{"gene":"LINGO2","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2019,"finding":"LINGO2 physically interacts with TFF3 (Trefoil factor 3) by co-immunoprecipitation, co-localizes with TFF3 on the intestinal epithelial cell membrane, and forms an inhibitory complex with EGFR. TFF3 binding to LINGO2 disrupts LINGO2-EGFR complexes, thereby de-repressing EGFR signaling and allowing TFF3 to block apoptosis and promote wound healing.","method":"Co-immunoprecipitation, co-localization imaging, Lingo2-deficient mouse model with colitis/helminth phenotypic readouts, apoptosis assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, co-localization, genetic knockout model with multiple orthogonal phenotypic readouts across barrier integrity, apoptosis, and infection paradigms","pmids":["31562318"],"is_preprint":false},{"year":2023,"finding":"In rat stroke (MCAO) model, liver-derived TFF3 co-immunoprecipitates with LINGO2 in the brain; LINGO2 siRNA knockdown or EGFR inhibition reversed TFF3-mediated increases in p-EGFR, p-Src, and Bcl-2, and worsened neuronal apoptosis and neurological deficits, establishing a LINGO2/EGFR/Src signaling axis mediating TFF3 neuroprotection.","method":"Co-immunoprecipitation, siRNA knockdown (intracerebroventricular), western blot, EGFR inhibitor pharmacology, immunofluorescence, behavioral assays in rats","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with defined pathway readouts and pharmacological validation in a single lab, consistent with the intestinal LINGO2-EGFR mechanism","pmids":["37935323"],"is_preprint":false},{"year":2024,"finding":"A soluble ectodomain form of Lingo2 (sLingo2) is produced by proteolytic cleavage mediated by the transmembrane metalloprotease ADAM10, and sLingo2 acts as an excitatory synapse organizer, inducing excitatory synapse formation in mouse and human neurons and increasing miniature excitatory postsynaptic current frequency.","method":"Quantitative secretome analysis, ADAM10 metalloprotease identification, in vitro synaptogenesis assays with mouse and human neurons, whole-cell electrophysiology (mEPSC recording)","journal":"Translational psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical identification of the sheddase (ADAM10), functional synaptogenesis assay in two neuronal systems with electrophysiological validation, single lab","pmids":["39443477"],"is_preprint":false},{"year":2024,"finding":"Downregulation of LINGO2 in cultured APPV717I (familial Alzheimer's disease) iPSC-derived neurons rescued neurite outgrowth deficits and reversed AD-associated transcriptional changes related to synaptic function, apoptosis, and cellular senescence, implicating LINGO2 as a downstream mediator of APP-driven neurodegeneration.","method":"LINGO2 knockdown in iPSC-derived APPV717I neurons, neurite outgrowth assay, single-nucleus RNA-sequencing, xenograft mouse model","journal":"Acta neuropathologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (neurite outgrowth) and transcriptomic rescue in isogenic human iPSC-derived neurons, single lab","pmids":["38918213"],"is_preprint":false},{"year":2025,"finding":"Mettl3-mediated m6A modification of Lingo2 mRNA recruits the m6A reader Ythdf2 to promote Lingo2 mRNA degradation, reducing Lingo2 protein levels; decreased Lingo2 enhances interaction between APP and Bace1, increasing Aβ production. Restoration of Lingo2 or Mettl3 inhibition reduced Aβ plaques and behavioral deficits in 5xFAD mice.","method":"m6A-seq/MeRIP, Ythdf2 binding assay, co-immunoprecipitation of APP and Bace1, heterozygous Mettl3 neuronal knockout and knock-in mouse models, ectopic Lingo2 overexpression, Mettl3 inhibitor (STM2457) treatment, behavioral assays","journal":"Molecular psychiatry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — m6A epitranscriptomic writing (Mettl3), reader (Ythdf2) binding established biochemically, APP-Bace1 co-IP as functional