{"gene":"FZD1","run_date":"2026-04-28T17:46:04","timeline":{"discoveries":[{"year":2005,"finding":"Wnt7b binds to FZD1 (and FZD10) on the cell surface and cooperatively activates canonical Wnt signaling together with LRP5 co-receptor; this interaction does not activate the noncanonical Wnt pathway.","method":"Cell surface binding assay, cell transfection with pathway reporters, biochemical co-receptor analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — direct binding demonstrated on cell surface with cooperative activation assay, multiple orthogonal readouts in single study","pmids":["15923619"],"is_preprint":false},{"year":2004,"finding":"LRP1 (via its minireceptor mLRP4T100) interacts with the FZD1 cysteine-rich domain (CRD) and represses canonical Wnt-3a signaling by sequestering FZD1 and disrupting FZD1–LRP6 complex formation, without requiring LRP1-mediated endocytosis.","method":"Co-immunoprecipitation, co-transfection with canonical Wnt reporter, endocytosis-defective LRP1 mutants, CRD interaction assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interaction shown, mechanism tested with multiple mutants and orthogonal assays","pmids":["14739301"],"is_preprint":false},{"year":2009,"finding":"FZD1 overexpression in doxorubicin-resistant neuroblastoma cells mediates sustained canonical Wnt/β-catenin pathway activation (nuclear β-catenin translocation, target gene transactivation); shRNA-mediated FZD1 silencing reduces MDR1 expression and restores drug sensitivity.","method":"shRNA knockdown, nuclear β-catenin localization, target gene expression, drug sensitivity assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotype and pathway placement, single lab","pmids":["19421142"],"is_preprint":false},{"year":2012,"finding":"FZD1 silencing in multidrug-resistant breast cancer cells (MCF-7/ADM) reduces MDR1/P-gp expression and cytoplasmic/nuclear β-catenin levels, restoring sensitivity to multiple chemotherapy drugs via the Wnt/β-catenin pathway.","method":"siRNA knockdown, Western blot for β-catenin localization, drug sensitivity assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — defined KD phenotype with pathway placement, single lab","pmids":["22484497"],"is_preprint":false},{"year":2014,"finding":"FZD1 regulates PKCδ/AP-1 signaling in multidrug-resistant MES-SA/Dx5 cells: FZD1 inhibition (curcumin or shRNA) reduces ABCB1 (P-gp) expression and drug-pump activity; PKCδ inhibition or knockdown phenocopies FZD1 inhibition, placing PKCδ downstream of FZD1.","method":"FZD1 shRNA/inhibitor, PKCδ inhibitor (Rottlerin), PKCδ shRNA, ABCB1 expression and drug efflux assays, AP-1 activity assay","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis established by double knockdown/inhibition, multiple pathway readouts, single lab","pmids":["24814288"],"is_preprint":false},{"year":2012,"finding":"FZD1 knockout in mice causes subfertility associated with blunted expression of cumulus-oocyte complex genes (Ptgs2, Ptx3, Il6, etc.) and oocyte maturation genes in response to the ovulatory signal; FZD1 is not required for WNT4 target gene expression, indicating FZD1 does not serve as the sole ovarian WNT4 receptor.","method":"Gene targeting (knockout mice), microarray, qRT-PCR of cumulus-oocyte complex genes, ovarian histology, fertility assay","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 — clean KO with specific phenotypic and transcriptomic readout, epistasis with WNT4 pathway established","pmids":["22954793"],"is_preprint":false},{"year":2009,"finding":"A promoter SNP (rs2232158) in FZD1 creates an Egr1 binding site with higher Egr1 binding affinity, resulting in greater FZD1 promoter activity in osteoblast-like cells (MG63, SaOS-2), providing a cis-regulatory mechanism for FZD1 transcriptional control in bone cells.","method":"Luciferase promoter reporter assay, EMSA for transcription factor binding, cell transfection","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 — functional promoter assay with EMSA validation, single lab","pmids":["18715140"],"is_preprint":false},{"year":2010,"finding":"A second FZD1 promoter SNP (rs2232157) creates an E2F1 binding site in an allele-specific manner; the TC haplotype (rs2232157T/rs2232158C) produces ~3-fold higher FZD1 promoter activity in osteoblast-like cells compared to the common GG haplotype.","method":"EMSA, luciferase promoter reporter assay with haplotype-specific