{"gene":"FZD6","run_date":"2026-04-28T17:46:04","timeline":{"discoveries":[{"year":2004,"finding":"HFz6 acts as a negative regulator of canonical Wnt/β-catenin signaling by inhibiting TCF/LEF binding to target DNA without affecting β-catenin stabilization or nuclear TCF4 levels. HFz6 activates the TAK1-NLK pathway, which blocks TCF/LEF binding to target promoters, thereby inhibiting β-catenin-driven transcription. Both N- and C-terminal sequences of HFz6 are required for this repressive activity.","method":"Co-expression assays, luciferase reporter assays, electrophoretic mobility shift assays (EMSA), deletion mutagenesis, LiCl-mediated GSK-3β inhibition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (EMSA, reporter assays, mutagenesis) in a single highly-cited study establishing mechanism","pmids":["14747478"],"is_preprint":false},{"year":2016,"finding":"FZD6 activates CaMKII-TAK1-NLK signaling, which attenuates canonical Wnt pathway activity while promoting STAT3 and NF-κB signaling, establishing FZD6 as a negative regulator of Wnt/β-catenin and a driver of the mesenchymal GBM phenotype. A TCF4-miR-125b/miR-20b-FZD6 regulatory circuit controls GBM subtype identity.","method":"Gain- and loss-of-function assays, pathway reporter assays, GBM cell line models, in vivo xenograft validation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal functional assays in vitro and in vivo with mechanistic pathway placement","pmids":["27698350"],"is_preprint":false},{"year":2012,"finding":"Loss-of-function mutations in FZD6 cause autosomal-recessive nail dysplasia in humans. Immunohistochemistry showed strong FZD6 expression in the ventral nail matrix and nail bed, indicating a pivotal role in nail plate growth and guidance via Wnt signaling.","method":"Genome-wide linkage analysis, Sanger sequencing, immunohistochemistry on nail sections","journal":"The British journal of dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — human genetic loss-of-function with localization data; replicated by multiple subsequent families","pmids":["22211385"],"is_preprint":false},{"year":2011,"finding":"Viral vector-mediated inhibition of Fzd6 in the hippocampus of rodents produced anxiety- and depressive-like behavior, establishing Fzd6 as a CREB target gene regulated by chronic electroconvulsive seizure with a functional role in mood-related behavior.","method":"Chromatin immunoprecipitation-microarray (ChIP-chip), viral vector-mediated gene knockdown, behavioral models of depression (open field, forced swim, tail suspension)","journal":"Biological psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus viral KD with defined behavioral phenotype in rodent model","pmids":["21937024"],"is_preprint":false},{"year":2019,"finding":"NPTX2 physically interacts with FZD6 to promote β-catenin nuclear translocation and activate canonical Wnt/β-catenin target gene expression (MYC, cyclin D1, snail, N-cadherin) in colorectal cancer cells. FZD6 knockdown nearly completely reversed NPTX2-mediated proliferative effects.","method":"Co-immunoprecipitation, siRNA knockdown, in vitro and in vivo proliferation/metastasis assays, western blot for pathway targets","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP demonstrating physical interaction plus functional rescue experiments","pmids":["30833544"],"is_preprint":false},{"year":2018,"finding":"A divergent lncRNA of FZD6 (lncFZD6) drives liver tumor-initiating cell (TIC) self-renewal by interacting with BRG1-embedded SWI/SNF complex and recruiting it to the FZD6 promoter, inducing chromatin remodeling and FZD6 transcription. WNT5A acts as a ligand of FZD6 in this context, activating Wnt/β-catenin signaling in liver TICs in an lncFZD6-BRG1-FZD6-dependent manner.","method":"RNA immunoprecipitation, ChIP, promoter reporter assays, loss- and gain-of-function, tumor sphere and tumor initiation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (RIP, ChIP, reporter assay) showing FZD6 transcriptional regulation mechanism by lncFZD6/BRG1","pmids":["29535420"],"is_preprint":false},{"year":2021,"finding":"PCAT-1 lncRNA directly interacts with FZD6 protein to regulate its stability and activate Wnt/β-catenin signaling in AML cells. FZD6 overexpression partially rescued the effects of PCAT-1 knockdown on proliferation, cell cycle, and apoptosis.","method":"RNA-protein interaction assays, gain- and loss-of-function, rescue experiments, western blot for Wnt pathway components","journal":"American journal of translational research","confidence":"Low","confidence_rationale":"Tier 3 — single lab, interaction demonstrated but method for protein binding not detailed rigorously","pmids":["31814913"],"is_preprint":false},{"year":2022,"finding":"FZD6 knockdown or knockout significantly reduces the invasive ability of melanoma cells and dramatically reduces lung metastasis in the Pten/BRaf mouse model, with mechanistic studies revealing involvement of canonical Wnt signaling and epithelial-mesenchymal transition in the FZD6-mediated invasive phenotype.","method":"siRNA knockdown, CRISPR-KO, in vitro invasion assays, in vivo mouse melanoma model, western blot for Wnt/EMT markers","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with defined in vivo phenotype and mechanistic pathway analysis","pmids":["36368445"],"is_preprint":false},{"year":2023,"finding":"FZD6 knockdown in prostate cancer cells impairs DNA double-strand break (DSB) repair and reduces activities of SRC kinase and STAT3. DNA damage repair