{"gene":"FZD10","run_date":"2026-04-28T17:46:04","timeline":{"discoveries":[{"year":2005,"finding":"Wnt7b binds directly to FZD10 (and FZD1) on the cell surface and cooperatively activates canonical Wnt/β-catenin signaling in the presence of LRP5 co-receptor, but does not activate the noncanonical Wnt pathway through this interaction.","method":"Cell surface binding assay, cell transfection with canonical vs. noncanonical pathway reporters, biochemical co-receptor analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 — direct binding assay combined with pathway-specific functional readouts and co-receptor requirement demonstrated","pmids":["15923619"],"is_preprint":false},{"year":2017,"finding":"FZD10 selectively interacts with and signals through the heterotrimeric G protein Gα13 (but not Gα12, Gαi1, GαoA, Gαs, or Gαq); WNT stimulation induces dissociation of Gα13 from FZD10 and triggers Gα12/13-dependent cell responses; FZD10-Gα13 signaling activates YAP/TAZ transcriptional activity.","method":"G protein interaction assays, dynamic mass redistribution measurements, YAP/TAZ reporter assays, FZD10 expression in embryonic CNS endothelial cells by immunofluorescence","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (G protein selectivity panel, DMR, transcriptional reporters) in a single study","pmids":["28126591"],"is_preprint":false},{"year":2014,"finding":"BRMS1L epigenetically silences FZD10 by recruiting HDAC1 and promoting histone H3K9 deacetylation at the FZD10 promoter, thereby suppressing WNT3-FZD10-β-catenin signaling and inhibiting breast cancer cell migration, invasion, and epithelial-mesenchymal transition.","method":"ChIP for HDAC1 and histone marks at FZD10 promoter, RNAi knockdown of BRMS1L, rescue experiments with FZD10 overexpression, in vivo xenograft metastasis assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — reciprocal ChIP, functional RNAi, and in vivo metastasis model with defined molecular mechanism","pmids":["25406648"],"is_preprint":false},{"year":2019,"finding":"m6A modification of FZD10 mRNA, regulated by demethylases FTO and ALKBH5, increases FZD10 mRNA stability and upregulates the Wnt/β-catenin pathway, contributing to PARP inhibitor resistance in BRCA-mutated ovarian cancer cells.","method":"Global m6A profiling (m6A-seq), mRNA stability assay, FZD10 depletion, FTO/ALKBH5 knockdown, Wnt/β-catenin pathway reporters, in vivo xenograft model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — m6A sequencing, mRNA stability, RNAi epistasis, and in vivo validation in single study","pmids":["30967398"],"is_preprint":false},{"year":2023,"finding":"METTL3-dependent m6A methylation of FZD10 mRNA activates FZD10 expression in liver cancer stem cells; FZD10 promotes self-renewal via activating β-catenin and YAP1; a positive feedback loop exists where FZD10-β-catenin/c-Jun transcriptionally activates METTL3; the FZD10/β-catenin/c-Jun/MEK/ERK axis mediates lenvatinib resistance.","method":"RNA-seq, RNA binding protein immunoprecipitation (RIP), luciferase reporter assays, in vitro/in vivo functional studies, patient-derived tumor organoids and xenografts","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (RIP, luciferase, PDX/organoids) with defined feedback loop and pathway placement","pmids":["36764493"],"is_preprint":false},{"year":2020,"finding":"In the developing spinal cord, FZD10 is required for Wnt1-induced ventral expansion of dorsal neural markers (Pax6, Pax7) and neural tube patterning; FZD10 acts with LRP6 co-receptor to mediate Wnt1 canonical signaling, and excess FZD10 inhibits Wnt1 activity in the absence of LRP6.","method":"Morpholino-based knockdown in Xenopus/chick, gain-of-function overexpression, epistasis with Wnt1, Wnt3a, and Lrp6 co-injection","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis and loss/gain-of-function in vivo with defined co-receptor requirement, single lab","pmids":["32531778"],"is_preprint":false},{"year":2008,"finding":"A monoclonal antibody (MAb 92-13) against FZD10 binds native FZD10 on the cell surface of synovial sarcoma cells and is efficiently internalized after binding, enabling targeted radioimmunotherapy.","method":"Cell binding assay, in vivo fluorescent imaging with labeled antibody, internalization assay, biodistribution study","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 — direct cell-surface binding and internalization documented with in vivo imaging confirmation","pmids":["18271942"],"is_preprint":false},{"year":2019,"finding":"FZD10 protein and FZD10 mRNA are packaged into exosomes secreted by colorectal, gastric, hepatic, and cholangio cancer cell lines; exosomal delivery of FZD10 to recipient cells restores cell viability and FZD10 levels in FZD10-silenced cells, sustaining cancer cell proliferation.","method":"Exosome isolation and characterization, siRNA silencing, exosome transfer/rescue assay, cell viability