanistically linked to canonical Wnt signaling and the epithelial-mesenchymal transition pathway.","method":"CRISPR/Cas9 knockout of FZD6, in vitro invasion assays, in vivo melanoma mouse model (Pten/BRaf), Wnt signaling and EMT marker analysis","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean CRISPR KO with specific phenotypic readout (invasion but not proliferation), validated in both in vitro and in vivo models, mechanistic pathway confirmed","pmids":["36368445"],"is_preprint":false},{"year":2023,"finding":"FZD6 knockdown (CRISPR/Cas9 Fzd6-Δ5 mice) produces depressive-like behavior (increased immobility in FST, reduced sucrose preference, decreased locomotion, reduced open-arm time in EPM) and reduces hippocampal cell proliferation (reduced Ki67+ and PCNA+ cells). Mechanistically, FZD6 KD decreases Gsk3β mRNA, phosphorylated GSK3β, and cytoplasmic β-catenin in hippocampus, establishing FZD6 as a positive regulator of canonical Wnt/β-catenin signaling in this context.","method":"CRISPR/Cas9 KO mouse model, behavioral tests (OFT, EPM, FST, TST, SPT), immunofluorescence for Ki67/PCNA, qRT-PCR and Western blot for Wnt pathway components","journal":"Journal of advanced research","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean CRISPR KO mouse model with multiple behavioral phenotypes, histological validation, and molecular pathway analysis, multiple orthogonal methods","pmids":["37321345"],"is_preprint":false},{"year":2025,"finding":"FZD6 knockdown in prostate cancer suppresses growth in vitro and in vivo, impairs DNA double-strand break repair (measured by γH2AX foci resolution and DSB repair reporter assays), and reduces activities of SRC kinase and STAT3. DNA damage repair deficiency is mechanistically mediated through WEE1 downregulation via PLK1. A kinome-wide CRISPR-Cas9 screen reveals FZD6 inhibition sensitizes cells to PKMYT1 inhibition.","method":"shRNA knockdown, patient-derived xenograft models, γH2AX foci assay, DSB repair reporter assay, kinome-wide CRISPR-Cas9 screen, SRC/STAT3 activity assays, WEE1/PLK1 protein analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including in vivo PDX, functional DNA repair assays, genome-wide CRISPR screen, and mechanistic epistasis through PLK1-WEE1 axis, single rigorous study","pmids":["41286306"],"is_preprint":false},{"year":2025,"finding":"FZD6 overexpression promotes nuclear translocation of β-catenin, reduces NLRP3/caspase-1/GSDMD-mediated classical pyroptosis, and increases 5-fluorouracil resistance in colorectal cancer cells. Conversely, FZD6 knockdown decreases nuclear β-catenin, enhances pyroptosis, and reduces 5-FU resistance.","method":"Lentiviral FZD6 KD/OE, immunofluorescence and Western blot for nuclear β-catenin, microscopy and electron microscopy for pyroptosis morphology, CCK-8/colony formation/EdU assays","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays linking FZD6 to β-catenin nuclear translocation and pyroptosis suppression, single lab","pmids":["40810359"],"is_preprint":false},{"year":2024,"finding":"In endothelial cells, shear stress triggers spatial reorganization of Fzd6 at the plasma membrane. The mutual exclusion of PCP proteins Fzd6 and Vangl1 at cell junctions augments differential junctional and cytoskeletal dynamics along the flow axis. This PCP signaling coordinates collective endothelial cell alignment to flow direction and proper vessel sprouting.","method":"Live imaging, subcellular fractionation/localization, biomimetic flow chambers, in vivo zebrafish vessel studies, mathematical modeling, loss-of-function for Vangl1 with Fzd6 localization readout","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiments tied to functional consequence (cell alignment, vessel sprouting) using multiple orthogonal approaches including in vivo; preprint not yet peer-reviewed","pmids":["bio_10.1101_2024.06.25.600357"],"is_preprint":true},{"year":2011,"finding":"Viral vector-mediated inhibition of Fzd6 expression in the rat hippocampus produced anxiety- and depressive-like effects in behavioral models of depression, establishing Fzd6 as a functional CREB target gene regulated by chronic electroconvulsive seizure in the hippocampus.","method":"Chromatin immunoprecipitation-microarray (CREB binding), viral vector-mediated gene knockdown in rat hippocampus, behavioral models of depression/anxiety","journal":"Biological psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-array identifies CREB occupancy, viral KD with specific behavioral phenotype, single lab","pmids":["21937024"],"is_preprint":false},{"year":2012,"finding":"A homozygous nonsense mutation (p.E584X) in FZD6 causes autosomal-recessive nail dysplasia. Immunohistochemistry shows FZD6 is strongly expressed in the ventral nail matrix and nail bed, placing it as a critical regulator of nail plate growth and guidance. The mutation maps to the C-terminal domain, consistent with earlier findings that C-terminal sequences are required for FZD6 signaling function.","method":"Genome-wide linkage analysis, Sanger sequencing for mutation identification, immunohistochemistry on nail sections","journal":"The British journal of dermatology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — loss-of-function mutation in humans with defined tissue phenotype and localization data, single study","pmids":["22211385"],"is_preprint":false},{"year":2018,"finding":"WNT5A (a ligand highly expressed in liver non-TICs) activates FZD6 to drive Wnt/β-catenin signaling and liver tumor-initiating cell (TIC) self-renewal. FZD6 is the only Frizzled receptor overexpressed during liver tumorigenesis among FZD1-10. The lncRNA lncFZD6 recruits the BRG1-embedded SWI/SNF chromatin remodeling complex to the FZD6 promoter to activate FZD6 transcription; FZD6 drives liver TIC self-renewal in an FZD6-dependent manner.","method":"Expression profiling of FZD1-10, ChIP for BRG1 at FZD6 promoter, co-immunoprecipitation of lncFZD6-BRG1 complex, loss-of-function and rescue experiments for FZD6 in liver TIC self-renewal and tumor initiation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for promoter occupancy, protein complex detection, functional rescue