deficiency following FZD6 loss is mechanistically linked to WEE1 downregulation via PLK1. A CRISPR kinome screen revealed that FZD6 inhibition sensitizes prostate cancer cells to PKMYT1 inhibition.","method":"siRNA knockdown, patient-derived xenograft models, γH2AX foci resolution, DNA DSB repair reporter assays, CRISPR-Cas9 kinome-wide screen, western blot for SRC/STAT3/WEE1/PLK1","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal mechanistic assays (reporter, kinome screen, in vivo PDX) establishing pathway position","pmids":["41286306"],"is_preprint":false},{"year":2021,"finding":"WNT10B drives Wnt activation through the FZD6 receptor complex in T-ALL cells, forming a WNT10B/FZD6 protein complex. shRNA-mediated knockdown of WNT10BIVS1 or pharmacological inhibition of WNT secretion (LGK974/PORCN inhibitor) reduces WNT10B/FZD6 complex formation and impairs downstream Wnt effectors and leukemic expansion.","method":"Co-immunoprecipitation (WNT10B/FZD6 complex), shRNA-mediated gene silencing, small molecule PORCN inhibition, leukemic cell proliferation assays","journal":"Hematological oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 — Co-IP demonstrating ligand-receptor complex plus pharmacological and genetic validation","pmids":["33497493"],"is_preprint":false},{"year":2024,"finding":"Shear stress triggers spatial reorganization of Frizzled6 (Fzd6) at the plasma membrane through a Vangl1-dependent mechanism. Membrane enrichment of Vangl1 (via Coronin1C-dependent endo/exocytosis shift) results in mutual exclusion of core PCP proteins Fzd6 and Vangl1, augmenting differential junctional and cytoskeletal dynamics along the flow axis in endothelial cells to coordinate collective cell alignment and vessel sprouting.","method":"Live imaging, subcellular fractionation, endocytosis/exocytosis assays, Vangl1 loss-of-function, in vivo vascular studies, mathematical modeling","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization experiments with functional consequence; multiple orthogonal approaches including in vivo validation","pmids":["bio_10.1101_2024.06.25.600357"],"is_preprint":true},{"year":2023,"finding":"FZD6 overexpression promotes nuclear translocation of β-catenin, reduces NLRP3/caspase-1/GSDMD-mediated pyroptosis, and increases 5-FU resistance in colorectal cancer cells. Conversely, FZD6 knockdown decreases nuclear β-catenin, enhances pyroptosis, and reduces 5-FU resistance, establishing a FZD6→β-catenin nuclear translocation→pyroptosis suppression axis.","method":"Lentiviral FZD6 KD/OE, immunofluorescence for β-catenin localization, western blot for pyroptosis markers, electron microscopy for pyroptosis morphology, CCK-8/colony formation assays","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization assay (β-catenin nuclear translocation) linked to functional outcome with genetic manipulation","pmids":["40810359"],"is_preprint":false},{"year":2023,"finding":"CRISPR/Cas9-mediated Fzd6 knockdown in mice decreases phosphorylated GSK3β and cytoplasmic β-catenin in the hippocampus, decreases hippocampal cell proliferation (Ki67+, PCNA+ cells), and produces depressive-like behaviors, placing Fzd6 upstream of GSK3β and β-catenin in the canonical Wnt pathway in the hippocampus.","method":"CRISPR/Cas9 Fzd6 knockdown mouse model, behavioral tests (FST, SPT, OFT, EPM), immunofluorescence (Ki67, PCNA), western blot for GSK3β/β-catenin, qRT-PCR","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO model with defined cellular (hippocampal proliferation) and molecular (GSK3β/β-catenin) phenotype","pmids":["37321345"],"is_preprint":false},{"year":2023,"finding":"Fzd6 mutation (Fzd6Q152E) in mice decreases serum BDNF, 5-HT, and noradrenaline, increases Dkk2 and Gsk-3β expression, and decreases Lrp6 and Fzd6 protein levels, implicating Fzd6 in regulation of the Wnt pathway and neurotransmitter systems relevant to depression.","method":"CRISPR/Cas9 Fzd6Q152E knock-in mice, ELISA for BDNF/5-HT/NE, western blot and qRT-PCR for Wnt pathway genes, Nissl staining","journal":"Molecular biology reports","confidence":"Low","confidence_rationale":"Tier 3 — single lab, mechanistic follow-up limited; Wnt pathway changes observed without detailed epistasis","pmids":["35980530"],"is_preprint":false},{"year":2024,"finding":"FLD (Fengshi Liuhe Decoction) downregulates Fzd6 expression in CIA rat fibroblast-like synoviocytes and suppresses NF-κB signaling (reducing p-p65 and p-IκBα), inhibiting nuclear translocation of NF-κB p65 and reducing inflammatory cytokines (COX-2, IL-8, TNF-α), identifying a Fzd6/NF-κB signaling axis in synovial inflammation.","method":"qPCR, western blot, ELISA for cytokines, nuclear translocation assay for NF-κB p65, CIA rat FLS model","journal":"Gene","confidence":"Low","confidence_rationale":"Tier 3 — single lab, pharmacological intervention without direct FZD6 loss-of-function to confirm pathway causality","pmids":["38710294"],"is_preprint":false},{"year":2025,"finding":"HOXC10 transcription factor binds to the FZD6 promoter region and reduces FZD6 expression, thereby activating the Wnt/β-catenin signaling pathway to delay skin cell senescence and aging.","method":"Single-cell transcriptomics, ChIP (HOXC10 binding to FZD6 promoter), gain- and loss-of-function in fibroblasts, in vivo aging models","journal":"Research (Washington, D.C.)","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP demonstrating direct transcription factor-promoter binding plus functional rescue experiments","pmids":["41268215"],"is_preprint":false}],"current_model":"FZD6 is a seven-transmembrane Frizzled receptor that functions as a context-dependent molecular switch: it negatively regulates canonical Wnt/β-catenin signaling by activating a TAK1-NLK pathway that blocks TCF/LEF-DNA binding (without affecting β-catenin destruction), while positively regulating non-canonical planar cell polarity (PCP) signaling to coordinate cell polarity, tissue morphogenesis, nail growth, neural tube closure, and endothelial alignment in response to shear stress; in cancer contexts it can also activate canonical Wnt/β-catenin-mediated proliferation and invasion, impair DNA double-strand break repair via SRC/STAT3 and WEE1/PLK1, and regulate pyroptosis through β-catenin nuclear translocation."