{"gene":"FZD10","run_date":"2026-06-09T23:54:44","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 the co-receptor LRP5, but does not activate the non-canonical Wnt pathway through this interaction.","method":"Cell surface binding assay, cell transfection with canonical and non-canonical Wnt pathway reporters, biochemical binding analysis","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cell-surface binding demonstrated with functional pathway readouts in transfected cells; single lab but multiple orthogonal methods","pmids":["15923619"],"is_preprint":false},{"year":2008,"finding":"FZD10 protein is expressed on the cell surface of synovial sarcoma cells and is efficiently internalized following binding of an anti-FZD10 monoclonal antibody (MAb 92-13), demonstrating receptor-mediated internalization capacity.","method":"Cell binding assay, in vivo fluorescent imaging, radioisotope tracking, immunohistochemistry","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cell-surface binding and internalization demonstrated in vitro and in vivo with multiple methods; single lab","pmids":["18271942"],"is_preprint":false},{"year":2008,"finding":"In colorectal cancer tissues, FZD10-immunopositive cancer cells show significantly reduced nuclear accumulation of β-catenin compared to FZD10-negative cells, indicating an inverse correlation between FZD10 expression and canonical Wnt/β-catenin nuclear signaling.","method":"Immunohistochemistry on paired tumor samples (n=104 patients)","journal":"Cancer science","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — correlation observed by IHC across a large patient cohort but no direct mechanistic experiment manipulating FZD10; single method","pmids":["19134005"],"is_preprint":false},{"year":2014,"finding":"BRMS1L, a component of the Sin3A-HDAC co-repressor complex, epigenetically silences FZD10 transcription by recruiting HDAC1 and inducing histone H3K9 deacetylation at the FZD10 promoter, thereby inhibiting WNT3-FZD10-β-catenin signaling and breast cancer cell migration and invasion.","method":"ChIP assay (HDAC1 recruitment and H3K9 deacetylation at FZD10 promoter), RNAi knockdown, overexpression, in vivo xenograft metastasis assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal functional experiments (KD and OE), ChIP demonstrating direct promoter regulation, in vivo validation; multiple orthogonal methods","pmids":["25406648"],"is_preprint":false},{"year":2017,"finding":"FZD10 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 leads to Gα12/13-dependent cell changes; FZD10-mediated Gα13 activation drives YAP/TAZ transcriptional activity.","method":"Co-immunoprecipitation, dynamic mass redistribution (DMR) assay, YAP/TAZ transcriptional reporter assay, selective G protein co-expression experiments","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional DMR and reporter assays with multiple G protein comparators; single lab","pmids":["28126591"],"is_preprint":false},{"year":2019,"finding":"m6A modification of FZD10 mRNA (mediated by METTL3 and reversible by FTO/ALKBH5 demethylases) increases FZD10 mRNA stability, upregulates FZD10 protein, and activates the Wnt/β-catenin pathway to promote PARP inhibitor resistance in BRCA-mutated ovarian cancer cells.","method":"Global m6A profiling, m6A-seq, mRNA stability assay, RNAi knockdown of FZD10/FTO/ALKBH5, in vitro and in vivo xenograft PARPi sensitivity assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — m6A profiling with functional mRNA stability readout, loss-of-function experiments, and in vivo xenograft validation; multiple orthogonal methods","pmids":["30967398"],"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 FZD10 can be transferred to silenced recipient cells, restoring FZD10 levels and cell viability.","method":"Exosome isolation, Western blot, RT-PCR, siRNA silencing, cell viability assay with exosome re-addition","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — exosome isolation and functional rescue experiment; single lab with multiple cell lines","pmids":["31349740"],"is_preprint":false},{"year":2020,"finding":"FZD10 is required for Wnt1-induced ventral expansion of dorsal neural tube markers (Pax6, Pax7) in the developing spinal cord; FZD10 knockdown blocks Wnt1-mediated effects but not Wnt3a-mediated dorsalization; co-expression of the co-receptor Lrp6 dramatically enhances Wnt1/FZD10-dependent activation of dorsal markers.","method":"Morpholino knockdown in Xenopus/chick neural tube, gain-of-function overexpression, Lrp6 co-expression epistasis experiments, in situ hybridization for dorsal marker expression","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with KD and OE in developmental model organism; single lab with multiple functional readouts","pmids":["32531778"],"is_preprint":false},{"year":2020,"finding":"Exosomes derived from metastatic colon cancer cells deliver FZD10 protein to normal colonic epithelial cells (HCEC-1CT), inducing epithelial-mesenchymal transition (EMT) as evidenced by acquisition of mesenchymal markers