constructs, bioinformatics","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 — functional haplotype-specific promoter assay with EMSA, single lab","pmids":["20051274"],"is_preprint":false},{"year":2021,"finding":"MBD2a binds to the FZD1 promoter CpG islands (outcompeting MBD2c) to activate FZD1 transcription under hypoxia (via HIF1-mediated suppression of SRSF2-dependent MBD2 alternative splicing), thereby promoting EMT and metastasis.","method":"ChIP at FZD1 promoter, alternative splicing manipulation, HIF1 activation, EMT and metastasis assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP shows direct promoter binding, multiple functional readouts, single lab","pmids":["33402389"],"is_preprint":false},{"year":2016,"finding":"miR-135b directly targets the 3'-UTR of FZD1 mRNA to repress FZD1 expression; miR-135b overexpression or FZD1 siRNA knockdown sensitizes cisplatin-resistant NSCLC cells to chemotherapy.","method":"Dual-luciferase 3'-UTR reporter assay, miRNA mimic transfection, siRNA knockdown, drug sensitivity assay","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 — direct 3'-UTR targeting confirmed by luciferase assay, single lab","pmids":["27643554"],"is_preprint":false},{"year":2021,"finding":"RBM38 RNA-binding protein directly interacts with FZD1 mRNA and enhances its stability, thereby promoting HL-60 leukemia cell proliferation and cell cycle progression.","method":"RNA immunoprecipitation-qPCR (RIP-qPCR), actinomycin D mRNA stability assay, lentiviral overexpression/knockdown, CCK-8 proliferation assay, flow cytometry","journal":"Zhongguo shi yan xue ye xue za zhi","confidence":"Medium","confidence_rationale":"Tier 2 — RIP confirms direct binding, stability assay demonstrates functional consequence, single lab","pmids":["34893109"],"is_preprint":false},{"year":2025,"finding":"IGF2BP3 (m6A reader) directly binds the 3'-UTR of FZD1 mRNA in an m6A-dependent manner (m6A methylation written by RBM15), stabilizing FZD1 transcripts and promoting FZD1/FZD7 heterodimerization, which activates β-catenin nuclear translocation and drives cancer stem cell stemness and carboplatin resistance in TNBC.","method":"RIP, m6A-RIP, FZD1 mRNA stability assay, IGF2BP3 KD, RBM15 manipulation, β-catenin nuclear fractionation, functional stem cell and drug resistance assays, Fz7-21 inhibitor","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — m6A-dependent RNA binding and mRNA stabilization shown with multiple orthogonal methods, single lab","pmids":["40706743"],"is_preprint":false},{"year":2026,"finding":"SIRT2 deacetylates H3K27 at the FZD1 promoter, reducing FZD1 transcription and blocking Wnt/β-catenin pathway activation; FZD1 overexpression rescues the inhibitory effects of SIRT2 on tongue cancer cell proliferation, invasion, and metastasis.","method":"ChIP for H3K27ac at FZD1 promoter, SIRT2 overexpression/knockdown, FZD1 rescue experiments, in vivo xenograft model, Western blot for β-catenin","journal":"Toxicology and applied pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP shows epigenetic mechanism at FZD1 promoter, epistasis established by rescue experiment, single lab","pmids":["41485500"],"is_preprint":false}],"current_model":"FZD1 is a cell-surface Wnt receptor that binds Wnt ligands (e.g., Wnt7b) and, together with LRP5/6 co-receptors, activates the canonical β-catenin pathway; its signaling output and expression are regulated by multiple upstream mechanisms including LRP1-mediated sequestration, m6A-dependent mRNA stabilization by IGF2BP3, miRNA-mediated repression (miR-135b, miR-384-5p, miR-5006-5p), epigenetic transcriptional control via SIRT2/H3K27 deacetylation and MBD2a promoter binding, and cis-regulatory promoter variants (Egr1/E2F1 binding sites), with downstream consequences including PKCδ/AP-1 activation, MDR1/P-gp upregulation driving chemoresistance, and regulation of cumulus-oocyte gene expression required for female fertility."