experiments, single lab; lncFZD6-BRG1 mechanism is partially indirect but FZD6 functional role is directly tested","pmids":["29535420"],"is_preprint":false},{"year":2018,"finding":"Luteolin upregulates FZD6 transcriptionally in prostate cancer cells, and FZD6 upregulation inhibits canonical Wnt signaling and suppresses prostate cancer stemness. FZD6 identified as a tumor suppressor that can abolish PCa stemness.","method":"iTRAQ-based quantitative proteomics, transcriptional upregulation analysis, Wnt signaling reporter assays, prostate cancer stem cell marker assays, proliferation and self-renewal assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus functional Wnt reporter and stemness assays, mechanistic link from FZD6 to Wnt inhibition established, single lab","pmids":["29867083"],"is_preprint":false},{"year":2021,"finding":"FZD6 silencing in cervical cancer cells retards proliferation, invasion, and EMT, and inactivates Wnt/β-catenin signaling. Mechanistically, FTO demethylase stabilizes lncRNA HOXC13-AS (by reducing m6A modification), which then augments FZD6 expression through CBP-mediated H3K27 acetylation at the FZD6 locus.","method":"qRT-PCR, CCK-8, colony formation, Transwell assays; luciferase reporter, FISH, subcellular fractionation, ChIP, RNA immunoprecipitation for mechanism","journal":"Journal of B.U.ON.","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — ChIP and RIP validate epigenetic mechanism for FZD6 transcriptional regulation; FZD6 functional role in EMT/invasion established by KD, single lab","pmids":["34564982"],"is_preprint":false},{"year":2025,"finding":"HOXC10 transcription factor directly targets the FZD6 promoter to reduce FZD6 expression, thereby activating Wnt/β-catenin signaling and delaying skin fibroblast senescence and skin aging.","method":"Single-cell transcriptomics, ChIP for HOXC10 at FZD6 promoter, overexpression/KD in fibroblasts, senescence assays, in vivo aging models","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP validates direct promoter targeting, functional in vitro and in vivo aging phenotype, single lab","pmids":["41268215"],"is_preprint":false},{"year":2024,"finding":"In CIA rat fibroblast-like synoviocytes, Fzd6 expression is elevated and drives NF-κB signaling activation (p-p65/p65 and p-IκBα/IκBα) along with pro-inflammatory cytokine expression (COX-2, IL-8, TNF-α). Fengshi Liuhe Decoction downregulates Fzd6 and suppresses this Fzd6/NF-κB signaling axis.","method":"qPCR and Western blot comparison of normal vs CIA rat FLS, ELISA for inflammatory cytokines, nuclear translocation assay for NF-κB p65","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 / Weak — correlation between Fzd6 and NF-κB pathway in a single model without direct mechanistic epistasis or rescue experiment for the FZD6-NF-κB link specifically","pmids":["38710294"],"is_preprint":false},{"year":2023,"finding":"In colorectal cancer cells, linc00659 binds to IGF2BP1 (validated by RNA pulldown and RIP), and IGF2BP1 stabilizes FZD6 mRNA (validated by RNA stability assay), thereby activating Wnt/β-catenin signaling and promoting CRC cell proliferation.","method":"RNA pulldown and RNA immunoprecipitation for linc00659-IGF2BP1 interaction, RNA stability assay for FZD6 mRNA, Wnt/β-catenin Western blot, in vivo xenograft","journal":"The journal of gene medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RNA pulldown and RIP validate interaction, RNA stability assay validates FZD6 mRNA regulation, single lab with multiple orthogonal methods","pmids":["38009760"],"is_preprint":false},{"year":2025,"finding":"FZD6 negatively regulates adipogenesis of bone marrow mesenchymal stem cells: FZD6 expression is decreased during adipogenic differentiation and in aplastic anemia BM-MSCs, and FZD6 overexpression alleviates miR-199a-5p-driven adipogenic differentiation. FZD6 is a direct target of miR-199a-5p (validated experimentally).","method":"miR-199a-5p inhibition experiments, luciferase reporter assay for miR-199a-5p targeting FZD6, FZD6 overexpression rescue of adipogenesis phenotype, expression profiling","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — luciferase validation of miRNA-target relationship plus functional rescue experiments for FZD6 in adipogenesis, single lab","pmids":["41198743"],"is_preprint":false}],"current_model":"FZD6 is a Frizzled-family Wnt receptor that functions as a context-dependent molecular switch: it negatively regulates canonical Wnt/β-catenin-TCF/LEF transcriptional activity (by activating TAK1-NLK signaling to block TCF/LEF-DNA binding, without affecting β-catenin stabilization) while positively activating non-canonical planar cell polarity (PCP) signaling; in endothelial cells, shear stress-induced Vangl1 membrane enrichment drives spatial reorganization of Fzd6 to coordinate collective cell polarity and vascular remodeling; in prostate cancer, FZD6 supports tumor growth and DNA double-strand break repair through SRC-STAT3 and PLK1-WEE1 axes; and loss-of-function mutations cause autosomal-recessive nail dysplasia and neural tube defects in humans, consistent with its essential role in PCP-dependent tissue patterning."},"narrative":{"mechanistic_narrative":"FZD6 is a Frizzled-family Wnt receptor that acts as a context-dependent switch between canonical Wnt/β-catenin signaling and non-canonical planar cell polarity (PCP) signaling, governing tissue patterning, cell motility, and tumor behavior [PMID:14747478, PMID:36368445, PMID:bio_10.1101_2024.06.25.600357]. In its founding biochemical characterization, FZD6 functioned as a negative regulator of canonical Wnt/β-catenin signaling: it did not affect β-catenin stabilization, nuclear TCF4 levels, or β-catenin·TCF4 complex formation, but instead activated the TAK1–NLK cascade to block TCF/LEF binding to target promoters, with both N- and C-terminal sequences required for this repressive activity [PMID:14747478]. This TAK1–NLK-dependent restraint of canonical signaling is reiterated in glioblastoma, where FZD6 engages CaMKII–TAK1–NLK signaling [PMID:27698350]. FZD6 also operates as a PCP receptor: in endothelial cells, shear stress drives spatial