{"gene":"FZD2","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2008,"finding":"Ror2 positively modulates Wnt3a-activated canonical (β-catenin-dependent) Wnt signaling in lung carcinoma H441 cells through cooperative interaction with Fzd2 but not Fzd7; this cooperation requires the extracellular CRD of Ror2 but not its intracellular PRD domain, and is inhibited by Dkk1 and Krm1, indicating Lrp-dependence.","method":"Overexpression/knockdown in H441 cells, domain-deletion constructs, STF luciferase reporter assay, Dkk1/Krm1 inhibition","journal":"BMC molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-deletion analysis plus reporter assay with pharmacological controls, single lab","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":"Not detailed in abstract (reported as brief communication/summary)","journal":"Cancer discovery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — abstract contains only a one-sentence summary with no experimental detail","pmids":["34450691"],"is_preprint":false},{"year":2020,"finding":"FZD2 binds Wnt5a/b and Wnt3 ligands and activates oncogenic noncanonical Wnt pathways including IL-6/STAT3, YAP1, and TGF-β1/Smad3, promoting mesenchymal-like stemness and drug resistance in breast cancer cells; FZD2 knockdown impairs mammosphere formation and reduces the Lgr5+ subpopulation.","method":"Co-immunoprecipitation (FZD2–Wnt ligand binding), FZD2 KD by siRNA, mammosphere assay, flow cytometry for Lgr5+ cells, migration/invasion assays, western blot for pathway markers","journal":"Oncology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for ligand binding plus multiple functional assays, single lab","pmids":["31907106"],"is_preprint":false},{"year":2020,"finding":"WNT2 ligand stabilizes FZD2 protein by attenuating its ubiquitination and inducing its phosphorylation, leading to activation of STAT3 signaling and promotion of esophageal squamous cell carcinoma cell migration and invasion.","method":"Co-expression experiments, ubiquitination assay, phosphorylation analysis, FZD2 knockdown/overexpression, STAT3 pathway readouts, in vivo xenograft metastasis model","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination and phosphorylation assays with functional readouts, single lab","pmids":["32766155"],"is_preprint":false},{"year":2021,"finding":"FZD2 promotes TGF-β1-induced EMT in breast cancer cells by activating the Notch signaling pathway; FZD2 knockdown inactivates Notch signaling and suppresses EMT markers.","method":"siRNA knockdown of FZD2, western blot and immunofluorescence for EMT markers, pathway inhibitor/activation experiments, in vivo xenograft","journal":"Cancer cell international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single KD approach with pathway readout, no direct mechanistic link between FZD2 and Notch established","pmids":["33832493"],"is_preprint":false},{"year":2022,"finding":"Wnt5a/FZD2-mediated noncanonical Wnt signaling is upregulated in enzalutamide-resistant prostate cancer; blocking Wnt5a/FZD2 signal transduction suppresses noncanonical Wnt signaling and reduces constitutively active androgen receptor (AR) and AR splice variants.","method":"siRNA knockdown (BERA-Wnt5a siRNA construct), western blot for noncanonical Wnt and AR pathway markers, in vivo tumor xenograft model","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro experiments with defined pathway readouts, single lab","pmids":["35930737"],"is_preprint":false},{"year":2023,"finding":"FZD2 controls limb development by mediating both canonical Wnt/β-catenin and noncanonical WNT5A/planar cell polarity (PCP) pathways; a frameshift mutation in the Dishevelled-interacting domain of Fzd2 in mice decreases canonical Wnt signaling in limb mesenchyme and disrupts digit chondrocyte elongation/orientation controlled by the WNT5A/PCP pathway, causing shortened limbs resembling Robinow syndrome/OMOD2.","method":"Mouse genetic model (single-nucleotide insertion causing frameshift in Fzd2), conditional FZD function disruption in limb mesenchyme, β-catenin signaling reporters, skeletal analysis","journal":"Disease models & mechanisms","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo genetic model with defined mutation, multiple pathway readouts (canonical and non-canonical), phenocopy of human disease","pmids":["36867021"],"is_preprint":false},{"year":2024,"finding":"FZD2 missense variants associated with Robinow syndrome (Gly434Val and Pro142Lys) have dominant-negative effects on canonical Wnt signaling in frontonasal mass cells, increase nuclear β-catenin and TWIST1 expression, and inhibit chondrogenesis; the Pro142Lys variant additionally fails to activate a non-canonical reporter and is unresponsive to exogenous WNT5A, representing the first single amino acid change shown to selectively alter ligand binding in an FZD receptor.","method":"Retroviral overexpression in chicken embryo frontonasal mass, primary cell culture, SOX9 