},"narrative":{"teleology":[{"year":2004,"claim":"Establishing how FZD1 signaling is negatively regulated: LRP1 was shown to sequester FZD1 via its CRD and disrupt FZD1–LRP6 complex formation, providing the first mechanism for non-endocytic attenuation of canonical Wnt signaling at the receptor level.","evidence":"Co-immunoprecipitation, endocytosis-defective LRP1 mutants, canonical Wnt reporter assays in transfected cells","pmids":["14739301"],"confidence":"High","gaps":["Physiological tissues where LRP1-mediated FZD1 sequestration operates remain undefined","Whether LRP1 similarly regulates other Frizzled family members through CRD interaction is untested","Structural basis of the LRP1–FZD1 CRD interaction is unknown"]},{"year":2005,"claim":"Defining ligand specificity: Wnt7b was identified as a direct FZD1 ligand that activates canonical but not noncanonical Wnt signaling in cooperation with LRP5, establishing FZD1 as a pathway-selective Wnt receptor.","evidence":"Cell surface binding assay and pathway reporter transfection with biochemical co-receptor analysis","pmids":["15923619"],"confidence":"High","gaps":["Full Wnt ligand selectivity profile for FZD1 is incomplete","Whether FZD1 activates noncanonical pathways in other cellular contexts is unresolved"]},{"year":2009,"claim":"Linking FZD1 to drug resistance: FZD1 overexpression was found to sustain canonical Wnt/β-catenin activation in drug-resistant neuroblastoma cells, with FZD1 knockdown reducing MDR1 expression and restoring doxorubicin sensitivity, establishing the FZD1–β-catenin–MDR1 axis in chemoresistance.","evidence":"shRNA knockdown, nuclear β-catenin localization, MDR1 expression, and drug sensitivity assays in neuroblastoma cells","pmids":["19421142"],"confidence":"Medium","gaps":["Whether FZD1 is a cause versus consequence of the drug-resistant state is unclear","Not confirmed in in vivo drug resistance models at this stage"]},{"year":2009,"claim":"Revealing cis-regulatory control of FZD1 transcription: promoter SNPs rs2232158 and rs2232157 were shown to create Egr1 and E2F1 binding sites, respectively, producing allele-specific increases in FZD1 promoter activity in bone cells, linking genetic variation to FZD1 expression levels.","evidence":"EMSA for transcription factor binding and luciferase promoter reporter assays with haplotype-specific constructs in osteoblast-like cells","pmids":["18715140","20051274"],"confidence":"Medium","gaps":["Downstream effects of these promoter variants on Wnt pathway output in bone are not demonstrated","Association with bone phenotypes in human cohorts is not established"]},{"year":2012,"claim":"Extending the chemoresistance role to breast cancer and demonstrating in vivo reproductive function: FZD1 silencing in MCF-7/ADM cells reduced MDR1/P-gp and β-catenin, while FZD1 knockout mice showed subfertility with blunted cumulus-oocyte gene expression, establishing FZD1 as required for ovarian function independently of WNT4.","evidence":"siRNA knockdown with drug sensitivity assays in breast cancer cells; gene-targeted knockout mice with microarray, qRT-PCR, and fertility assays","pmids":["22484497","22954793"],"confidence":"High","gaps":["Which Wnt ligand signals through FZD1 in the ovary is unknown","The FZD1–MDR1 connection lacks in vivo validation in tumor models"]},{"year":2014,"claim":"Identifying a noncanonical signaling branch downstream of FZD1: PKCδ and AP-1 were placed downstream of FZD1 in multidrug-resistant cells, with PKCδ inhibition phenocopying FZD1 knockdown for ABCB1 repression, demonstrating FZD1 controls drug resistance through both β-catenin and PKCδ/AP-1 pathways.","evidence":"Epistasis with FZD1 shRNA, PKCδ inhibitor (Rottlerin), PKCδ shRNA, ABCB1 expression, drug efflux, and AP-1 activity assays in MES-SA/Dx5 cells","pmids":["24814288"],"confidence":"Medium","gaps":["Rottlerin has known off-target effects, so PKCδ specificity requires confirmation","Whether canonical and noncanonical FZD1 branches are activated simultaneously or context-dependently is unclear"]},{"year":2016,"claim":"Establishing post-transcriptional repression of FZD1 by miRNA: miR-135b was shown to directly target the FZD1 3′-UTR, and its overexpression phenocopied FZD1 knockdown in sensitizing cisplatin-resistant NSCLC cells, linking miRNA regulation to FZD1-mediated chemoresistance.","evidence":"Dual-luciferase 3′-UTR reporter assay, miRNA mimic transfection, drug sensitivity assay in NSCLC cells","pmids":["27643554"],"confidence":"Medium","gaps":["In vivo relevance of miR-135b–FZD1 axis in drug resistance is not tested","Whether miR-135b regulation of FZD1 is context-specific or generalizable is unknown"]},{"year":2021,"claim":"Uncovering epigenetic and epitranscriptomic layers of FZD1 regulation: MBD2a was shown to bind FZD1 promoter CpG islands under hypoxia to activate transcription promoting EMT, while RBM38 was