reorganization of Fzd6 at the plasma membrane, where mutual exclusion of Fzd6 and Vangl1 at junctions coordinates collective cell alignment to flow and proper vessel sprouting [PMID:bio_10.1101_2024.06.25.600357]. Across cancers FZD6 shows strongly context-dependent roles—restraining proliferation and invasion in some settings (melanoma invasion, prostate stemness) while supporting growth in others; in melanoma it is required for invasion and metastasis but not proliferation [PMID:36368445, PMID:29867083], and in prostate cancer it supports tumor growth and DNA double-strand break repair through SRC–STAT3 activity and a PLK1–WEE1 axis [PMID:41286306]. In the nervous system, Fzd6 functions as a positive regulator of canonical Wnt/β-catenin signaling in hippocampus, where its loss produces depressive-like behavior and reduced hippocampal proliferation [PMID:37321345]. In humans, a homozygous nonsense mutation (p.E584X) in FZD6 causes autosomal-recessive nail dysplasia, with FZD6 strongly expressed in the ventral nail matrix and nail bed [PMID:22211385].","teleology":[{"year":2004,"claim":"Established the foundational and counterintuitive mechanism by which FZD6 restrains rather than activates canonical Wnt signaling, defining its action downstream of the β-catenin destruction complex.","evidence":"Wnt reporter assays, co-expression with HFz1/Dvl1/stabilized β-catenin, EMSA for TCF/LEF-DNA binding, and terminal deletion mutagenesis in cell lines","pmids":["14747478"],"confidence":"High","gaps":["Does not resolve how FZD6 selects between canonical repression and PCP activation","Ligand specificity for the repressive output not defined","No structural basis for the N-/C-terminal requirement"]},{"year":2011,"claim":"Connected FZD6 to neuropsychiatric regulation by identifying it as a CREB target whose hippocampal suppression produces affective phenotypes.","evidence":"ChIP-microarray for CREB occupancy and viral-vector knockdown in rat hippocampus with behavioral testing","pmids":["21937024"],"confidence":"Medium","gaps":["Does not establish which Wnt arm mediates the behavioral effect","Downstream effectors in hippocampus not defined"]},{"year":2012,"claim":"Linked FZD6 to a human Mendelian disease, demonstrating its essential role in nail patterning consistent with PCP-dependent tissue guidance.","evidence":"Genome-wide linkage, Sanger sequencing identifying a homozygous p.E584X nonsense mutation, and immunohistochemistry on nail sections","pmids":["22211385"],"confidence":"Medium","gaps":["Does not test the mutant protein's signaling output directly","Mechanism connecting FZD6 loss to nail dysplasia not resolved"]},{"year":2016,"claim":"Placed FZD6 in defined oncogenic signaling circuits, showing context-specific coupling to TAK1-NLK and downstream STAT3/NF-κB in GBM and non-canonical Wnt suppression of proliferation in gastric cancer.","evidence":"Pathway perturbation and subtype expression analysis in GBM cells; gain/loss-of-function with proliferation/migration and miR-21 target validation in gastric cancer cells","pmids":["27698350","27347343"],"confidence":"Medium","gaps":["Opposing directionality across tumor types not mechanistically reconciled","Direct ligand engagement not defined in these models"]},{"year":2019,"claim":"Identified physical partners and RNA-based regulators that route FZD6 toward β-catenin nuclear translocation in specific cancers, reframing FZD6 as a positive Wnt effector in these contexts.","evidence":"Co-IP of NPTX2-FZD6 with siRNA rescue in colorectal cancer; RNA-protein interaction of lncRNA PCAT-1 with FZD6 plus rescue in AML cells","pmids":["30833544","31814913"],"confidence":"Medium","gaps":["Reciprocal interaction validation limited","How partner binding switches FZD6 output toward canonical signaling unknown"]},{"year":2021,"claim":"Demonstrated ligand-driven receptor complex formation, showing WNT10B activates Wnt signaling through a FZD6 receptor complex in leukemia.","evidence":"Reciprocal Co-IP of WNT10B/FZD6, shRNA silencing, and PORCN inhibition (LGK974) with proliferation readouts in T-ALL","pmids":["33497493"],"confidence":"Medium","gaps":["Stoichiometry and co-receptor composition of the complex not defined","Downstream effector branch not fully mapped"]},{"year":2022,"claim":"Established a clean genetic requirement for FZD6 in metastatic behavior, dissociating its role in invasion from proliferation.","evidence":"CRISPR/Cas9 knockout with in vitro invasion assays and in vivo Pten/BRaf melanoma model linked to canonical Wnt/EMT markers","pmids":["36368445"],"confidence":"High","gaps":["Molecular link between FZD6 and the EMT program not fully resolved","Whether canonical or non-canonical signaling drives invasion not disentangled"]},{"year":2023,"claim":"Defined FZD6 as a positive canonical Wnt regulator in hippocampus and established a behavioral phenotype from its loss, contrasting with its repressive role in other systems.","evidence":"CRISPR/Cas9 Fzd6-Δ5 mouse model with behavioral batteries, Ki67/PCNA immunofluorescence, and Wnt pathway qRT-PCR/Western blot","pmids":["37321345"],"confidence":"High","gaps":["Mechanism of cell-type/context-dependent directional switching unresolved","Receptor ligand in hippocampus not identified"]},{"year":2024,"claim":"Provided direct mechanistic insight into FZD6 PCP function by showing shear-stress-driven membrane reorganization and mutual exclusion with Vangl1 coordinates endothelial polarity.","evidence":"Live imaging, subcellular localization, biomimetic flow chambers, zebrafish vessel studies, and Vangl1 loss-of-function with Fzd6 localization readout (preprint)","pmids":["bio_10.1101_2024.06.25.600357"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Molecular basis of Fzd6/Vangl1 mutual exclusion not defined","Link to vascular disease not established"]},{"year":2025,"claim":"Uncovered a non-Wnt-centric oncogenic role for FZD6 in supporting DNA double-strand break repair and tumor growth in prostate cancer through kinase signaling.","evidence":"shRNA knockdown, patient-derived xenografts, γH2AX/DSB repair reporter assays, kinome-wide CRISPR screen, and SRC/STAT3/WEE1/PLK1 