{"gene":"FZD2","run_date":"2026-04-28T17:46:04","timeline":{"discoveries":[{"year":2008,"finding":"Ror2 positively modulates Wnt3a-activated canonical Wnt signaling in lung carcinoma cells through cooperative interaction with Fzd2 (but not Fzd7); this requires the extracellular CRD of Ror2 and is Lrp-dependent (inhibited by Dkk1/Krm1).","method":"Co-transfection, reporter assay (STF), domain deletion mutants, inhibitor treatment in H441 cells","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — functional epistasis with domain mapping, single lab, multiple complementary methods","pmids":["18215320"],"is_preprint":false},{"year":2014,"finding":"FZD2 and WNT5A drive epithelial-to-mesenchymal transition (EMT) and metastasis via a noncanonical signaling pathway involving FYN kinase and STAT3.","method":"Functional cell-based assays, pathway analysis (reported in Cancer Discovery summary)","journal":"Cancer discovery","confidence":"Medium","confidence_rationale":"Tier 2 — pathway placement with defined effectors, but abstract is a brief summary without full experimental detail","pmids":["34450691"],"is_preprint":false},{"year":2020,"finding":"FZD2 modulates noncanonical Wnt signaling by binding Wnt5a/b and Wnt3 ligands to activate oncogenic IL-6/STAT3, YAP1, and TGF-β1/Smad3 pathways, promoting breast cancer cell mesenchymal stemness and drug resistance.","method":"FZD2 knockdown/overexpression, co-immunoprecipitation (binding with Wnt ligands), mammosphere formation, pathway reporter assays","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct binding shown by Co-IP, multiple pathway readouts, single lab","pmids":["31907106"],"is_preprint":false},{"year":2020,"finding":"WNT2 ligand stabilizes and phosphorylates the FZD2 receptor by attenuating FZD2 ubiquitination, leading to activation of STAT3 signaling and promotion of esophageal cancer cell metastasis.","method":"Co-immunoprecipitation, ubiquitination assay, phosphorylation assay, knockdown/overexpression with migration/invasion readouts, in vivo xenograft","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal biochemical methods (ubiquitination, phosphorylation, Co-IP) establishing post-translational regulation, single lab","pmids":["32766155"],"is_preprint":false},{"year":2021,"finding":"FZD2 promotes TGF-β1-induced EMT in breast cancer cells through activation of the Notch signaling pathway; FZD2 knockdown leads to Notch inactivation and suppression of EMT markers.","method":"siRNA knockdown, western blot for EMT and Notch pathway markers, in vivo xenograft, immunofluorescence","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2-3 — loss-of-function with defined pathway placement (Notch), multiple readouts, single lab","pmids":["33832493"],"is_preprint":false},{"year":2022,"finding":"Wnt5a/FZD2-mediated noncanonical Wnt pathway activation drives enzalutamide resistance in prostate cancer; blocking this pathway suppresses constitutively activated androgen receptor (AR) and AR variants.","method":"siRNA knockdown, BERA-Wnt5a siRNA construct, in vivo tumor xenograft, AR pathway reporter assays","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo validation with defined pathway (noncanonical Wnt → AR), single lab with multiple methods","pmids":["35930737"],"is_preprint":false},{"year":2023,"finding":"FZD2 controls limb development by mediating both canonical Wnt/β-catenin signaling (required for limb mesenchyme proliferation) and noncanonical WNT5A/planar cell polarity (PCP) signaling (required for digit chondrocyte elongation and orientation); frameshift mutation in the Dishevelled-interacting domain causes shortened limbs resembling Robinow syndrome/OMOD2.","method":"CRISPR/Cas9 knock-in mouse model (Fzd2em1Smill), conditional FZD function disruption in limb mesenchyme, β-catenin reporter assay, PCP pathway readouts, skeletal analysis","journal":"Disease models & mechanisms","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo genetic model with domain-specific mutation, multiple pathway readouts, recapitulates human disease phenotype","pmids":["36867021"],"is_preprint":false},{"year":2024,"finding":"Two pathogenic FZD2 missense variants (G434V; P142K) associated with Robinow syndrome inhibit chondrogenesis, increase nuclear β-catenin shuttling and TWIST1 expression; the P142K variant selectively fails to activate non-canonical Wnt signaling and is unresponsive to WNT5A, representing the first single amino-acid change shown to selectively alter ligand binding in a FZD receptor. Both variants act as dominant negatives on wild-type FZD2 in canonical Wnt reporter assays.","method":"Retroviral overexpression in chicken embryo frontonasal mass, primary cell cultures, SOX9 and canonical/non-canonical Wnt luciferase reporters, β-catenin nuclear localization assay","journal":"Disease models & mechanisms","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo and in vitro functional validation of specific variants with multiple orthogonal assays establishing mechanism of dominant-negative action and selective ligand binding","pmids":["38967226"],"is_preprint":false},{"year":2024,"finding":"FZD2 suppresses YAP activity and prevents adult cardiomyocytes from re-entering the cell cycle through a mechanism independent of canonical Wnt/β-catenin transcription and LATS1/2-mediated Hippo signaling; FZD2 deletion leads to cardiomegaly with increased proliferation markers and upregulation of YAP target genes Mycl and Bcl2l1.","method":"Conditional knockout (Fzd2 CKO) in adult mouse cardiomyocytes, YAP knockdown/overexpression epistasis, β-catenin knockdown, LATS-site YAP mutant, neonatal ventricular CM gain/loss-of-function, MI model","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — clean genetic KO with defined cellular phenotype and epistasis experiments placing FZD2 upstream of YAP independently of canonical pathways; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2024.07.26.605158"],"is_preprint":true},{"year":2025,"finding":"FZD2 activation by