found to stabilize FZD1 mRNA in leukemia cells, and IGF2BP3 was later shown to stabilize FZD1 mRNA in an m6A-dependent manner promoting FZD1/FZD7 heterodimerization and cancer stemness.","evidence":"ChIP at FZD1 promoter, HIF1/SRSF2 splicing manipulation, EMT assays; RIP-qPCR and actinomycin D stability assays; m6A-RIP, IGF2BP3 KD, FZD1 mRNA stability, β-catenin fractionation, and Fz7-21 inhibitor experiments","pmids":["33402389","34893109","40706743"],"confidence":"Medium","gaps":["Whether m6A modification and RBM38 binding act on the same or distinct FZD1 mRNA pools is unknown","The structural basis and stoichiometry of FZD1/FZD7 heterodimerization are undefined","Single-lab findings for each mechanism; independent confirmation is lacking"]},{"year":2026,"claim":"Identifying SIRT2-mediated histone deacetylation as an epigenetic brake on FZD1: SIRT2 deacetylates H3K27 at the FZD1 promoter to repress FZD1 transcription and Wnt/β-catenin activation, with FZD1 overexpression rescuing SIRT2's tumor-suppressive effects, establishing a direct epigenetic–transcriptional mechanism.","evidence":"ChIP for H3K27ac at FZD1 promoter, SIRT2 overexpression/knockdown, FZD1 rescue, in vivo xenograft, Western blot for β-catenin in tongue cancer cells","pmids":["41485500"],"confidence":"Medium","gaps":["Whether SIRT2 regulation of FZD1 is specific or reflects broader chromatin remodeling is untested","Single lab; awaits independent confirmation"]},{"year":null,"claim":"Key unresolved questions include the structural basis of Wnt–FZD1 and FZD1–co-receptor interactions, how FZD1 selectively activates canonical versus noncanonical pathways in different tissues, and whether therapeutic targeting of FZD1 can overcome chemoresistance in vivo.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of FZD1 in complex with any ligand or co-receptor","Systematic in vivo studies of FZD1 in tumor drug resistance are absent","The full repertoire of Wnt ligands and co-receptors partnering with FZD1 is incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3,4]}],"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":[0,1,2,3,4,11,12]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,4,9]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[5]}],"complexes":[],"partners":["LRP5","LRP6","LRP1","FZD7","IGF2BP3","RBM38","MBD2A","SIRT2"],"other_free_text":[]},"mechanistic_narrative":"FZD1 is a seven-transmembrane Wnt receptor that activates the canonical β-catenin signaling pathway and contributes to multidrug resistance, epithelial-mesenchymal transition, and female reproductive function. FZD1 binds Wnt ligands such as Wnt7b through its extracellular cysteine-rich domain and cooperates with LRP5/6 co-receptors to trigger β-catenin nuclear translocation and target gene transactivation, while LRP1 antagonizes this signaling by sequestering the FZD1 CRD and disrupting FZD1–LRP6 complex formation [PMID:15923619, PMID:14739301]. In drug-resistant cancer cells, FZD1 drives MDR1/P-gp expression through both canonical Wnt/β-catenin and PKCδ/AP-1 signaling branches, and its silencing restores chemosensitivity in neuroblastoma, breast cancer, and NSCLC models [PMID:19421142, PMID:22484497, PMID:24814288]. FZD1 transcription and mRNA stability are regulated by epigenetic mechanisms including SIRT2-mediated H3K27 deacetylation, MBD2a promoter binding, cis-regulatory promoter variants affecting Egr1/E2F1 occupancy, m6A-dependent mRNA stabilization by IGF2BP3, and miRNA targeting, while FZD1 knockout in mice causes subfertility due to impaired cumulus-oocyte complex gene expression [PMID:41485500, PMID:33402389, PMID:18715140, PMID:40706743, PMID:22954793]."},"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":157,"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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zhi","url":"https://pubmed.ncbi.nlm.nih.gov/34893109","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":12454,"output_tokens":3108,"usd":0.041991},"stage2":{"model":"claude-opus-4-6","input_tokens":6538,"output_tokens":3209,"usd":0.169373},"total_usd":0.211364,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"Wnt7b binds to FZD1 (and FZD10) on the cell surface and cooperatively activates canonical Wnt signaling together with LRP5 co-receptor; this interaction does not activate the noncanonical Wnt pathway.