consequence, multiple genetic models with orthogonal pharmacological validation in a single study","pmids":["40169805"],"is_preprint":false},{"year":2024,"finding":"T cell-specific deletion of Lingo2 (the TFF3 receptor) impairs TH2 cell commitment and allows proliferative expansion of IFNγ+ CD4+ TH1 cells during Trichuris muris infection, blocking worm expulsion through an IFNγ-dependent mechanism, demonstrating that TFF3-LINGO2 signaling in T cells restrains TH1 expansion and promotes type-2 immunity.","method":"T cell-specific Lingo2 conditional knockout mice, helminth infection model, flow cytometry for TH1/TH2 subset analysis, IFNγ blockade epistasis","journal":"Mucosal immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific genetic knockout with defined cellular phenotype (TH1/TH2 balance) and epistasis (IFNγ-dependent mechanism) in an infection model","pmids":["38336020"],"is_preprint":false},{"year":2019,"finding":"LINGO2 silencing in gastric cancer cells reduced AKT/ERK/MEK phosphorylation and decreased EMT markers (N-Cadherin, Vimentin) and stemness markers (OCT4, IHH), while decreasing the CD44+ cancer stem cell population, indicating LINGO2 promotes pro-tumorigenic signaling through these kinase pathways.","method":"siRNA-mediated LINGO2 knockdown in gastric cancer cell lines, western blot for phospho-kinases and EMT markers, flow cytometry (CD44), cell motility and tumorigenicity assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function with multiple downstream readouts (kinase phosphorylation, EMT markers, stemness markers) but no upstream binding partner or direct mechanism established, single lab","pmids":["30696080"],"is_preprint":false}],"current_model":"LINGO2 is a transmembrane leucine-rich repeat/Ig-domain protein that (1) forms an inhibitory complex with EGFR on epithelial and neuronal cell surfaces, which is de-repressed when TFF3 binds LINGO2, activating EGFR/Src signaling to drive wound healing, anti-helminth immunity (via TH1/TH2 balance), and neuroprotection; (2) has its ectodomain shed by ADAM10 to generate a soluble form that organizes excitatory synapses; and (3) in neurons is post-transcriptionally regulated by Mettl3-mediated m6A modification that recruits Ythdf2 to degrade Lingo2 mRNA, with reduced Lingo2 enhancing APP–Bace1 interaction and Aβ production in Alzheimer's disease models."},"narrative":{"mechanistic_narrative":"LINGO2 is a transmembrane leucine-rich repeat/Ig-domain cell-surface receptor that couples the trefoil factor TFF3 to EGFR-dependent cytoprotective signaling and that independently shapes neuronal synapse biology and neurodegenerative pathology [PMID:31562318, PMID:39443477, PMID:40169805]. At epithelial surfaces LINGO2 forms an inhibitory complex with EGFR; TFF3 binding to LINGO2 disrupts this complex, de-repressing EGFR signaling to block apoptosis and promote wound healing [PMID:31562318], and the same TFF3-LINGO2 axis drives EGFR/Src activation and Bcl-2 induction to confer neuroprotection in ischemic brain [PMID:37935323]. In T cells the TFF3-LINGO2 interaction restrains IFNγ+ TH1 expansion and favors TH2 commitment, enabling type-2 immunity and helminth clearance [PMID:38336020]. Beyond receptor signaling, LINGO2 contributes to neuronal connectivity: its ectodomain is shed by ADAM10 to yield a soluble fragment (sLingo2) that organizes excitatory synapses and increases excitatory transmission [PMID:39443477]. In Alzheimer's disease models LINGO2 levels are set post-transcriptionally by Mettl3-mediated m6A modification, which recruits Ythdf2 to degrade Lingo2 mRNA; reduced LINGO2 enhances APP–Bace1 interaction and Aβ production, and loss of LINGO2 mediates APP-driven neurite and transcriptional deficits [PMID:38918213, PMID:40169805]. In gastric cancer LINGO2 promotes AKT/ERK/MEK signaling, EMT, and a CD44+ stem-like population [PMID:30696080].","teleology":[{"year":2019,"claim":"Established