{"gene":"FZD1","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2005,"finding":"Wnt7b binds to FZD1 on the cell surface and cooperatively activates canonical Wnt signaling together with FZD1 and LRP5 co-receptor; this interaction was demonstrated by biochemical binding assays and cell transfection studies showing activation of canonical (but not non-canonical) Wnt pathway.","method":"Cell surface binding assay, cell transfection/reporter assay (canonical vs. non-canonical Wnt pathway readouts)","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical binding and functional reporter assay in cell transfection, single lab, two orthogonal methods","pmids":["15923619"],"is_preprint":false},{"year":2004,"finding":"LRP1 (via its minireceptor mLRP4T100) interacts with HFz1 (FZD1) and represses canonical Wnt-3a signaling, not by enhancing FZD1 internalization/degradation but by sequestering FZD1 and disrupting the FZD1-LRP6 co-receptor complex formation; endocytosis-defective LRP1 mutants retained the inhibitory effect.","method":"Co-immunoprecipitation, cell transfection with reporter assay, endocytosis-defective mutant analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding experiments with functional reporter and mechanistic mutant analysis, single lab, multiple orthogonal approaches","pmids":["14739301"],"is_preprint":false},{"year":2009,"finding":"FZD1 upregulation mediates sustained activation of the Wnt/β-catenin pathway in neuroblastoma chemoresistant cells, as shown by nuclear β-catenin translocation and target gene transactivation; shRNAmir-mediated FZD1 silencing decreased MDR1 expression and restored drug sensitivity.","method":"shRNAmir knockdown, nuclear β-catenin localization assay, target gene expression analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular and cellular phenotype, single lab, multiple readouts","pmids":["19421142"],"is_preprint":false},{"year":2012,"finding":"FZD1 silencing in multidrug-resistant breast cancer cells (MCF-7/ADM) decreased MDR1/P-glycoprotein expression, reduced cytoplasmic and nuclear β-catenin levels, and restored chemosensitivity, establishing FZD1 as a regulator of MDR1 through the Wnt/β-catenin pathway.","method":"siRNA knockdown, Western blot for β-catenin (cytoplasmic/nuclear fractionation), drug sensitivity assay","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple molecular readouts, single lab","pmids":["22484497"],"is_preprint":false},{"year":2014,"finding":"FZD1 activates a PKCδ/AP-1 signaling pathway in multidrug-resistant MES-SA/Dx5 cells; FZD1 inhibition (curcumin or shRNA knockdown) reduced PKCδ activity, decreased AP-1 target gene expression (HGF, EGR1), and reduced ABCB1/P-gp expression and drug efflux.","method":"shRNA knockdown, pharmacological inhibition (Rottlerin, curcumin), mRNA/protein expression analysis, drug pump-out assay","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with multiple molecular and functional readouts, single lab","pmids":["24814288"],"is_preprint":false},{"year":2012,"finding":"FZD1 is required for normal female fertility in mice; Fzd1-null females showed subfertility with blunted expression of oocyte and cumulus cell genes (e.g., Zp3, Ptgs2, Ptx3) in response to the ovulatory signal, but FZD1 is unlikely to be the sole ovarian WNT4 receptor since Fzd1-null mice lack WNT4 target gene expression changes.","method":"Gene targeting (Fzd1-null mice), microarray, gene expression analysis of cumulus-oocyte complexes","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO mouse model with specific fertility phenotype and gene expression readouts, genetic epistasis with Wnt4","pmids":["22954793"],"is_preprint":false},{"year":2009,"finding":"A promoter polymorphism (rs2232158) in FZD1 creates an Egr1 transcription factor binding site; the minor C allele shows higher Egr1 binding affinity and greater FZD1 promoter activity in osteoblast-like cells (MG63, SaOS-2), establishing a cis-regulatory mechanism for FZD1 transcriptional control.","method":"Promoter reporter assay, electrophoretic mobility shift assay (EMSA) for Egr1 binding","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter assay plus EMSA in two cell lines, single lab","pmids":["18715140"],"is_preprint":false},{"year":2010,"finding":"The rs2232157 polymorphism in the FZD1 promoter creates an E2F1 binding site with allele-specific nuclear protein complex binding; the TC haplotype (rs2232157 T + rs2232158 C) confers ~3-fold higher FZD1 promoter activity in human osteoblast-like cells compared to the common GG haplotype.","method":"Promoter reporter assay (transient transfection), EMSA, bioinformatics","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter assay in two cell lines plus EMSA, single lab, consistent with prior study","pmids":["20051274"],"is_preprint":false},{"year":2021,"finding":"MBD2a (a splice variant of MBD2) binds to the FZD1 promoter CpG islands to activate FZD1 expression under hypoxia, promoting epithelial-to-mesenchymal transition and breast cancer metastasis; MBD2c competes with MBD2a for FZD1 promoter binding and suppresses this activation.","method":"Promoter binding assay (CpG island binding), alternative splicing manipulation, EMT and metastasis functional assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding and competitive mechanism established, single lab, multiple functional readouts","pmids":["33402389"],"is_preprint":false},{"year":2016,"finding":"miR-135b directly targets the 3'-UTR of FZD1, as confirmed