\",\n      \"method\": \"Cell surface binding assay, cell transfection with pathway reporters, biochemical co-receptor analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding demonstrated on cell surface with cooperative activation assay, multiple orthogonal readouts in single study\",\n      \"pmids\": [\"15923619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"LRP1 (via its minireceptor mLRP4T100) interacts with the FZD1 cysteine-rich domain (CRD) and represses canonical Wnt-3a signaling by sequestering FZD1 and disrupting FZD1–LRP6 complex formation, without requiring LRP1-mediated endocytosis.\",\n      \"method\": \"Co-immunoprecipitation, co-transfection with canonical Wnt reporter, endocytosis-defective LRP1 mutants, CRD interaction assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interaction shown, mechanism tested with multiple mutants and orthogonal assays\",\n      \"pmids\": [\"14739301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"FZD1 overexpression in doxorubicin-resistant neuroblastoma cells mediates sustained canonical Wnt/β-catenin pathway activation (nuclear β-catenin translocation, target gene transactivation); shRNA-mediated FZD1 silencing reduces MDR1 expression and restores drug sensitivity.\",\n      \"method\": \"shRNA knockdown, nuclear β-catenin localization, target gene expression, drug sensitivity assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype and pathway placement, single lab\",\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) reduces MDR1/P-gp expression and cytoplasmic/nuclear β-catenin levels, restoring sensitivity to multiple chemotherapy drugs via the Wnt/β-catenin pathway.\",\n      \"method\": \"siRNA knockdown, Western blot for β-catenin localization, drug sensitivity assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined KD phenotype with pathway placement, single lab\",\n      \"pmids\": [\"22484497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FZD1 regulates PKCδ/AP-1 signaling in multidrug-resistant MES-SA/Dx5 cells: FZD1 inhibition (curcumin or shRNA) reduces ABCB1 (P-gp) expression and drug-pump activity; PKCδ inhibition or knockdown phenocopies FZD1 inhibition, placing PKCδ downstream of FZD1.\",\n      \"method\": \"FZD1 shRNA/inhibitor, PKCδ inhibitor (Rottlerin), PKCδ shRNA, ABCB1 expression and drug efflux assays, AP-1 activity assay\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established by double knockdown/inhibition, multiple pathway readouts, single lab\",\n      \"pmids\": [\"24814288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FZD1 knockout in mice causes subfertility associated with blunted expression of cumulus-oocyte complex genes (Ptgs2, Ptx3, Il6, etc.) and oocyte maturation genes in response to the ovulatory signal; FZD1 is not required for WNT4 target gene expression, indicating FZD1 does not serve as the sole ovarian WNT4 receptor.\",\n      \"method\": \"Gene targeting (knockout mice), microarray, qRT-PCR of cumulus-oocyte complex genes, ovarian histology, fertility assay\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific phenotypic and transcriptomic readout, epistasis with WNT4 pathway established\",\n      \"pmids\": [\"22954793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A promoter SNP (rs2232158) in FZD1 creates an Egr1 binding site with higher Egr1 binding affinity, resulting in greater FZD1 promoter activity in osteoblast-like cells (MG63, SaOS-2), providing a cis-regulatory mechanism for FZD1 transcriptional control in bone cells.\",\n      \"method\": \"Luciferase promoter reporter assay, EMSA for transcription factor binding, cell transfection\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional promoter assay with EMSA validation, single lab\",\n      \"pmids\": [\"18715140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A second FZD1 promoter SNP (rs2232157) creates an E2F1 binding site in an allele-specific manner; the TC haplotype (rs2232157T/rs2232158C) produces ~3-fold higher FZD1 promoter activity in osteoblast-like cells compared to the common GG haplotype.\",\n      \"method\": \"EMSA, luciferase promoter reporter assay with haplotype-specific constructs, bioinformatics\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional haplotype-specific promoter assay with EMSA, single lab\",\n      \"pmids\": [\"20051274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MBD2a binds to the FZD1 promoter CpG islands (outcompeting MBD2c) to activate FZD1 transcription under hypoxia (via HIF1-mediated suppression of SRSF2-dependent MBD2 alternative splicing), thereby promoting EMT and metastasis.