and migration capability.","method":"Exosome isolation and transfer, immunofluorescence for EMT markers, migration assay (scratch test)","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single set of experiments; mechanism of FZD10-driven EMT not dissected beyond correlation with exosome FZD10 content","pmids":["32933173"],"is_preprint":false},{"year":2021,"finding":"Exosome-released FZD10 from colorectal and gastric cancer cells increases Ki-67 expression via phospho-ERK1/2 (MAPK3); FZD10 silencing reduces pERK1/2 and Ki-67, while addition of exogenous exosomes partially restores their expression.","method":"FZD10 siRNA silencing, Western blot for pERK1/2 and Ki-67, exosome re-addition rescue experiment","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method per readout; exosome-mediated pathway activation not mechanistically dissected","pmids":["34671555"],"is_preprint":false},{"year":2022,"finding":"Exosomal FZD10 derived from NSCLC cells promotes HUVEC tube formation and upregulates VEGFA and Ang-1 in vitro; this pro-angiogenic effect is dependent on activation of PI3K and ERK1/2 signaling pathways (but not YAP/TAZ), as demonstrated by FZD10 knockdown experiments.","method":"Exosome isolation, FZD10-siRNA knockdown, in vitro tube formation assay, ELISA (VEGFA, Ang-1), Western blot (PI3K, pERK1/2, YAP/TAZ)","journal":"Nan fang yi ke da xue xue bao","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, functional assay with pathway inhibition; exosomal FZD10 not directly shown to be the active species vs other exosomal cargo","pmids":["36210708"],"is_preprint":false},{"year":2023,"finding":"METTL3-dependent m6A methylation of FZD10 mRNA activates FZD10 expression in liver cancer stem cells (CSCs); FZD10 promotes CSC self-renewal and lenvatinib resistance via activation of β-catenin and YAP1; a FZD10-β-catenin/c-Jun axis transcriptionally activates METTL3, forming a positive feedback loop; and the FZD10/β-catenin/c-Jun/MEK/ERK axis determines lenvatinib response.","method":"RNA-seq, RNA-binding protein immunoprecipitation (RIP), luciferase reporter assay, in vitro and in vivo functional studies, patient-derived tumor organoids, patient-derived xenografts, AAV-mediated FZD10 knockdown","journal":"Gastroenterology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RIP, luciferase, in vivo PDX/organoid models, genetic manipulation) across multiple model systems; single lab but comprehensive","pmids":["36764493"],"is_preprint":false},{"year":2023,"finding":"miR-26b-3p directly targets FZD10 mRNA (validated by luciferase assay); FZD10 downregulation increases GSK3β phosphorylation, decreases β-catenin, and promotes enteric glial cell (EGC) apoptosis; miR-26b-3p antagomir relieves intestinal dysmotility in vivo by restoring FZD10/GSK3β/β-catenin signaling in EGCs.","method":"Luciferase reporter assay (miR-26b-3p/FZD10 targeting), siRNA knockdown of FZD10, Western blot (p-GSK3β, β-catenin), flow cytometry (apoptosis), in vivo mouse model (loperamide-induced constipation) with miR-26b-3p antagomir","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase validation of direct miRNA-target interaction plus in vivo epistasis rescue; single lab","pmids":["37728849"],"is_preprint":false},{"year":2026,"finding":"The transcription factor E2F2 directly regulates FZD10 expression; E2F2/FZD10 axis activates the Wnt/β-catenin pathway to sustain breast cancer stem cell-like properties induced by chronic arsenic exposure in mammary epithelial cells.","method":"Transcriptomic profiling, functional studies with E2F2 and FZD10 manipulation, Wnt/β-catenin pathway readouts","journal":"Food and chemical toxicology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab; abstract does not detail the method establishing direct E2F2 binding to FZD10 promoter (e.g., ChIP not explicitly described)","pmids":["41672294"],"is_preprint":false}],"current_model":"FZD10 is a Frizzled-family G protein-coupled receptor that functions as a cell-surface Wnt receptor: it binds Wnt7b in cooperation with the LRP5 co-receptor to activate canonical β-catenin signaling; it couples to Gα13 (but not other Gα subunits) to drive YAP/TAZ transcriptional activity; its transcription is epigenetically silenced by the BRMS1L/HDAC1 complex via H3K9 deacetylation, and its mRNA stability is post-transcriptionally enhanced by METTL3-dependent m6A methylation (with FTO/ALKBH5 as erasers), creating a FZD10/β-catenin/c-Jun/METTL3 positive feedback loop; in development, FZD10 specifically transduces Wnt1 (but not Wnt3a) signaling in the dorsal neural tube in an LRP6-dependent manner; and FZD10 protein is packaged into exosomes and can be transferred to recipient cells to activate ERK1/2 and PI3K signaling."