by dual-luciferase reporter assay; increased miR-135b suppressed FZD1 expression and reversed cisplatin resistance in lung cancer cells.","method":"Dual-luciferase reporter assay (3'-UTR), miR-135b mimic transfection, RT-qPCR","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'-UTR targeting confirmed by reporter assay with functional consequence, single lab","pmids":["27643554"],"is_preprint":false},{"year":2021,"finding":"RBM38 RNA-binding protein directly binds FZD1 mRNA and enhances its stability, as shown by RIP-qPCR and actinomycin D mRNA stability assays; RBM38 overexpression promoted HL-60 cell proliferation via FZD1 mRNA stabilization.","method":"RNA immunoprecipitation (RIP-qPCR), actinomycin D mRNA decay assay, lentiviral overexpression/knockdown","journal":"Zhongguo shi yan xue ye xue za zhi","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA binding and mRNA stability shown by two orthogonal methods, single lab","pmids":["34893109"],"is_preprint":false},{"year":2025,"finding":"IGF2BP3 directly binds to the 3'-UTR of FZD1 mRNA in an m6A-dependent manner (facilitated by RBM15-mediated m6A methylation), stabilizing FZD1 transcripts and promoting FZD1/FZD7 heterodimerization, which activates β-catenin nuclear translocation and maintains cancer stem cell properties and carboplatin resistance in TNBC.","method":"RNA binding assay, m6A modification analysis, knockdown experiments (IGF2BP3, RBM15), β-catenin nuclear translocation assay, FACS","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct m6A-dependent RNA binding and functional consequences established, single lab, multiple orthogonal methods","pmids":["40706743"],"is_preprint":false},{"year":2026,"finding":"SIRT2 deacetylates H3K27 at the FZD1 promoter region, reducing FZD1 transcriptional expression and blocking Wnt/β-catenin pathway activity; FZD1 overexpression rescued the inhibitory effects of SIRT2 on tongue cancer cell proliferation, invasion, and migration.","method":"ChIP assay (H3K27ac enrichment at FZD1 promoter), Western blot, rescue experiment with FZD1 overexpression, in vivo xenograft model","journal":"Toxicology and applied pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for histone modification at FZD1 promoter plus rescue experiments in vitro and in vivo, single lab","pmids":["41485500"],"is_preprint":false},{"year":2026,"finding":"SULF1 directly binds FZD1 and facilitates Wnt7B-FZD1 complex formation; JOSD1 deubiquitinase stabilizes SULF1, which in turn activates Wnt/β-catenin signaling through FZD1, driving gastric cancer progression.","method":"Co-immunoprecipitation, ubiquitination assay, rescue experiments","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP demonstrating SULF1-FZD1 interaction and Wnt7B-FZD1 complex formation with functional rescue, single lab","pmids":["42140034"],"is_preprint":false},{"year":2026,"finding":"FZD1 cooperates with LRP6 as co-receptor for Wnt5b to trigger β-catenin cytoplasmic stabilization and nuclear translocation under hypoxic conditions, driving renal fibroblast activation; Wnt5b secreted by epithelial cells via exosomes activates this canonical signaling in fibroblasts.","method":"Knockdown experiments (Wnt5b), exosome isolation, β-catenin nuclear translocation assay, in vivo hypoxia mouse model","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with in vitro and in vivo confirmation of FZD1/LRP6 co-receptor role, single lab","pmids":["42256303"],"is_preprint":false}],"current_model":"FZD1 is a cell-surface Wnt receptor that binds multiple Wnt ligands (Wnt7b, Wnt3a, Wnt5b, Wnt7B) and cooperates with LRP5/6 co-receptors to activate canonical Wnt/β-catenin signaling, driving nuclear β-catenin translocation and target gene (including MDR1) transactivation; its expression is transcriptionally regulated by Egr1 and E2F1 via promoter polymorphisms and by SIRT2-mediated H3K27 deacetylation, while FZD1 mRNA stability is post-transcriptionally controlled by RBM38 and IGF2BP3 (m6A-dependent); FZD1 can also signal through a non-canonical PKCδ/AP-1 pathway to regulate drug transporter expression, and LRP1 negatively regulates FZD1-mediated signaling by sequestering FZD1 and disrupting its co-receptor complex with LRP6."},"narrative":{"mechanistic_narrative":"FZD1 is a cell-surface Wnt receptor that binds multiple Wnt ligands and cooperates with LRP5/6 co-receptors to activate canonical Wnt/β-catenin signaling, driving cytoplasmic β-catenin stabilization and nuclear translocation [PMID:15923619, PMID:42256303]. It engages distinct Wnt ligands in different contexts: Wnt7b together with LRP5 [PMID:15923619], Wnt5b together with LRP6 to drive renal fibroblast activation under hypoxia [PMID:42256303], and Wnt7B in complexes facilitated by SULF1 [PMID:42140034]. A recurrent functional output of FZD1-driven Wnt/β-catenin signaling is transactivation of the drug transporter MDR1/P-glycoprotein, and FZD1 silencing reduces nuclear β-catenin, lowers MDR1/ABCB1 expression, and restores chemosensitivity across neuroblastoma and breast cancer models [PMID:19421142, PMID:22484497]. In multidrug-resistant cells FZD1 additionally signals through a non-canonical PKCδ/AP-1 pathway to control AP-1 target genes and ABCB1 expression [PMID:24814288]. FZD1 signaling is restrained by LRP1, which sequesters FZD1 and disrupts its FZD1-LRP6 co-receptor complex independently of receptor internalization [PMID:14739301]. FZD1 abundance is tightly regulated at multiple levels: cis-regulatory promoter polymorphisms