{"gene":"FOLR1","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":1994,"finding":"FR-α (FOLR1) is the isoform selectively expressed in human placental syncytiotrophoblast and choriocarcinoma cells, not FR-β as previously believed. RT-PCR with isoform-specific primers and Northern blot analysis of placental trophoblast cells and JAR choriocarcinoma cells confirmed only FR-α mRNA, with nucleotide sequences identical to FR-α cDNA.","method":"RT-PCR with isoform-specific primers, Northern blot analysis, DNA sequencing","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (RT-PCR and Northern blot) in a single study; no functional mutagenesis follow-up","pmids":["8061055"],"is_preprint":false},{"year":1999,"finding":"DNA vaccination with FRα (FOLR1) cDNA induces both IgG2a antibody responses and cytotoxic T lymphocyte activity against FRα-expressing tumor cells in mice, and delays tumor growth upon challenge with FRα-transduced cells, demonstrating immunogenicity of the surface-expressed protein.","method":"In vivo DNA vaccination, FACS-based antibody detection, cytotoxic T lymphocyte assay, tumor challenge model","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal in vivo assays in a single study confirming FOLR1 as a functional immunogen; single lab","pmids":["10419053"],"is_preprint":false},{"year":2007,"finding":"Folr1 knockout mouse embryos develop cardiovascular abnormalities including outflow tract defects, aortic arch artery anomalies, and dextracardia, with abnormal heart looping and disrupted migration of cardiac neural crest cells; maternal folinic acid supplementation rescues these defects in a dose-dependent manner, implicating FOLR1-mediated folate transport in cardiac neural crest cell function and pharyngeal arch/secondary heart field signaling.","method":"Folr1 knockout mouse model, folinic acid dose-response rescue study, histological analysis of cardiac development","journal":"Birth defects research. Part A, Clinical and molecular teratology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined phenotype, dose-response rescue, replicated across developmental stages; strong mechanistic readout","pmids":["17286298"],"is_preprint":false},{"year":2007,"finding":"Folr1 gene ablation alters expression of genes involved in cell migration, cytoskeletal organization, cell-cell adhesion, and cellular redox status in developing cardiac and conotruncal tissues, suggesting FOLR1-dependent folate homeostasis regulates gene expression programs required for cardiovascular morphogenesis.","method":"Microarray analysis of Folr1 knockout embryo cardiac tissue at three developmental stages, validated by quantitative real-time PCR","journal":"BMC developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with defined transcriptional phenotype, validated by qPCR; single lab, no direct protein-level mechanistic follow-up","pmids":["18028541"],"is_preprint":false},{"year":2010,"finding":"Loss-of-function homozygous missense mutation p.Cys105Arg in FOLR1 abolishes a predicted disulfide bond required for correct protein folding, causing defective cerebral folate transport across the blood-CSF barrier and profound CSF 5-methyltetrahydrofolate deficiency, establishing that FOLR1 is the primary folate transporter at the choroid plexus.","method":"FOLR1 gene sequencing in patient with cerebral folate deficiency, CSF 5-MTHF measurement by HPLC, structural prediction of disulfide bond disruption","journal":"Journal of inherited metabolic disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human loss-of-function genetics with biochemical phenotype (CSF 5-MTHF); single family, no in vitro reconstitution of transport","pmids":["20857335"],"is_preprint":false},{"year":2010,"finding":"FOLR1-dependent 5-methyltetrahydrofolate (MTHF) uptake in KB cells follows saturation kinetics consistent with high-affinity receptor-mediated transport at physiological MTHF concentrations; reactive oxygen species (but not valproate or carbamazepine) significantly decrease FOLR1-mediated MTHF uptake, as confirmed by PIPLC cleavage and siRNA silencing of FOLR1.","method":"KB cell culture assay, phosphatidylinositol-specific phospholipase C (PIPLC) cleavage, siRNA knockdown, MTHF uptake quantification","journal":"Molecular genetics and metabolism","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro transport assay with specific enzymatic cleavage and siRNA knockdown confirming FOLR1 as the transporting entity; multiple orthogonal methods","pmids":["20619709"],"is_preprint":false},{"year":2011,"finding":"Folr1-deficient mouse embryonic fibroblasts show attenuated TGFβ1/Smad signaling (measured by Smad-dependent reporter assay) and increased canonical Wnt pathway activity (Wnt-3a-stimulated Axin2 expression), demonstrating that FOLR1 loss alters developmental signaling pathways relevant to neural tube closure.","method":"Primary Folr1-/- mouse embryonic fibroblast cultures, luciferase reporter assay (p3TP-lux), quantitative gene expression analysis of Wnt target genes","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO cell model with reporter assays and gene expression; single lab, mechanistic follow-up limited","pmids":["21649587"],"is_preprint":false},{"year":2012,"finding":"FOLR1 overexpression in ovarian cancer cells promotes folate uptake and enhances cell proliferation, migration, and invasion in response to folate; stable knockdown of FOLR1 blocks folate-induced cancer cell migration and invasion and reverses downregulation of E-cadherin. Ectopic overexpression of RFC (reduced folate carrier) phenocopies FRα knockdown, suggesting RFC counterbalances FRα-mediated pro-tumorigenic signaling.","method":"Stable FRα knockdown and RFC overexpression in ovarian cancer cell lines, in vitro proliferation, migration and invasion assays, E-cadherin Western blot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — stable KD and OE with multiple phenotypic readouts; single lab","pmids":["23144806"],"is_preprint":false},{"year":2013,"finding":"Homology modeling and molecular dynamics of FOLR1 using the riboflavin-binding protein crystal structure as template revealed a full disulfide bridge network and identified key residues in the folate-binding pocket; docking studies showed that folic acid and vintafolide share the same binding site, with Trp and His residues contributing to ligand specificity.","method":"Homology modeling, molecular dynamics simulation, in silico ligand docking","journal":"Journal of molecular graphics & modelling","confidence":"Low","confidence_rationale":"Tier 4 / Weak — purely computational; no experimental structural or mutagenesis validation","pmids":["23880302"],"is_preprint":false},{"year":2013,"finding":"The anti-FOLR1 monoclonal antibody farletuzumab (MORAb-003) mediates its antitumor effect against ovarian cancer xenografts primarily through antibody-dependent cellular cytotoxicity (ADCC), as demonstrated in an experimental ovarian cancer model.","method":"ADCC assay, human ovarian cancer xenograft mouse model with farletuzumab treatment","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro ADCC plus in vivo xenograft; single lab, mechanism confirmed by ADCC assay","pmids":["24025360"],"is_preprint":false},{"year":2015,"finding":"FOLR1 knockdown in triple-negative breast cancer cell lines with high endogenous FOLR1 expression causes growth inhibition, while FOLR1 overexpression promotes folate uptake and confers growth advantage under low-folate conditions, directly linking surface FOLR1 expression to folate import and cell proliferation.","method":"RNA interference knockdown, FOLR1 overexpression, folate uptake assay, cell proliferation assay in low-folate medium","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional functional experiments (KD and OE) with biochemical readout; single lab","pmids":["25816016"],"is_preprint":false},{"year":2015,"finding":"Folic acid (FA) inhibits colon cancer cell proliferation through a FOLR1-dependent signaling cascade: FA binding to FRα activates c-SRC, which activates ERK1/2, leading to NFκB nuclear translocation, TP53 upregulation, and increased CDKN1A/CDKN1B expression causing G0/G1 arrest. Knockdown of FOLR1 abolishes FA-induced c-SRC pathway activation and downstream effects.","method":"FRα siRNA knockdown, TP53 siRNA knockdown, Western blot (c-SRC, ERK1/2, NFκB, TP53, CDKN1A, CDKN1B), cell cycle analysis, in vivo xenograft","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple KD experiments with epistasis and signaling readouts; single lab, no reconstitution","pmids":["26056802"],"is_preprint":false},{"year":2015,"finding":"FOLR1 surface expression level is a major determinant of sensitivity to anti-FOLR1 antibody-drug conjugate (ADC) IMGN853/mirvetuximab soravtansine; cells with low or no FRα are resistant, while high FRα-expressing cells are highly sensitive, and bystander cytotoxic activity is observed against FRα-negative cells co-cultured with FRα-positive cells.","method":"FRα expression quantification by immunohistochemistry, in vitro cytotoxicity assays, FRα-positive and FRα-negative co-culture bystander assay, xenograft models","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative correlation of surface receptor with ADC potency in vitro and in vivo; single lab, multiple model systems","pmids":["25904506"],"is_preprint":false},{"year":2015,"finding":"Genetic variation in the Folr1 promoter of spontaneously hypertensive rats (SHR) reduces renal Folr1 expression and folate reabsorption, causing decreased serum folate, hypercysteinemia, adiposity, reduced insulin sensitivity, and increased blood pressure; transgenic rescue with a Folr1 transgene in SHR ameliorates these metabolic