LINGO2 as a TFF3 receptor that gates EGFR signaling, answering how the secreted trefoil factor TFF3 transduces a cytoprotective signal at the epithelial surface.","evidence":"Reciprocal co-IP, co-localization, and Lingo2-deficient mice with colitis/helminth and apoptosis readouts in intestinal epithelium","pmids":["31562318"],"confidence":"High","gaps":["Structural basis of the LINGO2-EGFR inhibitory complex unresolved","Stoichiometry and direct vs. indirect nature of LINGO2-EGFR contact not defined"]},{"year":2019,"claim":"Showed LINGO2 drives pro-tumorigenic kinase signaling, extending its functional reach beyond epithelial repair into cancer.","evidence":"siRNA knockdown in gastric cancer cell lines with phospho-kinase, EMT/stemness marker, and tumorigenicity readouts","pmids":["30696080"],"confidence":"Medium","gaps":["No upstream binding partner or direct mechanism linking LINGO2 to AKT/ERK/MEK established","Relationship to the EGFR axis not tested"]},{"year":2023,"claim":"Generalized the TFF3-LINGO2-EGFR axis to the CNS, showing it mediates TFF3 neuroprotection after ischemic stroke.","evidence":"Co-IP, intracerebroventricular siRNA knockdown, EGFR inhibitor pharmacology, and behavioral assays in a rat MCAO model","pmids":["37935323"],"confidence":"Medium","gaps":["Single-lab pharmacology and knockdown","Cell types in brain mediating the axis not resolved"]},{"year":2024,"claim":"Defined a distinct LINGO2 function in synapse formation via regulated ectodomain shedding, separating its receptor role from a secreted synaptogenic role.","evidence":"Secretome analysis, ADAM10 sheddase identification, synaptogenesis assays in mouse and human neurons, and mEPSC electrophysiology","pmids":["39443477"],"confidence":"Medium","gaps":["Postsynaptic receptor/partner for sLingo2 unknown","Relationship between shedding and EGFR signaling not addressed"]},{"year":2024,"claim":"Implicated LINGO2 as a downstream effector of APP-driven neurodegeneration, showing its loss rescues familial AD neuronal phenotypes.","evidence":"LINGO2 knockdown in isogenic APPV717I iPSC-derived neurons with neurite outgrowth, snRNA-seq rescue, and xenograft models","pmids":["38918213"],"confidence":"Medium","gaps":["Mechanism linking APP to LINGO2 not defined in this study","Direction of effect appears opposite to the m6A study and is not reconciled"]},{"year":2024,"claim":"Demonstrated a cell-autonomous role for LINGO2 in T cells, showing TFF3-LINGO2 signaling restrains TH1 expansion to permit type-2 immunity.","evidence":"T cell-specific conditional Lingo2 knockout in Trichuris muris infection with TH1/TH2 flow cytometry and IFNγ blockade epistasis","pmids":["38336020"],"confidence":"High","gaps":["Downstream signaling in T cells (EGFR involvement) not shown","Direct TFF3-LINGO2 binding in T cells not biochemically confirmed"]},{"year":2025,"claim":"Established epitranscriptomic control of LINGO2 and connected its levels to amyloid processing, answering how LINGO2 abundance is regulated and how it modulates Aβ production.","evidence":"m6A-seq/MeRIP, Ythdf2 binding, APP-Bace1 co-IP, Mettl3 knockout/knock-in mice, Lingo2 overexpression, and STM2457 in 5xFAD mice","pmids":["40169805"],"confidence":"High","gaps":["Molecular mechanism by which LINGO2 restrains APP-Bace1 interaction unknown","Apparent contradiction with iPSC study where LINGO2 loss is protective not reconciled"]},{"year":null,"claim":"Whether LINGO2's epithelial/T-cell receptor role, its synaptogenic shed-ectodomain role, and its amyloid-modulating role share a unifying biochemical mechanism remains unknown.