assay","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 3 — single lab with silencing and rescue experiments demonstrating functional transfer via exosomes","pmids":["31349740"],"is_preprint":false},{"year":2021,"finding":"Exosomal FZD10 silencing in colorectal and gastric cancer cells reduces phospho-ERK1/2 and Ki-67 expression; treatment with exogenous FZD10-containing exosomes partially restores pERK1/2 and Ki-67 levels, placing FZD10 upstream of the ERK1/2/Ki-67 proliferative axis.","method":"FZD10 siRNA silencing, exosome treatment rescue, Western blotting for pERK1/2, Ki-67 immunostaining","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 3 — silencing plus exosome rescue with defined downstream signaling readout, single lab","pmids":["34671555"],"is_preprint":false},{"year":2020,"finding":"Tumor-derived exosomes carrying FZD10 induce epithelial-mesenchymal transition in normal colonic epithelial cells (HCEC-1CT), including acquisition of mesenchymal markers and migration capacity; metastatic cell-derived exosomes with higher FZD10 content are more potent EMT inducers.","method":"Exosome isolation and transfer to normal epithelial cells, migration assay, mesenchymal marker expression analysis","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 — single lab, single method set, no direct FZD10 gain/loss-of-function in recipient cells","pmids":["32933173"],"is_preprint":false},{"year":2022,"finding":"Exosomal FZD10 derived from non-small cell lung cancer cells promotes HUVEC tube formation and upregulates VEGFA and Ang-1 in HUVECs by activating PI3K and ERK1/2 signaling pathways, but not YAP/TAZ signaling.","method":"Exosome isolation, FZD10 siRNA knockdown, in vitro angiogenesis (tube formation) assay, ELISA for VEGFA/Ang-1, Western blotting for PI3K/ERK1/2/YAP/TAZ","journal":"Journal of Southern Medical University","confidence":"Low","confidence_rationale":"Tier 3 — single lab, silencing approach without direct receptor reconstitution","pmids":["36210708"],"is_preprint":false},{"year":2023,"finding":"miR-26b-3p directly targets FZD10 (validated by luciferase assay); FZD10 downregulation increases GSK3β phosphorylation and decreases β-catenin, promoting enteric glial cell apoptosis and intestinal dysmotility.","method":"Luciferase reporter assay for miR-26b-3p/FZD10 targeting, siRNA knockdown of FZD10, flow cytometry for apoptosis, Western blotting for GSK3β/β-catenin, in vivo mouse model","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 — luciferase validation of miRNA target, combined with in vivo epistasis, moderate evidence","pmids":["37728849"],"is_preprint":false},{"year":2026,"finding":"Transcription factor E2F2 directly regulates FZD10 expression; FZD10 activates the Wnt/β-catenin pathway to sustain a breast cancer stem-like phenotype induced by arsenic exposure in mammary epithelial cells.","method":"Transcriptomic profiling, functional studies of E2F2/FZD10 axis, Wnt/β-catenin pathway activation assays, stem cell marker quantification","journal":"Food and chemical toxicology","confidence":"Low","confidence_rationale":"Tier 3 — single lab, limited mechanistic detail on E2F2-FZD10 direct regulation provided","pmids":["41672294"],"is_preprint":false}],"current_model":"FZD10 is a Frizzled-family GPCR that functions as a cell-surface receptor for Wnt ligands (particularly Wnt7b and Wnt1), coupling to Gα13 and to LRP5/LRP6 co-receptors to activate canonical β-catenin signaling as well as YAP/TAZ transcriptional activity; its expression is epigenetically regulated by BRMS1L/HDAC1-mediated H3K9 deacetylation and by METTL3/FTO/ALKBH5-dependent m6A modification of its mRNA, the latter controlling mRNA stability; FZD10 can also be packaged into exosomes and transferred intercellularly to activate ERK1/2 and PI3K signaling in recipient cells, and miR-26b-3p directly suppresses FZD10 to modulate GSK3β/β-catenin-dependent apoptosis."},"narrative":{"teleology":[{"year":2005,"claim":"Establishing FZD10 as a bona fide Wnt receptor resolved which Frizzled family members mediate canonical signaling: Wnt7b directly binds FZD10 on the cell surface and activates β-catenin signaling specifically in the presence of LRP5, ruling out noncanonical pathway activation through this receptor.","evidence":"Cell surface binding assays and canonical versus noncanonical reporter assays in transfected cells","pmids":["15923619"],"confidence":"High","gaps":["Structural basis of the Wnt7b–FZD10 interaction not determined","Whether FZD10 has ligand preferences beyond Wnt7b was not systematically tested","Downstream signaling intermediates between FZD10-LRP5 and β-catenin stabilization not mapped"]},{"year":2008,"claim":"Demonstrating that a monoclonal antibody against native FZD10 is efficiently internalized upon binding confirmed that FZD10 resides on the cell surface and undergoes ligand/antibody-induced endocytosis, relevant to its