disturbances, establishing FOLR1-mediated renal folate reabsorption as a regulator of sulfur amino acid metabolism and metabolic syndrome.","method":"QTL mapping, SHR.BN-chr.1 congenic strain analysis, luciferase promoter reporter assay, Folr1 transgenic rescue experiment, metabolic phenotyping","journal":"Hypertension","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — promoter reporter assay plus transgenic rescue plus congenic strain phenotyping; multiple orthogonal methods with functional rescue","pmids":["26667416"],"is_preprint":false},{"year":2016,"finding":"mTORC1 and mTORC2 positively regulate folate uptake in primary human trophoblast cells by controlling the plasma membrane abundance of FR-α (FOLR1) and RFC through post-translational mechanisms, without affecting total protein levels; silencing of raptor (mTORC1) or rictor (mTORC2) markedly decreases surface FR-α and reduces folate uptake; mTORC2 but not mTORC1 mediates insulin+IGF-1-stimulated folate uptake.","method":"siRNA silencing of raptor/rictor, plasma membrane fractionation, folate uptake assay in primary human trophoblast cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — targeted KD with membrane fractionation and functional uptake assay; single lab, primary cell model","pmids":["27562465"],"is_preprint":false},{"year":2016,"finding":"FolR1 specifically marks midbrain dopaminergic (mesDA) neural progenitors and immature dopamine neurons during mouse development (E9.5–E14.5) and in ESC-derived cultures; FACS/MACS-sorted FolR1+ neural progenitors give rise to TH+ and Pitx3+ dopamine neurons, while FolR1-negative cells generate non-dopaminergic neurons and glia.","method":"Immunofluorescence co-staining with Lmx1a, FACS/MACS cell sorting, in vitro differentiation assay of sorted populations","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — prospective isolation with functional differentiation readout; single lab, no KO/KD mechanistic follow-up","pmids":["27580818"],"is_preprint":false},{"year":2017,"finding":"Folic acid (FA) bound to FRα induces MEK/ERK1/2 activation and increases TSLC1 and E-cadherin expression in nasopharyngeal cancer cells; blocking ERK1/2 activation attenuates FA-mediated TSLC1 upregulation; TSLC1 knockdown abolishes FA-mediated inhibition of proliferation, invasion and migration, defining an FRα/ERK1/2/TSLC1 signaling pathway.","method":"ERK1/2 inhibitor treatment, siRNA knockdown of TSLC1, Western blot, proliferation/invasion/migration assays","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic epistasis establishing pathway order; single lab","pmids":["29070520"],"is_preprint":false},{"year":2019,"finding":"Folic acid modifies epithelial cell shape during morphogenesis via FOLR1 and MLCK in a RhoA/ROCK-independent but Src-kinase-dependent manner; co-expression of Folr1 rescues the apical constriction defect of a Rho-kinase-binding mutant of Shroom3 in vitro; treatment with FA is accompanied by elevated phospho-myosin light chain and MLCK; doubly heterozygous mice lacking one copy each of Shroom3 and Folr1 show neural tube defects with reduced activated myosin and MLCK.","method":"Epithelial cell culture apical constriction model, chick embryo neural epithelium rescue assay, MLCK inhibitor and Src-kinase inhibitor treatment, double heterozygous mouse genetics, phospho-MLC Western blot","journal":"Biology open","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal systems (cell culture, chick embryo, mouse genetics), pharmacological pathway dissection, epistasis; consistent mechanistic outcome","pmids":["30670450"],"is_preprint":false},{"year":2020,"finding":"CIC (capicua) transcription factor directly binds to octameric sequences in the FOLR1 promoter; CIC loss-of-function variants (including a nonsense mutation p.R353X) downregulate FOLR1 expression in HeLa cells and patient-derived iPSCs, and decrease cellular folic acid binding, establishing CIC as a transcriptional regulator of FOLR1 expression.","method":"Whole exome sequencing, promoter binding assay (CIC ChIP/reporter), siRNA in HeLa cells, iPSC-derived cells from CFD proband, folic acid binding assay","journal":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — promoter binding confirmed by functional assay, siRNA in two cell systems including patient iPSCs, biochemical binding assay; multiple orthogonal methods","pmids":["32820034"],"is_preprint":false},{"year":2021,"finding":"Core-fucosylation of FOLR1 (particularly at glycosite Asn-201) positively regulates cellular folate uptake capacity; FUT8 is a driver of HGF/TGF-β1-induced EMT in HCC cells, and FUT8 silencing reduces FOLR1 core-fucosylation and partially blocks EMT. Enhanced folate uptake mediated by core-fucosylated FOLR1 promotes EMT progression.","method":"Mass spectrometry-based glycoproteomics, FUT8 siRNA knockdown, intact glycopeptide quantification, molecular biology assays for EMT markers, folate uptake assay","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-specific glycosylation identified by MS, functional KD with uptake and EMT readouts; single lab","pmids":["34093861"],"is_preprint":false},{"year":2021,"finding":"Folr1 overexpression and folinic acid treatment stimulate β-cell differentiation from ductal cells in zebrafish and in neonatal pig islet cultures; comparative metabolomics of zebrafish with/without β-cell ablation and folinic acid treatment implicates pyrimidine, carnitine, and serine pathways as downstream effectors of FOLR1/one-carbon metabolism in β-cell regeneration.","method":"Zebrafish genetic screen, folr1 overexpression and folinic acid treatment, neonatal pig islet culture, comparative metabolomics","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological gain-of-function with metabolomic pathway mapping in two model systems; single lab","pmids":["34099692"],"is_preprint":false},{"year":2021,"finding":"FOLR1 overexpression drives sorafenib resistance in HCC cells; immunoprecipitation-mass spectrometry identified interaction between FOLR1 and autophagy-related proteins; FOLR1-induced resistance is accompanied by autophagy activation; autophagy inhibition significantly reduces FOLR1-induced drug resistance.","method":"Label-free quantitative proteomics, siRNA knockdown, FOLR1 overexpression, immunoprecipitation-mass spectrometry, autophagy inhibitor treatment, cell viability assay","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS identifying FOLR1-autophagy protein interaction, functional KD/OE with autophagy inhibitor epistasis; single lab","pmids":["33677528"],"is_preprint":false},{"year":2023,"finding":"FOLR1 overexpression increases APOBEC3B expression and suppresses VSV viral replication in HeLa cells and in vivo by causing intracellular folate deficiency; the antiviral effect is dependent on folate deficiency rather than direct antiviral signaling, as exogenous folate supplementation reverses FOLR1-mediated viral suppression.","method":"FOLR1 overexpression in HeLa cells and mice, VSV infection assay, APOBEC3B knockdown, folate supplementation rescue, in vivo mouse model","journal":"Virologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — OE with rescue experiment and KD epistasis in vitro and in vivo; single lab","pmids":["37028598"],"is_preprint":false},{"year":2023,"finding":"FOLR1 promotes proliferation and migration of laryngeal squamous cell carcinoma cells by stabilizing β-catenin through the EGFR/AKT/GSK-3β signaling axis; FOLR1 inhibits β-catenin ubiquitination and degradation; blocking EGFR or the AKT/GSK-3β axis abolishes FOLR1's effects on β-catenin expression and nuclear translocation; β-catenin siRNA knockdown abolishes FOLR1-induced proliferation and migration.","method":"siRNA knockdown of FOLR1 and β-catenin, EGFR inhibitor treatment, AKT inhibitor treatment, co-immunoprecipitation/ubiquitination assay, Western blot for β-catenin nuclear localization","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic epistasis with ubiquitination assay; single lab, single study","pmids":["37702010"],"is_preprint":false},{"year":2023,"finding":"YAP1 and its partner transcription factor TEAD2 regulate FOLR1 expression in gliomas; chromatin immunoprecipitation and YAP1-TEAD inhibitor (verteporfin) treatment demonstrated direct transcriptional control; FOLR1 depletion in IDH1 wild-type glioma cells increases sensitivity to temozolomide-mediated cell death and heightens DNA damage markers (γH2AX, ATM phosphorylation).","method":"Chromatin immunoprecipitation (ChIP), mutant YAP1 overexpression, verteporfin treatment (YAP1-TEAD inhibitor), FOLR1 siRNA knockdown, γH2AX and pATM assay, cell death assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus pharmacological epistasis plus KD functional readout; single lab","pmids":["37269960"],"is_preprint":false},{"year":2025,"finding":"NSD2-mediated H3K36me2 recruits nuclear FOLR1 to promoters of glycolytic genes (HK2, TIGAR, G6PD) in pulmonary artery endothelial cells; FOLR1 acts as a transcription factor, and its nuclear translocation depends on NSD2 activity; NSD2 or FOLR1 knockdown reduces promoter activity and expression of glycolytic genes, and reverses the metabolic shift toward aerobic glycolysis in monocrotaline-induced PAH.","method":"NSD2 and FOLR1 siRNA knockdown, ChIP for H3K36me2 and FOLR1 at glycolytic gene promoters, promoter activity assay, metabolic flux analysis (OCR, ECAR), in vivo monocrotaline PAH mouse model","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating nuclear FOLR1 binding to gene promoters, promoter activity assay, functional KD in vitro and in vivo; single lab","pmids":["39798773"],"is_preprint":false}],"current_model":"FOLR1 (FRα) is a GPI-anchored glycoprotein that functions as a high-affinity folate transporter mediating receptor-mediated endocytosis of 5-methyltetrahydrofolate at the cell surface, with surface abundance regulated post-translationally by mTORC1/2 and by core-fucosylation at Asn-201 (catalyzed by FUT8); beyond folate import, FOLR1 engages non-canonical signaling roles including activation of FRα/c-SRC/ERK1/2/NFκB/TP53, FRα/ERK1/2/TSLC1, and EGFR/AKT/GSK-3β/β-catenin pathways that regulate proliferation, migration, and drug resistance, and in certain contexts FOLR1 translocates to the nucleus where it acts as a transcription factor recruited by NSD2/H3K36me2 to upregulate glycolytic gene promoters; its expression is transcriptionally controlled by the CIC/capicua transcription factor and by YAP1-TEAD2, while promoter variants in the SHR rat reduce renal FOLR1 expression, impairing folate reabsorption and causing metabolic syndrome features that are rescued by Folr1 transgene expression."