luciferase reporter assay, canonical and non-canonical Wnt luciferase assays, β-catenin nuclear localization assay, chondrogenesis assay","journal":"Disease models & mechanisms","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal functional assays (reporter assays, nuclear shuttling, chondrogenesis) with defined mutations and in vivo validation","pmids":["38967226"],"is_preprint":false},{"year":2024,"finding":"FZD2 knockdown in glioma cells suppresses proliferation, stemness, migration, invasion, EMT, and vasculogenic mimicry via blockade of the Notch/NF-κB signaling pathway; activation of Notch by JAG1 partially rescues FZD2 knockdown phenotypes.","method":"siRNA knockdown of FZD2, CCK-8, EdU, colony formation, wound healing, Transwell, sphere formation assays, western blot for Notch/NF-κB pathway proteins, Notch agonist rescue experiment","journal":"Experimental and therapeutic medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, KD with rescue but no direct mechanistic link established between FZD2 and Notch","pmids":["39091630"],"is_preprint":false},{"year":2025,"finding":"VMP1 and TMEM41B (ER-resident scramblases) are required for maturation and stability of FZD2, linking ER lipid metabolism to FZD2-dependent WNT signaling during primitive endoderm specification in mouse embryonic stem cells.","method":"Genetic mutation of Vmp1 and Tmem41b in mouse ESCs, differentiation assays, protein stability/maturation analysis of FZD2","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined protein maturation readout, single lab","pmids":["39968886"],"is_preprint":false},{"year":2025,"finding":"Conditional knockout of Fzd2 in mesenchymal cells impairs lung regeneration after bleomycin injury by promoting transition from alveolar fibroblast 1 (AF1) to fibroblast 2 (AF2) cells, suppressing Wnt2 expression and preventing alveolar type 2 cell expansion; Fzd2 maintains AF1 identity via PI3K-AKT signaling. In endothelial cells, canonical Wnt/β-catenin signaling via Fzd2 is essential for proliferation and vascular development; in mesenchymal cells, non-canonical Fzd2 signaling regulates proliferation and survival.","method":"Conditional knockout mouse models (cell-type-specific Fzd2 deletion), bleomycin lung injury model, single-cell RNA sequencing, western blot for PI3K-AKT and Wnt pathway markers","journal":"Cell communication and signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional knockouts with multiple pathway readouts and in vivo injury model, single lab but multiple orthogonal approaches","pmids":["41257888"],"is_preprint":false},{"year":2025,"finding":"FZD2 activation in human pluripotent stem cells promotes sustained Wnt/β-catenin signaling and guides differentiation toward paraxial mesoderm while blocking lateral mesoderm; FZD2 and FZD7 activate β-catenin with different kinetics, conferring non-redundant roles in mesoderm specification.","method":"Selective FZD2- and FZD7-specific antibody-based agonists applied to hPSCs, directed mesoderm differentiation assays, β-catenin signaling kinetics measurement, membrane receptor localization","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — selective receptor agonists with functional differentiation readouts, single lab","pmids":["39824186"],"is_preprint":false},{"year":2025,"finding":"MBD2 promotes EMT and pulmonary fibrosis by modulating FZD2 expression; MBD2 knockout in mice reduces bleomycin- and LPS-induced pulmonary fibrosis and EMT, and ChIP assay identified FZD2 as a transcriptional target of MBD2.","method":"MBD2 knockout mice, bleomycin/LPS lung injury models, ChIP assay, RNA-Seq, TGF-β-induced EMT in alveolar epithelial cells, western blot","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP assay for direct MBD2-FZD2 transcriptional regulation plus in vivo genetic model, single lab","pmids":["40081619"],"is_preprint":false},{"year":2024,"finding":"FZD2 in adult murine cardiomyocytes inhibits YAP activity and prevents cell cycle re-entry; FZD2 deletion causes cardiomyocyte proliferation marker expression, YAP target gene upregulation (Mycl, Bcl2l1), and β-catenin accumulation at membranes (not nuclear). The YAP-inhibitory effect of FZD2 is independent of both canonical Wnt/β-catenin and Hippo/LATS1/2 signaling, suggesting distinct effectors. FZD2-deleted mice show improved cardiac function and less scarring after myocardial infarction.","method":"Conditional FZD2 knockout in adult mouse cardiomyocytes, FZD2 KD and overexpression in neonatal ventricular CMs, YAP activity assays, β-catenin localization, β-catenin KD and YAP LATS-site mutation, myocardial infarction model","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple mechanistic dissections (β-catenin, Hippo independence), preprint not yet peer-reviewed","pmids":["bio_10.1101_2024.07.26.605158"],"is_preprint":true}],"current_model":"FZD2 is a Wnt receptor that mediates both canonical (β-catenin-dependent) and noncanonical (PCP, Wnt5a/FYN/STAT3, PI3K-AKT) Wnt signaling in a cell-type-specific manner; it cooperates with co-receptors (Ror2, LRP) and specific Wnt ligands (Wnt3a, Wnt5a/b, Wnt3, Wnt2), controls limb and lung development, regulates cardiomyocyte YAP activity and cell cycle re-entry, promotes EMT and stemness in cancer via STAT3/Notch pathways, and its stability depends on ER-resident scramblases VMP1/TMEM41B; loss-of-function mutations cause Robinow syndrome and OMOD2 through disruption of both canonical and noncanonical Wnt signaling in limb mesenchyme."