analysis","pmids":["41286306"],"confidence":"High","gaps":["How a Frizzled receptor couples to SRC-STAT3 and PLK1-WEE1 mechanistically unresolved","Direct versus indirect control of DSB repair not separated"]},{"year":2025,"claim":"Expanded the context-dependent FZD6 outputs to chemoresistance, adipogenesis, and tissue aging through β-catenin and transcriptional/post-transcriptional regulation.","evidence":"FZD6 KD/OE with pyroptosis and 5-FU resistance readouts in CRC; miR-199a-5p target validation and adipogenesis rescue in BM-MSCs; HOXC10 ChIP at the FZD6 promoter in fibroblast senescence models","pmids":["40810359","41198743","41268215"],"confidence":"Medium","gaps":["Directionality of FZD6 on β-catenin differs across these contexts without unifying mechanism","Causal versus correlative regulation in some models incompletely separated"]},{"year":null,"claim":"The central unresolved question is what determines whether FZD6 represses or activates canonical Wnt/β-catenin signaling, and how a single receptor coordinates this switch with PCP signaling and kinase-driven outputs across tissues.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of FZD6 in distinct signaling states","Ligand/co-receptor combinations dictating output not systematically mapped","Mechanism coupling FZD6 to SRC-STAT3 and PLK1-WEE1 unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,5,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,5]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,8,12]}],"complexes":[],"partners":["VANGL1","NPTX2","WNT10B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60353","full_name":"Frizzled-6","aliases":[],"length_aa":706,"mass_kda":79.3,"function":"Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues. Together with FZD3, is involved in the neural tube closure and plays a role in the regulation of the establishment of planar cell polarity (PCP), particularly in the orientation of asymmetric bundles of stereocilia on the apical faces of a subset of auditory and vestibular sensory cells located in the inner ear (By similarity)","subcellular_location":"Membrane; Cell membrane; Cell surface; Apical cell membrane; Cytoplasmic vesicle membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/O60353/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FZD6","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/FZD6","total_profiled":1310},"omim":[{"mim_id":"612856","title":"ASTROTACTIN 2; ASTN2","url":"https://www.omim.org/entry/612856"},{"mim_id":"610007","title":"LIMB REGION 1 HOMOLOG-LIKE; LMBR1L","url":"https://www.omim.org/entry/610007"},{"mim_id":"604523","title":"CADHERIN EGF LAG SEVEN-PASS G-TYPE RECEPTOR 1; CELSR1","url":"https://www.omim.org/entry/604523"},{"mim_id":"603409","title":"FRIZZLED CLASS RECEPTOR 6; FZD6","url":"https://www.omim.org/entry/603409"},{"mim_id":"600533","title":"VANGL PLANAR CELL POLARITY PROTEIN 2; VANGL2","url":"https://www.omim.org/entry/600533"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FZD6"},"hgnc":{"alias_symbol":["Hfz6"],"prev_symbol":[]},"alphafold":{"accession":"O60353","domains":[{"cath_id":"1.10.2000.10","chopping":"26-126","consensus_level":"high","plddt":87.6254,"start":26,"end":126},{"cath_id":"1.20.1070.10","chopping":"164-505","consensus_level":"high","plddt":89.4309,"start":164,"end":505}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60353","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60353-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60353-F1-predicted_aligned_error_v6.png","plddt_mean":72.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FZD6","jax_strain_url":"https://www.jax.org/strain/search?query=FZD6"},"sequence":{"accession":"O60353","fasta_url":"https://rest.uniprot.org/uniprotkb/O60353.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60353/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60353"}},"corpus_meta":[{"pmid":"14747478","id":"PMC_14747478","title":"The human Frizzled 6 (HFz6) acts as a negative regulator of the canonical Wnt. beta-catenin signaling cascade.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14747478","citation_count":118,"is_preprint":false},{"pmid":"28737757","id":"PMC_28737757","title":"Non-canonical WNT/PCP signalling in cancer: Fzd6 takes centre stage.","date":"2017","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/28737757","citation_count":96,"is_preprint":false},{"pmid":"27698350","id":"PMC_27698350","title":"A regulatory circuit of miR-125b/miR-20b and Wnt signalling controls glioblastoma phenotypes through FZD6-modulated pathways.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27698350","citation_count":83,"is_preprint":false},{"pmid":"22045688","id":"PMC_22045688","title":"FZD6 is a novel gene for human neural tube defects.","date":"2011","source":"Human 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activate the canonical pathway in response to Wnt-1 or Wnt-5a group ligands, and represses Wnt-3a-induced canonical signaling when co-expressed with HFz1. The repression operates downstream of the β-catenin destruction complex (does not affect β-catenin stabilization or TCF4 nuclear levels or β-catenin·TCF4 complex formation), but inhibits TCF/LEF binding to target DNA as shown by EMSA. HFz6 activates the TAK1-NLK pathway, which blocks TCF/LEF binding to target promoters. N'- and C'-terminal sequences of HFz6 are required for its repressive activity.\",\n      \"method\": \"Reporter assays (canonical Wnt luciferase), co-expression with HFz1/Dvl1/stabilized β-catenin(S33Y)/LiCl, EMSA for TCF/LEF-DNA binding, deletion mutagenesis of HFz6 termini, Western blotting for β-catenin and TCF4 levels\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal functional assays (reporter, EMSA, mutagenesis, epistasis with downstream mediators) in a single rigorous study, replicated across several Wnt pathway stimuli\",\n      \"pmids\": [\"14747478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FZD6 activates CaMKII-TAK1-NLK signaling downstream, which attenuates canonical Wnt pathway activity while promoting STAT3 and NF-κB signaling, thereby driving a mesenchymal GBM phenotype. This places FZD6 in a regulatory circuit with TCF4-miR-125b/miR-20b.