},"narrative":{"mechanistic_narrative":"FOLR1 (FRα) is a high-affinity, GPI-anchored cell-surface receptor that mediates receptor-mediated import of 5-methyltetrahydrofolate, functioning as the principal folate-uptake entity in epithelial and barrier tissues [PMID:20619709, PMID:25816016]. Its transport activity follows saturation kinetics, is sensitive to reactive oxygen species, and is abolished by GPI cleavage or silencing, confirming FOLR1 itself as the transporting moiety [PMID:20619709]. FOLR1-dependent folate delivery is required for normal development: knockout mouse embryos display cardiovascular and cardiac neural crest defects rescuable by folinic acid [PMID:17286298], FRα marks midbrain dopaminergic progenitors [PMID:27580818], and FOLR1 cooperates genetically with Shroom3 to drive Src-kinase/MLCK-dependent apical constriction during neural tube closure [PMID:30670450]. In humans, a loss-of-function p.Cys105Arg mutation disrupts a folding-critical disulfide bond, causing cerebral folate deficiency and establishing FOLR1 as the folate transporter of the choroid plexus blood–CSF barrier [PMID:20857335]. Surface abundance is set post-translationally by mTORC1/mTORC2 signaling and by FUT8-mediated core-fucosylation at Asn-201, both of which tune folate-uptake capacity [PMID:27562465, PMID:34093861], while transcription is controlled by CIC/capicua and by YAP1–TEAD2 [PMID:32820034, PMID:37269960]. Beyond folate import, FOLR1 engages non-canonical signaling: ligand-bound FRα activates c-SRC/ERK1/2/NF-κB/TP53 to enforce cell-cycle arrest in colon cancer [PMID:26056802], an ERK1/2/TSLC1 axis in nasopharyngeal cancer [PMID:29070520], and an EGFR/AKT/GSK-3β axis that stabilizes β-catenin to promote proliferation and migration [PMID:37702010]; it can also translocate to the nucleus, where NSD2/H3K36me2 recruits it to glycolytic gene promoters to act as a transcriptional driver of aerobic glycolysis [PMID:39798773]. These activities underlie FOLR1's role in tumor folate uptake, proliferation, invasion, and drug resistance, making it a validated target for anti-FRα antibodies and antibody-drug conjugates whose efficacy tracks with surface receptor density [PMID:23144806, PMID:25816016, PMID:25904506].","teleology":[{"year":1994,"claim":"Establishing which folate receptor isoform is expressed in placental trophoblast resolved that FRα (FOLR1), not FRβ, is the relevant transporter in this tissue, anchoring later transport and developmental work to the correct gene product.","evidence":"Isoform-specific RT-PCR, Northern blot, and sequencing in placental trophoblast and JAR cells","pmids":["8061055"],"confidence":"Medium","gaps":["No functional transport assay in this study","Does not address regulation or signaling roles"]},{"year":2007,"claim":"Folr1 knockout in mouse and transcriptomic profiling showed that FOLR1-mediated folate transport is required for cardiac neural crest migration and cardiovascular morphogenesis, framing FOLR1 as a developmental folate-delivery gene rather than a passive carrier.","evidence":"Folr1 knockout mouse embryos with folinic acid rescue and microarray/qPCR of cardiac tissue","pmids":["17286298","18028541"],"confidence":"High","gaps":["Mechanism linking folate to neural crest gene programs not resolved at protein level","Whether effects are purely metabolic or also signaling"]},{"year":2010,"claim":"Human loss-of-function genetics and in vitro kinetic analysis established FOLR1 as the high-affinity folate transporter at the blood–CSF barrier and demonstrated saturable receptor-mediated uptake sensitive to oxidative stress.","evidence":"Patient FOLR1 sequencing with CSF 5-MTHF measurement; KB-cell uptake assays with PIPLC cleavage and siRNA","pmids":["20857335","20619709"],"confidence":"Medium","gaps":["No in vitro reconstitution of transport","Single family for the disease mutation","Cycling/endocytic mechanism of uptake not detailed"]},{"year":2011,"claim":"Folr1-null fibroblasts linked FOLR1 loss to altered TGFβ/Smad and Wnt signaling, indicating folate status feeds into developmental signaling pathways relevant to neural tube closure.","evidence":"Primary Folr1-/- MEF reporter assays and Wnt target gene expression","pmids":["21649587"],"confidence":"Medium","gaps":["Direct molecular link between FOLR1 and these pathways not established","Single lab, reporter-based readouts"]},{"year":2012,"claim":"Bidirectional manipulation in ovarian cancer cells defined FOLR1 as a pro-tumorigenic driver of folate-dependent proliferation, migration, and invasion counterbalanced by RFC, moving FOLR1 from a transporter to a phenotype-controlling oncology target.","evidence":"Stable FRα knockdown, RFC overexpression, migration/invasion assays, E-cadherin Western blot","pmids":["23144806"],"confidence":"Medium","gaps":["Signaling intermediaries not identified","Single lab"]},{"year":2013,"claim":"Computational modeling and antibody studies began defining the folate-binding pocket and validated FOLR1 surface expression as an immunotherapy/ADCC target.","evidence":"Homology modeling/MD/docking; farletuzumab ADCC and ovarian xenograft assays","pmids":["23880302","24025360"],"confidence":"Medium","gaps":["Structural model lacks experimental validation","ADCC mechanism shown without crystallographic epitope mapping"]},{"year":2015,"claim":"A series of studies linked FOLR1 surface level directly to folate import, proliferation under low folate, and sensitivity to FRα-targeted ADCs, while defining a folate-bound FRα/c-SRC/ERK/NF-κB/TP53 cascade controlling cell cycle.","evidence":"FOLR1 KD/OE in TNBC, ADC cytotoxicity/bystander/xenograft assays, and siRNA epistasis with signaling Western blots in colon cancer","pmids":["25816016","25904506","26056802"],"confidence":"Medium","gaps":["Direct physical coupling of FRα to c-SRC not demonstrated","Context-dependence of pro- vs anti-proliferative signaling unresolved"]},{"year":2015,"claim":"QTL mapping and transgenic rescue in SHR rats established renal FOLR1-mediated folate reabsorption as a determinant of sulfur amino acid metabolism and metabolic syndrome traits.","evidence":"Congenic strains, promoter reporter assay, Folr1 transgenic rescue, metabolic phenotyping","pmids":["26667416"],"confidence":"High","gaps":["Causal promoter variant mechanism in human metabolic disease not addressed","Tissue-specific contributions not dissected"]},{"year":2016,"claim":"Identification of mTORC1/mTORC2 as post-translational regulators of FRα plasma-membrane abundance, and prospective FolR1+ isolation of dopaminergic progenitors, expanded FOLR1 regulation and lineage-marker roles.","evidence":"raptor/rictor siRNA with membrane fractionation in trophoblasts; FACS/MACS sorting and differentiation of FolR1+ neural progenitors","pmids":["27562465","27580818"],"confidence":"Medium","gaps":["Trafficking machinery downstream of mTOR not identified","Whether FolR1 marking is functional or incidental in dopaminergic lineage unknown"]},{"year":2017,"claim":"Epistasis dissection defined an FRα/ERK1/2/TSLC1 pathway through which folate-bound FOLR1 suppresses nasopharyngeal cancer cell proliferation and invasion, adding a second tumor-suppressive signaling branch.","evidence":"ERK inhibitor and TSLC1 siRNA with proliferation/invasion/migration assays","pmids":["29070520"],"confidence":"Medium","gaps":["Mechanism of FRα-to-MEK/ERK coupling unresolved","Single lab"]},{"year":2019,"claim":"Multi-system genetics showed FOLR1 cooperates with Shroom3 via a Src-kinase/MLCK/phospho-myosin axis to drive apical constriction, mechanistically connecting folate signaling to morphogenetic cell-shape change and neural tube closure.","evidence":"Cell-culture and chick embryo apical constriction rescue, MLCK/Src inhibitors, Shroom3;Folr1 double-heterozygous mice, phospho-MLC Western blot","pmids":["30670450"],"confidence":"High","gaps":["Direct biochemical link between FRα and MLCK not shown","How folate signal reaches the cytoskeleton from a GPI-anchored receptor unclear"]},{"year":2021,"claim":"FUT8-dependent core-fucosylation at Asn-201, FOLR1-driven sorafenib resistance via autophagy, and folinic acid/Folr1-stimulated β-cell differentiation broadened FOLR1's roles into glycan-regulated uptake, drug resistance, and one-carbon-metabolism-driven regeneration.","evidence":"Glycoproteomics with FUT8 siRNA; IP-MS and autophagy-inhibitor epistasis in HCC; zebrafish/pig islet gain-of-function with metabolomics","pmids":["34093861","33677528","34099692"],"confidence":"Medium","gaps":["FOLR1 autophagy-protein interactors not individually validated","Causal metabolite mediators of β-cell regeneration not proven","Single labs per finding"]},{"year":2023,"claim":"FOLR1 was shown to drive an EGFR/AKT/GSK-3β axis stabilizing β-catenin, an APOBEC3B-dependent