selective antibody-based agonists triggers β-catenin signaling with sustained kinetics that promotes paraxial mesoderm differentiation while blocking lateral mesoderm in human pluripotent stem cells, revealing a non-redundant role distinct from FZD7.","method":"Selective FZD2 and FZD7 antibody agonists, directed differentiation of hPSCs, β-catenin signaling kinetics assay, flow cytometry for mesoderm markers","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — receptor-selective activation with defined downstream signaling kinetics and lineage outcomes, single lab","pmids":["39824186"],"is_preprint":false},{"year":2025,"finding":"ER-resident scramblases VMP1 and TMEM41B are required for proper maturation, stability, and secretion/trafficking of FZD2, which is essential for WNT signaling during primitive endoderm specification in mouse embryonic stem cells.","method":"Vmp1/Tmem41b CRISPR knockout in mouse ESCs, differentiation assays, western blot for FZD2 protein stability, WNT signaling readouts","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with defined biochemical consequence (FZD2 maturation/stability) and functional developmental phenotype, single lab","pmids":["39968886"],"is_preprint":false},{"year":2025,"finding":"Fzd2 mediates canonical Wnt/β-catenin signaling in lung endothelial cells (required for endothelial proliferation and vascular development) and non-canonical Wnt signaling in mesenchymal cells (required for proliferation and survival); additionally, Fzd2 in mesenchymal cells mediates PI3K-AKT signaling to maintain alveolar fibroblast 1 (AF1) identity and prevent fibrotic AF2 transition.","method":"Conditional knockout mouse models (cell type-specific Fzd2 deletion), bleomycin injury model, single-cell RNA-seq, β-catenin reporter assay, PI3K-AKT pathway analysis","journal":"Cell communication and signaling","confidence":"High","confidence_rationale":"Tier 1-2 — multiple cell-type-specific conditional knockouts with orthogonal pathway readouts (canonical vs. non-canonical), in vivo injury models, mechanistically rigorous","pmids":["41257888"],"is_preprint":false},{"year":2025,"finding":"MBD2 promotes EMT and pulmonary fibrosis by modulating FZD2 expression; MBD2 binds the FZD2 locus (identified by ChIP-seq) and MBD2 knockout reduces FZD2 levels and alleviates TGF-β-induced EMT in alveolar epithelial cells.","method":"MBD2 knockout mice, RNA-seq, ChIP assay, TGF-β-induced EMT model in MLE-12 cells, western blot for EMT markers","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP establishes direct epigenetic regulation of FZD2 by MBD2, functional rescue in vivo and in vitro, single lab","pmids":["40081619"],"is_preprint":false}],"current_model":"FZD2 is a Frizzled-family Wnt receptor that can activate both canonical Wnt/β-catenin signaling (with sustained kinetics favoring paraxial mesoderm and requiring the Dishevelled-interacting domain) and noncanonical pathways including WNT5A/PCP (controlling chondrocyte polarity), FYN/STAT3 (driving EMT and metastasis), and PI3K-AKT (maintaining fibroblast identity); its surface stability depends on ER scramblases VMP1/TMEM41B, its expression is epigenetically regulated by MBD2, and it can be post-translationally stabilized by WNT2 via reduced ubiquitination; in adult cardiomyocytes FZD2 suppresses YAP activity through a non-canonical, β-catenin- and LATS-independent mechanism to prevent cell cycle re-entry, while pathogenic missense mutations cause dominant-negative effects on both canonical and noncanonical branches, leading to Robinow syndrome/OMOD2 skeletal defects."},"narrative":{"teleology":[{"year":2008,"claim":"The question of whether FZD2 participates in canonical Wnt signaling and how co-receptors modulate it was addressed by showing that ROR2 cooperates with FZD2 (but not FZD7) to potentiate Wnt3a-induced canonical signaling in an LRP-dependent manner.","evidence":"Co-transfection and STF reporter assays with domain deletion mutants and Dkk1/Krm1 inhibitors in H441 lung carcinoma cells","pmids":["18215320"],"confidence":"Medium","gaps":["No in vivo validation of the ROR2–FZD2 cooperative mechanism","Downstream pathway components beyond β-catenin not mapped","Specificity of CRD interaction not structurally resolved"]},{"year":2014,"claim":"The identification of a noncanonical FZD2 signaling axis was advanced by demonstrating that WNT5A/FZD2 activates FYN kinase and STAT3 to drive EMT and metastasis, establishing FZD2 as a mediator of tumor invasion distinct from canonical β-catenin signaling.","evidence":"Functional cell-based assays and pathway analysis in cancer cells","pmids":["34450691"],"confidence":"Medium","gaps":["Detailed upstream mechanism linking FZD2 to FYN activation unresolved","Independence from canonical pathway not fully dissected"]},{"year":2020,"claim":"The range of noncanonical effectors downstream of FZD2 was broadened by showing it binds WNT5A/B and WNT3 to activate IL-6/STAT3, YAP1, and TGF-β1/SMAD3, and that WNT2 stabilizes FZD2 protein by reducing its ubiquitination, providing the first evidence of ligand-dependent post-translational regulation of FZD2.","evidence":"Co-IP for ligand binding, ubiquitination/phosphorylation assays, mammosphere formation, xenograft models in breast and esophageal cancer cells","pmids":["31907106","32766155"],"confidence":"Medium","gaps":["E3 ligase responsible for FZD2 ubiquitination not identified","Relative contributions of individual Wnt ligands to each downstream branch unclear","Mechanistic link from FZD2 to YAP1 activation not delineated"]},{"year":2021,"claim":"The connection between FZD2 and Notch signaling was established by showing that FZD2 knockdown inactivates Notch and suppresses TGF-β1-induced EMT in breast cancer, adding Notch as another downstream effector.","evidence":"siRNA knockdown, western blot for EMT/Notch markers, xenograft","pmids":["33832493"],"confidence":"Medium","gaps":["Direct versus indirect link between FZD2 and Notch pathway components unresolved","Mechanism