create Egr1 and E2F1 binding sites that elevate promoter activity [PMID:18715140, PMID:20051274]; MBD2a activates and SIRT2-mediated H3K27 deacetylation represses the promoter [PMID:33402389, PMID:41485500]; and mRNA levels are set by miR-135b targeting of the 3'-UTR [PMID:27643554] and by stabilizing RNA-binding proteins RBM38 and the m6A-reader IGF2BP3 [PMID:34893109, PMID:40706743]. Genetically, FZD1 is required for normal female fertility in mice, where Fzd1-null females show subfertility and blunted ovulatory induction of oocyte and cumulus cell genes [PMID:22954793].","teleology":[{"year":2004,"claim":"Established that FZD1-mediated canonical Wnt signaling is subject to negative regulation by a co-receptor competitor, defining a mechanism of pathway restraint at the receptor complex.","evidence":"Co-IP, reporter assays, and endocytosis-defective LRP1 mutants in transfected cells","pmids":["14739301"],"confidence":"Medium","gaps":["Physiological context of LRP1-FZD1 antagonism not defined","Stoichiometry of FZD1-LRP6 complex disruption not resolved"]},{"year":2005,"claim":"Identified a specific Wnt ligand (Wnt7b) that binds FZD1 and showed it selectively activates the canonical rather than non-canonical pathway with LRP5, defining FZD1 ligand specificity.","evidence":"Cell-surface binding assay and canonical vs non-canonical reporter assays in transfected cells","pmids":["15923619"],"confidence":"Medium","gaps":["No structural basis for Wnt7b-FZD1 binding","Single ligand tested for pathway selectivity"]},{"year":2009,"claim":"Linked FZD1 to a cancer phenotype by showing its upregulation sustains Wnt/β-catenin signaling and MDR1 expression to drive chemoresistance, framing FZD1 as a resistance effector.","evidence":"shRNAmir knockdown with nuclear β-catenin and MDR1 readouts in neuroblastoma cells","pmids":["19421142"],"confidence":"Medium","gaps":["Upstream cause of FZD1 upregulation in resistant cells not defined","Direct β-catenin occupancy of MDR1 promoter not shown"]},{"year":2009,"claim":"Resolved a cis-regulatory determinant of FZD1 expression by showing a promoter polymorphism creates an Egr1 binding site with allele-specific transcriptional output.","evidence":"Promoter reporter assay and EMSA for Egr1 binding in osteoblast-like cell lines","pmids":["18715140"],"confidence":"Medium","gaps":["In vivo relevance of the polymorphism not established","Egr1-driven FZD1 induction signal not defined"]},{"year":2010,"claim":"Extended the cis-regulatory model by identifying a second polymorphism creating an E2F1 site and a haplotype with higher promoter activity.","evidence":"Promoter reporter assay, EMSA, and bioinformatics in osteoblast-like cells","pmids":["20051274"],"confidence":"Medium","gaps":["Endogenous E2F1 control of FZD1 not demonstrated","Functional consequence on bone biology not tested"]},{"year":2012,"claim":"Generalized the FZD1-Wnt/β-catenin-MDR1 resistance axis to breast cancer and confirmed it controls cytoplasmic and nuclear β-catenin and P-glycoprotein.","evidence":"siRNA knockdown with β-catenin fractionation Western blot and drug sensitivity assays in MCF-7/ADM cells","pmids":["22484497"],"confidence":"Medium","gaps":["Ligand driving the signaling not identified","Mechanism of MDR1 transactivation not directly shown"]},{"year":2012,"claim":"Defined an in vivo physiological requirement for FZD1 in female fertility, distinguishing it from being the sole ovarian WNT4 receptor.","evidence":"Fzd1-null mouse model with microarray and cumulus-oocyte complex gene expression analysis","pmids":["22954793"],"confidence":"High","gaps":["Ovarian Wnt ligand for FZD1 not identified","Pathway (canonical vs non-canonical) in fertility not resolved"]},{"year":2014,"claim":"Revealed a non-canonical FZD1 output, showing FZD1 drives a PKCδ/AP-1 cascade controlling ABCB1 and drug efflux, broadening FZD1 signaling beyond β-catenin.","evidence":"shRNA knockdown, pharmacological inhibition, and drug pump-out assays in MES-SA/Dx5 cells","pmids":["24814288"],"confidence":"Medium","gaps":["Link between FZD1 and PKCδ activation not biochemically defined","Relationship to canonical β-catenin branch unclear"]},{"year":2016,"claim":"Added post-transcriptional regulation of FZD1 by identifying direct miR-135b targeting of its 3'-UTR with consequences for chemoresistance.","evidence":"Dual-luciferase 3'-UTR reporter, miR-135b mimic, and RT-qPCR in lung cancer cells","pmids":["27643554"],"confidence":"Medium","gaps":["Endogenous miR-135b regulation of FZD1 in vivo not shown","Other 3'-UTR regulators not surveyed"]},{"year":2021,"claim":"Identified RNA-stability control of FZD1 by RBM38 and a CpG-island promoter activation mechanism via MBD2a, expanding the regulatory layers controlling FZD1 abundance.","evidence":"RIP-qPCR and actinomycin D decay assays (RBM38); CpG-island binding and splice-variant manipulation with EMT/metastasis assays (MBD2a)","pmids":["34893109","33402389"],"confidence":"Medium","gaps":["RBM38 effect tested in a single cell model","MBD2a/MBD2c balance regulation in vivo not defined"]},{"year":2025,"claim":"Connected m6A RNA modification to FZD1 by showing IGF2BP3 stabilizes FZD1 transcripts in an m6A-dependent manner and promotes FZD1/FZD7 heterodimerization to sustain stemness and chemoresistance.","evidence":"RNA binding and m6A analysis, IGF2BP3/RBM15 knockdown, and β-catenin translocation/FACS in TNBC","pmids":["40706743"],"confidence":"Medium","gaps":["FZD1/FZD7 heterodimer functional stoichiometry not