\",\n      \"method\": \"Pathway inhibition/activation assays, gene expression analysis in PN vs MES GBM subtypes, functional validation targeting differentially enriched pathways\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pathway readouts in GBM cell models, single lab, mechanistic pathway placement confirmed experimentally\",\n      \"pmids\": [\"27698350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FZD6 represses gastric cancer cell proliferation and migration via activation of the non-canonical Wnt pathway, and activation of non-canonical Wnt by FZD6 in turn ameliorates (reduces) canonical Wnt pathway activity. FZD6 is a direct target of miR-21, which suppresses FZD6 expression.\",\n      \"method\": \"Gain/loss-of-function experiments in gastric cancer cells, proliferation and migration assays, pathway reporter assays, miR-21 target validation\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD/OE with specific cellular phenotype readouts and pathway placement, single lab\",\n      \"pmids\": [\"27347343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NPTX2 physically interacts with FZD6 to promote β-catenin nuclear translocation in colorectal cancer cells, resulting in increased MYC, cyclin D1, snail, and N-cadherin and decreased E-cadherin. siRNA knockdown of FZD6 almost completely reversed NPTX2-induced proliferative effects.\",\n      \"method\": \"Co-immunoprecipitation (physical interaction between NPTX2 and FZD6), siRNA knockdown of FZD6, β-catenin nuclear translocation assay, in vitro and in vivo proliferation/metastasis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP for physical interaction plus functional rescue by FZD6 siRNA, single lab, two orthogonal methods\",\n      \"pmids\": [\"30833544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"lncRNA PCAT-1 directly interacts with FZD6 protein to regulate its stability; PCAT-1 activates the Wnt/β-catenin signaling pathway in an FZD6-dependent manner in AML cells. Overexpression of FZD6 partially abolishes the effects of PCAT-1 silencing on AML cell proliferation and apoptosis.\",\n      \"method\": \"RNA-protein interaction assay, gain/loss-of-function experiments, cell proliferation and apoptosis assays, Wnt/β-catenin pathway readouts\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — RNA-protein interaction plus functional rescue experiments, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"31814913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In T-ALL, WNT10B drives Wnt pathway activation primarily through the FZD6 receptor complex via ligand binding. shRNA-mediated silencing of FZD6 or pharmacological inhibition of WNT secretion (LGK974 PORCN inhibitor) reduces WNT10B/FZD6 protein complex formation, impairs intracellular effectors, and reduces leukemic cell expansion.\",\n      \"method\": \"Co-immunoprecipitation (WNT10B/FZD6 protein complex), shRNA gene silencing, small molecule (LGK974) inhibition, Wnt pathway effector analysis, cell proliferation assays\",\n      \"journal\": \"Hematological oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal protein complex detection, ligand-receptor interaction validated by both genetic and pharmacological perturbation, single lab\",\n      \"pmids\": [\"33497493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FZD6 knockout in melanoma does not affect cell proliferation but significantly reduces invasive ability in vitro and dramatically reduces lung metastasis in the Pten/BRaf mouse model. The invasive phenotype is mechanistically linked to canonical Wnt signaling and the epithelial-mesenchymal transition pathway.\",\n      \"method\": \"CRISPR/Cas9 knockout of FZD6, in vitro invasion assays, in vivo melanoma mouse model (Pten/BRaf), Wnt signaling and EMT marker analysis\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean CRISPR KO with specific phenotypic readout (invasion but not proliferation), validated in both in vitro and in vivo models, mechanistic pathway confirmed\",\n      \"pmids\": [\"36368445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FZD6 knockdown (CRISPR/Cas9 Fzd6-Δ5 mice) produces depressive-like behavior (increased immobility in FST, reduced sucrose preference, decreased locomotion, reduced open-arm time in EPM) and reduces hippocampal cell proliferation (reduced Ki67+ and PCNA+ cells). Mechanistically, FZD6 KD decreases Gsk3β mRNA, phosphorylated GSK3β, and cytoplasmic β-catenin in hippocampus, establishing FZD6 as a positive regulator of canonical Wnt/β-catenin signaling in this context.\",\n      \"method\": \"CRISPR/Cas9 KO mouse model, behavioral tests (OFT, EPM, FST, TST, SPT), immunofluorescence for Ki67/PCNA, qRT-PCR and Western blot for Wnt pathway components\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean CRISPR KO mouse model with multiple behavioral phenotypes, histological validation, and molecular pathway analysis, multiple orthogonal methods\",\n      \"pmids\": [\"37321345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FZD6 knockdown in prostate cancer suppresses growth in vitro and in vivo, impairs DNA double-strand break repair (measured by γH2AX foci resolution and DSB repair reporter assays), and reduces activities of SRC kinase and STAT3. DNA damage repair deficiency is mechanistically mediated through WEE1 downregulation via PLK1. A kinome-wide CRISPR-Cas9 screen reveals FZD6 inhibition sensitizes cells to PKMYT1 inhibition.\",\n      \"method\": \"shRNA knockdown, patient-derived xenograft models, γH2AX foci assay, DSB repair reporter assay, kinome-wide CRISPR-Cas9 screen, SRC/STAT3 activity assays, WEE1/PLK1 protein analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including in vivo PDX, functional DNA repair assays, genome-wide CRISPR screen, and mechanistic epistasis through PLK1-WEE1 axis, single rigorous study\",\n      \"pmids\": [\"41286306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FZD6 overexpression promotes nuclear translocation of β-catenin, reduces NLRP3/caspase-1/GSDMD-mediated classical pyroptosis, and increases 5-fluorouracil resistance in colorectal cancer cells. Conversely, FZD6 knockdown decreases nuclear β-catenin, enhances pyroptosis, and reduces 5-FU resistance.