of Notch activation by FZD2 unknown"]},{"year":2022,"claim":"The WNT5A/FZD2 noncanonical axis was shown to drive enzalutamide resistance in prostate cancer by maintaining constitutive AR signaling, extending FZD2's role to therapy resistance.","evidence":"siRNA knockdown, BERA-WNT5A construct, xenograft, AR reporter assays in prostate cancer cells","pmids":["35930737"],"confidence":"Medium","gaps":["Intermediary signaling steps between FZD2 and AR activation not identified","Whether FZD2 directly complexes with AR pathway components unknown"]},{"year":2023,"claim":"A long-standing question about how FZD2 coordinates both canonical and noncanonical limb development was resolved by a CRISPR knock-in mouse carrying a Dishevelled-interacting-domain frameshift, which disrupted β-catenin-dependent proliferation and WNT5A/PCP-dependent chondrocyte polarity, recapitulating Robinow syndrome/OMOD2.","evidence":"CRISPR/Cas9 knock-in mouse (Fzd2em1Smill), β-catenin reporter, PCP readouts, skeletal phenotyping","pmids":["36867021"],"confidence":"High","gaps":["Whether other Frizzled receptors partially compensate in vivo not tested","Signaling intermediates between FZD2 and PCP effectors in chondrocytes not mapped"]},{"year":2024,"claim":"Variant-specific pathogenicity of FZD2 was established: the P142K Robinow-associated mutation selectively ablates noncanonical WNT5A responsiveness while both P142K and G434V act as dominant negatives on canonical signaling, providing the first evidence that a single amino-acid change in a Frizzled receptor can selectively alter ligand-binding specificity.","evidence":"Retroviral overexpression in chicken frontonasal mass, SOX9 and Wnt reporter assays, β-catenin nuclear localization","pmids":["38967226"],"confidence":"High","gaps":["Structural basis for selective WNT5A binding loss not determined","Whether P142K affects binding of other noncanonical Wnt ligands untested"]},{"year":2024,"claim":"FZD2 was placed upstream of YAP in adult cardiomyocytes, where its deletion causes cardiomegaly and cell-cycle re-entry through a mechanism independent of both canonical β-catenin transcription and LATS-mediated Hippo signaling, revealing a novel non-canonical route to YAP suppression.","evidence":"(preprint) Conditional Fzd2 knockout in adult mouse cardiomyocytes, YAP/LATS epistasis experiments, MI injury model","pmids":["bio_10.1101_2024.07.26.605158"],"confidence":"Medium","gaps":["Preprint; not yet peer-reviewed","Molecular intermediary between FZD2 and YAP unknown","Whether this mechanism operates in non-cardiac tissues untested"]},{"year":2025,"claim":"Receptor-selective agonism revealed that FZD2 activates β-catenin with sustained kinetics distinct from FZD7, promoting paraxial mesoderm while suppressing lateral mesoderm, demonstrating non-redundant roles among Frizzled family members in human stem cell fate decisions.","evidence":"Selective antibody agonists against FZD2 and FZD7, hPSC directed differentiation, β-catenin signaling kinetics, flow cytometry","pmids":["39824186"],"confidence":"Medium","gaps":["Mechanism generating sustained versus transient β-catenin kinetics through FZD2 versus FZD7 unresolved","Whether kinetic difference depends on co-receptors unknown"]},{"year":2025,"claim":"The cell-type-specific duality of FZD2 signaling was resolved in the lung: FZD2 drives canonical β-catenin in endothelial cells and noncanonical/PI3K-AKT in mesenchymal cells, where it maintains fibroblast identity and prevents fibrotic transition, and its transcription is epigenetically regulated by MBD2.","evidence":"Cell-type-specific conditional knockouts, bleomycin injury model, scRNA-seq, PI3K-AKT analysis; MBD2 ChIP-seq/knockout in alveolar epithelial cells","pmids":["41257888","40081619","39968886"],"confidence":"High","gaps":["How cell-type context switches FZD2 between canonical and noncanonical modes mechanistically unknown","Whether PI3K-AKT engagement is direct or requires adaptor proteins not determined","MBD2 regulation of FZD2 shown only in lung epithelium; generalizability untested"]},{"year":null,"claim":"Key unresolved questions include: (1) the structural basis for FZD2's selective ligand recognition and how single mutations alter it, (2) the molecular mechanism by which cellular context dictates canonical versus noncanonical output, and (3) the identity of the intermediary that connects FZD2 to YAP suppression independently of LATS and β-catenin.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of FZD2 in complex with any Wnt ligand","Context-dependent pathway switching mechanism undefined","FZD2-to-YAP intermediary unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,6,7,9,11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,10]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,3,5,6,7,8,9,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,7,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2,4,5]}],"complexes":[],"partners":["ROR2","WNT5A","WNT2","WNT3","FYN","MBD2","VMP1","TMEM41B"],"other_free_text":[]},"mechanistic_narrative":"FZD2 is a Frizzled-family seven-transmembrane Wnt receptor that integrates canonical Wnt/β-catenin and multiple noncanonical signaling branches to control cell fate, tissue morphogenesis, and homeostasis across diverse developmental and adult contexts. In canonical mode, FZD2 activates β-catenin with sustained kinetics that favor paraxial mesoderm specification over lateral mesoderm, requires Dishevelled interaction and cooperation with co-receptors such as ROR2/LRP, and drives endothelial proliferation and lung vascular development; in noncanonical mode it transduces WNT5A/PCP signals that orient chondrocytes during digit elongation, activates FYN/STAT3 to promote epithelial–mesenchymal transition and metastasis, and engages PI3K–AKT to maintain alveolar fibroblast identity and prevent fibrotic transition [PMID:18215320, PMID:36867021, PMID:39824186, PMID:41257888, PMID:34450691]. FZD2 surface availability is controlled by ER scramblases VMP1/TMEM41B, which are required for its maturation and trafficking, while WNT2 ligand stabilizes FZD2 post-translationally by attenuating its ubiquitination, and the methyl-CpG-binding protein MBD2 epigenetically promotes FZD2 transcription [PMID:39968886, PMID:32766155, PMID:40081619]. Pathogenic missense mutations in FZD2 cause Robinow syndrome through dominant-negative disruption of both canonical and noncanonical Wnt branches, with at least one variant (P142K) selectively abolishing WNT5A-dependent noncanonical signaling [PMID:38967226, PMID:36867021]."