signaling regulation and therapeutic targeting.","evidence":"Cell binding assay, internalization assay, and in vivo fluorescent imaging of labeled anti-FZD10 MAb in synovial sarcoma cells","pmids":["18271942"],"confidence":"Medium","gaps":["Whether internalization is clathrin- or caveolae-dependent was not addressed","The fate of internalized FZD10 (recycling vs. degradation) was not tracked"]},{"year":2014,"claim":"Identifying BRMS1L/HDAC1-mediated H3K9 deacetylation as a silencing mechanism at the FZD10 promoter revealed how epigenetic regulation of receptor expression controls Wnt/β-catenin output and metastatic behavior in breast cancer.","evidence":"ChIP for HDAC1 and H3K9 marks at FZD10 promoter, BRMS1L RNAi, FZD10 rescue, and in vivo xenograft metastasis assay","pmids":["25406648"],"confidence":"High","gaps":["Whether other histone marks or DNA methylation co-regulate FZD10 at this locus was not examined","Tissue specificity of BRMS1L–FZD10 regulation not explored beyond breast cancer"]},{"year":2017,"claim":"Mapping FZD10's selective coupling to Gα13 (excluding Gα12, Gαi1, GαoA, Gαs, Gαq) and showing Wnt-induced Gα13 dissociation with downstream YAP/TAZ activation established FZD10 as a G protein-coupled receptor with a defined heterotrimeric G protein selectivity profile.","evidence":"G protein interaction panel, dynamic mass redistribution measurements, and YAP/TAZ reporter assays","pmids":["28126591"],"confidence":"High","gaps":["Structural determinants within FZD10 that confer Gα13 selectivity are unknown","How Gα13 signaling converges on YAP/TAZ versus β-catenin downstream of FZD10 is not delineated"]},{"year":2019,"claim":"Discovery that m6A modification of FZD10 mRNA by FTO and ALKBH5 stabilizes the transcript and upregulates Wnt/β-catenin signaling revealed an epitranscriptomic layer of FZD10 regulation with functional consequences for PARP inhibitor resistance.","evidence":"m6A-seq, mRNA stability assays, FTO/ALKBH5 knockdown, pathway reporters, and in vivo xenograft validation in BRCA-mutated ovarian cancer cells","pmids":["30967398"],"confidence":"High","gaps":["Specific m6A reader proteins that recognize FZD10 mRNA were not identified","Whether m6A-dependent FZD10 regulation operates in normal physiology remains untested"]},{"year":2019,"claim":"Demonstrating that FZD10 protein and mRNA are packaged into exosomes and that exosomal transfer rescues proliferation in FZD10-depleted cancer cells established a paracrine mode of FZD10 signaling beyond canonical ligand–receptor interaction.","evidence":"Exosome isolation, FZD10 siRNA silencing, and exosome transfer/rescue assays in colorectal, gastric, hepatic, and cholangio cancer cells","pmids":["31349740"],"confidence":"Medium","gaps":["Mechanism of FZD10 sorting into exosomes is unknown","Whether exosomal FZD10 signals via the same β-catenin pathway as membrane-resident FZD10 was not tested","No in vivo validation of exosomal FZD10 transfer"]},{"year":2020,"claim":"In vivo loss- and gain-of-function studies in Xenopus/chick showed FZD10 is required for Wnt1-dependent dorsal neural tube patterning and that excess FZD10 inhibits Wnt1 in the absence of LRP6, extending FZD10's developmental role and co-receptor dependence to neural patterning.","evidence":"Morpholino knockdown and overexpression with Wnt1/Wnt3a/LRP6 epistasis in Xenopus and chick spinal cord","pmids":["32531778"],"confidence":"Medium","gaps":["Whether FZD10 functions redundantly with other Frizzled receptors in neural tube patterning not resolved","Downstream transcriptional targets in neural progenitors not identified"]},{"year":2021,"claim":"Placing FZD10 upstream of the ERK1/2/Ki-67 proliferative axis via exosome transfer experiments defined a non-canonical signaling output for exosomal FZD10 distinct from its established β-catenin role.","evidence":"FZD10 siRNA silencing and exosome rescue with pERK1/2 and Ki-67 readouts in colorectal and gastric cancer cells","pmids":["34671555"],"confidence":"Medium","gaps":["Direct interaction between FZD10 and ERK1/2 pathway components not demonstrated","Whether ERK1/2 activation by exosomal FZD10 requires LRP co-receptors is unknown"]},{"year":2023,"claim":"Identifying a METTL3–m6A–FZD10–β-catenin/c-Jun positive feedback loop in liver cancer stem cells unified the epitranscriptomic and transcriptional regulation of FZD10, showing that FZD10-driven β-catenin/c-Jun transcriptionally activates METTL3, which in turn m6A-methylates FZD10 mRNA to sustain self-renewal and drug resistance.","evidence":"RIP, luciferase reporters, patient-derived tumor organoids and xenografts in hepatocellular carcinoma","pmids":["36764493"],"confidence":"High","gaps":["Whether the METTL3–FZD10 feedback loop operates in non-hepatic cancers is unknown","Which m6A reader(s) mediate the stabilization of FZD10 mRNA downstream of METTL3 not identified"]},{"year":2023,"claim":"Validation of