antiviral effect via induced folate deficiency, and YAP1–TEAD2-controlled expression modulating glioma temozolomide sensitivity, extending its non-canonical signaling and transcriptional regulation.","evidence":"Inhibitor/siRNA epistasis and ubiquitination assays (LSCC); OE/KD with folate rescue and VSV assays; ChIP, verteporfin, and DNA-damage readouts in glioma","pmids":["37702010","37028598","37269960"],"confidence":"Medium","gaps":["Whether β-catenin stabilization is folate-dependent unclear","Direct FRα–EGFR coupling not shown","Single lab per study"]},{"year":2025,"claim":"Demonstration that NSD2/H3K36me2 recruits nuclear FOLR1 to glycolytic gene promoters established a moonlighting transcription-factor role driving aerobic glycolysis in pulmonary artery endothelial cells.","evidence":"ChIP for FOLR1 and H3K36me2, promoter activity and metabolic flux assays, NSD2/FOLR1 KD in vitro and monocrotaline PAH mouse model","pmids":["39798773"],"confidence":"Medium","gaps":["Mechanism and trafficking route of GPI-anchored FOLR1 to the nucleus unexplained","Whether nuclear FOLR1 binds DNA directly or via cofactors unknown","Single lab"]},{"year":null,"claim":"How a single GPI-anchored folate receptor mechanistically couples extracellular folate binding to intracellular kinase cascades and to nuclear transcriptional activity, and what determines tumor-suppressive versus pro-tumorigenic signaling outcomes, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural basis for FRα-to-cytoplasmic-effector coupling","Mechanism of nuclear translocation of a GPI-anchored protein unknown","Context-dependence of opposing signaling outputs not explained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[4,5,10,14]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[25]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[5,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,12,14]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[25]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[4,5,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,17]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,16,23]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[13,25]}],"complexes":[],"partners":["FUT8","NSD2","EGFR","TEAD2","YAP1","CIC"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P15328","full_name":"Folate receptor alpha","aliases":["Adult folate-binding protein","FBP","Folate receptor 1","Folate receptor, adult","KB cells FBP","Ovarian tumor-associated antigen MOv18"],"length_aa":257,"mass_kda":29.8,"function":"Binds to folate and reduced folic acid derivatives and mediates delivery of 5-methyltetrahydrofolate and folate analogs into the interior of cells (PubMed:19074442, PubMed:23851396, PubMed:23934049, PubMed:2527252, PubMed:8033114, PubMed:8567728). Has high affinity for folate and folic acid analogs at neutral pH (PubMed:23851396, PubMed:23934049, PubMed:2527252, PubMed:8033114, PubMed:8567728). Exposure to slightly acidic pH after receptor endocytosis triggers a conformation change that strongly reduces its affinity for folates and mediates their release (PubMed:8567728). Required for normal embryonic development and normal cell proliferation (By similarity)","subcellular_location":"Cell membrane; Apical cell membrane; Basolateral cell membrane; Secreted; Cytoplasmic vesicle; Cytoplasmic vesicle, clathrin-coated vesicle; Endosome","url":"https://www.uniprot.org/uniprotkb/P15328/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FOLR1","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/FOLR1","total_profiled":1310},"omim":[{"mim_id":"615737","title":"IZUMO1 RECEPTOR, JUNO; IZUMO1R","url":"https://www.omim.org/entry/615737"},{"mim_id":"613068","title":"NEURODEGENERATION DUE TO CEREBRAL FOLATE TRANSPORT DEFICIENCY; NCFTD","url":"https://www.omim.org/entry/613068"},{"mim_id":"602469","title":"FOLATE RECEPTOR 3; FOLR3","url":"https://www.omim.org/entry/602469"},{"mim_id":"136430","title":"FOLATE RECEPTOR, ALPHA; FOLR1","url":"https://www.omim.org/entry/136430"},{"mim_id":"136425","title":"FOLATE RECEPTOR, BETA; FOLR2","url":"https://www.omim.org/entry/136425"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"choroid plexus","ntpm":2860.9}],"url":"https://www.proteinatlas.org/search/FOLR1"},"hgnc":{"alias_symbol":["FRα"],"prev_symbol":["FOLR"]},"alphafold":{"accession":"P15328","domains":[{"cath_id":"-","chopping":"1-257","consensus_level":"medium","plddt":90.9099,"start":1,"end":257}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P15328","model_url":"https://alphafold.ebi.ac.uk/files/AF-P15328-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P15328-F1-predicted_aligned_error_v6.png","plddt_mean":91.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FOLR1","jax_strain_url":"https://www.jax.org/strain/search?query=FOLR1"},"sequence":{"accession":"P15328","fasta_url":"https://rest.uniprot.org/uniprotkb/P15328.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P15328/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P15328"}},"corpus_meta":[{"pmid":"38055253","id":"PMC_38055253","title":"Mirvetuximab Soravtansine in FRα-Positive, Platinum-Resistant Ovarian Cancer.","date":"2023","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38055253","citation_count":340,"is_preprint":false},{"pmid":"25904506","id":"PMC_25904506","title":"IMGN853, a Folate Receptor-α (FRα)-Targeting Antibody-Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRα-Expressing Tumors.","date":"2015","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/25904506","citation_count":187,"is_preprint":false},{"pmid":"35094917","id":"PMC_35094917","title":"Emerging roles for folate receptor FOLR1 in signaling and cancer.","date":"2022","source":"Trends in endocrinology and metabolism: TEM","url":"https://pubmed.ncbi.nlm.nih.gov/35094917","citation_count":133,"is_preprint":false},{"pmid":"28843653","id":"PMC_28843653","title":"Characterization of folate receptor alpha (FRα) expression in archival tumor and biopsy samples from relapsed epithelial ovarian cancer patients: A phase I expansion study of the FRα-targeting antibody-drug conjugate mirvetuximab soravtansine.","date":"2017","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/28843653","citation_count":119,"is_preprint":false},{"pmid":"32081463","id":"PMC_32081463","title":"Phase Ib study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer.","date":"2020","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32081463","citation_count":119,"is_preprint":false},{"pmid":"25816016","id":"PMC_25816016","title":"Folate receptor-α (FOLR1) expression and function in triple negative tumors.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25816016","citation_count":108,"is_preprint":false},{"pmid":"36736157","id":"PMC_36736157","title":"Safety and efficacy of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer.","date":"2023","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36736157","citation_count":99,"is_preprint":false},{"pmid":"37212825","id":"PMC_37212825","title":"FDA Approval Summary: Mirvetuximab Soravtansine-Gynx for FRα-Positive, Platinum-Resistant Ovarian Cancer.","date":"2023","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/37212825","citation_count":90,"is_preprint":false},{"pmid":"25349970","id":"PMC_25349970","title":"Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. 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proteomics identifies FOLR1 to drive sorafenib resistance via activating autophagy in hepatocellular carcinoma cells.","date":"2021","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/33677528","citation_count":11,"is_preprint":false},{"pmid":"23023342","id":"PMC_23023342","title":"Expression of genes FOLR1, BAG1 and LAPTM4B in functioning and non-functioning pituitary adenomas.","date":"2012","source":"Folia neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/23023342","citation_count":11,"is_preprint":false},{"pmid":"26667416","id":"PMC_26667416","title":"Genetic Variation in Renal Expression of Folate Receptor 1 (Folr1) Gene Predisposes Spontaneously Hypertensive Rats to Metabolic Syndrome.","date":"2015","source":"Hypertension (Dallas, Tex. : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/26667416","citation_count":11,"is_preprint":false},{"pmid":"34258135","id":"PMC_34258135","title":"Cerebral folate deficiency in two siblings caused by biallelic variants including a novel mutation of FOLR1 gene: Intrafamilial heterogeneity following early treatment and the role of ketogenic diet.","date":"2021","source":"JIMD reports","url":"https://pubmed.ncbi.nlm.nih.gov/34258135","citation_count":11,"is_preprint":false},{"pmid":"40700855","id":"PMC_40700855","title":"Safety and efficacy of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with pembrolizumab in patients with platinum-resistant ovarian cancer.","date":"2025","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40700855","citation_count":10,"is_preprint":false},{"pmid":"38282564","id":"PMC_38282564","title":"Development of an FRα Companion Diagnostic Immunohistochemical Assay for Mirvetuximab Soravtansine.","date":"2024","source":"Archives of pathology & laboratory 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/34008900","citation_count":10,"is_preprint":false},{"pmid":"33243190","id":"PMC_33243190","title":"First case report of cerebral folate deficiency caused by a novel mutation of FOLR1 gene in a Chinese patient.","date":"2020","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33243190","citation_count":10,"is_preprint":false},{"pmid":"37028598","id":"PMC_37028598","title":"FOLR1-induced folate deficiency reduces viral replication via modulating APOBEC3 family