},"narrative":{"mechanistic_narrative":"FZD10 is a Frizzled-family cell-surface Wnt receptor that transduces canonical Wnt/β-catenin signaling and governs cell migration, stemness, and developmental patterning [PMID:15923619, PMID:25406648]. At the membrane it binds Wnt7b directly and, in cooperation with the co-receptor LRP5, cooperatively activates canonical β-catenin signaling rather than the non-canonical pathway [PMID:15923619], and it engages the heterotrimeric G protein Gα13 selectively over other Gα subunits to drive YAP/TAZ transcriptional activity upon Wnt stimulation [PMID:28126591]. FZD10 expression is set by layered regulation: transcriptionally it is silenced by the BRMS1L–HDAC1 co-repressor complex through H3K9 deacetylation at its promoter, restraining Wnt3–FZD10–β-catenin-driven breast cancer migration and invasion [PMID:25406648]; post-transcriptionally its mRNA is stabilized by METTL3-dependent m6A methylation (reversed by FTO/ALKBH5) and destabilized by miR-26b-3p [PMID:30967398, PMID:37728849]. In cancer this regulation feeds a FZD10/β-catenin/c-Jun/METTL3 positive-feedback loop that sustains liver cancer stem-cell self-renewal and drug resistance via β-catenin and YAP1 [PMID:36764493], and m6A-driven FZD10 upregulation confers PARP-inhibitor resistance in BRCA-mutated ovarian cancer [PMID:30967398]. In development, FZD10 specifically transduces Wnt1 (but not Wnt3a) signaling to expand dorsal neural tube markers in an LRP6-dependent manner [PMID:32531778]. FZD10 is internalized upon antibody binding [PMID:18271942] and is packaged into exosomes that transfer the receptor to recipient cells, where it activates ERK1/2 and PI3K signaling [PMID:31349740, PMID:34671555].","teleology":[{"year":2005,"claim":"Established FZD10 as a functional Wnt receptor by showing which ligand it binds and which signaling branch it activates, defining its molecular identity.","evidence":"Cell-surface binding assay and canonical/non-canonical Wnt reporters in transfected cells","pmids":["15923619"],"confidence":"Medium","gaps":["Co-receptor requirement (LRP5) shown but structural basis of ternary complex undefined","Whether other Wnt ligands engage FZD10 not addressed"]},{"year":2008,"claim":"Demonstrated that surface FZD10 is internalized upon ligand/antibody binding, establishing receptor-mediated internalization and a route for targeting.","evidence":"Antibody (MAb 92-13) binding and internalization assays in synovial sarcoma cells, in vivo imaging","pmids":["18271942"],"confidence":"Medium","gaps":["Internalization machinery and trafficking fate not dissected","Link between internalization and signaling output unaddressed"]},{"year":2009,"claim":"Observed in patient tissue an inverse correlation between FZD10 expression and nuclear β-catenin, raising the question of context-dependent signaling output.","evidence":"Immunohistochemistry on paired colorectal tumor samples (n=104)","pmids":["19134005"],"confidence":"Low","gaps":["Correlative only — no manipulation of FZD10","Mechanism of the inverse relationship unknown"]},{"year":2014,"claim":"Identified transcriptional silencing of FZD10 by the BRMS1L–HDAC1 co-repressor via H3K9 deacetylation, linking epigenetic control of the receptor to Wnt-driven metastasis.","evidence":"ChIP, RNAi knockdown, overexpression, and in vivo xenograft metastasis assays","pmids":["25406648"],"confidence":"High","gaps":["Upstream signals that engage BRMS1L at the FZD10 promoter unknown","Generality across non-breast tissues not tested"]},{"year":2017,"claim":"Defined the transducer downstream of FZD10 by showing selective coupling to Gα13 and resulting YAP/TAZ activation, extending FZD10 beyond β-catenin.","evidence":"Co-IP, dynamic mass redistribution assay, YAP/TAZ reporter, selective G protein co-expression","pmids":["28126591"],"confidence":"Medium","gaps":["Single-lab Co-IP without reciprocal/structural validation","How Gα13 and β-catenin outputs are partitioned not resolved"]},{"year":2019,"claim":"Showed FZD10 mRNA is post-transcriptionally controlled by m6A methylation, linking RNA modification to FZD10 protein levels and PARP-inhibitor resistance.","evidence":"m6A-seq, mRNA stability assay, RNAi of FZD10/FTO/ALKBH5, in vivo PARPi sensitivity xenografts","pmids":["30967398"],"confidence":"High","gaps":["m6A reader mediating stabilization not identified","Direct site mapping on FZD10 transcript not detailed"]},{"year":2019,"claim":"Revealed that FZD10 protein and mRNA are exported in exosomes and functionally transferred between cells, proposing a non-cell-autonomous mode of FZD10 action.","evidence":"Exosome isolation, Western blot, RT-PCR, siRNA silencing, viability rescue by exosome re-addition across multiple cancer lines","pmids":["31349740"],"confidence":"Medium","gaps":["Mechanism of FZD10 sorting into exosomes unknown","Whether transferred FZD10 acts as a functional receptor vs cargo unclear"]},{"year":2020,"claim":"Assigned FZD10 a developmental role by showing it specifically transduces Wnt1 (not Wnt3a) signaling in the dorsal neural tube in an LRP6-dependent manner.","evidence":"Morpholino knockdown and overexpression in Xenopus/chick neural tube, Lrp6 epistasis, in situ hybridization","pmids":["32531778"],"confidence":"Medium","gaps":["Basis of Wnt1 vs Wnt3a ligand selectivity not defined","Mammalian neural-tube relevance not directly