miR-26b-3p as a direct negative regulator of FZD10, with FZD10 loss increasing GSK3β phosphorylation and decreasing β-catenin to promote enteric glial cell apoptosis, connected microRNA-mediated FZD10 regulation to a non-cancer physiological context (intestinal motility).","evidence":"Luciferase reporter validation, FZD10 siRNA, flow cytometry, GSK3β/β-catenin Western blot, in vivo mouse model","pmids":["37728849"],"confidence":"Medium","gaps":["Other miRNAs targeting FZD10 not systematically surveyed","Whether miR-26b-3p–FZD10 axis operates in intestinal stem cells is unknown"]},{"year":null,"claim":"The structural basis of FZD10's selectivity for Gα13 over other Gα subunits, the identity of m6A readers that stabilize FZD10 mRNA, and the mechanism by which FZD10 is sorted into exosomes remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of FZD10 in complex with Gα13 or Wnt ligand","m6A reader proteins acting on FZD10 mRNA not identified","Mechanism of FZD10 sorting into exosomes completely undefined","Relative contribution of β-catenin vs. YAP/TAZ arms downstream of FZD10 in different tissues not quantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,6]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[7,8]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,2,3,4,5,11]}],"complexes":[],"partners":["WNT7B","WNT1","LRP5","LRP6","GNA13","METTL3","BRMS1L","HDAC1"],"other_free_text":[]},"mechanistic_narrative":"FZD10 is a Frizzled-family seven-transmembrane receptor that transduces canonical Wnt/β-catenin signaling in development and disease. FZD10 binds Wnt ligands (Wnt7b, Wnt1) at the cell surface and cooperates with LRP5/LRP6 co-receptors to activate β-catenin-dependent transcription, while selectively coupling to Gα13 to co-activate YAP/TAZ transcriptional programs [PMID:15923619, PMID:28126591, PMID:32531778]. FZD10 expression is regulated epigenetically through BRMS1L/HDAC1-mediated H3K9 deacetylation at its promoter and post-transcriptionally through METTL3-, FTO-, and ALKBH5-dependent m6A modification of its mRNA, which controls mRNA stability and feeds back via a β-catenin/c-Jun/METTL3 positive loop to sustain Wnt signaling in cancer stem cells [PMID:25406648, PMID:30967398, PMID:36764493]. FZD10 protein and mRNA are also packaged into tumor-derived exosomes and transferred intercellularly, where they activate ERK1/2 and PI3K signaling to promote proliferation and angiogenesis in recipient cells [PMID:31349740, PMID:34671555]."},"prefetch_data":{"uniprot":{"accession":"Q9ULW2","full_name":"Frizzled-10","aliases":["FzE7"],"length_aa":581,"mass_kda":65.3,"function":"Receptor for Wnt proteins. Functions in the canonical Wnt/beta-catenin signaling pathway (By similarity). The canonical Wnt/beta-catenin signaling pathway leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues (Probable)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9ULW2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FZD10","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FZD10","total_profiled":1310},"omim":[{"mim_id":"617905","title":"HYPOXIA-INDUCIBLE LIPID DROPLET-ASSOCIATED PROTEIN; HILPDA","url":"https://www.omim.org/entry/617905"},{"mim_id":"606147","title":"FRIZZLED CLASS RECEPTOR 10; FZD10","url":"https://www.omim.org/entry/606147"},{"mim_id":"180600","title":"RINGED HAIR","url":"https://www.omim.org/entry/180600"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"esophagus","ntpm":15.7},{"tissue":"skin 1","ntpm":8.9}],"url":"https://www.proteinatlas.org/search/FZD10"},"hgnc":{"alias_symbol":["CD350"],"prev_symbol":[]},"alphafold":{"accession":"Q9ULW2","domains":[{"cath_id":"1.10.2000.10","chopping":"36-137","consensus_level":"high","plddt":90.3586,"start":36,"end":137},{"cath_id":"1.20.1070.10","chopping":"205-428_435-533","consensus_level":"high","plddt":91.5838,"start":205,"end":533}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULW2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULW2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULW2-F1-predicted_aligned_error_v6.png","plddt_mean":80.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FZD10","jax_strain_url":"https://www.jax.org/strain/search?query=FZD10"},"sequence":{"accession":"Q9ULW2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULW2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULW2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULW2"}},"corpus_meta":[{"pmid":"36764493","id":"PMC_36764493","title":"N6-Methyladenosine-Mediated 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FZD10.