},"narrative":{"teleology":[{"year":2004,"claim":"Establishing that FZD6 negatively regulates canonical Wnt signaling resolved how a Frizzled receptor could paradoxically repress the pathway it was expected to transduce, revealing a TAK1–NLK mechanism that blocks TCF/LEF–DNA binding without destabilizing β-catenin.","evidence":"Co-expression and luciferase reporter assays, EMSA, and deletion mutagenesis in mammalian cells with LiCl-mediated GSK-3β inhibition","pmids":["14747478"],"confidence":"High","gaps":["Endogenous ligand activating FZD6's repressive mode was not identified","No co-receptor requirement investigated","Structural basis for N- and C-terminal requirement undefined"]},{"year":2012,"claim":"Identification of FZD6 loss-of-function mutations as the cause of autosomal-recessive nail dysplasia established the first human disease directly attributable to FZD6 deficiency and linked it to Wnt-dependent nail morphogenesis.","evidence":"Genome-wide linkage analysis, Sanger sequencing, and immunohistochemistry of human nail tissue","pmids":["22211385"],"confidence":"Medium","gaps":["Specific downstream Wnt branch (canonical vs. PCP) disrupted in nail dysplasia not resolved","Functional rescue of mutant alleles not performed","Mechanism of nail plate guidance not defined"]},{"year":2011,"claim":"Demonstrating that Fzd6 knockdown in the hippocampus produces anxiety- and depressive-like behavior revealed a CNS function for FZD6 as a CREB target gene linking Wnt signaling to mood regulation.","evidence":"ChIP-chip identification of CREB binding, viral vector-mediated Fzd6 knockdown in rodent hippocampus, behavioral phenotyping","pmids":["21937024"],"confidence":"Medium","gaps":["Downstream Wnt effectors mediating the behavioral phenotype not identified","Cell-type specificity within hippocampus not resolved"]},{"year":2016,"claim":"Placement of FZD6 within a CaMKII–TAK1–NLK–STAT3/NF-κB signaling network in glioblastoma demonstrated how the same TAK1–NLK axis originally shown in non-cancer cells could redirect signaling to promote the mesenchymal tumor subtype, resolving the dual identity of FZD6 as both Wnt repressor and pro-tumorigenic effector.","evidence":"Gain/loss-of-function assays, pathway reporters, GBM cell lines, and in vivo xenograft models","pmids":["27698350"],"confidence":"High","gaps":["Ligand driving FZD6 signaling in GBM microenvironment not established","Whether STAT3/NF-κB activation requires direct FZD6 scaffolding or is indirect unknown"]},{"year":2018,"claim":"Discovery that lncFZD6 recruits BRG1/SWI-SNF to the FZD6 promoter, and that WNT5A acts as a FZD6 ligand activating canonical Wnt/β-catenin signaling in liver tumor-initiating cells, established a feed-forward transcriptional circuit controlling FZD6 expression and its cancer-promoting canonical Wnt output.","evidence":"RNA immunoprecipitation, ChIP, promoter reporters, tumor sphere and tumor initiation assays in liver TIC models","pmids":["29535420"],"confidence":"Medium","gaps":["How the same receptor transduces canonical activation via WNT5A while repressing canonical signaling via TAK1–NLK in other contexts is mechanistically unresolved","Co-receptor requirements for WNT5A–FZD6 not tested"]},{"year":2019,"claim":"Demonstration that NPTX2 physically interacts with FZD6 to promote β-catenin nuclear translocation and canonical Wnt target expression identified an unconventional non-Wnt ligand capable of activating FZD6-mediated canonical signaling in colorectal cancer.","evidence":"Co-immunoprecipitation, siRNA knockdown and rescue, in vitro/in vivo proliferation and metastasis assays","pmids":["30833544"],"confidence":"Medium","gaps":["Binding interface between NPTX2 and FZD6 undefined","Whether NPTX2 competes with Wnt ligands for FZD6 binding not tested"]},{"year":2021,"claim":"Identification of WNT10B as a ligand forming a protein complex with FZD6 in T-ALL established a disease-specific Wnt–FZD6 axis druggable by PORCN inhibition, extending the receptor's ligand repertoire beyond WNT5A.","evidence":"Co-immunoprecipitation of WNT10B/FZD6 complex, shRNA knockdown, PORCN inhibitor LGK974 treatment in T-ALL cells","pmids":["33497493"],"confidence":"Medium","gaps":["Co-receptor (e.g., LRP5/6) involvement not characterized","Downstream effector branch (canonical vs. non-canonical) not fully resolved"]},{"year":2022,"claim":"Genetic deletion of FZD6 in melanoma cells dramatically reduced invasion and lung metastasis in vivo, linking FZD6 to EMT and establishing it as a functional driver of metastatic spread.","evidence":"siRNA/CRISPR-KO, invasion assays, Pten/BRaf mouse melanoma model, Wnt/EMT marker analysis","pmids":["36368445"],"confidence":"Medium","gaps":["Specific ligand