},"narrative":{"mechanistic_narrative":"FZD2 is a Wnt receptor that transduces both canonical (β-catenin-dependent) and noncanonical Wnt signaling in a cell-type- and ligand-specific manner to control developmental morphogenesis and tissue regeneration [PMID:36867021, PMID:41257888]. In limb mesenchyme it integrates canonical Wnt/β-catenin signaling with the noncanonical WNT5A/planar cell polarity pathway, and a frameshift mutation in its Dishevelled-interacting domain reduces canonical signaling and disrupts digit chondrocyte elongation and orientation [PMID:36867021]. Loss-of-function and dominant-negative FZD2 variants cause Robinow syndrome/OMOD2: missense variants increase nuclear β-catenin and TWIST1 and inhibit chondrogenesis in frontonasal cells, and the Pro142Lys variant selectively abolishes noncanonical reporter activation and responsiveness to WNT5A, defining a single residue that alters ligand selectivity [PMID:38967226]. FZD2 acts with co-receptors and partners — cooperating with Ror2 in an LRP-dependent manner to potentiate Wnt3a-driven canonical signaling [PMID:18215320] — and engages Wnt5a/b, Wnt3, and Wnt2 ligands [PMID:31907106, PMID:32766155]. In tissue regeneration, mesenchymal FZD2 maintains alveolar fibroblast identity and supports alveolar repair via PI3K-AKT signaling, while endothelial FZD2 drives canonical Wnt/β-catenin–dependent proliferation [PMID:41257888], and in cardiomyocytes FZD2 restrains YAP activity and cell-cycle re-entry through an effector independent of canonical Wnt and Hippo/LATS signaling [PMID:bio_10.1101_2024.07.26.605158]. FZD2 receptor maturation and stability depend on the ER-resident scramblases VMP1 and TMEM41B, linking ER lipid metabolism to FZD2-dependent Wnt signaling [PMID:39968886]. In cancer, FZD2 drives epithelial-to-mesenchymal transition, stemness, and therapy resistance through noncanonical outputs including STAT3, YAP1, and TGF-β1/Smad3 [PMID:31907106, PMID:32766155].","teleology":[{"year":2008,"claim":"Established that FZD2 does not act alone but cooperates selectively with the co-receptor Ror2 to potentiate canonical Wnt signaling, defining receptor partner specificity.","evidence":"Overexpression/knockdown with domain-deletion constructs and STF luciferase reporter assays plus Dkk1/Krm1 inhibition in H441 lung carcinoma cells","pmids":["18215320"],"confidence":"Medium","gaps":["Whether Ror2-FZD2 cooperation operates in non-carcinoma or developmental contexts not tested","Direct physical interaction surfaces beyond CRD-dependence not mapped"]},{"year":2014,"claim":"Linked FZD2/WNT5A noncanonical signaling to EMT and metastasis through FYN and STAT3, implicating the receptor in cancer dissemination.","evidence":"Brief communication summary (no experimental detail in abstract)","pmids":["34450691"],"confidence":"Low","gaps":["No experimental detail available in the abstract","Direct FZD2-FYN-STAT3 mechanistic connection not demonstrated"]},{"year":2020,"claim":"Showed FZD2 binds specific Wnt ligands and that ligand engagement and protein stabilization route into discrete oncogenic outputs, connecting ligand identity to downstream pathway choice.","evidence":"Co-immunoprecipitation of FZD2-Wnt binding, siRNA knockdown, mammosphere/flow cytometry, and ubiquitination/phosphorylation assays with STAT3 readouts in breast and esophageal cancer cells","pmids":["31907106","32766155"],"confidence":"Medium","gaps":["Ubiquitin ligase mediating FZD2 turnover not identified","Kinase driving WNT2-induced FZD2 phosphorylation unknown"]},{"year":2021,"claim":"Implicated FZD2 in TGF-β1-induced EMT via Notch signaling in breast cancer, extending its noncanonical signaling repertoire.","evidence":"siRNA knockdown, EMT marker western/IF, pathway modulation, and xenograft","pmids":["33832493"],"confidence":"Low","gaps":["No direct mechanistic link between FZD2 and Notch established","Single knockdown approach without rescue"]},{"year":2022,"claim":"Connected Wnt5a/FZD2 noncanonical signaling to androgen receptor activity in enzalutamide-resistant prostate cancer, framing FZD2 as a therapy-resistance node.","evidence":"BERA-Wnt5a siRNA knockdown, AR/noncanonical pathway western blots, and xenograft tumor model","pmids":["35930737"],"confidence":"Medium","gaps":["Mechanism coupling FZD2 to AR splice variant stabilization not defined","Whether effect is FZD2-specific vs other Wnt5a receptors not