tested"]},{"year":2021,"claim":"Linked exosomal FZD10 to proliferative signaling, showing it activates ERK1/2 and Ki-67 in recipient cancer cells.","evidence":"FZD10 siRNA silencing, Western blot for pERK1/2 and Ki-67, exosome re-addition rescue","pmids":["34671555"],"confidence":"Low","gaps":["Exosomal FZD10 not isolated as the active species vs other cargo","Mechanism connecting FZD10 to ERK1/2 not dissected"]},{"year":2022,"claim":"Extended exosomal FZD10 to angiogenesis, showing PI3K/ERK1/2-dependent (not YAP/TAZ) pro-angiogenic effects on endothelial cells.","evidence":"Exosome isolation, FZD10-siRNA knockdown, tube formation assay, ELISA, Western blot","pmids":["36210708"],"confidence":"Low","gaps":["Exosomal FZD10 not directly shown to be the active species","How FZD10 selects PI3K/ERK over YAP/TAZ in this context unknown"]},{"year":2023,"claim":"Integrated transcriptional, m6A, and downstream outputs into a FZD10/β-catenin/c-Jun/METTL3 feedback loop driving liver cancer stem-cell self-renewal and lenvatinib resistance.","evidence":"RNA-seq, RIP, luciferase, patient-derived organoids/xenografts, AAV-mediated FZD10 knockdown","pmids":["36764493"],"confidence":"High","gaps":["How c-Jun engages the METTL3 promoter mechanistically not fully resolved","Generality of the loop beyond liver CSCs untested"]},{"year":2023,"claim":"Identified miR-26b-3p as a direct destabilizer of FZD10 mRNA and tied FZD10/GSK3β/β-catenin signaling to enteric glial survival and intestinal motility.","evidence":"Luciferase target validation, FZD10 siRNA, Western blot, apoptosis flow cytometry, in vivo antagomir rescue","pmids":["37728849"],"confidence":"Medium","gaps":["Single-lab; broader miRNA network on FZD10 not mapped","Receptor-level signaling events upstream of GSK3β in EGCs not detailed"]},{"year":2026,"claim":"Implicated the transcription factor E2F2 as an activator of FZD10 expression sustaining arsenic-induced breast cancer stem-like properties via Wnt/β-catenin.","evidence":"Transcriptomic profiling and E2F2/FZD10 manipulation with Wnt/β-catenin readouts","pmids":["41672294"],"confidence":"Low","gaps":["Direct E2F2 binding to the FZD10 promoter (e.g., ChIP) not demonstrated","Single lab, single carcinogen context"]},{"year":null,"claim":"How FZD10's distinct outputs (canonical β-catenin, Gα13–YAP/TAZ, and exosomal ERK/PI3K) are selected in a given cell, and the structural basis of its Wnt-ligand and co-receptor selectivity, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of FZD10–Wnt–LRP complexes","Determinants partitioning β-catenin vs YAP/TAZ vs exosomal signaling unknown","Mechanism of FZD10 sorting into exosomes uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,4]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[6,9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,11]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,5,11]}],"complexes":[],"partners":["WNT7B","LRP5","GNA13","LRP6","WNT1"],"other_free_text":[]}},"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 Up-Regulation of FZD10 Regulates Liver Cancer Stem Cells' Properties and Lenvatinib Resistance Through WNT/β-Catenin and Hippo Signaling Pathways.","date":"2023","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/36764493","citation_count":235,"is_preprint":false},{"pmid":"15923619","id":"PMC_15923619","title":"Wnt7b activates canonical signaling in epithelial and vascular smooth muscle cells through interactions with Fzd1, Fzd10, and LRP5.","date":"2005","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15923619","citation_count":159,"is_preprint":false},{"pmid":"30967398","id":"PMC_30967398","title":"N6-Methylation of Adenosine of FZD10 mRNA Contributes to PARP Inhibitor Resistance.","date":"2019","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/30967398","citation_count":146,"is_preprint":false},{"pmid":"25406648","id":"PMC_25406648","title":"BRMS1L suppresses breast cancer metastasis by inducing epigenetic silence of 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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":15898,"output_tokens":3707,"usd":0.05165,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11331,"output_tokens":4950,"usd":0.090203,"stage2_stop_reason":"end_turn"},"total_usd":0.141853,"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\": 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 the co-receptor LRP5, but does not activate the non-canonical Wnt pathway through this interaction.\",\n      \"method\": \"Cell surface binding assay, cell transfection with canonical and non-canonical Wnt pathway reporters, biochemical binding analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cell-surface binding demonstrated with functional pathway readouts in transfected cells; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"15923619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"FZD10 protein is expressed on the cell surface of synovial sarcoma cells and is efficiently internalized following binding of an anti-FZD10 monoclonal antibody (MAb 92-13), demonstrating receptor-mediated internalization capacity.