resolved","Direct m6A sites on FZD1 not mapped"]},{"year":2026,"claim":"Identified new modulators of FZD1 signaling: SULF1 (stabilized by JOSD1) facilitating Wnt7B-FZD1 complex formation, SIRT2-mediated H3K27 deacetylation repressing FZD1 transcription, and FZD1/LRP6 acting as a Wnt5b co-receptor in fibrosis.","evidence":"Co-IP and ubiquitination assays (SULF1/JOSD1); ChIP and rescue/xenograft (SIRT2); Wnt5b knockdown, exosome isolation, and hypoxia mouse model (Wnt5b)","pmids":["42140034","41485500","42256303"],"confidence":"Medium","gaps":["Mechanism by which SULF1 promotes Wnt7B-FZD1 complex not structurally defined","Tissue-specificity of each regulatory input not integrated"]},{"year":null,"claim":"How FZD1 selects between canonical β-catenin and non-canonical PKCδ/AP-1 outputs, and the structural basis of its ligand and co-receptor complexes, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of FZD1-Wnt-LRP complexes","Determinants of canonical vs non-canonical branch choice unknown","Normal physiological Wnt ligands for FZD1 in most tissues undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,14]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,14]}],"complexes":[],"partners":["WNT7B","LRP5","LRP6","LRP1","SULF1","FZD7","WNT5B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UP38","full_name":"Frizzled-1","aliases":["FzE1"],"length_aa":647,"mass_kda":71.2,"function":"Receptor for Wnt proteins (PubMed:10557084). Activated by WNT3A, WNT3, WNT1 and to a lesser extent WNT2, but apparently not by WNT4, WNT5A, WNT5B, WNT6, WNT7A or WNT7B (PubMed:10557084). Contradictory results showing activation by WNT7B have been described for mouse (By similarity). Functions in the canonical Wnt/beta-catenin signaling pathway (PubMed:10557084). 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 (PubMed:10557084). 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) (Microbial infection) Acts as a receptor for C.difficile toxin TcdB in the colonic epithelium","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9UP38/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FZD1","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FZD1","total_profiled":1310},"omim":[{"mim_id":"621527","title":"TRANSMEMBRANE PROTEIN 145; TMEM145","url":"https://www.omim.org/entry/621527"},{"mim_id":"620781","title":"TRANSMEMBRANE PROTEIN 208; TMEM208","url":"https://www.omim.org/entry/620781"},{"mim_id":"606227","title":"MEMBRANE-TYPE FRIZZLED-RELATED PROTEIN; MFRP","url":"https://www.omim.org/entry/606227"},{"mim_id":"605083","title":"FRIZZLED-RELATED PROTEIN; FRZB","url":"https://www.omim.org/entry/605083"},{"mim_id":"604579","title":"FRIZZLED CLASS RECEPTOR 4; FZD4","url":"https://www.omim.org/entry/604579"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FZD1"},"hgnc":{"alias_symbol":["DKFZp564G072","Hfz1"],"prev_symbol":[]},"alphafold":{"accession":"Q9UP38","domains":[{"cath_id":"1.10.2000.10","chopping":"117-218","consensus_level":"high","plddt":92.7315,"start":117,"end":218},{"cath_id":"1.20.1070.10","chopping":"311-639","consensus_level":"high","plddt":90.2213,"start":311,"end":639}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UP38","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UP38-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UP38-F1-predicted_aligned_error_v6.png","plddt_mean":78.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FZD1","jax_strain_url":"https://www.jax.org/strain/search?query=FZD1"},"sequence":{"accession":"Q9UP38","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UP38.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UP38/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UP38"}},"corpus_meta":[{"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":"19421142","id":"PMC_19421142","title":"The Wnt receptor FZD1 mediates chemoresistance in neuroblastoma through activation of the Wnt/beta-catenin pathway.","date":"2009","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/19421142","citation_count":155,"is_preprint":false},{"pmid":"14739301","id":"PMC_14739301","title":"The low density lipoprotein receptor-1, LRP1, interacts with the human frizzled-1 (HFz1) and down-regulates the canonical Wnt signaling pathway.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14739301","citation_count":98,"is_preprint":false},{"pmid":"22484497","id":"PMC_22484497","title":"Interference of Frizzled 1 (FZD1) reverses multidrug resistance in breast cancer cells through the Wnt/β-catenin pathway.","date":"2012","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/22484497","citation_count":95,"is_preprint":false},{"pmid":"33402389","id":"PMC_33402389","title":"Hypoxia-Induced Suppression of Alternative Splicing of MBD2 Promotes Breast Cancer Metastasis via Activation of FZD1.","date":"2021","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/33402389","citation_count":49,"is_preprint":false},{"pmid":"27643554","id":"PMC_27643554","title":"miR-135b reverses chemoresistance of non-small cell lung cancer cells by downregulation of FZD1.","date":"2016","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/27643554","citation_count":42,"is_preprint":false},{"pmid":"22954793","id":"PMC_22954793","title":"FZD1 regulates cumulus expansion genes and is required for normal female fertility in 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Upregulation.","date":"2021","source":"Technology in cancer research & treatment","url":"https://pubmed.ncbi.nlm.nih.gov/34253104","citation_count":16,"is_preprint":false},{"pmid":"20051274","id":"PMC_20051274","title":"Functional