\",\n      \"method\": \"Lentiviral FZD6 KD/OE, immunofluorescence and Western blot for nuclear β-catenin, microscopy and electron microscopy for pyroptosis morphology, CCK-8/colony formation/EdU assays\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays linking FZD6 to β-catenin nuclear translocation and pyroptosis suppression, single lab\",\n      \"pmids\": [\"40810359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In endothelial cells, shear stress triggers spatial reorganization of Fzd6 at the plasma membrane. The mutual exclusion of PCP proteins Fzd6 and Vangl1 at cell junctions augments differential junctional and cytoskeletal dynamics along the flow axis. This PCP signaling coordinates collective endothelial cell alignment to flow direction and proper vessel sprouting.\",\n      \"method\": \"Live imaging, subcellular fractionation/localization, biomimetic flow chambers, in vivo zebrafish vessel studies, mathematical modeling, loss-of-function for Vangl1 with Fzd6 localization readout\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiments tied to functional consequence (cell alignment, vessel sprouting) using multiple orthogonal approaches including in vivo; preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.06.25.600357\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Viral vector-mediated inhibition of Fzd6 expression in the rat hippocampus produced anxiety- and depressive-like effects in behavioral models of depression, establishing Fzd6 as a functional CREB target gene regulated by chronic electroconvulsive seizure in the hippocampus.\",\n      \"method\": \"Chromatin immunoprecipitation-microarray (CREB binding), viral vector-mediated gene knockdown in rat hippocampus, behavioral models of depression/anxiety\",\n      \"journal\": \"Biological psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-array identifies CREB occupancy, viral KD with specific behavioral phenotype, single lab\",\n      \"pmids\": [\"21937024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A homozygous nonsense mutation (p.E584X) in FZD6 causes autosomal-recessive nail dysplasia. Immunohistochemistry shows FZD6 is strongly expressed in the ventral nail matrix and nail bed, placing it as a critical regulator of nail plate growth and guidance. The mutation maps to the C-terminal domain, consistent with earlier findings that C-terminal sequences are required for FZD6 signaling function.\",\n      \"method\": \"Genome-wide linkage analysis, Sanger sequencing for mutation identification, immunohistochemistry on nail sections\",\n      \"journal\": \"The British journal of dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — loss-of-function mutation in humans with defined tissue phenotype and localization data, single study\",\n      \"pmids\": [\"22211385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"WNT5A (a ligand highly expressed in liver non-TICs) activates FZD6 to drive Wnt/β-catenin signaling and liver tumor-initiating cell (TIC) self-renewal. FZD6 is the only Frizzled receptor overexpressed during liver tumorigenesis among FZD1-10. The lncRNA lncFZD6 recruits the BRG1-embedded SWI/SNF chromatin remodeling complex to the FZD6 promoter to activate FZD6 transcription; FZD6 drives liver TIC self-renewal in an FZD6-dependent manner.\",\n      \"method\": \"Expression profiling of FZD1-10, ChIP for BRG1 at FZD6 promoter, co-immunoprecipitation of lncFZD6-BRG1 complex, loss-of-function and rescue experiments for FZD6 in liver TIC self-renewal and tumor initiation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for promoter occupancy, protein complex detection, functional rescue experiments, single lab; lncFZD6-BRG1 mechanism is partially indirect but FZD6 functional role is directly tested\",\n      \"pmids\": [\"29535420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Luteolin upregulates FZD6 transcriptionally in prostate cancer cells, and FZD6 upregulation inhibits canonical Wnt signaling and suppresses prostate cancer stemness. FZD6 identified as a tumor suppressor that can abolish PCa stemness.\",\n      \"method\": \"iTRAQ-based quantitative proteomics, transcriptional upregulation analysis, Wnt signaling reporter assays, prostate cancer stem cell marker assays, proliferation and self-renewal assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus functional Wnt reporter and stemness assays, mechanistic link from FZD6 to Wnt inhibition established, single lab\",\n      \"pmids\": [\"29867083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FZD6 silencing in cervical cancer cells retards proliferation, invasion, and EMT, and inactivates Wnt/β-catenin signaling. Mechanistically, FTO demethylase stabilizes lncRNA HOXC13-AS (by reducing m6A modification), which then augments FZD6 expression through CBP-mediated H3K27 acetylation at the FZD6 locus.\",\n      \"method\": \"qRT-PCR, CCK-8, colony formation, Transwell assays; luciferase reporter, FISH, subcellular fractionation, ChIP, RNA immunoprecipitation for mechanism\",\n      \"journal\": \"Journal of B.U.ON.\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — ChIP and RIP validate epigenetic mechanism for FZD6 transcriptional regulation; FZD6 functional role in EMT/invasion established by KD, single lab\",\n      \"pmids\": [\"34564982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HOXC10 transcription factor directly targets the FZD6 promoter to reduce FZD6 expression, thereby activating Wnt/β-catenin signaling and delaying skin fibroblast senescence and skin aging.\",\n      \"method\": \"Single-cell transcriptomics, ChIP for HOXC10 at FZD6 promoter, overexpression/KD in fibroblasts, senescence assays, in vivo aging models\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP validates direct promoter targeting, functional in vitro and in vivo aging phenotype, single lab\",\n      \"pmids\": [\"41268215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In CIA rat fibroblast-like synoviocytes, Fzd6 expression is elevated and drives NF-κB signaling activation (p-p65/p65 and p-IκBα/IκBα) along with pro-inflammatory cytokine expression (COX-2, IL-8, TNF-α). Fengshi Liuhe Decoction downregulates Fzd6 and suppresses this Fzd6/NF-κB signaling axis.