\",\n      \"method\": \"Cell binding assay, in vivo fluorescent imaging, radioisotope tracking, immunohistochemistry\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cell-surface binding and internalization demonstrated in vitro and in vivo with multiple methods; single lab\",\n      \"pmids\": [\"18271942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In colorectal cancer tissues, FZD10-immunopositive cancer cells show significantly reduced nuclear accumulation of β-catenin compared to FZD10-negative cells, indicating an inverse correlation between FZD10 expression and canonical Wnt/β-catenin nuclear signaling.\",\n      \"method\": \"Immunohistochemistry on paired tumor samples (n=104 patients)\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — correlation observed by IHC across a large patient cohort but no direct mechanistic experiment manipulating FZD10; single method\",\n      \"pmids\": [\"19134005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BRMS1L, a component of the Sin3A-HDAC co-repressor complex, epigenetically silences FZD10 transcription by recruiting HDAC1 and inducing histone H3K9 deacetylation at the FZD10 promoter, thereby inhibiting WNT3-FZD10-β-catenin signaling and breast cancer cell migration and invasion.\",\n      \"method\": \"ChIP assay (HDAC1 recruitment and H3K9 deacetylation at FZD10 promoter), RNAi knockdown, overexpression, in vivo xenograft metastasis assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal functional experiments (KD and OE), ChIP demonstrating direct promoter regulation, in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"25406648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FZD10 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 leads to Gα12/13-dependent cell changes; FZD10-mediated Gα13 activation drives YAP/TAZ transcriptional activity.\",\n      \"method\": \"Co-immunoprecipitation, dynamic mass redistribution (DMR) assay, YAP/TAZ transcriptional reporter assay, selective G protein co-expression experiments\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional DMR and reporter assays with multiple G protein comparators; single lab\",\n      \"pmids\": [\"28126591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"m6A modification of FZD10 mRNA (mediated by METTL3 and reversible by FTO/ALKBH5 demethylases) increases FZD10 mRNA stability, upregulates FZD10 protein, and activates the Wnt/β-catenin pathway to promote PARP inhibitor resistance in BRCA-mutated ovarian cancer cells.\",\n      \"method\": \"Global m6A profiling, m6A-seq, mRNA stability assay, RNAi knockdown of FZD10/FTO/ALKBH5, in vitro and in vivo xenograft PARPi sensitivity assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — m6A profiling with functional mRNA stability readout, loss-of-function experiments, and in vivo xenograft validation; multiple orthogonal methods\",\n      \"pmids\": [\"30967398\"],\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 FZD10 can be transferred to silenced recipient cells, restoring FZD10 levels and cell viability.\",\n      \"method\": \"Exosome isolation, Western blot, RT-PCR, siRNA silencing, cell viability assay with exosome re-addition\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — exosome isolation and functional rescue experiment; single lab with multiple cell lines\",\n      \"pmids\": [\"31349740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FZD10 is required for Wnt1-induced ventral expansion of dorsal neural tube markers (Pax6, Pax7) in the developing spinal cord; FZD10 knockdown blocks Wnt1-mediated effects but not Wnt3a-mediated dorsalization; co-expression of the co-receptor Lrp6 dramatically enhances Wnt1/FZD10-dependent activation of dorsal markers.\",\n      \"method\": \"Morpholino knockdown in Xenopus/chick neural tube, gain-of-function overexpression, Lrp6 co-expression epistasis experiments, in situ hybridization for dorsal marker expression\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with KD and OE in developmental model organism; single lab with multiple functional readouts\",\n      \"pmids\": [\"32531778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Exosomes derived from metastatic colon cancer cells deliver FZD10 protein to normal colonic epithelial cells (HCEC-1CT), inducing epithelial-mesenchymal transition (EMT) as evidenced by acquisition of mesenchymal markers and migration capability.\",\n      \"method\": \"Exosome isolation and transfer, immunofluorescence for EMT markers, migration assay (scratch test)\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single set of experiments; mechanism of FZD10-driven EMT not dissected beyond correlation with exosome FZD10 content\",\n      \"pmids\": [\"32933173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Exosome-released FZD10 from colorectal and gastric cancer cells increases Ki-67 expression via phospho-ERK1/2 (MAPK3); FZD10 silencing reduces pERK1/2 and Ki-67, while addition of exogenous exosomes partially restores their expression.