activating FZD6 in melanoma not identified","Whether the EMT role is TAK1–NLK-dependent or β-catenin-dependent not distinguished"]},{"year":2023,"claim":"Multiple 2023 studies convergently expanded FZD6's mechanistic repertoire: FZD6 knockdown in prostate cancer impaired DNA DSB repair via SRC/STAT3 and WEE1/PLK1; FZD6 promoted β-catenin nuclear translocation to suppress pyroptosis and confer 5-FU resistance in colorectal cancer; and hippocampal Fzd6 loss reduced GSK3β phosphorylation and β-catenin, decreasing neural proliferation and producing depressive behavior.","evidence":"CRISPR kinome screen plus PDX models (prostate cancer); lentiviral KD/OE with immunofluorescence and pyroptosis markers (CRC); CRISPR/Cas9 KD mouse with behavioral phenotyping and western blot (hippocampus)","pmids":["41286306","40810359","37321345"],"confidence":"High","gaps":["How FZD6 engages SRC kinase directly versus through intermediate adaptors is unknown","Structural or biochemical basis for FZD6-dependent β-catenin nuclear translocation not defined","Whether hippocampal and cancer phenotypes share common downstream effectors is unclear"]},{"year":2024,"claim":"Shear-stress-induced spatial reorganization of FZD6 at the plasma membrane through Vangl1-dependent mutual exclusion provided the first direct evidence for FZD6 functioning in mammalian planar cell polarity signaling to coordinate endothelial alignment and vessel sprouting.","evidence":"Live imaging, subcellular fractionation, endocytosis/exocytosis assays, Vangl1 loss-of-function, in vivo vascular studies (preprint)","pmids":["bio_10.1101_2024.06.25.600357"],"confidence":"Medium","gaps":["Peer review pending","Direct physical interaction between FZD6 and Vangl1 not demonstrated biochemically","Whether asymmetric FZD6 localization requires Dvl scaffolding not tested"]},{"year":null,"claim":"A central unresolved question is how the same FZD6 receptor switches between TAK1–NLK-mediated canonical Wnt repression, β-catenin nuclear translocation and canonical activation, and planar cell polarity signaling in different cellular contexts — the molecular determinants of this context-dependent switch remain unknown.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of FZD6 ligand–receptor–co-receptor complexes exists","Identity of the adaptor(s) or co-receptors that dictate pathway choice at FZD6 is unknown","Whether post-translational modifications of FZD6 control pathway switching has not been tested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,4,5,9,10]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,11]}],"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":[0,1,4,5,9,11,12]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,4,7,8,9,11]}],"complexes":[],"partners":["NPTX2","WNT10B","WNT5A","VANGL1","TAK1","NLK"],"other_free_text":[]},"mechanistic_narrative":"FZD6 is a seven-transmembrane Frizzled family receptor that functions as a context-dependent modulator of Wnt signaling, acting as either a negative regulator of the canonical Wnt/β-catenin pathway or a positive transducer depending on cellular context. In its repressive mode, FZD6 activates the CaMKII–TAK1–NLK cascade to block TCF/LEF binding to target DNA without affecting β-catenin stabilization, thereby attenuating canonical Wnt-driven transcription [PMID:14747478, PMID:27698350]; in cancer and neuronal contexts, FZD6 instead promotes β-catenin nuclear translocation, engaging canonical Wnt target genes and additionally regulating DNA double-strand break repair through SRC/STAT3 and WEE1/PLK1 [PMID:30833544, PMID:41286306, PMID:40810359]. Loss-of-function mutations in FZD6 cause autosomal-recessive nail dysplasia in humans, and Fzd6 loss in the hippocampus reduces GSK3β phosphorylation and β-catenin levels, decreasing neural progenitor proliferation and producing depressive-like behavior [PMID:22211385, PMID:37321345]."},"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":"22045688","id":"PMC_22045688","title":"FZD6 is a novel gene for human neural tube defects.","date":"2011","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/22045688","citation_count":81,"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":81,"is_preprint":false},{"pmid":"32557673","id":"PMC_32557673","title":"Mesenchymal stem cell-derived extracellular vesicles suppress the fibroblast proliferation by downregulating FZD6 expression in fibroblasts via micrRNA-29b-3p in idiopathic pulmonary fibrosis.","date":"2020","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/32557673","citation_count":63,"is_preprint":false},{"pmid":"31118816","id":"PMC_31118816","title":"Long noncoding RNA DLX6-AS1 promotes tumorigenesis by modulating miR-497-5p/FZD4/FZD6/Wnt/β-catenin pathway in pancreatic cancer.","date":"2019","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/31118816","citation_count":62,"is_preprint":false},{"pmid":"29535420","id":"PMC_29535420","title":"LncFZD6 initiates Wnt/β-catenin and liver TIC self-renewal through BRG1-mediated FZD6 transcriptional activation.","date":"2018","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/29535420","citation_count":61,"is_preprint":false},{"pmid":"30833544","id":"PMC_30833544","title":"NPTX2 promotes colorectal cancer growth and liver metastasis by the activation of the canonical Wnt/β-catenin pathway via FZD6.