\",\n      \"method\": \"qPCR and Western blot comparison of normal vs CIA rat FLS, ELISA for inflammatory cytokines, nuclear translocation assay for NF-κB p65\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — correlation between Fzd6 and NF-κB pathway in a single model without direct mechanistic epistasis or rescue experiment for the FZD6-NF-κB link specifically\",\n      \"pmids\": [\"38710294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In colorectal cancer cells, linc00659 binds to IGF2BP1 (validated by RNA pulldown and RIP), and IGF2BP1 stabilizes FZD6 mRNA (validated by RNA stability assay), thereby activating Wnt/β-catenin signaling and promoting CRC cell proliferation.\",\n      \"method\": \"RNA pulldown and RNA immunoprecipitation for linc00659-IGF2BP1 interaction, RNA stability assay for FZD6 mRNA, Wnt/β-catenin Western blot, in vivo xenograft\",\n      \"journal\": \"The journal of gene medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RNA pulldown and RIP validate interaction, RNA stability assay validates FZD6 mRNA regulation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38009760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FZD6 negatively regulates adipogenesis of bone marrow mesenchymal stem cells: FZD6 expression is decreased during adipogenic differentiation and in aplastic anemia BM-MSCs, and FZD6 overexpression alleviates miR-199a-5p-driven adipogenic differentiation. FZD6 is a direct target of miR-199a-5p (validated experimentally).\",\n      \"method\": \"miR-199a-5p inhibition experiments, luciferase reporter assay for miR-199a-5p targeting FZD6, FZD6 overexpression rescue of adipogenesis phenotype, expression profiling\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — luciferase validation of miRNA-target relationship plus functional rescue experiments for FZD6 in adipogenesis, single lab\",\n      \"pmids\": [\"41198743\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FZD6 is a Frizzled-family Wnt receptor that functions as a context-dependent molecular switch: it negatively regulates canonical Wnt/β-catenin-TCF/LEF transcriptional activity (by activating TAK1-NLK signaling to block TCF/LEF-DNA binding, without affecting β-catenin stabilization) while positively activating non-canonical planar cell polarity (PCP) signaling; in endothelial cells, shear stress-induced Vangl1 membrane enrichment drives spatial reorganization of Fzd6 to coordinate collective cell polarity and vascular remodeling; in prostate cancer, FZD6 supports tumor growth and DNA double-strand break repair through SRC-STAT3 and PLK1-WEE1 axes; and loss-of-function mutations cause autosomal-recessive nail dysplasia and neural tube defects in humans, consistent with its essential role in PCP-dependent tissue patterning.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FZD6 is a Frizzled-family Wnt receptor that acts as a context-dependent switch between canonical Wnt/\\u03b2-catenin signaling and non-canonical planar cell polarity (PCP) signaling, governing tissue patterning, cell motility, and tumor behavior [#0, #6, #10]. In its founding biochemical characterization, FZD6 functioned as a negative regulator of canonical Wnt/\\u03b2-catenin signaling: it did not affect \\u03b2-catenin stabilization, nuclear TCF4 levels, or \\u03b2-catenin\\u00b7TCF4 complex formation, but instead activated the TAK1\\u2013NLK cascade to block TCF/LEF binding to target promoters, with both N- and C-terminal sequences required for this repressive activity [#0]. This TAK1\\u2013NLK-dependent restraint of canonical signaling is reiterated in glioblastoma, where FZD6 engages CaMKII\\u2013TAK1\\u2013NLK signaling [#1]. FZD6 also operates as a PCP receptor: in endothelial cells, shear stress drives spatial reorganization of Fzd6 at the plasma membrane, where mutual exclusion of Fzd6 and Vangl1 at junctions coordinates collective cell alignment to flow and proper vessel sprouting [#10]. Across cancers FZD6 shows strongly context-dependent roles\\u2014restraining proliferation and invasion in some settings (melanoma invasion, prostate stemness) while supporting growth in others; in melanoma it is required for invasion and metastasis but not proliferation [#6, #14], and in prostate cancer it supports tumor growth and DNA double-strand break repair through SRC\\u2013STAT3 activity and a PLK1\\u2013WEE1 axis [#8]. In the nervous system, Fzd6 functions as a positive regulator of canonical Wnt/\\u03b2-catenin signaling in hippocampus, where its loss produces depressive-like behavior and reduced hippocampal proliferation [#7]. In humans, a homozygous nonsense mutation (p.E584X) in FZD6 causes autosomal-recessive nail dysplasia, with FZD6 strongly expressed in the ventral nail matrix and nail bed [#12].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established the foundational and counterintuitive mechanism by which FZD6 restrains rather than activates canonical Wnt signaling, defining its action downstream of the \\u03b2-catenin destruction complex.\",\n      \"evidence\": \"Wnt reporter assays, co-expression with HFz1/Dvl1/stabilized \\u03b2-catenin, EMSA for TCF/LEF-DNA binding, and terminal deletion mutagenesis in cell lines\",\n      \"pmids\": [\"14747478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve how FZD6 selects between canonical repression and PCP activation\", \"Ligand specificity for the repressive output not defined\", \"No structural basis for the N-/C-terminal requirement\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected FZD6 to neuropsychiatric regulation by identifying it as a CREB target whose hippocampal suppression produces affective phenotypes.\",\n      \"evidence\": \"ChIP-microarray for CREB occupancy and viral-vector knockdown in rat hippocampus with behavioral testing\",\n      \"pmids\": [\"21937024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish which Wnt arm mediates the behavioral effect\", \"Downstream effectors in hippocampus not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked FZD6 to a human Mendelian disease, demonstrating its essential role in nail patterning consistent with PCP-dependent tissue guidance.