},"prefetch_data":{"uniprot":{"accession":"Q14332","full_name":"Frizzled-2","aliases":["FzE2"],"length_aa":565,"mass_kda":63.6,"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 (PubMed:25759469). 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 (Microbial infection) Acts as a receptor for C.difficile toxin TcdB in the colonic epithelium (PubMed:27680706, PubMed:29748286). TcdB occupies the binding site for Wnt-adducted palmitoleate in frizzled receptors and TcdB-binding prevents Wnt-binding and downstream Wnt signaling (PubMed:29748286)","subcellular_location":"Membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q14332/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FZD2","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FZD2","total_profiled":1310},"omim":[{"mim_id":"606570","title":"SECRETED FRIZZLED-RELATED PROTEIN 4; SFRP4","url":"https://www.omim.org/entry/606570"},{"mim_id":"605083","title":"FRIZZLED-RELATED PROTEIN; FRZB","url":"https://www.omim.org/entry/605083"},{"mim_id":"604579","title":"FRIZZLED CLASS RECEPTOR 4; FZD4","url":"https://www.omim.org/entry/604579"},{"mim_id":"603410","title":"FRIZZLED CLASS RECEPTOR 7; FZD7","url":"https://www.omim.org/entry/603410"},{"mim_id":"603408","title":"FRIZZLED CLASS RECEPTOR 1; FZD1","url":"https://www.omim.org/entry/603408"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Nucleoplasm","reliability":"Uncertain"},{"location":"Nuclear bodies","reliability":"Uncertain"},{"location":"Cell Junctions","reliability":"Uncertain"},{"location":"Actin filaments","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"blood vessel","ntpm":9.4},{"tissue":"choroid plexus","ntpm":8.9}],"url":"https://www.proteinatlas.org/search/FZD2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q14332","domains":[{"cath_id":"1.10.2000.10","chopping":"38-139","consensus_level":"high","plddt":92.7819,"start":38,"end":139},{"cath_id":"1.20.1070.10","chopping":"208-555","consensus_level":"high","plddt":91.2109,"start":208,"end":555}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14332","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14332-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14332-F1-predicted_aligned_error_v6.png","plddt_mean":83.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FZD2","jax_strain_url":"https://www.jax.org/strain/search?query=FZD2"},"sequence":{"accession":"Q14332","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14332.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14332/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14332"}},"corpus_meta":[{"pmid":"18215320","id":"PMC_18215320","title":"Ror2 modulates the canonical Wnt signaling in lung epithelial cells through cooperation with Fzd2.","date":"2008","source":"BMC molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18215320","citation_count":79,"is_preprint":false},{"pmid":"23826406","id":"PMC_23826406","title":"Expression of Wnt5a and its receptor Fzd2 is changed in the spinal cord of adult amyotrophic lateral sclerosis transgenic mice.","date":"2013","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23826406","citation_count":35,"is_preprint":false},{"pmid":"31907106","id":"PMC_31907106","title":"Fzd2 Contributes to Breast Cancer Cell Mesenchymal-Like Stemness and Drug Resistance.","date":"2020","source":"Oncology research","url":"https://pubmed.ncbi.nlm.nih.gov/31907106","citation_count":26,"is_preprint":false},{"pmid":"31595151","id":"PMC_31595151","title":"FZD2 regulates cell proliferation and invasion in tongue squamous cell carcinoma.","date":"2019","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31595151","citation_count":25,"is_preprint":false},{"pmid":"23748645","id":"PMC_23748645","title":"Immunoreactivity of Wnt5a, Fzd2, Fzd6, and Ryk in glioblastoma: evaluative methodology for DAB chromogenic immunostaining.","date":"2013","source":"Brain tumor pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23748645","citation_count":22,"is_preprint":false},{"pmid":"35930737","id":"PMC_35930737","title":"Bioengineered BERA-Wnt5a siRNA Targeting Wnt5a/FZD2 Signaling Suppresses Advanced Prostate Cancer Tumor Growth and Enhances Enzalutamide Treatment.","date":"2022","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/35930737","citation_count":21,"is_preprint":false},{"pmid":"32766155","id":"PMC_32766155","title":"WNT2-Mediated FZD2 Stabilization Regulates Esophageal Cancer Metastasis via STAT3 Signaling.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32766155","citation_count":20,"is_preprint":false},{"pmid":"29383834","id":"PMC_29383834","title":"Nonsense mutations in FZD2 cause autosomal-dominant omodysplasia: Robinow syndrome-like phenotypes.","date":"2018","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/29383834","citation_count":20,"is_preprint":false},{"pmid":"25695658","id":"PMC_25695658","title":"FZD2 inhibits the cell growth and migration of salivary adenoid cystic carcinomas.","date":"2015","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/25695658","citation_count":17,"is_preprint":false},{"pmid":"33832493","id":"PMC_33832493","title":"FZD2 promotes TGF-β-induced epithelial-to-mesenchymal transition in breast cancer via activating notch signaling pathway.","date":"2021","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/33832493","citation_count":15,"is_preprint":false},{"pmid":"31524268","id":"PMC_31524268","title":"Casiopeina II‑gly acts on lncRNA MALAT1 by