expression.","date":"2023","source":"Virologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/37028598","citation_count":9,"is_preprint":false},{"pmid":"37647218","id":"PMC_37647218","title":"BiTE secretion by adoptively transferred stem-like T cells improves FRα+ ovarian cancer control.","date":"2023","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37647218","citation_count":9,"is_preprint":false},{"pmid":"28826993","id":"PMC_28826993","title":"Expression and characterization of the zebrafish orthologue of the human FOLR1 gene during embryogenesis.","date":"2017","source":"Gene expression patterns : GEP","url":"https://pubmed.ncbi.nlm.nih.gov/28826993","citation_count":8,"is_preprint":false},{"pmid":"21649587","id":"PMC_21649587","title":"Altered signal transduction in Folr1-/- mouse embryo fibroblasts.","date":"2011","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/21649587","citation_count":8,"is_preprint":false},{"pmid":"33561557","id":"PMC_33561557","title":"Identification of proteins related with pemetrexed resistance by iTRAQ and PRM-based comparative proteomic analysis and exploration of IGF2BP2 and FOLR1 functions in non-small cell lung cancer cells.","date":"2021","source":"Journal of proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/33561557","citation_count":8,"is_preprint":false},{"pmid":"24401732","id":"PMC_24401732","title":"Decitabine impact on the endocytosis regulator RhoA, the folate carriers RFC1 and FOLR1, and the glucose transporter GLUT4 in human tumors.","date":"2014","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/24401732","citation_count":8,"is_preprint":false},{"pmid":"25532689","id":"PMC_25532689","title":"[FRα: a target for prophylactic photodynamic therapy of ovarian peritoneal metastasis?].","date":"2014","source":"Bulletin du cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25532689","citation_count":8,"is_preprint":false},{"pmid":"30113208","id":"PMC_30113208","title":"Dissecting the role of Folr1 and Folh1 genes in the pathogenesis of metabolic syndrome in spontaneously hypertensive rats.","date":"2018","source":"Physiological research","url":"https://pubmed.ncbi.nlm.nih.gov/30113208","citation_count":7,"is_preprint":false},{"pmid":"41132836","id":"PMC_41132836","title":"A dual-targeting peptide-drug conjugate based on CXCR4 and FOLR1 inhibits triple-negative breast cancer.","date":"2025","source":"Acta pharmaceutica Sinica. 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Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38239817","citation_count":5,"is_preprint":false},{"pmid":"39085882","id":"PMC_39085882","title":"PARP-1, EpCAM, and FRα as potential targets for intraoperative detection and delineation of endometriosis: a quantitative tissue expression analysis.","date":"2024","source":"Reproductive biology and endocrinology : RB&E","url":"https://pubmed.ncbi.nlm.nih.gov/39085882","citation_count":5,"is_preprint":false},{"pmid":"38513348","id":"PMC_38513348","title":"Exosomal or follicular FNDC3A decreases FOLR1 mRNA abundance and progesterone and lactate synthesis in bovine granulosa cells.","date":"2024","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38513348","citation_count":4,"is_preprint":false},{"pmid":"40121972","id":"PMC_40121972","title":"Patient outcomes in advanced ovarian cancer treated with an anti-FOLR1 antibody-drug conjugate.","date":"2025","source":"Gynecologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40121972","citation_count":3,"is_preprint":false},{"pmid":"37702010","id":"PMC_37702010","title":"FOLR1-stabilized β-catenin promotes laryngeal carcinoma progression through EGFR/AKT/GSK-3β pathway.","date":"2023","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/37702010","citation_count":3,"is_preprint":false},{"pmid":"37269960","id":"PMC_37269960","title":"Reduced YAP1 and FOLR1 in gliomas predict better response to chemotherapeutics.","date":"2023","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/37269960","citation_count":3,"is_preprint":false},{"pmid":"40769949","id":"PMC_40769949","title":"Folate receptor alpha (FRα/FOLR1) and HER2 immunohistochemical staining in high-grade endometrial carcinoma with aberrant p53 expression.","date":"2025","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/40769949","citation_count":3,"is_preprint":false},{"pmid":"38915965","id":"PMC_38915965","title":"Expression of the Folate Receptor Proteins FOLR1 and FOLR2 in Correlation With Clinicopathological Variables of Gastric Cancer.","date":"2024","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/38915965","citation_count":3,"is_preprint":false},{"pmid":"39798773","id":"PMC_39798773","title":"NSD2 mediated H3K36me2 promotes pulmonary arterial hypertension by recruiting FOLR1 and metabolism reprogramming.","date":"2025","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/39798773","citation_count":3,"is_preprint":false},{"pmid":"35273364","id":"PMC_35273364","title":"Association of polymorphisms of FOLR1 gene and FOLR2 gene and maternal folic acid supplementation with risk of ventricular septal defect: a case-control study.","date":"2022","source":"European journal of clinical nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/35273364","citation_count":3,"is_preprint":false},{"pmid":"39594628","id":"PMC_39594628","title":"Identification and Characterization of Fully Human FOLR1-Targeting CAR T Cells for the Treatment of Ovarian Cancer.","date":"2024","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/39594628","citation_count":3,"is_preprint":false},{"pmid":"40293943","id":"PMC_40293943","title":"The Anti-FRα Antibody-Drug Conjugate Luveltamab Tazevibulin Demonstrates Efficacy in Non-Small Cell Lung Cancer Preclinical Models and Induces Immunogenic Cell Death.","date":"2025","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/40293943","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":56055,"output_tokens":6950,"usd":0.136208,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16249,"output_tokens":5091,"usd":0.10426,"stage2_stop_reason":"end_turn"},"total_usd":0.240468,"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\": 1994,\n      \"finding\": \"FR-α (FOLR1) is the isoform selectively expressed in human placental syncytiotrophoblast and choriocarcinoma cells, not FR-β as previously believed. RT-PCR with isoform-specific primers and Northern blot analysis of placental trophoblast cells and JAR choriocarcinoma cells confirmed only FR-α mRNA, with nucleotide sequences identical to FR-α cDNA.\",\n      \"method\": \"RT-PCR with isoform-specific primers, Northern blot analysis, DNA sequencing\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (RT-PCR and Northern blot) in a single study; no functional mutagenesis follow-up\",\n      \"pmids\": [\"8061055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"DNA vaccination with FRα (FOLR1) cDNA induces both IgG2a antibody responses and cytotoxic T lymphocyte activity against FRα-expressing tumor cells in mice, and delays tumor growth upon challenge with FRα-transduced cells, demonstrating immunogenicity of the surface-expressed protein.\",\n      \"method\": \"In vivo DNA vaccination, FACS-based antibody detection, cytotoxic T lymphocyte assay, tumor challenge model\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal in vivo assays in a single study confirming FOLR1 as a functional immunogen; single lab\",\n      \"pmids\": [\"10419053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Folr1 knockout mouse embryos develop cardiovascular abnormalities including outflow tract defects, aortic arch artery anomalies, and dextracardia, with abnormal heart looping and disrupted migration of cardiac neural crest cells; maternal folinic acid supplementation rescues these defects in a dose-dependent manner, implicating FOLR1-mediated folate transport in cardiac neural crest cell function and pharyngeal arch/secondary heart field signaling.\",\n      \"method\": \"Folr1 knockout mouse model, folinic acid dose-response rescue study, histological analysis of cardiac development\",\n      \"journal\": \"Birth defects research. Part A, Clinical and molecular teratology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined phenotype, dose-response rescue, replicated across developmental stages; strong mechanistic readout\",\n      \"pmids\": [\"17286298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Folr1 gene ablation alters expression of genes involved in cell migration, cytoskeletal organization, cell-cell adhesion, and cellular redox status in developing cardiac and conotruncal tissues, suggesting FOLR1-dependent folate homeostasis regulates gene expression programs required for cardiovascular morphogenesis.\",\n      \"method\": \"Microarray analysis of Folr1 knockout embryo cardiac tissue at three developmental stages, validated by quantitative real-time PCR\",\n      \"journal\": \"BMC developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined transcriptional phenotype, validated by qPCR; single lab, no direct protein-level mechanistic follow-up\",\n      \"pmids\": [\"18028541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Loss-of-function homozygous missense mutation p.Cys105Arg in FOLR1 abolishes a predicted disulfide bond required for correct protein folding, causing defective cerebral folate transport across the blood-CSF barrier and profound CSF 5-methyltetrahydrofolate deficiency, establishing that FOLR1 is the primary folate transporter at the choroid plexus.