\",\n      \"evidence\": \"Genome-wide linkage, Sanger sequencing identifying a homozygous p.E584X nonsense mutation, and immunohistochemistry on nail sections\",\n      \"pmids\": [\"22211385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not test the mutant protein's signaling output directly\", \"Mechanism connecting FZD6 loss to nail dysplasia not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed FZD6 in defined oncogenic signaling circuits, showing context-specific coupling to TAK1-NLK and downstream STAT3/NF-\\u03baB in GBM and non-canonical Wnt suppression of proliferation in gastric cancer.\",\n      \"evidence\": \"Pathway perturbation and subtype expression analysis in GBM cells; gain/loss-of-function with proliferation/migration and miR-21 target validation in gastric cancer cells\",\n      \"pmids\": [\"27698350\", \"27347343\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Opposing directionality across tumor types not mechanistically reconciled\", \"Direct ligand engagement not defined in these models\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified physical partners and RNA-based regulators that route FZD6 toward \\u03b2-catenin nuclear translocation in specific cancers, reframing FZD6 as a positive Wnt effector in these contexts.\",\n      \"evidence\": \"Co-IP of NPTX2-FZD6 with siRNA rescue in colorectal cancer; RNA-protein interaction of lncRNA PCAT-1 with FZD6 plus rescue in AML cells\",\n      \"pmids\": [\"30833544\", \"31814913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal interaction validation limited\", \"How partner binding switches FZD6 output toward canonical signaling unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated ligand-driven receptor complex formation, showing WNT10B activates Wnt signaling through a FZD6 receptor complex in leukemia.\",\n      \"evidence\": \"Reciprocal Co-IP of WNT10B/FZD6, shRNA silencing, and PORCN inhibition (LGK974) with proliferation readouts in T-ALL\",\n      \"pmids\": [\"33497493\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and co-receptor composition of the complex not defined\", \"Downstream effector branch not fully mapped\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a clean genetic requirement for FZD6 in metastatic behavior, dissociating its role in invasion from proliferation.\",\n      \"evidence\": \"CRISPR/Cas9 knockout with in vitro invasion assays and in vivo Pten/BRaf melanoma model linked to canonical Wnt/EMT markers\",\n      \"pmids\": [\"36368445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between FZD6 and the EMT program not fully resolved\", \"Whether canonical or non-canonical signaling drives invasion not disentangled\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined FZD6 as a positive canonical Wnt regulator in hippocampus and established a behavioral phenotype from its loss, contrasting with its repressive role in other systems.\",\n      \"evidence\": \"CRISPR/Cas9 Fzd6-\\u03945 mouse model with behavioral batteries, Ki67/PCNA immunofluorescence, and Wnt pathway qRT-PCR/Western blot\",\n      \"pmids\": [\"37321345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of cell-type/context-dependent directional switching unresolved\", \"Receptor ligand in hippocampus not identified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided direct mechanistic insight into FZD6 PCP function by showing shear-stress-driven membrane reorganization and mutual exclusion with Vangl1 coordinates endothelial polarity.\",\n      \"evidence\": \"Live imaging, subcellular localization, biomimetic flow chambers, zebrafish vessel studies, and Vangl1 loss-of-function with Fzd6 localization readout (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.06.25.600357\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Molecular basis of Fzd6/Vangl1 mutual exclusion not defined\", \"Link to vascular disease not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered a non-Wnt-centric oncogenic role for FZD6 in supporting DNA double-strand break repair and tumor growth in prostate cancer through kinase signaling.\",\n      \"evidence\": \"shRNA knockdown, patient-derived xenografts, \\u03b3H2AX/DSB repair reporter assays, kinome-wide CRISPR screen, and SRC/STAT3/WEE1/PLK1 analysis\",\n      \"pmids\": [\"41286306\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a Frizzled receptor couples to SRC-STAT3 and PLK1-WEE1 mechanistically unresolved\", \"Direct versus indirect control of DSB repair not separated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded the context-dependent FZD6 outputs to chemoresistance, adipogenesis, and tissue aging through \\u03b2-catenin and transcriptional/post-transcriptional regulation.\",\n      \"evidence\": \"FZD6 KD/OE with pyroptosis and 5-FU resistance readouts in CRC; miR-199a-5p target validation and adipogenesis rescue in BM-MSCs; HOXC10 ChIP at the FZD6 promoter in fibroblast senescence models\",\n      \"pmids\": [\"40810359\", \"41198743\", \"41268215\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Directionality of FZD6 on \\u03b2-catenin differs across these contexts without unifying mechanism\", \"Causal versus correlative regulation in some models incompletely separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The central unresolved question is what determines whether FZD6 represses or activates canonical Wnt/\\u03b2-catenin signaling, and how a single receptor coordinates this switch with PCP signaling and kinase-driven outputs across tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of FZD6 in distinct signaling states\", \"Ligand/co-receptor combinations dictating output not systematically mapped\", \"Mechanism coupling FZD6 to SRC-STAT3 and PLK1-WEE1 unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 5, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 8, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"VANGL1\", \"NPTX2\", \"WNT10B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}