miR‑17‑5p to inhibit FZD2 expression via the Wnt signaling pathway during the treatment of cervical carcinoma.","date":"2019","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/31524268","citation_count":14,"is_preprint":false},{"pmid":"29230162","id":"PMC_29230162","title":"A Novel de novo FZD2 Mutation in a Patient with Autosomal Dominant Omodysplasia.","date":"2017","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/29230162","citation_count":12,"is_preprint":false},{"pmid":"38244148","id":"PMC_38244148","title":"Total Flavonoids of Aurantii Fructus Immaturus Regulate miR-5100 to Improve Constipation by Targeting Fzd2 to Alleviate Calcium Balance and Autophagy in Interstitial Cells of Cajal.","date":"2024","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/38244148","citation_count":8,"is_preprint":false},{"pmid":"36867021","id":"PMC_36867021","title":"FZD2 regulates limb development by mediating β-catenin-dependent and -independent Wnt signaling pathways.","date":"2023","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/36867021","citation_count":7,"is_preprint":false},{"pmid":"39091630","id":"PMC_39091630","title":"Interference of FZD2 suppresses proliferation, vasculogenic mimicry and stemness in glioma cells via blocking the Notch/NF‑κB signaling pathway.","date":"2024","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39091630","citation_count":4,"is_preprint":false},{"pmid":"40081619","id":"PMC_40081619","title":"MBD2 promotes epithelial-to-mesenchymal transition (EMT) and ARDS-related pulmonary fibrosis by modulating FZD2.","date":"2025","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/40081619","citation_count":3,"is_preprint":false},{"pmid":"34450691","id":"PMC_34450691","title":"Noncanonical FZD2 Signaling Induces EMT and Tumor Progression.","date":"2014","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/34450691","citation_count":3,"is_preprint":false},{"pmid":"39824186","id":"PMC_39824186","title":"Selective activation of FZD2 and FZD7 reveals non-redundant function during mesoderm differentiation.","date":"2025","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/39824186","citation_count":2,"is_preprint":false},{"pmid":"38967226","id":"PMC_38967226","title":"Craniofacial studies in chicken embryos confirm the pathogenicity of human FZD2 variants associated with Robinow syndrome.","date":"2024","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/38967226","citation_count":2,"is_preprint":false},{"pmid":"40978162","id":"PMC_40978162","title":"Bioinspired nanoparticles prevent blue-light-induced skin hyperpigmentation via FZD2-TYR-melanin pathway.","date":"2025","source":"Materials today. Bio","url":"https://pubmed.ncbi.nlm.nih.gov/40978162","citation_count":1,"is_preprint":false},{"pmid":"39968886","id":"PMC_39968886","title":"Scrambling stem cell development: VMP1 and TMEM41B regulate FZD2/FRIZZLED2 secretion during primitive endoderm specification.","date":"2025","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/39968886","citation_count":0,"is_preprint":false},{"pmid":"41257888","id":"PMC_41257888","title":"Fzd2 orchestrates canonical and non-canonical Wnt signaling to regulate lung development and fibrosis.","date":"2025","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/41257888","citation_count":0,"is_preprint":false},{"pmid":"29219261","id":"PMC_29219261","title":"[Relationship between Wound Age and the Expression of Fzd2 in Rats Skeletal Muscle after Contusion].","date":"2017","source":"Fa yi xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/29219261","citation_count":0,"is_preprint":false},{"pmid":"41022130","id":"PMC_41022130","title":"[Omodysplasia Type II - first publication of de novo Mutation in FZD2 Gene].","date":"2025","source":"Zeitschrift fur Geburtshilfe und Neonatologie","url":"https://pubmed.ncbi.nlm.nih.gov/41022130","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.07.28.667009","title":"<i>De Novo</i> design of a potent Wnt Surrogate specific for the frizzled7 subtype members","date":"2025-07-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.28.667009","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.26.605158","title":"FZD2 inhibits YAP and prevents cell cycle reentry in adult murine cardiomyocytes","date":"2024-07-26","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.26.605158","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14046,"output_tokens":3308,"usd":0.045879},"stage2":{"model":"claude-opus-4-6","input_tokens":6735,"output_tokens":3137,"usd":0.16815},"total_usd":0.214029,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"Ror2 positively modulates Wnt3a-activated canonical Wnt signaling in lung carcinoma cells through cooperative interaction with Fzd2 (but not Fzd7); this requires the extracellular CRD of Ror2 and is Lrp-dependent (inhibited by Dkk1/Krm1).\",\n      \"method\": \"Co-transfection, reporter assay (STF), domain deletion mutants, inhibitor treatment in H441 cells\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional epistasis with domain mapping, single lab, multiple complementary methods\",\n      \"pmids\": [\"18215320\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FZD2 and WNT5A drive epithelial-to-mesenchymal transition (EMT) and metastasis via a noncanonical signaling pathway involving FYN kinase and STAT3.\",\n      \"method\": \"Functional cell-based assays, pathway analysis (reported in Cancer Discovery summary)\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pathway placement with defined effectors, but abstract is a brief summary without full experimental detail\",\n      \"pmids\": [\"34450691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FZD2 modulates noncanonical Wnt signaling by binding Wnt5a/b and Wnt3 ligands to activate oncogenic IL-6/STAT3, YAP1, and TGF-β1/Smad3 pathways, promoting breast cancer cell mesenchymal stemness and drug resistance.