\",\n      \"method\": \"FZD10 siRNA silencing, Western blot for pERK1/2 and Ki-67, exosome re-addition rescue experiment\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method per readout; exosome-mediated pathway activation not mechanistically dissected\",\n      \"pmids\": [\"34671555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Exosomal FZD10 derived from NSCLC cells promotes HUVEC tube formation and upregulates VEGFA and Ang-1 in vitro; this pro-angiogenic effect is dependent on activation of PI3K and ERK1/2 signaling pathways (but not YAP/TAZ), as demonstrated by FZD10 knockdown experiments.\",\n      \"method\": \"Exosome isolation, FZD10-siRNA knockdown, in vitro tube formation assay, ELISA (VEGFA, Ang-1), Western blot (PI3K, pERK1/2, YAP/TAZ)\",\n      \"journal\": \"Nan fang yi ke da xue xue bao\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, functional assay with pathway inhibition; exosomal FZD10 not directly shown to be the active species vs other exosomal cargo\",\n      \"pmids\": [\"36210708\"],\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 (CSCs); FZD10 promotes CSC self-renewal and lenvatinib resistance via activation of β-catenin and YAP1; a FZD10-β-catenin/c-Jun axis transcriptionally activates METTL3, forming a positive feedback loop; and the FZD10/β-catenin/c-Jun/MEK/ERK axis determines lenvatinib response.\",\n      \"method\": \"RNA-seq, RNA-binding protein immunoprecipitation (RIP), luciferase reporter assay, in vitro and in vivo functional studies, patient-derived tumor organoids, patient-derived xenografts, AAV-mediated FZD10 knockdown\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RIP, luciferase, in vivo PDX/organoid models, genetic manipulation) across multiple model systems; single lab but comprehensive\",\n      \"pmids\": [\"36764493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"miR-26b-3p directly targets FZD10 mRNA (validated by luciferase assay); FZD10 downregulation increases GSK3β phosphorylation, decreases β-catenin, and promotes enteric glial cell (EGC) apoptosis; miR-26b-3p antagomir relieves intestinal dysmotility in vivo by restoring FZD10/GSK3β/β-catenin signaling in EGCs.\",\n      \"method\": \"Luciferase reporter assay (miR-26b-3p/FZD10 targeting), siRNA knockdown of FZD10, Western blot (p-GSK3β, β-catenin), flow cytometry (apoptosis), in vivo mouse model (loperamide-induced constipation) with miR-26b-3p antagomir\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase validation of direct miRNA-target interaction plus in vivo epistasis rescue; single lab\",\n      \"pmids\": [\"37728849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"The transcription factor E2F2 directly regulates FZD10 expression; E2F2/FZD10 axis activates the Wnt/β-catenin pathway to sustain breast cancer stem cell-like properties induced by chronic arsenic exposure in mammary epithelial cells.\",\n      \"method\": \"Transcriptomic profiling, functional studies with E2F2 and FZD10 manipulation, Wnt/β-catenin pathway readouts\",\n      \"journal\": \"Food and chemical toxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab; abstract does not detail the method establishing direct E2F2 binding to FZD10 promoter (e.g., ChIP not explicitly described)\",\n      \"pmids\": [\"41672294\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FZD10 is a Frizzled-family G protein-coupled receptor that functions as a cell-surface Wnt receptor: it binds Wnt7b in cooperation with the LRP5 co-receptor to activate canonical β-catenin signaling; it couples to Gα13 (but not other Gα subunits) to drive YAP/TAZ transcriptional activity; its transcription is epigenetically silenced by the BRMS1L/HDAC1 complex via H3K9 deacetylation, and its mRNA stability is post-transcriptionally enhanced by METTL3-dependent m6A methylation (with FTO/ALKBH5 as erasers), creating a FZD10/β-catenin/c-Jun/METTL3 positive feedback loop; in development, FZD10 specifically transduces Wnt1 (but not Wnt3a) signaling in the dorsal neural tube in an LRP6-dependent manner; and FZD10 protein is packaged into exosomes and can be transferred to recipient cells to activate ERK1/2 and PI3K signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FZD10 is a Frizzled-family cell-surface Wnt receptor that transduces canonical Wnt/\\u03b2-catenin signaling and governs cell migration, stemness, and developmental patterning [#0, #3]. At the membrane it binds Wnt7b directly and, in cooperation with the co-receptor LRP5, cooperatively activates canonical \\u03b2-catenin signaling rather than the non-canonical pathway [#0], and it engages the heterotrimeric G protein G\\u03b113 selectively over other G\\u03b1 subunits to drive YAP/TAZ transcriptional activity upon Wnt stimulation [#4]. FZD10 expression is set by layered regulation: transcriptionally it is silenced by the BRMS1L\\u2013HDAC1 co-repressor complex through H3K9 deacetylation at its promoter, thereby restraining Wnt3\\u2013FZD10\\u2013\\u03b2-catenin-driven breast cancer migration and invasion [#3], and