\",\n      \"method\": \"FOLR1 gene sequencing in patient with cerebral folate deficiency, CSF 5-MTHF measurement by HPLC, structural prediction of disulfide bond disruption\",\n      \"journal\": \"Journal of inherited metabolic disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human loss-of-function genetics with biochemical phenotype (CSF 5-MTHF); single family, no in vitro reconstitution of transport\",\n      \"pmids\": [\"20857335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"FOLR1-dependent 5-methyltetrahydrofolate (MTHF) uptake in KB cells follows saturation kinetics consistent with high-affinity receptor-mediated transport at physiological MTHF concentrations; reactive oxygen species (but not valproate or carbamazepine) significantly decrease FOLR1-mediated MTHF uptake, as confirmed by PIPLC cleavage and siRNA silencing of FOLR1.\",\n      \"method\": \"KB cell culture assay, phosphatidylinositol-specific phospholipase C (PIPLC) cleavage, siRNA knockdown, MTHF uptake quantification\",\n      \"journal\": \"Molecular genetics and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro transport assay with specific enzymatic cleavage and siRNA knockdown confirming FOLR1 as the transporting entity; multiple orthogonal methods\",\n      \"pmids\": [\"20619709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Folr1-deficient mouse embryonic fibroblasts show attenuated TGFβ1/Smad signaling (measured by Smad-dependent reporter assay) and increased canonical Wnt pathway activity (Wnt-3a-stimulated Axin2 expression), demonstrating that FOLR1 loss alters developmental signaling pathways relevant to neural tube closure.\",\n      \"method\": \"Primary Folr1-/- mouse embryonic fibroblast cultures, luciferase reporter assay (p3TP-lux), quantitative gene expression analysis of Wnt target genes\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO cell model with reporter assays and gene expression; single lab, mechanistic follow-up limited\",\n      \"pmids\": [\"21649587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FOLR1 overexpression in ovarian cancer cells promotes folate uptake and enhances cell proliferation, migration, and invasion in response to folate; stable knockdown of FOLR1 blocks folate-induced cancer cell migration and invasion and reverses downregulation of E-cadherin. Ectopic overexpression of RFC (reduced folate carrier) phenocopies FRα knockdown, suggesting RFC counterbalances FRα-mediated pro-tumorigenic signaling.\",\n      \"method\": \"Stable FRα knockdown and RFC overexpression in ovarian cancer cell lines, in vitro proliferation, migration and invasion assays, E-cadherin Western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stable KD and OE with multiple phenotypic readouts; single lab\",\n      \"pmids\": [\"23144806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Homology modeling and molecular dynamics of FOLR1 using the riboflavin-binding protein crystal structure as template revealed a full disulfide bridge network and identified key residues in the folate-binding pocket; docking studies showed that folic acid and vintafolide share the same binding site, with Trp and His residues contributing to ligand specificity.\",\n      \"method\": \"Homology modeling, molecular dynamics simulation, in silico ligand docking\",\n      \"journal\": \"Journal of molecular graphics & modelling\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — purely computational; no experimental structural or mutagenesis validation\",\n      \"pmids\": [\"23880302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The anti-FOLR1 monoclonal antibody farletuzumab (MORAb-003) mediates its antitumor effect against ovarian cancer xenografts primarily through antibody-dependent cellular cytotoxicity (ADCC), as demonstrated in an experimental ovarian cancer model.\",\n      \"method\": \"ADCC assay, human ovarian cancer xenograft mouse model with farletuzumab treatment\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro ADCC plus in vivo xenograft; single lab, mechanism confirmed by ADCC assay\",\n      \"pmids\": [\"24025360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FOLR1 knockdown in triple-negative breast cancer cell lines with high endogenous FOLR1 expression causes growth inhibition, while FOLR1 overexpression promotes folate uptake and confers growth advantage under low-folate conditions, directly linking surface FOLR1 expression to folate import and cell proliferation.\",\n      \"method\": \"RNA interference knockdown, FOLR1 overexpression, folate uptake assay, cell proliferation assay in low-folate medium\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional functional experiments (KD and OE) with biochemical readout; single lab\",\n      \"pmids\": [\"25816016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Folic acid (FA) inhibits colon cancer cell proliferation through a FOLR1-dependent signaling cascade: FA binding to FRα activates c-SRC, which activates ERK1/2, leading to NFκB nuclear translocation, TP53 upregulation, and increased CDKN1A/CDKN1B expression causing G0/G1 arrest. Knockdown of FOLR1 abolishes FA-induced c-SRC pathway activation and downstream effects.\",\n      \"method\": \"FRα siRNA knockdown, TP53 siRNA knockdown, Western blot (c-SRC, ERK1/2, NFκB, TP53, CDKN1A, CDKN1B), cell cycle analysis, in vivo xenograft\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple KD experiments with epistasis and signaling readouts; single lab, no reconstitution\",\n      \"pmids\": [\"26056802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"FOLR1 surface expression level is a major determinant of sensitivity to anti-FOLR1 antibody-drug conjugate (ADC) IMGN853/mirvetuximab soravtansine; cells with low or no FRα are resistant, while high FRα-expressing cells are highly sensitive, and bystander cytotoxic activity is observed against FRα-negative cells co-cultured with FRα-positive cells.\",\n      \"method\": \"FRα expression quantification by immunohistochemistry, in vitro cytotoxicity assays, FRα-positive and FRα-negative co-culture bystander assay, xenograft models\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative correlation of surface receptor with ADC potency in vitro and in vivo; single lab, multiple model systems\",\n      \"pmids\": [\"25904506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Genetic variation in the Folr1 promoter of spontaneously hypertensive rats (SHR) reduces renal Folr1 expression and folate reabsorption, causing decreased serum folate, hypercysteinemia, adiposity, reduced insulin sensitivity, and increased blood pressure; transgenic rescue with a Folr1 transgene in SHR ameliorates these metabolic disturbances, establishing FOLR1-mediated renal folate reabsorption as a regulator of sulfur amino acid metabolism and metabolic syndrome.\",\n      \"method\": \"QTL mapping, SHR.BN-chr.1 congenic strain analysis, luciferase promoter reporter assay, Folr1 transgenic rescue experiment, metabolic phenotyping\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — promoter reporter assay plus transgenic rescue plus congenic strain phenotyping; multiple orthogonal methods with functional rescue\",\n      \"pmids\": [\"26667416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"mTORC1 and mTORC2 positively regulate folate uptake in primary human trophoblast cells by controlling the plasma membrane abundance of FR-α (FOLR1) and RFC through post-translational mechanisms, without affecting total protein levels; silencing of raptor (mTORC1) or rictor (mTORC2) markedly decreases surface FR-α and reduces folate uptake; mTORC2 but not mTORC1 mediates insulin+IGF-1-stimulated folate uptake.\",\n      \"method\": \"siRNA silencing of raptor/rictor, plasma membrane fractionation, folate uptake assay in primary human trophoblast cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — targeted KD with membrane fractionation and functional uptake assay; single lab, primary cell model\",\n      \"pmids\": [\"27562465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FolR1 specifically marks midbrain dopaminergic (mesDA) neural progenitors and immature dopamine neurons during mouse development (E9.5–E14.5) and in ESC-derived cultures; FACS/MACS-sorted FolR1+ neural progenitors give rise to TH+ and Pitx3+ dopamine neurons, while FolR1-negative cells generate non-dopaminergic neurons and glia.\",\n      \"method\": \"Immunofluorescence co-staining with Lmx1a, FACS/MACS cell sorting, in vitro differentiation assay of sorted populations\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — prospective isolation with functional differentiation readout; single lab, no KO/KD mechanistic follow-up\",\n      \"pmids\": [\"27580818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Folic acid (FA) bound to FRα induces MEK/ERK1/2 activation and increases TSLC1 and E-cadherin expression in nasopharyngeal cancer cells; blocking ERK1/2 activation attenuates FA-mediated TSLC1 upregulation; TSLC1 knockdown abolishes FA-mediated inhibition of proliferation, invasion and migration, defining an FRα/ERK1/2/TSLC1 signaling pathway.\",\n      \"method\": \"ERK1/2 inhibitor treatment, siRNA knockdown of TSLC1, Western blot, proliferation/invasion/migration assays\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic epistasis establishing pathway order; single lab\",\n      \"pmids\": [\"29070520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Folic acid modifies epithelial cell shape during morphogenesis via FOLR1 and MLCK in a RhoA/ROCK-independent but Src-kinase-dependent manner; co-expression of Folr1 rescues the apical constriction defect of a Rho-kinase-binding mutant of Shroom3 in vitro; treatment with FA is accompanied by elevated phospho-myosin light chain and MLCK; doubly heterozygous mice lacking one copy each of Shroom3 and Folr1 show neural tube defects with reduced activated myosin and MLCK.