\",\n      \"method\": \"FZD2 knockdown/overexpression, co-immunoprecipitation (binding with Wnt ligands), mammosphere formation, pathway reporter assays\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct binding shown by Co-IP, multiple pathway readouts, single lab\",\n      \"pmids\": [\"31907106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WNT2 ligand stabilizes and phosphorylates the FZD2 receptor by attenuating FZD2 ubiquitination, leading to activation of STAT3 signaling and promotion of esophageal cancer cell metastasis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, phosphorylation assay, knockdown/overexpression with migration/invasion readouts, in vivo xenograft\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical methods (ubiquitination, phosphorylation, Co-IP) establishing post-translational regulation, single lab\",\n      \"pmids\": [\"32766155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FZD2 promotes TGF-β1-induced EMT in breast cancer cells through activation of the Notch signaling pathway; FZD2 knockdown leads to Notch inactivation and suppression of EMT markers.\",\n      \"method\": \"siRNA knockdown, western blot for EMT and Notch pathway markers, in vivo xenograft, immunofluorescence\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — loss-of-function with defined pathway placement (Notch), multiple readouts, single lab\",\n      \"pmids\": [\"33832493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Wnt5a/FZD2-mediated noncanonical Wnt pathway activation drives enzalutamide resistance in prostate cancer; blocking this pathway suppresses constitutively activated androgen receptor (AR) and AR variants.\",\n      \"method\": \"siRNA knockdown, BERA-Wnt5a siRNA construct, in vivo tumor xenograft, AR pathway reporter assays\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo validation with defined pathway (noncanonical Wnt → AR), single lab with multiple methods\",\n      \"pmids\": [\"35930737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FZD2 controls limb development by mediating both canonical Wnt/β-catenin signaling (required for limb mesenchyme proliferation) and noncanonical WNT5A/planar cell polarity (PCP) signaling (required for digit chondrocyte elongation and orientation); frameshift mutation in the Dishevelled-interacting domain causes shortened limbs resembling Robinow syndrome/OMOD2.\",\n      \"method\": \"CRISPR/Cas9 knock-in mouse model (Fzd2em1Smill), conditional FZD function disruption in limb mesenchyme, β-catenin reporter assay, PCP pathway readouts, skeletal analysis\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo genetic model with domain-specific mutation, multiple pathway readouts, recapitulates human disease phenotype\",\n      \"pmids\": [\"36867021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Two pathogenic FZD2 missense variants (G434V; P142K) associated with Robinow syndrome inhibit chondrogenesis, increase nuclear β-catenin shuttling and TWIST1 expression; the P142K variant selectively fails to activate non-canonical Wnt signaling and is unresponsive to WNT5A, representing the first single amino-acid change shown to selectively alter ligand binding in a FZD receptor. Both variants act as dominant negatives on wild-type FZD2 in canonical Wnt reporter assays.\",\n      \"method\": \"Retroviral overexpression in chicken embryo frontonasal mass, primary cell cultures, SOX9 and canonical/non-canonical Wnt luciferase reporters, β-catenin nuclear localization assay\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo and in vitro functional validation of specific variants with multiple orthogonal assays establishing mechanism of dominant-negative action and selective ligand binding\",\n      \"pmids\": [\"38967226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FZD2 suppresses YAP activity and prevents adult cardiomyocytes from re-entering the cell cycle through a mechanism independent of canonical Wnt/β-catenin transcription and LATS1/2-mediated Hippo signaling; FZD2 deletion leads to cardiomegaly with increased proliferation markers and upregulation of YAP target genes Mycl and Bcl2l1.\",\n      \"method\": \"Conditional knockout (Fzd2 CKO) in adult mouse cardiomyocytes, YAP knockdown/overexpression epistasis, β-catenin knockdown, LATS-site YAP mutant, neonatal ventricular CM gain/loss-of-function, MI model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with defined cellular phenotype and epistasis experiments placing FZD2 upstream of YAP independently of canonical pathways; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.07.26.605158\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FZD2 activation by selective antibody-based agonists triggers β-catenin signaling with sustained kinetics that promotes paraxial mesoderm differentiation while blocking lateral mesoderm in human pluripotent stem cells, revealing a non-redundant role distinct from FZD7.\",\n      \"method\": \"Selective FZD2 and FZD7 antibody agonists, directed differentiation of hPSCs, β-catenin signaling kinetics assay, flow cytometry for mesoderm markers\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor-selective activation with defined downstream signaling kinetics and lineage outcomes, single lab\",\n      \"pmids\": [\"39824186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ER-resident scramblases VMP1 and TMEM41B are required for proper maturation, stability, and secretion/trafficking of FZD2, which is essential for WNT signaling during primitive endoderm specification in mouse embryonic stem cells.\",\n      \"method\": \"Vmp1/Tmem41b CRISPR knockout in mouse ESCs, differentiation assays, western blot for FZD2 protein stability, WNT signaling readouts\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined biochemical consequence (FZD2 maturation/stability) and functional developmental phenotype, single lab\",\n      \"pmids\": [\"39968886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Fzd2 mediates canonical Wnt/β-catenin signaling in lung endothelial cells (required for endothelial proliferation and vascular development) and non-canonical Wnt signaling in mesenchymal cells (required for proliferation and survival); additionally, Fzd2 in mesenchymal cells mediates PI3K-AKT signaling to maintain alveolar fibroblast 1 (AF1) identity and prevent fibrotic AF2 transition.