and association analysis of frizzled 1 (FZD1) promoter haplotypes with femoral neck geometry.","date":"2010","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/20051274","citation_count":11,"is_preprint":false},{"pmid":"31735061","id":"PMC_31735061","title":"Wnt receptor gene FZD1 was associated with schizophrenia in genome-wide SNP analysis of the Australian Schizophrenia Research Bank cohort.","date":"2019","source":"The Australian and New Zealand journal of psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/31735061","citation_count":10,"is_preprint":false},{"pmid":"40706743","id":"PMC_40706743","title":"Dual regulation of FZD1/7 by IGF2BP3 enhances stem-like properties and carboplatin resistance in triple-negative breast cancer.","date":"2025","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/40706743","citation_count":5,"is_preprint":false},{"pmid":"40624292","id":"PMC_40624292","title":"Pinocembrin Alleviates Postoperative Cognitive Dysfunction in Aged Mice by Modulating miR-384-5p/FZD1 Axis to Activate the Wnt/β-Catenin Pathway.","date":"2025","source":"Molecular neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/40624292","citation_count":5,"is_preprint":false},{"pmid":"41485500","id":"PMC_41485500","title":"Histone deacetylase SIRT2 regulates the development and metastasis of tongue cancer via FZD1-mediated Wnt/β-catenin pathway.","date":"2026","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41485500","citation_count":0,"is_preprint":false},{"pmid":"42140034","id":"PMC_42140034","title":"JOSD1 stabilizes SULF1 to activate Wnt7B-FZD1 signaling in gastric cancer.","date":"2026","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/42140034","citation_count":0,"is_preprint":false},{"pmid":"34893109","id":"PMC_34893109","title":"[RBM38 Mediates the Proliferation of Acute Myeloid Leukemia Cells HL-60 by Regulating FZD1 mRNA Stability].","date":"2021","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/34893109","citation_count":0,"is_preprint":false},{"pmid":"42256303","id":"PMC_42256303","title":"Wnt5b/FZD1/LRP6 signaling drives renal fibrosis by triggering cytoplasmic stabilization and nuclear translocation of β-catenin under hypoxia.","date":"2026","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/42256303","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.17.688924","title":"Autoencoder Denoising for Network-Based Spatial Transcriptomics Data with Applications for Cell Signaling Estimation","date":"2025-11-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.17.688924","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.28.667009","title":"<i>De Novo</i>  design of a potent Wnt Surrogate specific for the frizzled7 subtype members","date":"2025-07-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.28.667009","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14430,"output_tokens":3660,"usd":0.049095,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11289,"output_tokens":4024,"usd":0.078522,"stage2_stop_reason":"end_turn"},"total_usd":0.127617,"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 to FZD1 on the cell surface and cooperatively activates canonical Wnt signaling together with FZD1 and LRP5 co-receptor; this interaction was demonstrated by biochemical binding assays and cell transfection studies showing activation of canonical (but not non-canonical) Wnt pathway.\",\n      \"method\": \"Cell surface binding assay, cell transfection/reporter assay (canonical vs. non-canonical Wnt pathway readouts)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical binding and functional reporter assay in cell transfection, single lab, two orthogonal methods\",\n      \"pmids\": [\"15923619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"LRP1 (via its minireceptor mLRP4T100) interacts with HFz1 (FZD1) and represses canonical Wnt-3a signaling, not by enhancing FZD1 internalization/degradation but by sequestering FZD1 and disrupting the FZD1-LRP6 co-receptor complex formation; endocytosis-defective LRP1 mutants retained the inhibitory effect.\",\n      \"method\": \"Co-immunoprecipitation, cell transfection with reporter assay, endocytosis-defective mutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding experiments with functional reporter and mechanistic mutant analysis, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"14739301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FZD1 upregulation mediates sustained activation of the Wnt/β-catenin pathway in neuroblastoma chemoresistant cells, as shown by nuclear β-catenin translocation and target gene transactivation; shRNAmir-mediated FZD1 silencing decreased MDR1 expression and restored drug sensitivity.\",\n      \"method\": \"shRNAmir knockdown, nuclear β-catenin localization assay, target gene expression analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular and cellular phenotype, single lab, multiple readouts\",\n      \"pmids\": [\"19421142\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FZD1 silencing in multidrug-resistant breast cancer cells (MCF-7/ADM) decreased MDR1/P-glycoprotein expression, reduced cytoplasmic and nuclear β-catenin levels, and restored chemosensitivity, establishing FZD1 as a regulator of MDR1 through the Wnt/β-catenin pathway.