resolved"]},{"year":2023,"claim":"Demonstrated in vivo that FZD2 mediates both canonical and WNT5A/PCP signaling in limb mesenchyme, and that disruption of its Dishevelled-interacting domain phenocopies Robinow syndrome/OMOD2.","evidence":"Mouse genetic model with a frameshift mutation, conditional FZD disruption, β-catenin reporters, and skeletal analysis","pmids":["36867021"],"confidence":"High","gaps":["How a single domain mutation partitions canonical vs PCP outputs not fully resolved","Ligand specificity in limb mesenchyme not directly tested"]},{"year":2024,"claim":"Resolved how human FZD2 disease variants act, showing dominant-negative canonical effects and a single residue (Pro142Lys) that selectively alters noncanonical/ligand responsiveness.","evidence":"Retroviral overexpression in chicken frontonasal mass, canonical/noncanonical luciferase reporters, β-catenin nuclear localization, and chondrogenesis assays","pmids":["38967226"],"confidence":"High","gaps":["Structural basis of altered WNT5A binding not determined","Whether dominant-negative effect involves dimerization with wild-type FZD2 unknown"]},{"year":2024,"claim":"Identified a developmentally distinct FZD2 function restraining cardiomyocyte YAP activity and cell-cycle re-entry through an effector independent of canonical Wnt and Hippo signaling.","evidence":"Conditional cardiomyocyte FZD2 knockout, neonatal CM KD/overexpression, YAP activity and β-catenin localization assays, and myocardial infarction model (preprint)","pmids":["bio_10.1101_2024.07.26.605158"],"confidence":"Medium","gaps":["The β-catenin- and Hippo-independent effector linking FZD2 to YAP is unidentified","Not yet peer-reviewed"]},{"year":2025,"claim":"Established the cell-biological prerequisite for FZD2 signaling by showing ER scramblases VMP1/TMEM41B are required for FZD2 maturation and stability.","evidence":"Genetic mutation of Vmp1/Tmem41b in mouse ESCs, differentiation assays, and FZD2 protein maturation/stability analysis","pmids":["39968886"],"confidence":"Medium","gaps":["Mechanism by which lipid scrambling supports FZD2 folding/trafficking not defined","Whether other FZD receptors share this dependence not tested"]},{"year":2025,"claim":"Defined cell-type-resolved FZD2 functions in lung — mesenchymal AF1 identity maintenance via PI3K-AKT and endothelial canonical Wnt-driven proliferation — and identified upstream epigenetic control of FZD2 by MBD2.","evidence":"Cell-type-specific conditional knockouts, bleomycin/LPS lung injury models, scRNA-seq, MBD2 knockout with ChIP for FZD2 promoter binding","pmids":["41257888","40081619"],"confidence":"Medium","gaps":["How FZD2 selects PI3K-AKT vs canonical output in different cell types not mechanistically resolved","Direct effectors downstream of FZD2 in fibroblast identity not identified"]},{"year":2025,"claim":"Showed FZD2 and FZD7 activate β-catenin with distinct kinetics, conferring non-redundant roles in directing mesoderm fate, establishing temporal signaling specificity among Frizzleds.","evidence":"Selective FZD2- and FZD7-specific antibody agonists in hPSCs, directed differentiation, and β-catenin kinetics measurement","pmids":["39824186"],"confidence":"Medium","gaps":["Molecular basis of kinetic difference between FZD2 and FZD7 unknown","Whether kinetic specificity generalizes beyond mesoderm not tested"]},{"year":null,"claim":"The identity of the non-canonical effector by which FZD2 restrains YAP, and the general rules governing how FZD2 partitions canonical, PCP, PI3K-AKT, and STAT3 outputs across cell types, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model for FZD2 output selection","Structural determinants of ligand selectivity only partially mapped","Direct intracellular effectors largely undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,10,11]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[2,3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[11,13]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,6,10,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,7,10,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[6,7]}],"complexes":[],"partners":["ROR2","WNT5A","WNT3","WNT2","WNT3A","VMP1","TMEM41B"],"other_free_text":[]}},"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":80,"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":"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":26,"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":"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":"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. 