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25406648","citation_count":92,"is_preprint":false},{"pmid":"18271942","id":"PMC_18271942","title":"Radioimmunotherapy of human synovial sarcoma using a monoclonal antibody against FZD10.","date":"2008","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/18271942","citation_count":63,"is_preprint":false},{"pmid":"11743650","id":"PMC_11743650","title":"Up-regulation of Frizzled-10 (FZD10) by beta-estradiol in MCF-7 cells and by retinoic acid in NT2 cells.","date":"2002","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/11743650","citation_count":58,"is_preprint":false},{"pmid":"31349740","id":"PMC_31349740","title":"FZD10 Carried by Exosomes Sustains Cancer Cell 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journal published for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/41672294","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.12.05.24318588","title":"Assessment of MYC Gene and WNT Pathway Alterations in Early-Onset Colorectal Cancer Among Hispanic/Latino Patients Using Integrated Multi-Omics Approaches","date":"2024-12-08","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.05.24318588","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.19.633799","title":"The Role Of <i>Fzd8</i> For Bone Development And Homeostasis In A Mouse Model Generated By CRISPR/Cas9 Genome Editing","date":"2025-01-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.19.633799","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15123,"output_tokens":3242,"usd":0.046999},"stage2":{"model":"claude-opus-4-6","input_tokens":6695,"output_tokens":3161,"usd":0.16875},"total_usd":0.215749,"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\": 2005,\n      \"finding\": \"Wnt7b binds directly to FZD10 (and FZD1) on the cell surface and cooperatively activates canonical Wnt/β-catenin signaling in the presence of LRP5 co-receptor, but does not activate the noncanonical Wnt pathway through this interaction.\",\n      \"method\": \"Cell surface binding assay, cell transfection with canonical vs. noncanonical pathway reporters, biochemical co-receptor analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct binding assay combined with pathway-specific functional readouts and co-receptor requirement demonstrated\",\n      \"pmids\": [\"15923619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FZD10 selectively interacts with and signals through the heterotrimeric G protein Gα13 (but not Gα12, Gαi1, GαoA, Gαs, or Gαq); WNT stimulation induces dissociation of Gα13 from FZD10 and triggers Gα12/13-dependent cell responses; FZD10-Gα13 signaling activates YAP/TAZ transcriptional activity.\",\n      \"method\": \"G protein interaction assays, dynamic mass redistribution measurements, YAP/TAZ reporter assays, FZD10 expression in embryonic CNS endothelial cells by immunofluorescence\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (G protein selectivity panel, DMR, transcriptional reporters) in a single study\",\n      \"pmids\": [\"28126591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BRMS1L epigenetically silences FZD10 by recruiting HDAC1 and promoting histone H3K9 deacetylation at the FZD10 promoter, thereby suppressing WNT3-FZD10-β-catenin signaling and inhibiting breast cancer cell migration, invasion, and epithelial-mesenchymal transition.\",\n      \"method\": \"ChIP for HDAC1 and histone marks at FZD10 promoter, RNAi knockdown of BRMS1L, rescue experiments with FZD10 overexpression, in vivo xenograft metastasis assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal ChIP, functional RNAi, and in vivo metastasis model with defined molecular mechanism\",\n      \"pmids\": [\"25406648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"m6A modification of FZD10 mRNA, regulated by demethylases FTO and ALKBH5, increases FZD10 mRNA stability and upregulates the Wnt/β-catenin pathway, contributing to PARP inhibitor resistance in BRCA-mutated ovarian cancer cells.\",\n      \"method\": \"Global m6A profiling (m6A-seq), mRNA stability assay, FZD10 depletion, FTO/ALKBH5 knockdown, Wnt/β-catenin pathway reporters, in vivo xenograft model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — m6A sequencing, mRNA stability, RNAi epistasis, and in vivo validation in single study\",\n      \"pmids\": [\"30967398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL3-dependent m6A methylation of FZD10 mRNA activates FZD10 expression in liver cancer stem cells; FZD10 promotes self-renewal via activating β-catenin and YAP1; a positive feedback loop exists where FZD10-β-catenin/c-Jun transcriptionally activates METTL3; the FZD10/β-catenin/c-Jun/MEK/ERK axis mediates lenvatinib resistance.\",\n      \"method\": \"RNA-seq, RNA binding protein immunoprecipitation (RIP), luciferase reporter assays, in vitro/in vivo functional studies, patient-derived tumor organoids and xenografts\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (RIP, luciferase, PDX/organoids) with defined feedback loop and pathway placement\",\n      \"pmids\": [\"36764493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In the developing spinal cord, FZD10 is required for Wnt1-induced ventral expansion of dorsal neural markers (Pax6, Pax7) and neural tube patterning; FZD10 acts with LRP6 co-receptor to mediate Wnt1 canonical signaling, and excess FZD10 inhibits Wnt1 activity in the absence of LRP6.