activated by the transcription factor E2F2 [#13]; post-transcriptionally its mRNA is stabilized by METTL3-dependent m6A methylation (reversed by FTO/ALKBH5) and destabilized by miR-26b-3p [#5, #12]. In cancer this regulation feeds a FZD10/\\u03b2-catenin/c-Jun/METTL3 positive-feedback loop that sustains liver cancer stem-cell self-renewal and drug resistance via \\u03b2-catenin and YAP1 [#11], and m6A-driven FZD10 upregulation confers PARP-inhibitor resistance in BRCA-mutated ovarian cancer [#5]. In development, FZD10 specifically transduces Wnt1 (but not Wnt3a) signaling to expand dorsal neural tube markers in an LRP6-dependent manner [#7]. FZD10 is internalized upon antibody binding [#1] and is also packaged into exosomes that transfer the receptor to recipient cells, where it activates ERK1/2 and PI3K signaling [#6, #10].\"\n}\n\nI'll provide the complete JSON:\n\n{\n  \"mechanistic_narrative\": \"FZD10 is a Frizzled-family cell-surface Wnt receptor that transduces canonical Wnt/\\u03b2-catenin signaling and governs cell migration, stemness, and developmental patterning [#0, #3]. At the membrane it binds Wnt7b directly and, in cooperation with the co-receptor LRP5, cooperatively activates canonical \\u03b2-catenin signaling rather than the non-canonical pathway [#0], and it engages the heterotrimeric G protein G\\u03b113 selectively over other G\\u03b1 subunits to drive YAP/TAZ transcriptional activity upon Wnt stimulation [#4]. FZD10 expression is set by layered regulation: transcriptionally it is silenced by the BRMS1L\\u2013HDAC1 co-repressor complex through H3K9 deacetylation at its promoter, restraining Wnt3\\u2013FZD10\\u2013\\u03b2-catenin-driven breast cancer migration and invasion [#3]; post-transcriptionally its mRNA is stabilized by METTL3-dependent m6A methylation (reversed by FTO/ALKBH5) and destabilized by miR-26b-3p [#5, #12]. In cancer this regulation feeds a FZD10/\\u03b2-catenin/c-Jun/METTL3 positive-feedback loop that sustains liver cancer stem-cell self-renewal and drug resistance via \\u03b2-catenin and YAP1 [#11], and m6A-driven FZD10 upregulation confers PARP-inhibitor resistance in BRCA-mutated ovarian cancer [#5]. In development, FZD10 specifically transduces Wnt1 (but not Wnt3a) signaling to expand dorsal neural tube markers in an LRP6-dependent manner [#7]. FZD10 is internalized upon antibody binding [#1] and is packaged into exosomes that transfer the receptor to recipient cells, where it activates ERK1/2 and PI3K signaling [#6, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established FZD10 as a functional Wnt receptor by showing which ligand it binds and which signaling branch it activates, defining its molecular identity.\",\n      \"evidence\": \"Cell-surface binding assay and canonical/non-canonical Wnt reporters in transfected cells\",\n      \"pmids\": [\"15923619\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-receptor requirement (LRP5) shown but structural basis of ternary complex undefined\", \"Whether other Wnt ligands engage FZD10 not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that surface FZD10 is internalized upon ligand/antibody binding, establishing receptor-mediated internalization and a route for targeting.\",\n      \"evidence\": \"Antibody (MAb 92-13) binding and internalization assays in synovial sarcoma cells, in vivo imaging\",\n      \"pmids\": [\"18271942\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Internalization machinery and trafficking fate not dissected\", \"Link between internalization and signaling output unaddressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Observed in patient tissue an inverse correlation between FZD10 expression and nuclear \\u03b2-catenin, raising the question of context-dependent signaling output.\",\n      \"evidence\": \"Immunohistochemistry on paired colorectal tumor samples (n=104)\",\n      \"pmids\": [\"19134005\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Correlative only \\u2014 no manipulation of FZD10\", \"Mechanism of the inverse relationship unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified transcriptional silencing of FZD10 by the BRMS1L\\u2013HDAC1 co-repressor via H3K9 deacetylation, linking epigenetic control of the receptor to Wnt-driven metastasis.\",\n      \"evidence\": \"ChIP, RNAi knockdown, overexpression, and in vivo xenograft metastasis assays\",\n      \"pmids\": [\"25406648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals that engage BRMS1L at the FZD10 promoter unknown\", \"Generality across non-breast tissues not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the transducer downstream of FZD10 by showing selective coupling to G\\u03b113 and resulting YAP/TAZ activation, extending FZD10 beyond \\u03b2-catenin.\",\n      \"evidence\": \"Co-IP, dynamic mass redistribution assay, YAP/TAZ reporter, selective G protein co-expression\",\n      \"pmids\": [\"28126591\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab Co-IP without reciprocal/structural validation\", \"How G\\u03b113 and \\u03b2-catenin outputs are partitioned not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed FZD10 mRNA is post-transcriptionally controlled by m6A methylation, linking RNA modification to FZD10 protein levels and PARP-inhibitor resistance.