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Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/40081619","citation_count":3,"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":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":"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":2,"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":"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":"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":14780,"output_tokens":3786,"usd":0.050565,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11470,"output_tokens":4027,"usd":0.079012,"stage2_stop_reason":"end_turn"},"total_usd":0.129577,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"Ror2 positively modulates Wnt3a-activated canonical (β-catenin-dependent) Wnt signaling in lung carcinoma H441 cells through cooperative interaction with Fzd2 but not Fzd7; this cooperation requires the extracellular CRD of Ror2 but not its intracellular PRD domain, and is inhibited by Dkk1 and Krm1, indicating Lrp-dependence.\",\n      \"method\": \"Overexpression/knockdown in H441 cells, domain-deletion constructs, STF luciferase reporter assay, Dkk1/Krm1 inhibition\",\n      \"journal\": \"BMC molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-deletion analysis plus reporter assay with pharmacological controls, single lab\",\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\": \"Not detailed in abstract (reported as brief communication/summary)\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — abstract contains only a one-sentence summary with no experimental detail\",\n      \"pmids\": [\"34450691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FZD2 binds Wnt5a/b and Wnt3 ligands and activates oncogenic noncanonical Wnt pathways including IL-6/STAT3, YAP1, and TGF-β1/Smad3, promoting mesenchymal-like stemness and drug resistance in breast cancer cells; FZD2 knockdown impairs mammosphere formation and reduces the Lgr5+ subpopulation.\",\n      \"method\": \"Co-immunoprecipitation (FZD2–Wnt ligand binding), FZD2 KD by siRNA, mammosphere assay, flow cytometry for Lgr5+ cells, migration/invasion assays, western blot for pathway markers\",\n      \"journal\": \"Oncology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for ligand binding plus multiple functional assays, single lab\",\n      \"pmids\": [\"31907106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WNT2 ligand stabilizes FZD2 protein by attenuating its ubiquitination and inducing its phosphorylation, leading to activation of STAT3 signaling and promotion of esophageal squamous cell carcinoma cell migration and invasion.\",\n      \"method\": \"Co-expression experiments, ubiquitination assay, phosphorylation analysis, FZD2 knockdown/overexpression, STAT3 pathway readouts, in vivo xenograft metastasis model\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination and phosphorylation assays with functional readouts, 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 by activating the Notch signaling pathway; FZD2 knockdown inactivates Notch signaling and suppresses EMT markers.\",\n      \"method\": \"siRNA knockdown of FZD2, western blot and immunofluorescence for EMT markers, pathway inhibitor/activation experiments, in vivo xenograft\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single KD approach with pathway readout, no direct mechanistic link between FZD2 and Notch established\",\n      \"pmids\": [\"33832493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Wnt5a/FZD2-mediated noncanonical Wnt signaling is upregulated in enzalutamide-resistant prostate cancer; blocking Wnt5a/FZD2 signal transduction suppresses noncanonical Wnt signaling and reduces constitutively active androgen receptor (AR) and AR splice variants.\",\n      \"method\": \"siRNA knockdown (BERA-Wnt5a siRNA construct), western blot for noncanonical Wnt and AR pathway markers, in vivo tumor xenograft model\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro experiments with defined pathway readouts, single lab\",\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 and noncanonical WNT5A/planar cell polarity (PCP) pathways; a frameshift mutation in the Dishevelled-interacting domain of Fzd2 in mice decreases canonical Wnt signaling in limb mesenchyme and disrupts digit chondrocyte elongation/orientation controlled by the WNT5A/PCP pathway, causing shortened limbs resembling Robinow syndrome/OMOD2.\",\n      \"method\": \"Mouse genetic model (single-nucleotide insertion causing frameshift in Fzd2), conditional FZD function disruption in limb mesenchyme, β-catenin signaling reporters, skeletal analysis\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo genetic model with defined mutation, multiple pathway readouts (canonical and non-canonical), phenocopy of human disease\",\n      \"pmids\": [\"36867021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FZD2 missense variants associated with Robinow syndrome (Gly434Val and Pro142Lys) have dominant-negative effects on canonical Wnt signaling in frontonasal mass cells, increase nuclear β-catenin and TWIST1 expression, and inhibit chondrogenesis; the Pro142Lys variant additionally fails to activate a non-canonical reporter and is unresponsive to exogenous WNT5A, representing the first single amino acid change shown to selectively alter ligand binding in an FZD receptor.