\",\n      \"method\": \"Morpholino-based knockdown in Xenopus/chick, gain-of-function overexpression, epistasis with Wnt1, Wnt3a, and Lrp6 co-injection\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis and loss/gain-of-function in vivo with defined co-receptor requirement, single lab\",\n      \"pmids\": [\"32531778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A monoclonal antibody (MAb 92-13) against FZD10 binds native FZD10 on the cell surface of synovial sarcoma cells and is efficiently internalized after binding, enabling targeted radioimmunotherapy.\",\n      \"method\": \"Cell binding assay, in vivo fluorescent imaging with labeled antibody, internalization assay, biodistribution study\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct cell-surface binding and internalization documented with in vivo imaging confirmation\",\n      \"pmids\": [\"18271942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FZD10 protein and FZD10 mRNA are packaged into exosomes secreted by colorectal, gastric, hepatic, and cholangio cancer cell lines; exosomal delivery of FZD10 to recipient cells restores cell viability and FZD10 levels in FZD10-silenced cells, sustaining cancer cell proliferation.\",\n      \"method\": \"Exosome isolation and characterization, siRNA silencing, exosome transfer/rescue assay, cell viability assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab with silencing and rescue experiments demonstrating functional transfer via exosomes\",\n      \"pmids\": [\"31349740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Exosomal FZD10 silencing in colorectal and gastric cancer cells reduces phospho-ERK1/2 and Ki-67 expression; treatment with exogenous FZD10-containing exosomes partially restores pERK1/2 and Ki-67 levels, placing FZD10 upstream of the ERK1/2/Ki-67 proliferative axis.\",\n      \"method\": \"FZD10 siRNA silencing, exosome treatment rescue, Western blotting for pERK1/2, Ki-67 immunostaining\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — silencing plus exosome rescue with defined downstream signaling readout, single lab\",\n      \"pmids\": [\"34671555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Tumor-derived exosomes carrying FZD10 induce epithelial-mesenchymal transition in normal colonic epithelial cells (HCEC-1CT), including acquisition of mesenchymal markers and migration capacity; metastatic cell-derived exosomes with higher FZD10 content are more potent EMT inducers.\",\n      \"method\": \"Exosome isolation and transfer to normal epithelial cells, migration assay, mesenchymal marker expression analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, single method set, no direct FZD10 gain/loss-of-function in recipient cells\",\n      \"pmids\": [\"32933173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Exosomal FZD10 derived from non-small cell lung cancer cells promotes HUVEC tube formation and upregulates VEGFA and Ang-1 in HUVECs by activating PI3K and ERK1/2 signaling pathways, but not YAP/TAZ signaling.\",\n      \"method\": \"Exosome isolation, FZD10 siRNA knockdown, in vitro angiogenesis (tube formation) assay, ELISA for VEGFA/Ang-1, Western blotting for PI3K/ERK1/2/YAP/TAZ\",\n      \"journal\": \"Journal of Southern Medical University\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, silencing approach without direct receptor reconstitution\",\n      \"pmids\": [\"36210708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-26b-3p directly targets FZD10 (validated by luciferase assay); FZD10 downregulation increases GSK3β phosphorylation and decreases β-catenin, promoting enteric glial cell apoptosis and intestinal dysmotility.\",\n      \"method\": \"Luciferase reporter assay for miR-26b-3p/FZD10 targeting, siRNA knockdown of FZD10, flow cytometry for apoptosis, Western blotting for GSK3β/β-catenin, in vivo mouse model\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — luciferase validation of miRNA target, combined with in vivo epistasis, moderate evidence\",\n      \"pmids\": [\"37728849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Transcription factor E2F2 directly regulates FZD10 expression; FZD10 activates the Wnt/β-catenin pathway to sustain a breast cancer stem-like phenotype induced by arsenic exposure in mammary epithelial cells.