\",\n      \"method\": \"ChIP at FZD1 promoter, alternative splicing manipulation, HIF1 activation, EMT and metastasis assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP shows direct promoter binding, multiple functional readouts, single lab\",\n      \"pmids\": [\"33402389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"miR-135b directly targets the 3'-UTR of FZD1 mRNA to repress FZD1 expression; miR-135b overexpression or FZD1 siRNA knockdown sensitizes cisplatin-resistant NSCLC cells to chemotherapy.\",\n      \"method\": \"Dual-luciferase 3'-UTR reporter assay, miRNA mimic transfection, siRNA knockdown, drug sensitivity assay\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct 3'-UTR targeting confirmed by luciferase assay, single lab\",\n      \"pmids\": [\"27643554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RBM38 RNA-binding protein directly interacts with FZD1 mRNA and enhances its stability, thereby promoting HL-60 leukemia cell proliferation and cell cycle progression.\",\n      \"method\": \"RNA immunoprecipitation-qPCR (RIP-qPCR), actinomycin D mRNA stability assay, lentiviral overexpression/knockdown, CCK-8 proliferation assay, flow cytometry\",\n      \"journal\": \"Zhongguo shi yan xue ye xue za zhi\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RIP confirms direct binding, stability assay demonstrates functional consequence, single lab\",\n      \"pmids\": [\"34893109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IGF2BP3 (m6A reader) directly binds the 3'-UTR of FZD1 mRNA in an m6A-dependent manner (m6A methylation written by RBM15), stabilizing FZD1 transcripts and promoting FZD1/FZD7 heterodimerization, which activates β-catenin nuclear translocation and drives cancer stem cell stemness and carboplatin resistance in TNBC.\",\n      \"method\": \"RIP, m6A-RIP, FZD1 mRNA stability assay, IGF2BP3 KD, RBM15 manipulation, β-catenin nuclear fractionation, functional stem cell and drug resistance assays, Fz7-21 inhibitor\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — m6A-dependent RNA binding and mRNA stabilization shown with multiple orthogonal methods, single lab\",\n      \"pmids\": [\"40706743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SIRT2 deacetylates H3K27 at the FZD1 promoter, reducing FZD1 transcription and blocking Wnt/β-catenin pathway activation; FZD1 overexpression rescues the inhibitory effects of SIRT2 on tongue cancer cell proliferation, invasion, and metastasis.\",\n      \"method\": \"ChIP for H3K27ac at FZD1 promoter, SIRT2 overexpression/knockdown, FZD1 rescue experiments, in vivo xenograft model, Western blot for β-catenin\",\n      \"journal\": \"Toxicology and applied pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP shows epigenetic mechanism at FZD1 promoter, epistasis established by rescue experiment, single lab\",\n      \"pmids\": [\"41485500\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FZD1 is a cell-surface Wnt receptor that binds Wnt ligands (e.g., Wnt7b) and, together with LRP5/6 co-receptors, activates the canonical β-catenin pathway; its signaling output and expression are regulated by multiple upstream mechanisms including LRP1-mediated sequestration, m6A-dependent mRNA stabilization by IGF2BP3, miRNA-mediated repression (miR-135b, miR-384-5p, miR-5006-5p), epigenetic transcriptional control via SIRT2/H3K27 deacetylation and MBD2a promoter binding, and cis-regulatory promoter variants (Egr1/E2F1 binding sites), with downstream consequences including PKCδ/AP-1 activation, MDR1/P-gp upregulation driving chemoresistance, and regulation of cumulus-oocyte gene expression required for female fertility.