\",\n      \"method\": \"Retroviral overexpression in chicken embryo frontonasal mass, primary cell culture, SOX9 luciferase reporter assay, canonical and non-canonical Wnt luciferase assays, β-catenin nuclear localization assay, chondrogenesis assay\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal functional assays (reporter assays, nuclear shuttling, chondrogenesis) with defined mutations and in vivo validation\",\n      \"pmids\": [\"38967226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FZD2 knockdown in glioma cells suppresses proliferation, stemness, migration, invasion, EMT, and vasculogenic mimicry via blockade of the Notch/NF-κB signaling pathway; activation of Notch by JAG1 partially rescues FZD2 knockdown phenotypes.\",\n      \"method\": \"siRNA knockdown of FZD2, CCK-8, EdU, colony formation, wound healing, Transwell, sphere formation assays, western blot for Notch/NF-κB pathway proteins, Notch agonist rescue experiment\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, KD with rescue but no direct mechanistic link established between FZD2 and Notch\",\n      \"pmids\": [\"39091630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"VMP1 and TMEM41B (ER-resident scramblases) are required for maturation and stability of FZD2, linking ER lipid metabolism to FZD2-dependent WNT signaling during primitive endoderm specification in mouse embryonic stem cells.\",\n      \"method\": \"Genetic mutation of Vmp1 and Tmem41b in mouse ESCs, differentiation assays, protein stability/maturation analysis of FZD2\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined protein maturation readout, single lab\",\n      \"pmids\": [\"39968886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Conditional knockout of Fzd2 in mesenchymal cells impairs lung regeneration after bleomycin injury by promoting transition from alveolar fibroblast 1 (AF1) to fibroblast 2 (AF2) cells, suppressing Wnt2 expression and preventing alveolar type 2 cell expansion; Fzd2 maintains AF1 identity via PI3K-AKT signaling. In endothelial cells, canonical Wnt/β-catenin signaling via Fzd2 is essential for proliferation and vascular development; in mesenchymal cells, non-canonical Fzd2 signaling regulates proliferation and survival.\",\n      \"method\": \"Conditional knockout mouse models (cell-type-specific Fzd2 deletion), bleomycin lung injury model, single-cell RNA sequencing, western blot for PI3K-AKT and Wnt pathway markers\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional knockouts with multiple pathway readouts and in vivo injury model, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"41257888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FZD2 activation in human pluripotent stem cells promotes sustained Wnt/β-catenin signaling and guides differentiation toward paraxial mesoderm while blocking lateral mesoderm; FZD2 and FZD7 activate β-catenin with different kinetics, conferring non-redundant roles in mesoderm specification.\",\n      \"method\": \"Selective FZD2- and FZD7-specific antibody-based agonists applied to hPSCs, directed mesoderm differentiation assays, β-catenin signaling kinetics measurement, membrane receptor localization\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — selective receptor agonists with functional differentiation readouts, single lab\",\n      \"pmids\": [\"39824186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MBD2 promotes EMT and pulmonary fibrosis by modulating FZD2 expression; MBD2 knockout in mice reduces bleomycin- and LPS-induced pulmonary fibrosis and EMT, and ChIP assay identified FZD2 as a transcriptional target of MBD2.\",\n      \"method\": \"MBD2 knockout mice, bleomycin/LPS lung injury models, ChIP assay, RNA-Seq, TGF-β-induced EMT in alveolar epithelial cells, western blot\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP assay for direct MBD2-FZD2 transcriptional regulation plus in vivo genetic model, single lab\",\n      \"pmids\": [\"40081619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FZD2 in adult murine cardiomyocytes inhibits YAP activity and prevents cell cycle re-entry; FZD2 deletion causes cardiomyocyte proliferation marker expression, YAP target gene upregulation (Mycl, Bcl2l1), and β-catenin accumulation at membranes (not nuclear). The YAP-inhibitory effect of FZD2 is independent of both canonical Wnt/β-catenin and Hippo/LATS1/2 signaling, suggesting distinct effectors. FZD2-deleted mice show improved cardiac function and less scarring after myocardial infarction.