\",\n      \"method\": \"Transcriptomic profiling, functional studies of E2F2/FZD10 axis, Wnt/β-catenin pathway activation assays, stem cell marker quantification\",\n      \"journal\": \"Food and chemical toxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, limited mechanistic detail on E2F2-FZD10 direct regulation provided\",\n      \"pmids\": [\"41672294\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FZD10 is a Frizzled-family GPCR that functions as a cell-surface receptor for Wnt ligands (particularly Wnt7b and Wnt1), coupling to Gα13 and to LRP5/LRP6 co-receptors to activate canonical β-catenin signaling as well as YAP/TAZ transcriptional activity; its expression is epigenetically regulated by BRMS1L/HDAC1-mediated H3K9 deacetylation and by METTL3/FTO/ALKBH5-dependent m6A modification of its mRNA, the latter controlling mRNA stability; FZD10 can also be packaged into exosomes and transferred intercellularly to activate ERK1/2 and PI3K signaling in recipient cells, and miR-26b-3p directly suppresses FZD10 to modulate GSK3β/β-catenin-dependent apoptosis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FZD10 is a Frizzled-family seven-transmembrane receptor that transduces canonical Wnt/β-catenin signaling in development and disease. FZD10 binds Wnt ligands (Wnt7b, Wnt1) at the cell surface and cooperates with LRP5/LRP6 co-receptors to activate β-catenin-dependent transcription, while selectively coupling to Gα13 to co-activate YAP/TAZ transcriptional programs [PMID:15923619, PMID:28126591, PMID:32531778]. FZD10 expression is regulated epigenetically through BRMS1L/HDAC1-mediated H3K9 deacetylation at its promoter and post-transcriptionally through METTL3-, FTO-, and ALKBH5-dependent m6A modification of its mRNA, which controls mRNA stability and feeds back via a β-catenin/c-Jun/METTL3 positive loop to sustain Wnt signaling in cancer stem cells [PMID:25406648, PMID:30967398, PMID:36764493]. FZD10 protein and mRNA are also packaged into tumor-derived exosomes and transferred intercellularly, where they activate ERK1/2 and PI3K signaling to promote proliferation and angiogenesis in recipient cells [PMID:31349740, PMID:34671555].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing FZD10 as a bona fide Wnt receptor resolved which Frizzled family members mediate canonical signaling: Wnt7b directly binds FZD10 on the cell surface and activates β-catenin signaling specifically in the presence of LRP5, ruling out noncanonical pathway activation through this receptor.\",\n      \"evidence\": \"Cell surface binding assays and canonical versus noncanonical reporter assays in transfected cells\",\n      \"pmids\": [\"15923619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the Wnt7b–FZD10 interaction not determined\",\n        \"Whether FZD10 has ligand preferences beyond Wnt7b was not systematically tested\",\n        \"Downstream signaling intermediates between FZD10-LRP5 and β-catenin stabilization not mapped\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that a monoclonal antibody against native FZD10 is efficiently internalized upon binding confirmed that FZD10 resides on the cell surface and undergoes ligand/antibody-induced endocytosis, relevant to its signaling regulation and therapeutic targeting.\",\n      \"evidence\": \"Cell binding assay, internalization assay, and in vivo fluorescent imaging of labeled anti-FZD10 MAb in synovial sarcoma cells\",\n      \"pmids\": [\"18271942\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether internalization is clathrin- or caveolae-dependent was not addressed\",\n        \"The fate of internalized FZD10 (recycling vs. degradation) was not tracked\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying BRMS1L/HDAC1-mediated H3K9 deacetylation as a silencing mechanism at the FZD10 promoter revealed how epigenetic regulation of receptor expression controls Wnt/β-catenin output and metastatic behavior in breast cancer.\",\n      \"evidence\": \"ChIP for HDAC1 and H3K9 marks at FZD10 promoter, BRMS1L RNAi, FZD10 rescue, and in vivo xenograft metastasis assay\",\n      \"pmids\": [\"25406648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether other histone marks or DNA methylation co-regulate FZD10 at this locus was not examined\",\n        \"Tissue specificity of BRMS1L–FZD10 regulation not explored beyond breast cancer\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapping FZD10's selective coupling to Gα13 (excluding Gα12, Gαi1, GαoA, Gαs, Gαq) and showing Wnt-induced Gα13 dissociation with downstream YAP/TAZ activation established FZD10 as a G protein-coupled receptor with a defined heterotrimeric G protein selectivity profile.\",\n      \"evidence\": \"G protein interaction panel, dynamic mass redistribution measurements, and YAP/TAZ reporter assays\",\n      \"pmids\": [\"28126591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural determinants within FZD10 that confer Gα13 selectivity are unknown\",\n        \"How Gα13 signaling converges on YAP/TAZ versus β-catenin downstream of FZD10 is not delineated\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery that m6A modification of FZD10 mRNA by FTO and ALKBH5 stabilizes the transcript and upregulates Wnt/β-catenin signaling revealed an epitranscriptomic layer of FZD10 regulation with functional consequences for PARP inhibitor resistance.