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FZD1 is a seven-transmembrane Wnt receptor that activates the canonical β-catenin signaling pathway and contributes to multidrug resistance, epithelial-mesenchymal transition, and female reproductive function. FZD1 binds Wnt ligands such as Wnt7b through its extracellular cysteine-rich domain and cooperates with LRP5/6 co-receptors to trigger β-catenin nuclear translocation and target gene transactivation, while LRP1 antagonizes this signaling by sequestering the FZD1 CRD and disrupting FZD1–LRP6 complex formation [PMID:15923619, PMID:14739301]. In drug-resistant cancer cells, FZD1 drives MDR1/P-gp expression through both canonical Wnt/β-catenin and PKCδ/AP-1 signaling branches, and its silencing restores chemosensitivity in neuroblastoma, breast cancer, and NSCLC models [PMID:19421142, PMID:22484497, PMID:24814288]. FZD1 transcription and mRNA stability are regulated by epigenetic mechanisms including SIRT2-mediated H3K27 deacetylation, MBD2a promoter binding, cis-regulatory promoter variants affecting Egr1/E2F1 occupancy, m6A-dependent mRNA stabilization by IGF2BP3, and miRNA targeting, while FZD1 knockout in mice causes subfertility due to impaired cumulus-oocyte complex gene expression [PMID:41485500, PMID:33402389, PMID:18715140, PMID:40706743, PMID:22954793].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing how FZD1 signaling is negatively regulated: LRP1 was shown to sequester FZD1 via its CRD and disrupt FZD1–LRP6 complex formation, providing the first mechanism for non-endocytic attenuation of canonical Wnt signaling at the receptor level.\",\n      \"evidence\": \"Co-immunoprecipitation, endocytosis-defective LRP1 mutants, canonical Wnt reporter assays in transfected cells\",\n      \"pmids\": [\"14739301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physiological tissues where LRP1-mediated FZD1 sequestration operates remain undefined\",\n        \"Whether LRP1 similarly regulates other Frizzled family members through CRD interaction is untested\",\n        \"Structural basis of the LRP1–FZD1 CRD interaction is unknown\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defining ligand specificity: Wnt7b was identified as a direct FZD1 ligand that activates canonical but not noncanonical Wnt signaling in cooperation with LRP5, establishing FZD1 as a pathway-selective Wnt receptor.\",\n      \"evidence\": \"Cell surface binding assay and pathway reporter transfection with biochemical co-receptor analysis\",\n      \"pmids\": [\"15923619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full Wnt ligand selectivity profile for FZD1 is incomplete\",\n        \"Whether FZD1 activates noncanonical pathways in other cellular contexts is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linking FZD1 to drug resistance: FZD1 overexpression was found to sustain canonical Wnt/β-catenin activation in drug-resistant neuroblastoma cells, with FZD1 knockdown reducing MDR1 expression and restoring doxorubicin sensitivity, establishing the FZD1–β-catenin–MDR1 axis in chemoresistance.\",\n      \"evidence\": \"shRNA knockdown, nuclear β-catenin localization, MDR1 expression, and drug sensitivity assays in neuroblastoma cells\",\n      \"pmids\": [\"19421142\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether FZD1 is a cause versus consequence of the drug-resistant state is unclear\",\n        \"Not confirmed in in vivo drug resistance models at this stage\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Revealing cis-regulatory control of FZD1 transcription: promoter SNPs rs2232158 and rs2232157 were shown to create Egr1 and E2F1 binding sites, respectively, producing allele-specific increases in FZD1 promoter activity in bone cells, linking genetic variation to FZD1 expression levels.\",\n      \"evidence\": \"EMSA for transcription factor binding and luciferase promoter reporter assays with haplotype-specific constructs in osteoblast-like cells\",\n      \"pmids\": [\"18715140\", \"20051274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream effects of these promoter variants on Wnt pathway output in bone are not demonstrated\",\n        \"Association with bone phenotypes in human cohorts is not established\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extending the chemoresistance role to breast cancer and demonstrating in vivo reproductive function: FZD1 silencing in MCF-7/ADM cells reduced MDR1/P-gp and β-catenin, while FZD1 knockout mice showed subfertility with blunted cumulus-oocyte gene expression, establishing FZD1 as required for ovarian function independently of WNT4.