\",\n      \"method\": \"siRNA knockdown, Western blot for β-catenin (cytoplasmic/nuclear fractionation), drug sensitivity assay\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple molecular readouts, single lab\",\n      \"pmids\": [\"22484497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FZD1 activates a PKCδ/AP-1 signaling pathway in multidrug-resistant MES-SA/Dx5 cells; FZD1 inhibition (curcumin or shRNA knockdown) reduced PKCδ activity, decreased AP-1 target gene expression (HGF, EGR1), and reduced ABCB1/P-gp expression and drug efflux.\",\n      \"method\": \"shRNA knockdown, pharmacological inhibition (Rottlerin, curcumin), mRNA/protein expression analysis, drug pump-out assay\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with multiple molecular and functional readouts, single lab\",\n      \"pmids\": [\"24814288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FZD1 is required for normal female fertility in mice; Fzd1-null females showed subfertility with blunted expression of oocyte and cumulus cell genes (e.g., Zp3, Ptgs2, Ptx3) in response to the ovulatory signal, but FZD1 is unlikely to be the sole ovarian WNT4 receptor since Fzd1-null mice lack WNT4 target gene expression changes.\",\n      \"method\": \"Gene targeting (Fzd1-null mice), microarray, gene expression analysis of cumulus-oocyte complexes\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO mouse model with specific fertility phenotype and gene expression readouts, genetic epistasis with Wnt4\",\n      \"pmids\": [\"22954793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A promoter polymorphism (rs2232158) in FZD1 creates an Egr1 transcription factor binding site; the minor C allele shows higher Egr1 binding affinity and greater FZD1 promoter activity in osteoblast-like cells (MG63, SaOS-2), establishing a cis-regulatory mechanism for FZD1 transcriptional control.\",\n      \"method\": \"Promoter reporter assay, electrophoretic mobility shift assay (EMSA) for Egr1 binding\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter assay plus EMSA in two cell lines, single lab\",\n      \"pmids\": [\"18715140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The rs2232157 polymorphism in the FZD1 promoter creates an E2F1 binding site with allele-specific nuclear protein complex binding; the TC haplotype (rs2232157 T + rs2232158 C) confers ~3-fold higher FZD1 promoter activity in human osteoblast-like cells compared to the common GG haplotype.\",\n      \"method\": \"Promoter reporter assay (transient transfection), EMSA, bioinformatics\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter assay in two cell lines plus EMSA, single lab, consistent with prior study\",\n      \"pmids\": [\"20051274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MBD2a (a splice variant of MBD2) binds to the FZD1 promoter CpG islands to activate FZD1 expression under hypoxia, promoting epithelial-to-mesenchymal transition and breast cancer metastasis; MBD2c competes with MBD2a for FZD1 promoter binding and suppresses this activation.\",\n      \"method\": \"Promoter binding assay (CpG island binding), alternative splicing manipulation, EMT and metastasis functional assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding and competitive mechanism established, single lab, multiple functional readouts\",\n      \"pmids\": [\"33402389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-135b directly targets the 3'-UTR of FZD1, as confirmed by dual-luciferase reporter assay; increased miR-135b suppressed FZD1 expression and reversed cisplatin resistance in lung cancer cells.\",\n      \"method\": \"Dual-luciferase reporter assay (3'-UTR), miR-135b mimic transfection, RT-qPCR\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'-UTR targeting confirmed by reporter assay with functional consequence, single lab\",\n      \"pmids\": [\"27643554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBM38 RNA-binding protein directly binds FZD1 mRNA and enhances its stability, as shown by RIP-qPCR and actinomycin D mRNA stability assays; RBM38 overexpression promoted HL-60 cell proliferation via FZD1 mRNA stabilization.\",\n      \"method\": \"RNA immunoprecipitation (RIP-qPCR), actinomycin D mRNA decay assay, lentiviral overexpression/knockdown\",\n      \"journal\": \"Zhongguo shi yan xue ye xue za zhi\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA binding and mRNA stability shown by two orthogonal methods, single lab\",\n      \"pmids\": [\"34893109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IGF2BP3 directly binds to the 3'-UTR of FZD1 mRNA in an m6A-dependent manner (facilitated by RBM15-mediated m6A methylation), stabilizing FZD1 transcripts and promoting FZD1/FZD7 heterodimerization, which activates β-catenin nuclear translocation and maintains cancer stem cell properties and carboplatin resistance in TNBC.\",\n      \"method\": \"RNA binding assay, m6A modification analysis, knockdown experiments (IGF2BP3, RBM15), β-catenin nuclear translocation assay, FACS\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct m6A-dependent RNA binding and functional consequences established, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40706743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SIRT2 deacetylates H3K27 at the FZD1 promoter region, reducing FZD1 transcriptional expression and blocking Wnt/β-catenin pathway activity; FZD1 overexpression rescued the inhibitory effects of SIRT2 on tongue cancer cell proliferation, invasion, and migration.