\",\n      \"method\": \"Epithelial cell culture apical constriction model, chick embryo neural epithelium rescue assay, MLCK inhibitor and Src-kinase inhibitor treatment, double heterozygous mouse genetics, phospho-MLC Western blot\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal systems (cell culture, chick embryo, mouse genetics), pharmacological pathway dissection, epistasis; consistent mechanistic outcome\",\n      \"pmids\": [\"30670450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CIC (capicua) transcription factor directly binds to octameric sequences in the FOLR1 promoter; CIC loss-of-function variants (including a nonsense mutation p.R353X) downregulate FOLR1 expression in HeLa cells and patient-derived iPSCs, and decrease cellular folic acid binding, establishing CIC as a transcriptional regulator of FOLR1 expression.\",\n      \"method\": \"Whole exome sequencing, promoter binding assay (CIC ChIP/reporter), siRNA in HeLa cells, iPSC-derived cells from CFD proband, folic acid binding assay\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — promoter binding confirmed by functional assay, siRNA in two cell systems including patient iPSCs, biochemical binding assay; multiple orthogonal methods\",\n      \"pmids\": [\"32820034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Core-fucosylation of FOLR1 (particularly at glycosite Asn-201) positively regulates cellular folate uptake capacity; FUT8 is a driver of HGF/TGF-β1-induced EMT in HCC cells, and FUT8 silencing reduces FOLR1 core-fucosylation and partially blocks EMT. Enhanced folate uptake mediated by core-fucosylated FOLR1 promotes EMT progression.\",\n      \"method\": \"Mass spectrometry-based glycoproteomics, FUT8 siRNA knockdown, intact glycopeptide quantification, molecular biology assays for EMT markers, folate uptake assay\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-specific glycosylation identified by MS, functional KD with uptake and EMT readouts; single lab\",\n      \"pmids\": [\"34093861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Folr1 overexpression and folinic acid treatment stimulate β-cell differentiation from ductal cells in zebrafish and in neonatal pig islet cultures; comparative metabolomics of zebrafish with/without β-cell ablation and folinic acid treatment implicates pyrimidine, carnitine, and serine pathways as downstream effectors of FOLR1/one-carbon metabolism in β-cell regeneration.\",\n      \"method\": \"Zebrafish genetic screen, folr1 overexpression and folinic acid treatment, neonatal pig islet culture, comparative metabolomics\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological gain-of-function with metabolomic pathway mapping in two model systems; single lab\",\n      \"pmids\": [\"34099692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FOLR1 overexpression drives sorafenib resistance in HCC cells; immunoprecipitation-mass spectrometry identified interaction between FOLR1 and autophagy-related proteins; FOLR1-induced resistance is accompanied by autophagy activation; autophagy inhibition significantly reduces FOLR1-induced drug resistance.\",\n      \"method\": \"Label-free quantitative proteomics, siRNA knockdown, FOLR1 overexpression, immunoprecipitation-mass spectrometry, autophagy inhibitor treatment, cell viability assay\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS identifying FOLR1-autophagy protein interaction, functional KD/OE with autophagy inhibitor epistasis; single lab\",\n      \"pmids\": [\"33677528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOLR1 overexpression increases APOBEC3B expression and suppresses VSV viral replication in HeLa cells and in vivo by causing intracellular folate deficiency; the antiviral effect is dependent on folate deficiency rather than direct antiviral signaling, as exogenous folate supplementation reverses FOLR1-mediated viral suppression.\",\n      \"method\": \"FOLR1 overexpression in HeLa cells and mice, VSV infection assay, APOBEC3B knockdown, folate supplementation rescue, in vivo mouse model\",\n      \"journal\": \"Virologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — OE with rescue experiment and KD epistasis in vitro and in vivo; single lab\",\n      \"pmids\": [\"37028598\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOLR1 promotes proliferation and migration of laryngeal squamous cell carcinoma cells by stabilizing β-catenin through the EGFR/AKT/GSK-3β signaling axis; FOLR1 inhibits β-catenin ubiquitination and degradation; blocking EGFR or the AKT/GSK-3β axis abolishes FOLR1's effects on β-catenin expression and nuclear translocation; β-catenin siRNA knockdown abolishes FOLR1-induced proliferation and migration.\",\n      \"method\": \"siRNA knockdown of FOLR1 and β-catenin, EGFR inhibitor treatment, AKT inhibitor treatment, co-immunoprecipitation/ubiquitination assay, Western blot for β-catenin nuclear localization\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic epistasis with ubiquitination assay; single lab, single study\",\n      \"pmids\": [\"37702010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YAP1 and its partner transcription factor TEAD2 regulate FOLR1 expression in gliomas; chromatin immunoprecipitation and YAP1-TEAD inhibitor (verteporfin) treatment demonstrated direct transcriptional control; FOLR1 depletion in IDH1 wild-type glioma cells increases sensitivity to temozolomide-mediated cell death and heightens DNA damage markers (γH2AX, ATM phosphorylation).\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), mutant YAP1 overexpression, verteporfin treatment (YAP1-TEAD inhibitor), FOLR1 siRNA knockdown, γH2AX and pATM assay, cell death assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus pharmacological epistasis plus KD functional readout; single lab\",\n      \"pmids\": [\"37269960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NSD2-mediated H3K36me2 recruits nuclear FOLR1 to promoters of glycolytic genes (HK2, TIGAR, G6PD) in pulmonary artery endothelial cells; FOLR1 acts as a transcription factor, and its nuclear translocation depends on NSD2 activity; NSD2 or FOLR1 knockdown reduces promoter activity and expression of glycolytic genes, and reverses the metabolic shift toward aerobic glycolysis in monocrotaline-induced PAH.\",\n      \"method\": \"NSD2 and FOLR1 siRNA knockdown, ChIP for H3K36me2 and FOLR1 at glycolytic gene promoters, promoter activity assay, metabolic flux analysis (OCR, ECAR), in vivo monocrotaline PAH mouse model\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating nuclear FOLR1 binding to gene promoters, promoter activity assay, functional KD in vitro and in vivo; single lab\",\n      \"pmids\": [\"39798773\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FOLR1 (FRα) is a GPI-anchored glycoprotein that functions as a high-affinity folate transporter mediating receptor-mediated endocytosis of 5-methyltetrahydrofolate at the cell surface, with surface abundance regulated post-translationally by mTORC1/2 and by core-fucosylation at Asn-201 (catalyzed by FUT8); beyond folate import, FOLR1 engages non-canonical signaling roles including activation of FRα/c-SRC/ERK1/2/NFκB/TP53, FRα/ERK1/2/TSLC1, and EGFR/AKT/GSK-3β/β-catenin pathways that regulate proliferation, migration, and drug resistance, and in certain contexts FOLR1 translocates to the nucleus where it acts as a transcription factor recruited by NSD2/H3K36me2 to upregulate glycolytic gene promoters; its expression is transcriptionally controlled by the CIC/capicua transcription factor and by YAP1-TEAD2, while promoter variants in the SHR rat reduce renal FOLR1 expression, impairing folate reabsorption and causing metabolic syndrome features that are rescued by Folr1 transgene expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FOLR1 (FRα) is a high-affinity, GPI-anchored cell-surface receptor that mediates receptor-mediated import of 5-methyltetrahydrofolate, functioning as the principal folate-uptake entity in epithelial and barrier tissues [#5, #10]. Its transport activity follows saturation kinetics, is sensitive to reactive oxygen species, and is abolished by GPI cleavage or silencing, confirming FOLR1 itself as the transporting moiety [#5]. FOLR1-dependent folate delivery is required for normal development: knockout mouse embryos display cardiovascular and cardiac neural crest defects rescuable by folinic acid [#2], FRα marks midbrain dopaminergic progenitors [#15], and FOLR1 cooperates genetically with Shroom3 to drive Src-kinase/MLCK-dependent apical constriction during neural tube closure [#17]. In humans, a loss-of-function p.Cys105Arg mutation disrupts a folding-critical disulfide bond, causing cerebral folate deficiency and establishing FOLR1 as the folate transporter of the choroid plexus blood–CSF barrier [#4]. Surface abundance is set post-translationally by mTORC1/mTORC2 signaling and by FUT8-mediated core-fucosylation at Asn-201, both of which tune folate-uptake capacity [#14, #19], while transcription is controlled by CIC/capicua and by YAP1–TEAD2 [#18, #24]. Beyond folate import, FOLR1 engages non-canonical signaling: ligand-bound FRα activates c-SRC/ERK1/2/NF-κB/TP53 to enforce cell-cycle arrest in colon cancer [#11], an ERK1/2/TSLC1 axis in nasopharyngeal cancer [#16], and an EGFR/AKT/GSK-3β axis that stabilizes β-catenin to promote proliferation and migration [#23]; it can also translocate to the nucleus, where NSD2/H3K36me2 recruits it to glycolytic gene promoters to act as a transcriptional driver of aerobic glycolysis [#25]. These activities underlie FOLR1's role in tumor folate uptake, proliferation, invasion, and drug resistance, making it a validated target for anti-FRα antibodies and antibody-drug conjugates whose efficacy tracks with surface receptor density [#7, #10, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing which folate receptor isoform is expressed in placental trophoblast resolved that FRα (FOLR1), not FRβ, is the relevant transporter in this tissue, anchoring later transport and developmental work to the correct gene product.