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30833544","citation_count":54,"is_preprint":false},{"pmid":"25772759","id":"PMC_25772759","title":"FZD6 expression is negatively regulated by miR-199a-5p in human colorectal cancer.","date":"2015","source":"BMB reports","url":"https://pubmed.ncbi.nlm.nih.gov/25772759","citation_count":54,"is_preprint":false},{"pmid":"29867083","id":"PMC_29867083","title":"Luteolin attenuates Wnt signaling via upregulation of FZD6 to suppress prostate cancer stemness revealed by comparative proteomics.","date":"2018","source":"Scientific 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stabilization or nuclear TCF4 levels. HFz6 activates the TAK1-NLK pathway, which blocks TCF/LEF binding to target promoters, thereby inhibiting β-catenin-driven transcription. Both N- and C-terminal sequences of HFz6 are required for this repressive activity.\",\n      \"method\": \"Co-expression assays, luciferase reporter assays, electrophoretic mobility shift assays (EMSA), deletion mutagenesis, LiCl-mediated GSK-3β inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (EMSA, reporter assays, mutagenesis) in a single highly-cited study establishing mechanism\",\n      \"pmids\": [\"14747478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FZD6 activates CaMKII-TAK1-NLK signaling, which attenuates canonical Wnt pathway activity while promoting STAT3 and NF-κB signaling, establishing FZD6 as a negative regulator of Wnt/β-catenin and a driver of the mesenchymal GBM phenotype. A TCF4-miR-125b/miR-20b-FZD6 regulatory circuit controls GBM subtype identity.\",\n      \"method\": \"Gain- and loss-of-function assays, pathway reporter assays, GBM cell line models, in vivo xenograft validation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal functional assays in vitro and in vivo with mechanistic pathway placement\",\n      \"pmids\": [\"27698350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Loss-of-function mutations in FZD6 cause autosomal-recessive nail dysplasia in humans. Immunohistochemistry showed strong FZD6 expression in the ventral nail matrix and nail bed, indicating a pivotal role in nail plate growth and guidance via Wnt signaling.\",\n      \"method\": \"Genome-wide linkage analysis, Sanger sequencing, immunohistochemistry on nail sections\",\n      \"journal\": \"The British journal of dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human genetic loss-of-function with localization data; replicated by multiple subsequent families\",\n      \"pmids\": [\"22211385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Viral vector-mediated inhibition of Fzd6 in the hippocampus of rodents produced anxiety- and depressive-like behavior, establishing Fzd6 as a CREB target gene regulated by chronic electroconvulsive seizure with a functional role in mood-related behavior.\",\n      \"method\": \"Chromatin immunoprecipitation-microarray (ChIP-chip), viral vector-mediated gene knockdown, behavioral models of depression (open field, forced swim, tail suspension)\",\n      \"journal\": \"Biological psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus viral KD with defined behavioral phenotype in rodent model\",\n      \"pmids\": [\"21937024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NPTX2 physically interacts with FZD6 to promote β-catenin nuclear translocation and activate canonical Wnt/β-catenin target gene expression (MYC, cyclin D1, snail, N-cadherin) in colorectal cancer cells. FZD6 knockdown nearly completely reversed NPTX2-mediated proliferative effects.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, in vitro and in vivo proliferation/metastasis assays, western blot for pathway targets\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP demonstrating physical interaction plus functional rescue experiments\",\n      \"pmids\": [\"30833544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A divergent lncRNA of FZD6 (lncFZD6) drives liver tumor-initiating cell (TIC) self-renewal by interacting with BRG1-embedded SWI/SNF complex and recruiting it to the FZD6 promoter, inducing chromatin remodeling and FZD6 transcription. WNT5A acts as a ligand of FZD6 in this context, activating Wnt/β-catenin signaling in liver TICs in an lncFZD6-BRG1-FZD6-dependent manner.\",\n      \"method\": \"RNA immunoprecipitation, ChIP, promoter reporter assays, loss- and gain-of-function, tumor sphere and tumor initiation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (RIP, ChIP, reporter assay) showing FZD6 transcriptional regulation mechanism by lncFZD6/BRG1\",\n      \"pmids\": [\"29535420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PCAT-1 lncRNA directly interacts with FZD6 protein to regulate its stability and activate Wnt/β-catenin signaling in AML cells. FZD6 overexpression partially rescued the effects of PCAT-1 knockdown on proliferation, cell cycle, and apoptosis.\",\n      \"method\": \"RNA-protein interaction assays, gain- and loss-of-function, rescue experiments, western blot for Wnt pathway components\",\n      \"journal\": \"American journal of translational research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, interaction demonstrated but method for protein binding not detailed rigorously\",\n      \"pmids\": [\"31814913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FZD6 knockdown or knockout significantly reduces the invasive ability of melanoma cells and dramatically reduces lung metastasis in the Pten/BRaf mouse model, with mechanistic studies revealing involvement of canonical Wnt signaling and epithelial-mesenchymal transition in the FZD6-mediated invasive phenotype.