\",\n      \"method\": \"Conditional FZD2 knockout in adult mouse cardiomyocytes, FZD2 KD and overexpression in neonatal ventricular CMs, YAP activity assays, β-catenin localization, β-catenin KD and YAP LATS-site mutation, myocardial infarction model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple mechanistic dissections (β-catenin, Hippo independence), preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.07.26.605158\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"FZD2 is a Wnt receptor that mediates both canonical (β-catenin-dependent) and noncanonical (PCP, Wnt5a/FYN/STAT3, PI3K-AKT) Wnt signaling in a cell-type-specific manner; it cooperates with co-receptors (Ror2, LRP) and specific Wnt ligands (Wnt3a, Wnt5a/b, Wnt3, Wnt2), controls limb and lung development, regulates cardiomyocyte YAP activity and cell cycle re-entry, promotes EMT and stemness in cancer via STAT3/Notch pathways, and its stability depends on ER-resident scramblases VMP1/TMEM41B; loss-of-function mutations cause Robinow syndrome and OMOD2 through disruption of both canonical and noncanonical Wnt signaling in limb mesenchyme.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FZD2 is a Wnt receptor that transduces both canonical (β-catenin-dependent) and noncanonical Wnt signaling in a cell-type- and ligand-specific manner to control developmental morphogenesis and tissue regeneration [#6, #10]. In limb mesenchyme it integrates canonical Wnt/β-catenin signaling with the noncanonical WNT5A/planar cell polarity pathway, and a frameshift mutation in its Dishevelled-interacting domain reduces canonical signaling and disrupts digit chondrocyte elongation and orientation [#6]. Loss-of-function and dominant-negative FZD2 variants cause Robinow syndrome/OMOD2: missense variants increase nuclear β-catenin and TWIST1 and inhibit chondrogenesis in frontonasal cells, and the Pro142Lys variant selectively abolishes noncanonical reporter activation and responsiveness to WNT5A, defining a single residue that alters ligand selectivity [#7]. FZD2 acts with co-receptors and partners — cooperating with Ror2 in an LRP-dependent manner to potentiate Wnt3a-driven canonical signaling [#0] — and engages Wnt5a/b, Wnt3, and Wnt2 ligands [#2, #3]. In tissue regeneration, mesenchymal FZD2 maintains alveolar fibroblast identity and supports alveolar repair via PI3K-AKT signaling, while endothelial FZD2 drives canonical Wnt/β-catenin–dependent proliferation [#10], and in cardiomyocytes FZD2 restrains YAP activity and cell-cycle re-entry through an effector independent of canonical Wnt and Hippo/LATS signaling [#13]. FZD2 receptor maturation and stability depend on the ER-resident scramblases VMP1 and TMEM41B, linking ER lipid metabolism to FZD2-dependent Wnt signaling [#9]. In cancer, FZD2 drives epithelial-to-mesenchymal transition, stemness, and therapy resistance through noncanonical outputs including STAT3, YAP1, and TGF-β1/Smad3 [#2, #3].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that FZD2 does not act alone but cooperates selectively with the co-receptor Ror2 to potentiate canonical Wnt signaling, defining receptor partner specificity.\",\n      \"evidence\": \"Overexpression/knockdown with domain-deletion constructs and STF luciferase reporter assays plus Dkk1/Krm1 inhibition in H441 lung carcinoma cells\",\n      \"pmids\": [\"18215320\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Ror2-FZD2 cooperation operates in non-carcinoma or developmental contexts not tested\", \"Direct physical interaction surfaces beyond CRD-dependence not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked FZD2/WNT5A noncanonical signaling to EMT and metastasis through FYN and STAT3, implicating the receptor in cancer dissemination.\",\n      \"evidence\": \"Brief communication summary (no experimental detail in abstract)\",\n      \"pmids\": [\"34450691\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experimental detail available in the abstract\", \"Direct FZD2-FYN-STAT3 mechanistic connection not demonstrated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed FZD2 binds specific Wnt ligands and that ligand engagement and protein stabilization route into discrete oncogenic outputs, connecting ligand identity to downstream pathway choice.\",\n      \"evidence\": \"Co-immunoprecipitation of FZD2-Wnt binding, siRNA knockdown, mammosphere/flow cytometry, and ubiquitination/phosphorylation assays with STAT3 readouts in breast and esophageal cancer cells\",\n      \"pmids\": [\"31907106\", \"32766155\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin ligase mediating FZD2 turnover not identified\", \"Kinase driving WNT2-induced FZD2 phosphorylation unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Implicated FZD2 in TGF-β1-induced EMT via Notch signaling in breast cancer, extending its noncanonical signaling repertoire.\",\n      \"evidence\": \"siRNA knockdown, EMT marker western/IF, pathway modulation, and xenograft\",\n      \"pmids\": [\"33832493\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct mechanistic link between FZD2 and Notch established\", \"Single knockdown approach without rescue\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected Wnt5a/FZD2 noncanonical signaling to androgen receptor activity in enzalutamide-resistant prostate cancer, framing FZD2 as a therapy-resistance node.