\",\n      \"evidence\": \"Isoform-specific RT-PCR, Northern blot, and sequencing in placental trophoblast and JAR cells\",\n      \"pmids\": [\"8061055\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional transport assay in this study\", \"Does not address regulation or signaling roles\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Folr1 knockout in mouse and transcriptomic profiling showed that FOLR1-mediated folate transport is required for cardiac neural crest migration and cardiovascular morphogenesis, framing FOLR1 as a developmental folate-delivery gene rather than a passive carrier.\",\n      \"evidence\": \"Folr1 knockout mouse embryos with folinic acid rescue and microarray/qPCR of cardiac tissue\",\n      \"pmids\": [\"17286298\", \"18028541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking folate to neural crest gene programs not resolved at protein level\", \"Whether effects are purely metabolic or also signaling\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Human loss-of-function genetics and in vitro kinetic analysis established FOLR1 as the high-affinity folate transporter at the blood–CSF barrier and demonstrated saturable receptor-mediated uptake sensitive to oxidative stress.\",\n      \"evidence\": \"Patient FOLR1 sequencing with CSF 5-MTHF measurement; KB-cell uptake assays with PIPLC cleavage and siRNA\",\n      \"pmids\": [\"20857335\", \"20619709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of transport\", \"Single family for the disease mutation\", \"Cycling/endocytic mechanism of uptake not detailed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Folr1-null fibroblasts linked FOLR1 loss to altered TGFβ/Smad and Wnt signaling, indicating folate status feeds into developmental signaling pathways relevant to neural tube closure.\",\n      \"evidence\": \"Primary Folr1-/- MEF reporter assays and Wnt target gene expression\",\n      \"pmids\": [\"21649587\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between FOLR1 and these pathways not established\", \"Single lab, reporter-based readouts\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Bidirectional manipulation in ovarian cancer cells defined FOLR1 as a pro-tumorigenic driver of folate-dependent proliferation, migration, and invasion counterbalanced by RFC, moving FOLR1 from a transporter to a phenotype-controlling oncology target.\",\n      \"evidence\": \"Stable FRα knockdown, RFC overexpression, migration/invasion assays, E-cadherin Western blot\",\n      \"pmids\": [\"23144806\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Signaling intermediaries not identified\", \"Single lab\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Computational modeling and antibody studies began defining the folate-binding pocket and validated FOLR1 surface expression as an immunotherapy/ADCC target.\",\n      \"evidence\": \"Homology modeling/MD/docking; farletuzumab ADCC and ovarian xenograft assays\",\n      \"pmids\": [\"23880302\", \"24025360\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural model lacks experimental validation\", \"ADCC mechanism shown without crystallographic epitope mapping\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"A series of studies linked FOLR1 surface level directly to folate import, proliferation under low folate, and sensitivity to FRα-targeted ADCs, while defining a folate-bound FRα/c-SRC/ERK/NF-κB/TP53 cascade controlling cell cycle.\",\n      \"evidence\": \"FOLR1 KD/OE in TNBC, ADC cytotoxicity/bystander/xenograft assays, and siRNA epistasis with signaling Western blots in colon cancer\",\n      \"pmids\": [\"25816016\", \"25904506\", \"26056802\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical coupling of FRα to c-SRC not demonstrated\", \"Context-dependence of pro- vs anti-proliferative signaling unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"QTL mapping and transgenic rescue in SHR rats established renal FOLR1-mediated folate reabsorption as a determinant of sulfur amino acid metabolism and metabolic syndrome traits.\",\n      \"evidence\": \"Congenic strains, promoter reporter assay, Folr1 transgenic rescue, metabolic phenotyping\",\n      \"pmids\": [\"26667416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Causal promoter variant mechanism in human metabolic disease not addressed\", \"Tissue-specific contributions not dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of mTORC1/mTORC2 as post-translational regulators of FRα plasma-membrane abundance, and prospective FolR1+ isolation of dopaminergic progenitors, expanded FOLR1 regulation and lineage-marker roles.\",\n      \"evidence\": \"raptor/rictor siRNA with membrane fractionation in trophoblasts; FACS/MACS sorting and differentiation of FolR1+ neural progenitors\",\n      \"pmids\": [\"27562465\", \"27580818\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trafficking machinery downstream of mTOR not identified\", \"Whether FolR1 marking is functional or incidental in dopaminergic lineage unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Epistasis dissection defined an FRα/ERK1/2/TSLC1 pathway through which folate-bound FOLR1 suppresses nasopharyngeal cancer cell proliferation and invasion, adding a second tumor-suppressive signaling branch.\",\n      \"evidence\": \"ERK inhibitor and TSLC1 siRNA with proliferation/invasion/migration assays\",\n      \"pmids\": [\"29070520\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of FRα-to-MEK/ERK coupling unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Multi-system genetics showed FOLR1 cooperates with Shroom3 via a Src-kinase/MLCK/phospho-myosin axis to drive apical constriction, mechanistically connecting folate signaling to morphogenetic cell-shape change and neural tube closure.\",\n      \"evidence\": \"Cell-culture and chick embryo apical constriction rescue, MLCK/Src inhibitors, Shroom3;Folr1 double-heterozygous mice, phospho-MLC Western blot\",\n      \"pmids\": [\"30670450\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical link between FRα and MLCK not shown\", \"How folate signal reaches the cytoskeleton from a GPI-anchored receptor unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"FUT8-dependent core-fucosylation at Asn-201, FOLR1-driven sorafenib resistance via autophagy, and folinic acid/Folr1-stimulated β-cell differentiation broadened FOLR1's roles into glycan-regulated uptake, drug resistance, and one-carbon-metabolism-driven regeneration.\",\n      \"evidence\": \"Glycoproteomics with FUT8 siRNA; IP-MS and autophagy-inhibitor epistasis in HCC; zebrafish/pig islet gain-of-function with metabolomics\",\n      \"pmids\": [\"34093861\", \"33677528\", \"34099692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FOLR1 autophagy-protein interactors not individually validated\", \"Causal metabolite mediators of β-cell regeneration not proven\", \"Single labs per finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"FOLR1 was shown to drive an EGFR/AKT/GSK-3β axis stabilizing β-catenin, an APOBEC3B-dependent antiviral effect via induced folate deficiency, and YAP1–TEAD2-controlled expression modulating glioma temozolomide sensitivity, extending its non-canonical signaling and transcriptional regulation.\",\n      \"evidence\": \"Inhibitor/siRNA epistasis and ubiquitination assays (LSCC); OE/KD with folate rescue and VSV assays; ChIP, verteporfin, and DNA-damage readouts in glioma\",\n      \"pmids\": [\"37702010\", \"37028598\", \"37269960\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether β-catenin stabilization is folate-dependent unclear\", \"Direct FRα–EGFR coupling not shown\", \"Single lab per study\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstration that NSD2/H3K36me2 recruits nuclear FOLR1 to glycolytic gene promoters established a moonlighting transcription-factor role driving aerobic glycolysis in pulmonary artery endothelial cells.\",\n      \"evidence\": \"ChIP for FOLR1 and H3K36me2, promoter activity and metabolic flux assays, NSD2/FOLR1 KD in vitro and monocrotaline PAH mouse model\",\n      \"pmids\": [\"39798773\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism and trafficking route of GPI-anchored FOLR1 to the nucleus unexplained\", \"Whether nuclear FOLR1 binds DNA directly or via cofactors unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single GPI-anchored folate receptor mechanistically couples extracellular folate binding to intracellular kinase cascades and to nuclear transcriptional activity, and what determines tumor-suppressive versus pro-tumorigenic signaling outcomes, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural basis for FRα-to-cytoplasmic-effector coupling\", \"Mechanism of nuclear translocation of a GPI-anchored protein unknown\", \"Context-dependence of opposing signaling outputs not explained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [4, 5, 10, 14]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [25]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 12, 14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [4, 5, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 16, 23]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [13, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FUT8\", \"NSD2\", \"EGFR\", \"TEAD2\", \"YAP1\", \"CIC\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}