\",\n      \"method\": \"siRNA knockdown, CRISPR-KO, in vitro invasion assays, in vivo mouse melanoma model, western blot for Wnt/EMT markers\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined in vivo phenotype and mechanistic pathway analysis\",\n      \"pmids\": [\"36368445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FZD6 knockdown in prostate cancer cells impairs DNA double-strand break (DSB) repair and reduces activities of SRC kinase and STAT3. DNA damage repair deficiency following FZD6 loss is mechanistically linked to WEE1 downregulation via PLK1. A CRISPR kinome screen revealed that FZD6 inhibition sensitizes prostate cancer cells to PKMYT1 inhibition.\",\n      \"method\": \"siRNA knockdown, patient-derived xenograft models, γH2AX foci resolution, DNA DSB repair reporter assays, CRISPR-Cas9 kinome-wide screen, western blot for SRC/STAT3/WEE1/PLK1\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal mechanistic assays (reporter, kinome screen, in vivo PDX) establishing pathway position\",\n      \"pmids\": [\"41286306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"WNT10B drives Wnt activation through the FZD6 receptor complex in T-ALL cells, forming a WNT10B/FZD6 protein complex. shRNA-mediated knockdown of WNT10BIVS1 or pharmacological inhibition of WNT secretion (LGK974/PORCN inhibitor) reduces WNT10B/FZD6 complex formation and impairs downstream Wnt effectors and leukemic expansion.\",\n      \"method\": \"Co-immunoprecipitation (WNT10B/FZD6 complex), shRNA-mediated gene silencing, small molecule PORCN inhibition, leukemic cell proliferation assays\",\n      \"journal\": \"Hematological oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — Co-IP demonstrating ligand-receptor complex plus pharmacological and genetic validation\",\n      \"pmids\": [\"33497493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Shear stress triggers spatial reorganization of Frizzled6 (Fzd6) at the plasma membrane through a Vangl1-dependent mechanism. Membrane enrichment of Vangl1 (via Coronin1C-dependent endo/exocytosis shift) results in mutual exclusion of core PCP proteins Fzd6 and Vangl1, augmenting differential junctional and cytoskeletal dynamics along the flow axis in endothelial cells to coordinate collective cell alignment and vessel sprouting.\",\n      \"method\": \"Live imaging, subcellular fractionation, endocytosis/exocytosis assays, Vangl1 loss-of-function, in vivo vascular studies, mathematical modeling\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiments with functional consequence; multiple orthogonal approaches including in vivo validation\",\n      \"pmids\": [\"bio_10.1101_2024.06.25.600357\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FZD6 overexpression promotes nuclear translocation of β-catenin, reduces NLRP3/caspase-1/GSDMD-mediated pyroptosis, and increases 5-FU resistance in colorectal cancer cells. Conversely, FZD6 knockdown decreases nuclear β-catenin, enhances pyroptosis, and reduces 5-FU resistance, establishing a FZD6→β-catenin nuclear translocation→pyroptosis suppression axis.\",\n      \"method\": \"Lentiviral FZD6 KD/OE, immunofluorescence for β-catenin localization, western blot for pyroptosis markers, electron microscopy for pyroptosis morphology, CCK-8/colony formation assays\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization assay (β-catenin nuclear translocation) linked to functional outcome with genetic manipulation\",\n      \"pmids\": [\"40810359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CRISPR/Cas9-mediated Fzd6 knockdown in mice decreases phosphorylated GSK3β and cytoplasmic β-catenin in the hippocampus, decreases hippocampal cell proliferation (Ki67+, PCNA+ cells), and produces depressive-like behaviors, placing Fzd6 upstream of GSK3β and β-catenin in the canonical Wnt pathway in the hippocampus.\",\n      \"method\": \"CRISPR/Cas9 Fzd6 knockdown mouse model, behavioral tests (FST, SPT, OFT, EPM), immunofluorescence (Ki67, PCNA), western blot for GSK3β/β-catenin, qRT-PCR\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO model with defined cellular (hippocampal proliferation) and molecular (GSK3β/β-catenin) phenotype\",\n      \"pmids\": [\"37321345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Fzd6 mutation (Fzd6Q152E) in mice decreases serum BDNF, 5-HT, and noradrenaline, increases Dkk2 and Gsk-3β expression, and decreases Lrp6 and Fzd6 protein levels, implicating Fzd6 in regulation of the Wnt pathway and neurotransmitter systems relevant to depression.\",\n      \"method\": \"CRISPR/Cas9 Fzd6Q152E knock-in mice, ELISA for BDNF/5-HT/NE, western blot and qRT-PCR for Wnt pathway genes, Nissl staining\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, mechanistic follow-up limited; Wnt pathway changes observed without detailed epistasis\",\n      \"pmids\": [\"35980530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FLD (Fengshi Liuhe Decoction) downregulates Fzd6 expression in CIA rat fibroblast-like synoviocytes and suppresses NF-κB signaling (reducing p-p65 and p-IκBα), inhibiting nuclear translocation of NF-κB p65 and reducing inflammatory cytokines (COX-2, IL-8, TNF-α), identifying a Fzd6/NF-κB signaling axis in synovial inflammation.\",\n      \"method\": \"qPCR, western blot, ELISA for cytokines, nuclear translocation assay for NF-κB p65, CIA rat FLS model\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, pharmacological intervention without direct FZD6 loss-of-function to confirm pathway causality\",\n      \"pmids\": [\"38710294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HOXC10 transcription factor binds to the FZD6 promoter region and reduces FZD6 expression, thereby activating the Wnt/β-catenin signaling pathway to delay skin cell senescence and aging.