\",\n      \"evidence\": \"m6A-seq, mRNA stability assay, RNAi of FZD10/FTO/ALKBH5, in vivo PARPi sensitivity xenografts\",\n      \"pmids\": [\"30967398\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"m6A reader mediating stabilization not identified\", \"Direct site mapping on FZD10 transcript not detailed\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed that FZD10 protein and mRNA are exported in exosomes and functionally transferred between cells, proposing a non-cell-autonomous mode of FZD10 action.\",\n      \"evidence\": \"Exosome isolation, Western blot, RT-PCR, siRNA silencing, viability rescue by exosome re-addition across multiple cancer lines\",\n      \"pmids\": [\"31349740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of FZD10 sorting into exosomes unknown\", \"Whether transferred FZD10 acts as a functional receptor vs cargo unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Assigned FZD10 a developmental role by showing it specifically transduces Wnt1 (not Wnt3a) signaling in the dorsal neural tube in an LRP6-dependent manner.\",\n      \"evidence\": \"Morpholino knockdown and overexpression in Xenopus/chick neural tube, Lrp6 epistasis, in situ hybridization\",\n      \"pmids\": [\"32531778\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis of Wnt1 vs Wnt3a ligand selectivity not defined\", \"Mammalian neural-tube relevance not directly tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked exosomal FZD10 to proliferative signaling, showing it activates ERK1/2 and Ki-67 in recipient cancer cells.\",\n      \"evidence\": \"FZD10 siRNA silencing, Western blot for pERK1/2 and Ki-67, exosome re-addition rescue\",\n      \"pmids\": [\"34671555\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Exosomal FZD10 not isolated as the active species vs other cargo\", \"Mechanism connecting FZD10 to ERK1/2 not dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended exosomal FZD10 to angiogenesis, showing PI3K/ERK1/2-dependent (not YAP/TAZ) pro-angiogenic effects on endothelial cells.\",\n      \"evidence\": \"Exosome isolation, FZD10-siRNA knockdown, tube formation assay, ELISA, Western blot\",\n      \"pmids\": [\"36210708\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Exosomal FZD10 not directly shown to be the active species\", \"How FZD10 selects PI3K/ERK over YAP/TAZ in this context unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Integrated transcriptional, m6A, and downstream outputs into a FZD10/\\u03b2-catenin/c-Jun/METTL3 feedback loop driving liver cancer stem-cell self-renewal and lenvatinib resistance.\",\n      \"evidence\": \"RNA-seq, RIP, luciferase, patient-derived organoids/xenografts, AAV-mediated FZD10 knockdown\",\n      \"pmids\": [\"36764493\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How c-Jun engages the METTL3 promoter mechanistically not fully resolved\", \"Generality of the loop beyond liver CSCs untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified miR-26b-3p as a direct destabilizer of FZD10 mRNA and tied FZD10/GSK3\\u03b2/\\u03b2-catenin signaling to enteric glial survival and intestinal motility.\",\n      \"evidence\": \"Luciferase target validation, FZD10 siRNA, Western blot, apoptosis flow cytometry, in vivo antagomir rescue\",\n      \"pmids\": [\"37728849\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab; broader miRNA network on FZD10 not mapped\", \"Receptor-level signaling events upstream of GSK3\\u03b2 in EGCs not detailed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Implicated the transcription factor E2F2 as an activator of FZD10 expression sustaining arsenic-induced breast cancer stem-like properties via Wnt/\\u03b2-catenin.\",\n      \"evidence\": \"Transcriptomic profiling and E2F2/FZD10 manipulation with Wnt/\\u03b2-catenin readouts\",\n      \"pmids\": [\"41672294\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Direct E2F2 binding to the FZD10 promoter (e.g., ChIP) not demonstrated\", \"Single lab, single carcinogen context\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FZD10's distinct outputs (canonical \\u03b2-catenin, G\\u03b113\\u2013YAP/TAZ, and exosomal ERK/PI3K) are selected in a given cell, and the structural basis of its Wnt-ligand and co-receptor selectivity, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of FZD10\\u2013Wnt\\u2013LRP complexes\", \"Determinants partitioning \\u03b2-catenin vs YAP/TAZ vs exosomal signaling unknown\", \"Mechanism of FZD10 sorting into exosomes uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [6, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 11]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 5, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"WNT7B\", \"LRP5\", \"GNA13\", \"LRP6\", \"WNT1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}