\",\n      \"method\": \"Conditional knockout mouse models (cell type-specific Fzd2 deletion), bleomycin injury model, single-cell RNA-seq, β-catenin reporter assay, PI3K-AKT pathway analysis\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple cell-type-specific conditional knockouts with orthogonal pathway readouts (canonical vs. non-canonical), in vivo injury models, mechanistically rigorous\",\n      \"pmids\": [\"41257888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MBD2 promotes EMT and pulmonary fibrosis by modulating FZD2 expression; MBD2 binds the FZD2 locus (identified by ChIP-seq) and MBD2 knockout reduces FZD2 levels and alleviates TGF-β-induced EMT in alveolar epithelial cells.\",\n      \"method\": \"MBD2 knockout mice, RNA-seq, ChIP assay, TGF-β-induced EMT model in MLE-12 cells, western blot for EMT markers\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP establishes direct epigenetic regulation of FZD2 by MBD2, functional rescue in vivo and in vitro, single lab\",\n      \"pmids\": [\"40081619\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FZD2 is a Frizzled-family Wnt receptor that can activate both canonical Wnt/β-catenin signaling (with sustained kinetics favoring paraxial mesoderm and requiring the Dishevelled-interacting domain) and noncanonical pathways including WNT5A/PCP (controlling chondrocyte polarity), FYN/STAT3 (driving EMT and metastasis), and PI3K-AKT (maintaining fibroblast identity); its surface stability depends on ER scramblases VMP1/TMEM41B, its expression is epigenetically regulated by MBD2, and it can be post-translationally stabilized by WNT2 via reduced ubiquitination; in adult cardiomyocytes FZD2 suppresses YAP activity through a non-canonical, β-catenin- and LATS-independent mechanism to prevent cell cycle re-entry, while pathogenic missense mutations cause dominant-negative effects on both canonical and noncanonical branches, leading to Robinow syndrome/OMOD2 skeletal defects.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FZD2 is a Frizzled-family seven-transmembrane Wnt receptor that integrates canonical Wnt/β-catenin and multiple noncanonical signaling branches to control cell fate, tissue morphogenesis, and homeostasis across diverse developmental and adult contexts. In canonical mode, FZD2 activates β-catenin with sustained kinetics that favor paraxial mesoderm specification over lateral mesoderm, requires Dishevelled interaction and cooperation with co-receptors such as ROR2/LRP, and drives endothelial proliferation and lung vascular development; in noncanonical mode it transduces WNT5A/PCP signals that orient chondrocytes during digit elongation, activates FYN/STAT3 to promote epithelial–mesenchymal transition and metastasis, and engages PI3K–AKT to maintain alveolar fibroblast identity and prevent fibrotic transition [PMID:18215320, PMID:36867021, PMID:39824186, PMID:41257888, PMID:34450691]. FZD2 surface availability is controlled by ER scramblases VMP1/TMEM41B, which are required for its maturation and trafficking, while WNT2 ligand stabilizes FZD2 post-translationally by attenuating its ubiquitination, and the methyl-CpG-binding protein MBD2 epigenetically promotes FZD2 transcription [PMID:39968886, PMID:32766155, PMID:40081619]. Pathogenic missense mutations in FZD2 cause Robinow syndrome through dominant-negative disruption of both canonical and noncanonical Wnt branches, with at least one variant (P142K) selectively abolishing WNT5A-dependent noncanonical signaling [PMID:38967226, PMID:36867021].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"The question of whether FZD2 participates in canonical Wnt signaling and how co-receptors modulate it was addressed by showing that ROR2 cooperates with FZD2 (but not FZD7) to potentiate Wnt3a-induced canonical signaling in an LRP-dependent manner.\",\n      \"evidence\": \"Co-transfection and STF reporter assays with domain deletion mutants and Dkk1/Krm1 inhibitors in H441 lung carcinoma cells\",\n      \"pmids\": [\"18215320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo validation of the ROR2–FZD2 cooperative mechanism\", \"Downstream pathway components beyond β-catenin not mapped\", \"Specificity of CRD interaction not structurally resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The identification of a noncanonical FZD2 signaling axis was advanced by demonstrating that WNT5A/FZD2 activates FYN kinase and STAT3 to drive EMT and metastasis, establishing FZD2 as a mediator of tumor invasion distinct from canonical β-catenin signaling.\",\n      \"evidence\": \"Functional cell-based assays and pathway analysis in cancer cells\",\n      \"pmids\": [\"34450691\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Detailed upstream mechanism linking FZD2 to FYN activation unresolved\", \"Independence from canonical pathway not fully dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The range of noncanonical effectors downstream of FZD2 was broadened by showing it binds WNT5A/B and WNT3 to activate IL-6/STAT3, YAP1, and TGF-β1/SMAD3, and that WNT2 stabilizes FZD2 protein by reducing its ubiquitination, providing the first evidence of ligand-dependent post-translational regulation of FZD2.\",\n      \"evidence\": \"Co-IP for ligand binding, ubiquitination/phosphorylation assays, mammosphere formation, xenograft models in breast and esophageal cancer cells\",\n      \"pmids\": [\"31907106\", \"32766155\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"E3 ligase responsible for FZD2 ubiquitination not identified\", \"Relative contributions of individual Wnt ligands to each downstream branch unclear\", \"Mechanistic link from FZD2 to YAP1 activation not delineated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The connection between FZD2 and Notch signaling was established by showing that FZD2 knockdown inactivates Notch and suppresses TGF-β1-induced EMT in breast cancer, adding Notch as another downstream effector.