\",\n      \"method\": \"Single-cell transcriptomics, ChIP (HOXC10 binding to FZD6 promoter), gain- and loss-of-function in fibroblasts, in vivo aging models\",\n      \"journal\": \"Research (Washington, D.C.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrating direct transcription factor-promoter binding plus functional rescue experiments\",\n      \"pmids\": [\"41268215\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FZD6 is a seven-transmembrane Frizzled receptor that functions as a context-dependent molecular switch: it negatively regulates canonical Wnt/β-catenin signaling by activating a TAK1-NLK pathway that blocks TCF/LEF-DNA binding (without affecting β-catenin destruction), while positively regulating non-canonical planar cell polarity (PCP) signaling to coordinate cell polarity, tissue morphogenesis, nail growth, neural tube closure, and endothelial alignment in response to shear stress; in cancer contexts it can also activate canonical Wnt/β-catenin-mediated proliferation and invasion, impair DNA double-strand break repair via SRC/STAT3 and WEE1/PLK1, and regulate pyroptosis through β-catenin nuclear translocation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FZD6 is a seven-transmembrane Frizzled family receptor that functions as a context-dependent modulator of Wnt signaling, acting as either a negative regulator of the canonical Wnt/β-catenin pathway or a positive transducer depending on cellular context. In its repressive mode, FZD6 activates the CaMKII–TAK1–NLK cascade to block TCF/LEF binding to target DNA without affecting β-catenin stabilization, thereby attenuating canonical Wnt-driven transcription [PMID:14747478, PMID:27698350]; in cancer and neuronal contexts, FZD6 instead promotes β-catenin nuclear translocation, engaging canonical Wnt target genes and additionally regulating DNA double-strand break repair through SRC/STAT3 and WEE1/PLK1 [PMID:30833544, PMID:41286306, PMID:40810359]. Loss-of-function mutations in FZD6 cause autosomal-recessive nail dysplasia in humans, and Fzd6 loss in the hippocampus reduces GSK3β phosphorylation and β-catenin levels, decreasing neural progenitor proliferation and producing depressive-like behavior [PMID:22211385, PMID:37321345].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that FZD6 negatively regulates canonical Wnt signaling resolved how a Frizzled receptor could paradoxically repress the pathway it was expected to transduce, revealing a TAK1–NLK mechanism that blocks TCF/LEF–DNA binding without destabilizing β-catenin.\",\n      \"evidence\": \"Co-expression and luciferase reporter assays, EMSA, and deletion mutagenesis in mammalian cells with LiCl-mediated GSK-3β inhibition\",\n      \"pmids\": [\"14747478\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Endogenous ligand activating FZD6's repressive mode was not identified\",\n        \"No co-receptor requirement investigated\",\n        \"Structural basis for N- and C-terminal requirement undefined\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of FZD6 loss-of-function mutations as the cause of autosomal-recessive nail dysplasia established the first human disease directly attributable to FZD6 deficiency and linked it to Wnt-dependent nail morphogenesis.\",\n      \"evidence\": \"Genome-wide linkage analysis, Sanger sequencing, and immunohistochemistry of human nail tissue\",\n      \"pmids\": [\"22211385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific downstream Wnt branch (canonical vs. PCP) disrupted in nail dysplasia not resolved\",\n        \"Functional rescue of mutant alleles not performed\",\n        \"Mechanism of nail plate guidance not defined\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that Fzd6 knockdown in the hippocampus produces anxiety- and depressive-like behavior revealed a CNS function for FZD6 as a CREB target gene linking Wnt signaling to mood regulation.\",\n      \"evidence\": \"ChIP-chip identification of CREB binding, viral vector-mediated Fzd6 knockdown in rodent hippocampus, behavioral phenotyping\",\n      \"pmids\": [\"21937024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream Wnt effectors mediating the behavioral phenotype not identified\",\n        \"Cell-type specificity within hippocampus not resolved\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placement of FZD6 within a CaMKII–TAK1–NLK–STAT3/NF-κB signaling network in glioblastoma demonstrated how the same TAK1–NLK axis originally shown in non-cancer cells could redirect signaling to promote the mesenchymal tumor subtype, resolving the dual identity of FZD6 as both Wnt repressor and pro-tumorigenic effector.\",\n      \"evidence\": \"Gain/loss-of-function assays, pathway reporters, GBM cell lines, and in vivo xenograft models\",\n      \"pmids\": [\"27698350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Ligand driving FZD6 signaling in GBM microenvironment not established\",\n        \"Whether STAT3/NF-κB activation requires direct FZD6 scaffolding or is indirect unknown\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that lncFZD6 recruits BRG1/SWI-SNF to the FZD6 promoter, and that WNT5A acts as a FZD6 ligand activating canonical Wnt/β-catenin signaling in liver tumor-initiating cells, established a feed-forward transcriptional circuit controlling FZD6 expression and its cancer-promoting canonical Wnt output.