\",\n      \"evidence\": \"siRNA knockdown with drug sensitivity assays in breast cancer cells; gene-targeted knockout mice with microarray, qRT-PCR, and fertility assays\",\n      \"pmids\": [\"22484497\", \"22954793\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which Wnt ligand signals through FZD1 in the ovary is unknown\",\n        \"The FZD1–MDR1 connection lacks in vivo validation in tumor models\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying a noncanonical signaling branch downstream of FZD1: PKCδ and AP-1 were placed downstream of FZD1 in multidrug-resistant cells, with PKCδ inhibition phenocopying FZD1 knockdown for ABCB1 repression, demonstrating FZD1 controls drug resistance through both β-catenin and PKCδ/AP-1 pathways.\",\n      \"evidence\": \"Epistasis with FZD1 shRNA, PKCδ inhibitor (Rottlerin), PKCδ shRNA, ABCB1 expression, drug efflux, and AP-1 activity assays in MES-SA/Dx5 cells\",\n      \"pmids\": [\"24814288\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Rottlerin has known off-target effects, so PKCδ specificity requires confirmation\",\n        \"Whether canonical and noncanonical FZD1 branches are activated simultaneously or context-dependently is unclear\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Establishing post-transcriptional repression of FZD1 by miRNA: miR-135b was shown to directly target the FZD1 3′-UTR, and its overexpression phenocopied FZD1 knockdown in sensitizing cisplatin-resistant NSCLC cells, linking miRNA regulation to FZD1-mediated chemoresistance.\",\n      \"evidence\": \"Dual-luciferase 3′-UTR reporter assay, miRNA mimic transfection, drug sensitivity assay in NSCLC cells\",\n      \"pmids\": [\"27643554\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vivo relevance of miR-135b–FZD1 axis in drug resistance is not tested\",\n        \"Whether miR-135b regulation of FZD1 is context-specific or generalizable is unknown\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Uncovering epigenetic and epitranscriptomic layers of FZD1 regulation: MBD2a was shown to bind FZD1 promoter CpG islands under hypoxia to activate transcription promoting EMT, while RBM38 was found to stabilize FZD1 mRNA in leukemia cells, and IGF2BP3 was later shown to stabilize FZD1 mRNA in an m6A-dependent manner promoting FZD1/FZD7 heterodimerization and cancer stemness.\",\n      \"evidence\": \"ChIP at FZD1 promoter, HIF1/SRSF2 splicing manipulation, EMT assays; RIP-qPCR and actinomycin D stability assays; m6A-RIP, IGF2BP3 KD, FZD1 mRNA stability, β-catenin fractionation, and Fz7-21 inhibitor experiments\",\n      \"pmids\": [\"33402389\", \"34893109\", \"40706743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether m6A modification and RBM38 binding act on the same or distinct FZD1 mRNA pools is unknown\",\n        \"The structural basis and stoichiometry of FZD1/FZD7 heterodimerization are undefined\",\n        \"Single-lab findings for each mechanism; independent confirmation is lacking\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identifying SIRT2-mediated histone deacetylation as an epigenetic brake on FZD1: SIRT2 deacetylates H3K27 at the FZD1 promoter to repress FZD1 transcription and Wnt/β-catenin activation, with FZD1 overexpression rescuing SIRT2's tumor-suppressive effects, establishing a direct epigenetic–transcriptional mechanism.\",\n      \"evidence\": \"ChIP for H3K27ac at FZD1 promoter, SIRT2 overexpression/knockdown, FZD1 rescue, in vivo xenograft, Western blot for β-catenin in tongue cancer cells\",\n      \"pmids\": [\"41485500\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SIRT2 regulation of FZD1 is specific or reflects broader chromatin remodeling is untested\",\n        \"Single lab; awaits independent confirmation\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of Wnt–FZD1 and FZD1–co-receptor interactions, how FZD1 selectively activates canonical versus noncanonical pathways in different tissues, and whether therapeutic targeting of FZD1 can overcome chemoresistance in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of FZD1 in complex with any ligand or co-receptor\",\n        \"Systematic in vivo studies of FZD1 in tumor drug resistance are absent\",\n        \"The full repertoire of Wnt ligands and co-receptors partnering with FZD1 is incompletely mapped\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3, 4]}\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, 1, 2, 3, 4, 11, 12]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 4, 9]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"LRP5\",\n      \"LRP6\",\n      \"LRP1\",\n      \"FZD7\",\n      \"IGF2BP3\",\n      \"RBM38\",\n      \"MBD2A\",\n      \"SIRT2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}