\",\n      \"method\": \"ChIP assay (H3K27ac enrichment at FZD1 promoter), Western blot, rescue experiment with FZD1 overexpression, in vivo xenograft model\",\n      \"journal\": \"Toxicology and applied pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for histone modification at FZD1 promoter plus rescue experiments in vitro and in vivo, single lab\",\n      \"pmids\": [\"41485500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SULF1 directly binds FZD1 and facilitates Wnt7B-FZD1 complex formation; JOSD1 deubiquitinase stabilizes SULF1, which in turn activates Wnt/β-catenin signaling through FZD1, driving gastric cancer progression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, rescue experiments\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP demonstrating SULF1-FZD1 interaction and Wnt7B-FZD1 complex formation with functional rescue, single lab\",\n      \"pmids\": [\"42140034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FZD1 cooperates with LRP6 as co-receptor for Wnt5b to trigger β-catenin cytoplasmic stabilization and nuclear translocation under hypoxic conditions, driving renal fibroblast activation; Wnt5b secreted by epithelial cells via exosomes activates this canonical signaling in fibroblasts.\",\n      \"method\": \"Knockdown experiments (Wnt5b), exosome isolation, β-catenin nuclear translocation assay, in vivo hypoxia mouse model\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with in vitro and in vivo confirmation of FZD1/LRP6 co-receptor role, single lab\",\n      \"pmids\": [\"42256303\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FZD1 is a cell-surface Wnt receptor that binds multiple Wnt ligands (Wnt7b, Wnt3a, Wnt5b, Wnt7B) and cooperates with LRP5/6 co-receptors to activate canonical Wnt/β-catenin signaling, driving nuclear β-catenin translocation and target gene (including MDR1) transactivation; its expression is transcriptionally regulated by Egr1 and E2F1 via promoter polymorphisms and by SIRT2-mediated H3K27 deacetylation, while FZD1 mRNA stability is post-transcriptionally controlled by RBM38 and IGF2BP3 (m6A-dependent); FZD1 can also signal through a non-canonical PKCδ/AP-1 pathway to regulate drug transporter expression, and LRP1 negatively regulates FZD1-mediated signaling by sequestering FZD1 and disrupting its co-receptor complex with LRP6.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FZD1 is a cell-surface Wnt receptor that binds multiple Wnt ligands and cooperates with LRP5/6 co-receptors to activate canonical Wnt/\\u03b2-catenin signaling, driving cytoplasmic \\u03b2-catenin stabilization and nuclear translocation [#0, #14]. It engages distinct Wnt ligands in different contexts: Wnt7b together with LRP5 [#0], Wnt5b together with LRP6 to drive renal fibroblast activation under hypoxia [#14], and Wnt7B in complexes facilitated by SULF1 [#13]. A recurrent functional output of FZD1-driven Wnt/\\u03b2-catenin signaling is transactivation of the drug transporter MDR1/P-glycoprotein, and FZD1 silencing reduces nuclear \\u03b2-catenin, lowers MDR1/ABCB1 expression, and restores chemosensitivity across neuroblastoma and breast cancer models [#2, #3]. In multidrug-resistant cells FZD1 additionally signals through a non-canonical PKC\\u03b4/AP-1 pathway to control AP-1 target genes and ABCB1 expression [#4]. FZD1 signaling is restrained by LRP1, which sequesters FZD1 and disrupts its FZD1-LRP6 co-receptor complex independently of receptor internalization [#1]. FZD1 abundance is tightly regulated at multiple levels: cis-regulatory promoter polymorphisms create Egr1 and E2F1 binding sites that elevate promoter activity [#6, #7]; MBD2a activates and SIRT2-mediated H3K27 deacetylation represses the promoter [#8, #12]; and mRNA levels are set by miR-135b targeting of the 3'-UTR [#9] and by stabilizing RNA-binding proteins RBM38 and the m6A-reader IGF2BP3 [#10, #11]. Genetically, FZD1 is required for normal female fertility in mice, where Fzd1-null females show subfertility and blunted ovulatory induction of oocyte and cumulus cell genes [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that FZD1-mediated canonical Wnt signaling is subject to negative regulation by a co-receptor competitor, defining a mechanism of pathway restraint at the receptor complex.\",\n      \"evidence\": \"Co-IP, reporter assays, and endocytosis-defective LRP1 mutants in transfected cells\",\n      \"pmids\": [\"14739301\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological context of LRP1-FZD1 antagonism not defined\", \"Stoichiometry of FZD1-LRP6 complex disruption not resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified a specific Wnt ligand (Wnt7b) that binds FZD1 and showed it selectively activates the canonical rather than non-canonical pathway with LRP5, defining FZD1 ligand specificity.\",\n      \"evidence\": \"Cell-surface binding assay and canonical vs non-canonical reporter assays in transfected cells\",\n      \"pmids\": [\"15923619\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural basis for Wnt7b-FZD1 binding\", \"Single ligand tested for pathway selectivity\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked FZD1 to a cancer phenotype by showing its upregulation sustains Wnt/\\u03b2-catenin signaling and MDR1 expression to drive chemoresistance, framing FZD1 as a resistance effector.\",\n      \"evidence\": \"shRNAmir knockdown with nuclear \\u03b2-catenin and MDR1 readouts in neuroblastoma cells\",\n      \"pmids\": [\"19421142\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream cause of FZD1 upregulation in resistant cells not defined\", \"Direct \\u03b2-catenin occupancy of MDR1 promoter not shown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved a cis-regulatory determinant of FZD1 expression by showing a promoter polymorphism creates an Egr1 binding site with allele-specific transcriptional output.