\",\n      \"evidence\": \"RNA immunoprecipitation, ChIP, promoter reporters, tumor sphere and tumor initiation assays in liver TIC models\",\n      \"pmids\": [\"29535420\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How the same receptor transduces canonical activation via WNT5A while repressing canonical signaling via TAK1–NLK in other contexts is mechanistically unresolved\",\n        \"Co-receptor requirements for WNT5A–FZD6 not tested\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstration that NPTX2 physically interacts with FZD6 to promote β-catenin nuclear translocation and canonical Wnt target expression identified an unconventional non-Wnt ligand capable of activating FZD6-mediated canonical signaling in colorectal cancer.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA knockdown and rescue, in vitro/in vivo proliferation and metastasis assays\",\n      \"pmids\": [\"30833544\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Binding interface between NPTX2 and FZD6 undefined\",\n        \"Whether NPTX2 competes with Wnt ligands for FZD6 binding not tested\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of WNT10B as a ligand forming a protein complex with FZD6 in T-ALL established a disease-specific Wnt–FZD6 axis druggable by PORCN inhibition, extending the receptor's ligand repertoire beyond WNT5A.\",\n      \"evidence\": \"Co-immunoprecipitation of WNT10B/FZD6 complex, shRNA knockdown, PORCN inhibitor LGK974 treatment in T-ALL cells\",\n      \"pmids\": [\"33497493\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Co-receptor (e.g., LRP5/6) involvement not characterized\",\n        \"Downstream effector branch (canonical vs. non-canonical) not fully resolved\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Genetic deletion of FZD6 in melanoma cells dramatically reduced invasion and lung metastasis in vivo, linking FZD6 to EMT and establishing it as a functional driver of metastatic spread.\",\n      \"evidence\": \"siRNA/CRISPR-KO, invasion assays, Pten/BRaf mouse melanoma model, Wnt/EMT marker analysis\",\n      \"pmids\": [\"36368445\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific ligand activating FZD6 in melanoma not identified\",\n        \"Whether the EMT role is TAK1–NLK-dependent or β-catenin-dependent not distinguished\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Multiple 2023 studies convergently expanded FZD6's mechanistic repertoire: FZD6 knockdown in prostate cancer impaired DNA DSB repair via SRC/STAT3 and WEE1/PLK1; FZD6 promoted β-catenin nuclear translocation to suppress pyroptosis and confer 5-FU resistance in colorectal cancer; and hippocampal Fzd6 loss reduced GSK3β phosphorylation and β-catenin, decreasing neural proliferation and producing depressive behavior.\",\n      \"evidence\": \"CRISPR kinome screen plus PDX models (prostate cancer); lentiviral KD/OE with immunofluorescence and pyroptosis markers (CRC); CRISPR/Cas9 KD mouse with behavioral phenotyping and western blot (hippocampus)\",\n      \"pmids\": [\"41286306\", \"40810359\", \"37321345\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How FZD6 engages SRC kinase directly versus through intermediate adaptors is unknown\",\n        \"Structural or biochemical basis for FZD6-dependent β-catenin nuclear translocation not defined\",\n        \"Whether hippocampal and cancer phenotypes share common downstream effectors is unclear\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Shear-stress-induced spatial reorganization of FZD6 at the plasma membrane through Vangl1-dependent mutual exclusion provided the first direct evidence for FZD6 functioning in mammalian planar cell polarity signaling to coordinate endothelial alignment and vessel sprouting.\",\n      \"evidence\": \"Live imaging, subcellular fractionation, endocytosis/exocytosis assays, Vangl1 loss-of-function, in vivo vascular studies (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.06.25.600357\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Peer review pending\",\n        \"Direct physical interaction between FZD6 and Vangl1 not demonstrated biochemically\",\n        \"Whether asymmetric FZD6 localization requires Dvl scaffolding not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A central unresolved question is how the same FZD6 receptor switches between TAK1–NLK-mediated canonical Wnt repression, β-catenin nuclear translocation and canonical activation, and planar cell polarity signaling in different cellular contexts — the molecular determinants of this context-dependent switch remain unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of FZD6 ligand–receptor–co-receptor complexes exists\",\n        \"Identity of the adaptor(s) or co-receptors that dictate pathway choice at FZD6 is unknown\",\n        \"Whether post-translational modifications of FZD6 control pathway switching has not been tested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 4, 5, 9, 10]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0016055\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 4, 5, 9, 11, 12]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 4, 7, 8, 9, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NPTX2\",\n      \"WNT10B\",\n      \"WNT5A\",\n      \"VANGL1\",\n      \"TAK1\",\n      \"NLK\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}