\",\n      \"evidence\": \"m6A-seq, mRNA stability assays, FTO/ALKBH5 knockdown, pathway reporters, and in vivo xenograft validation in BRCA-mutated ovarian cancer cells\",\n      \"pmids\": [\"30967398\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific m6A reader proteins that recognize FZD10 mRNA were not identified\",\n        \"Whether m6A-dependent FZD10 regulation operates in normal physiology remains untested\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that FZD10 protein and mRNA are packaged into exosomes and that exosomal transfer rescues proliferation in FZD10-depleted cancer cells established a paracrine mode of FZD10 signaling beyond canonical ligand–receptor interaction.\",\n      \"evidence\": \"Exosome isolation, FZD10 siRNA silencing, and exosome transfer/rescue assays in colorectal, gastric, hepatic, and cholangio cancer cells\",\n      \"pmids\": [\"31349740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of FZD10 sorting into exosomes is unknown\",\n        \"Whether exosomal FZD10 signals via the same β-catenin pathway as membrane-resident FZD10 was not tested\",\n        \"No in vivo validation of exosomal FZD10 transfer\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"In vivo loss- and gain-of-function studies in Xenopus/chick showed FZD10 is required for Wnt1-dependent dorsal neural tube patterning and that excess FZD10 inhibits Wnt1 in the absence of LRP6, extending FZD10's developmental role and co-receptor dependence to neural patterning.\",\n      \"evidence\": \"Morpholino knockdown and overexpression with Wnt1/Wnt3a/LRP6 epistasis in Xenopus and chick spinal cord\",\n      \"pmids\": [\"32531778\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether FZD10 functions redundantly with other Frizzled receptors in neural tube patterning not resolved\",\n        \"Downstream transcriptional targets in neural progenitors not identified\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placing FZD10 upstream of the ERK1/2/Ki-67 proliferative axis via exosome transfer experiments defined a non-canonical signaling output for exosomal FZD10 distinct from its established β-catenin role.\",\n      \"evidence\": \"FZD10 siRNA silencing and exosome rescue with pERK1/2 and Ki-67 readouts in colorectal and gastric cancer cells\",\n      \"pmids\": [\"34671555\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct interaction between FZD10 and ERK1/2 pathway components not demonstrated\",\n        \"Whether ERK1/2 activation by exosomal FZD10 requires LRP co-receptors is unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying a METTL3–m6A–FZD10–β-catenin/c-Jun positive feedback loop in liver cancer stem cells unified the epitranscriptomic and transcriptional regulation of FZD10, showing that FZD10-driven β-catenin/c-Jun transcriptionally activates METTL3, which in turn m6A-methylates FZD10 mRNA to sustain self-renewal and drug resistance.\",\n      \"evidence\": \"RIP, luciferase reporters, patient-derived tumor organoids and xenografts in hepatocellular carcinoma\",\n      \"pmids\": [\"36764493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the METTL3–FZD10 feedback loop operates in non-hepatic cancers is unknown\",\n        \"Which m6A reader(s) mediate the stabilization of FZD10 mRNA downstream of METTL3 not identified\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Validation of miR-26b-3p as a direct negative regulator of FZD10, with FZD10 loss increasing GSK3β phosphorylation and decreasing β-catenin to promote enteric glial cell apoptosis, connected microRNA-mediated FZD10 regulation to a non-cancer physiological context (intestinal motility).\",\n      \"evidence\": \"Luciferase reporter validation, FZD10 siRNA, flow cytometry, GSK3β/β-catenin Western blot, in vivo mouse model\",\n      \"pmids\": [\"37728849\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Other miRNAs targeting FZD10 not systematically surveyed\",\n        \"Whether miR-26b-3p–FZD10 axis operates in intestinal stem cells is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis of FZD10's selectivity for Gα13 over other Gα subunits, the identity of m6A readers that stabilize FZD10 mRNA, and the mechanism by which FZD10 is sorted into exosomes remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of FZD10 in complex with Gα13 or Wnt ligand\",\n        \"m6A reader proteins acting on FZD10 mRNA not identified\",\n        \"Mechanism of FZD10 sorting into exosomes completely undefined\",\n        \"Relative contribution of β-catenin vs. YAP/TAZ arms downstream of FZD10 in different tissues not quantified\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 5, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"WNT7B\",\n      \"WNT1\",\n      \"LRP5\",\n      \"LRP6\",\n      \"GNA13\",\n      \"METTL3\",\n      \"BRMS1L\",\n      \"HDAC1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}