\",\n      \"evidence\": \"Promoter reporter assay and EMSA for Egr1 binding in osteoblast-like cell lines\",\n      \"pmids\": [\"18715140\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of the polymorphism not established\", \"Egr1-driven FZD1 induction signal not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended the cis-regulatory model by identifying a second polymorphism creating an E2F1 site and a haplotype with higher promoter activity.\",\n      \"evidence\": \"Promoter reporter assay, EMSA, and bioinformatics in osteoblast-like cells\",\n      \"pmids\": [\"20051274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous E2F1 control of FZD1 not demonstrated\", \"Functional consequence on bone biology not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Generalized the FZD1-Wnt/\\u03b2-catenin-MDR1 resistance axis to breast cancer and confirmed it controls cytoplasmic and nuclear \\u03b2-catenin and P-glycoprotein.\",\n      \"evidence\": \"siRNA knockdown with \\u03b2-catenin fractionation Western blot and drug sensitivity assays in MCF-7/ADM cells\",\n      \"pmids\": [\"22484497\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand driving the signaling not identified\", \"Mechanism of MDR1 transactivation not directly shown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined an in vivo physiological requirement for FZD1 in female fertility, distinguishing it from being the sole ovarian WNT4 receptor.\",\n      \"evidence\": \"Fzd1-null mouse model with microarray and cumulus-oocyte complex gene expression analysis\",\n      \"pmids\": [\"22954793\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ovarian Wnt ligand for FZD1 not identified\", \"Pathway (canonical vs non-canonical) in fertility not resolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed a non-canonical FZD1 output, showing FZD1 drives a PKC\\u03b4/AP-1 cascade controlling ABCB1 and drug efflux, broadening FZD1 signaling beyond \\u03b2-catenin.\",\n      \"evidence\": \"shRNA knockdown, pharmacological inhibition, and drug pump-out assays in MES-SA/Dx5 cells\",\n      \"pmids\": [\"24814288\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between FZD1 and PKC\\u03b4 activation not biochemically defined\", \"Relationship to canonical \\u03b2-catenin branch unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Added post-transcriptional regulation of FZD1 by identifying direct miR-135b targeting of its 3'-UTR with consequences for chemoresistance.\",\n      \"evidence\": \"Dual-luciferase 3'-UTR reporter, miR-135b mimic, and RT-qPCR in lung cancer cells\",\n      \"pmids\": [\"27643554\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous miR-135b regulation of FZD1 in vivo not shown\", \"Other 3'-UTR regulators not surveyed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified RNA-stability control of FZD1 by RBM38 and a CpG-island promoter activation mechanism via MBD2a, expanding the regulatory layers controlling FZD1 abundance.\",\n      \"evidence\": \"RIP-qPCR and actinomycin D decay assays (RBM38); CpG-island binding and splice-variant manipulation with EMT/metastasis assays (MBD2a)\",\n      \"pmids\": [\"34893109\", \"33402389\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RBM38 effect tested in a single cell model\", \"MBD2a/MBD2c balance regulation in vivo not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected m6A RNA modification to FZD1 by showing IGF2BP3 stabilizes FZD1 transcripts in an m6A-dependent manner and promotes FZD1/FZD7 heterodimerization to sustain stemness and chemoresistance.\",\n      \"evidence\": \"RNA binding and m6A analysis, IGF2BP3/RBM15 knockdown, and \\u03b2-catenin translocation/FACS in TNBC\",\n      \"pmids\": [\"40706743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FZD1/FZD7 heterodimer functional stoichiometry not resolved\", \"Direct m6A sites on FZD1 not mapped\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified new modulators of FZD1 signaling: SULF1 (stabilized by JOSD1) facilitating Wnt7B-FZD1 complex formation, SIRT2-mediated H3K27 deacetylation repressing FZD1 transcription, and FZD1/LRP6 acting as a Wnt5b co-receptor in fibrosis.\",\n      \"evidence\": \"Co-IP and ubiquitination assays (SULF1/JOSD1); ChIP and rescue/xenograft (SIRT2); Wnt5b knockdown, exosome isolation, and hypoxia mouse model (Wnt5b)\",\n      \"pmids\": [\"42140034\", \"41485500\", \"42256303\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SULF1 promotes Wnt7B-FZD1 complex not structurally defined\", \"Tissue-specificity of each regulatory input not integrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FZD1 selects between canonical \\u03b2-catenin and non-canonical PKC\\u03b4/AP-1 outputs, and the structural basis of its ligand and co-receptor complexes, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of FZD1-Wnt-LRP complexes\", \"Determinants of canonical vs non-canonical branch choice unknown\", \"Normal physiological Wnt ligands for FZD1 in most tissues undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 14]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"WNT7B\", \"LRP5\", \"LRP6\", \"LRP1\", \"SULF1\", \"FZD7\", \"WNT5B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}