\",\n      \"evidence\": \"siRNA knockdown, western blot for EMT/Notch markers, xenograft\",\n      \"pmids\": [\"33832493\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect link between FZD2 and Notch pathway components unresolved\", \"Mechanism of Notch activation by FZD2 unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The WNT5A/FZD2 noncanonical axis was shown to drive enzalutamide resistance in prostate cancer by maintaining constitutive AR signaling, extending FZD2's role to therapy resistance.\",\n      \"evidence\": \"siRNA knockdown, BERA-WNT5A construct, xenograft, AR reporter assays in prostate cancer cells\",\n      \"pmids\": [\"35930737\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Intermediary signaling steps between FZD2 and AR activation not identified\", \"Whether FZD2 directly complexes with AR pathway components unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"A long-standing question about how FZD2 coordinates both canonical and noncanonical limb development was resolved by a CRISPR knock-in mouse carrying a Dishevelled-interacting-domain frameshift, which disrupted β-catenin-dependent proliferation and WNT5A/PCP-dependent chondrocyte polarity, recapitulating Robinow syndrome/OMOD2.\",\n      \"evidence\": \"CRISPR/Cas9 knock-in mouse (Fzd2em1Smill), β-catenin reporter, PCP readouts, skeletal phenotyping\",\n      \"pmids\": [\"36867021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other Frizzled receptors partially compensate in vivo not tested\", \"Signaling intermediates between FZD2 and PCP effectors in chondrocytes not mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Variant-specific pathogenicity of FZD2 was established: the P142K Robinow-associated mutation selectively ablates noncanonical WNT5A responsiveness while both P142K and G434V act as dominant negatives on canonical signaling, providing the first evidence that a single amino-acid change in a Frizzled receptor can selectively alter ligand-binding specificity.\",\n      \"evidence\": \"Retroviral overexpression in chicken frontonasal mass, SOX9 and Wnt reporter assays, β-catenin nuclear localization\",\n      \"pmids\": [\"38967226\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for selective WNT5A binding loss not determined\", \"Whether P142K affects binding of other noncanonical Wnt ligands untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"FZD2 was placed upstream of YAP in adult cardiomyocytes, where its deletion causes cardiomegaly and cell-cycle re-entry through a mechanism independent of both canonical β-catenin transcription and LATS-mediated Hippo signaling, revealing a novel non-canonical route to YAP suppression.\",\n      \"evidence\": \"(preprint) Conditional Fzd2 knockout in adult mouse cardiomyocytes, YAP/LATS epistasis experiments, MI injury model\",\n      \"pmids\": [\"bio_10.1101_2024.07.26.605158\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint; not yet peer-reviewed\", \"Molecular intermediary between FZD2 and YAP unknown\", \"Whether this mechanism operates in non-cardiac tissues untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Receptor-selective agonism revealed that FZD2 activates β-catenin with sustained kinetics distinct from FZD7, promoting paraxial mesoderm while suppressing lateral mesoderm, demonstrating non-redundant roles among Frizzled family members in human stem cell fate decisions.\",\n      \"evidence\": \"Selective antibody agonists against FZD2 and FZD7, hPSC directed differentiation, β-catenin signaling kinetics, flow cytometry\",\n      \"pmids\": [\"39824186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism generating sustained versus transient β-catenin kinetics through FZD2 versus FZD7 unresolved\", \"Whether kinetic difference depends on co-receptors unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The cell-type-specific duality of FZD2 signaling was resolved in the lung: FZD2 drives canonical β-catenin in endothelial cells and noncanonical/PI3K-AKT in mesenchymal cells, where it maintains fibroblast identity and prevents fibrotic transition, and its transcription is epigenetically regulated by MBD2.\",\n      \"evidence\": \"Cell-type-specific conditional knockouts, bleomycin injury model, scRNA-seq, PI3K-AKT analysis; MBD2 ChIP-seq/knockout in alveolar epithelial cells\",\n      \"pmids\": [\"41257888\", \"40081619\", \"39968886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How cell-type context switches FZD2 between canonical and noncanonical modes mechanistically unknown\", \"Whether PI3K-AKT engagement is direct or requires adaptor proteins not determined\", \"MBD2 regulation of FZD2 shown only in lung epithelium; generalizability untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: (1) the structural basis for FZD2's selective ligand recognition and how single mutations alter it, (2) the molecular mechanism by which cellular context dictates canonical versus noncanonical output, and (3) the identity of the intermediary that connects FZD2 to YAP suppression independently of LATS and β-catenin.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of FZD2 in complex with any Wnt ligand\", \"Context-dependent pathway switching mechanism undefined\", \"FZD2-to-YAP intermediary unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 6, 7, 9, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 10]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 3, 5, 6, 7, 8, 9, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 7, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2, 4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ROR2\",\n      \"WNT5A\",\n      \"WNT2\",\n      \"WNT3\",\n      \"FYN\",\n      \"MBD2\",\n      \"VMP1\",\n      \"TMEM41B\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}