\",\n      \"evidence\": \"BERA-Wnt5a siRNA knockdown, AR/noncanonical pathway western blots, and xenograft tumor model\",\n      \"pmids\": [\"35930737\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism coupling FZD2 to AR splice variant stabilization not defined\", \"Whether effect is FZD2-specific vs other Wnt5a receptors not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated in vivo that FZD2 mediates both canonical and WNT5A/PCP signaling in limb mesenchyme, and that disruption of its Dishevelled-interacting domain phenocopies Robinow syndrome/OMOD2.\",\n      \"evidence\": \"Mouse genetic model with a frameshift mutation, conditional FZD disruption, β-catenin reporters, and skeletal analysis\",\n      \"pmids\": [\"36867021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single domain mutation partitions canonical vs PCP outputs not fully resolved\", \"Ligand specificity in limb mesenchyme not directly tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Resolved how human FZD2 disease variants act, showing dominant-negative canonical effects and a single residue (Pro142Lys) that selectively alters noncanonical/ligand responsiveness.\",\n      \"evidence\": \"Retroviral overexpression in chicken frontonasal mass, canonical/noncanonical luciferase reporters, β-catenin nuclear localization, and chondrogenesis assays\",\n      \"pmids\": [\"38967226\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of altered WNT5A binding not determined\", \"Whether dominant-negative effect involves dimerization with wild-type FZD2 unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a developmentally distinct FZD2 function restraining cardiomyocyte YAP activity and cell-cycle re-entry through an effector independent of canonical Wnt and Hippo signaling.\",\n      \"evidence\": \"Conditional cardiomyocyte FZD2 knockout, neonatal CM KD/overexpression, YAP activity and β-catenin localization assays, and myocardial infarction model (preprint)\",\n      \"pmids\": [\"bio_10.1101_2024.07.26.605158\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The β-catenin- and Hippo-independent effector linking FZD2 to YAP is unidentified\", \"Not yet peer-reviewed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established the cell-biological prerequisite for FZD2 signaling by showing ER scramblases VMP1/TMEM41B are required for FZD2 maturation and stability.\",\n      \"evidence\": \"Genetic mutation of Vmp1/Tmem41b in mouse ESCs, differentiation assays, and FZD2 protein maturation/stability analysis\",\n      \"pmids\": [\"39968886\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which lipid scrambling supports FZD2 folding/trafficking not defined\", \"Whether other FZD receptors share this dependence not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined cell-type-resolved FZD2 functions in lung — mesenchymal AF1 identity maintenance via PI3K-AKT and endothelial canonical Wnt-driven proliferation — and identified upstream epigenetic control of FZD2 by MBD2.\",\n      \"evidence\": \"Cell-type-specific conditional knockouts, bleomycin/LPS lung injury models, scRNA-seq, MBD2 knockout with ChIP for FZD2 promoter binding\",\n      \"pmids\": [\"41257888\", \"40081619\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How FZD2 selects PI3K-AKT vs canonical output in different cell types not mechanistically resolved\", \"Direct effectors downstream of FZD2 in fibroblast identity not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed FZD2 and FZD7 activate β-catenin with distinct kinetics, conferring non-redundant roles in directing mesoderm fate, establishing temporal signaling specificity among Frizzleds.\",\n      \"evidence\": \"Selective FZD2- and FZD7-specific antibody agonists in hPSCs, directed differentiation, and β-catenin kinetics measurement\",\n      \"pmids\": [\"39824186\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of kinetic difference between FZD2 and FZD7 unknown\", \"Whether kinetic specificity generalizes beyond mesoderm not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of the non-canonical effector by which FZD2 restrains YAP, and the general rules governing how FZD2 partitions canonical, PCP, PI3K-AKT, and STAT3 outputs across cell types, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model for FZD2 output selection\", \"Structural determinants of ligand selectivity only partially mapped\", \"Direct intracellular effectors largely undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 10, 11]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [2, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [11, 13]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 6, 10, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 7, 10, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ROR2\", \"WNT5A\", \"WNT3\", \"WNT2\", \"WNT3A\", \"VMP1\", \"TMEM41B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}