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of LINGO2 or its complexes","Opposing directionality of LINGO2 effects across AD models unresolved","Whether EGFR signaling underlies the synaptic and neurodegenerative phenotypes untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4]}],"complexes":["LINGO2-EGFR inhibitory complex"],"partners":["TFF3","EGFR","ADAM10"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7L985","full_name":"Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 2","aliases":["Leucine-rich repeat neuronal protein 3","Leucine-rich repeat neuronal protein 6C"],"length_aa":606,"mass_kda":68.1,"function":"","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q7L985/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LINGO2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LINGO2","total_profiled":1310},"omim":[{"mim_id":"609793","title":"LEUCINE-RICH REPEAT- AND Ig DOMAIN-CONTAINING NOGO RECEPTOR-INTERACTING PROTEIN 2; LINGO2","url":"https://www.omim.org/entry/609793"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytoplasmic bodies","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"endometrium 1","ntpm":7.3},{"tissue":"smooth muscle","ntpm":8.2}],"url":"https://www.proteinatlas.org/search/LINGO2"},"hgnc":{"alias_symbol":["LERN3"],"prev_symbol":["LRRN6C"]},"alphafold":{"accession":"Q7L985","domains":[{"cath_id":"3.80.10.10","chopping":"286-407","consensus_level":"medium","plddt":93.3998,"start":286,"end":407},{"cath_id":"2.60.40.10","chopping":"409-502","consensus_level":"high","plddt":92.3134,"start":409,"end":502}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7L985","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7L985-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7L985-F1-predicted_aligned_error_v6.png","plddt_mean":84.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LINGO2","jax_strain_url":"https://www.jax.org/strain/search?query=LINGO2"},"sequence":{"accession":"Q7L985","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7L985.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7L985/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7L985"}},"corpus_meta":[{"pmid":"20369371","id":"PMC_20369371","title":"LINGO1 and LINGO2 variants are associated with essential tremor and Parkinson disease.","date":"2010","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/20369371","citation_count":104,"is_preprint":false},{"pmid":"31562318","id":"PMC_31562318","title":"TFF3 interacts with LINGO2 to regulate EGFR activation for protection against colitis and gastrointestinal helminths.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31562318","citation_count":76,"is_preprint":false},{"pmid":"21287203","id":"PMC_21287203","title":"Lingo2 variants associated with essential tremor and Parkinson's disease.","date":"2011","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21287203","citation_count":44,"is_preprint":false},{"pmid":"30696080","id":"PMC_30696080","title":"Novel Gastric Cancer Stem Cell-Related Marker LINGO2 Is Associated with Cancer Cell Phenotype and Patient Outcome.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30696080","citation_count":36,"is_preprint":false},{"pmid":"26254004","id":"PMC_26254004","title":"Analysis and meta-analysis of five polymorphisms of the LINGO1 and LINGO2 genes in Parkinson's disease and multiple system atrophy in a Chinese population.","date":"2015","source":"Journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/26254004","citation_count":17,"is_preprint":false},{"pmid":"25711307","id":"PMC_25711307","title":"Association of the LINGO2-related SNP rs10968576 with body mass in a cohort of elderly Swedes.","date":"2015","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/25711307","citation_count":14,"is_preprint":false},{"pmid":"38918213","id":"PMC_38918213","title":"Xenografted human iPSC-derived neurons with the familial Alzheimer's disease APPV717I mutation reveal dysregulated transcriptome signatures linked to synaptic function and implicate LINGO2 as a disease signaling mediator.","date":"2024","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/38918213","citation_count":9,"is_preprint":false},{"pmid":"40169805","id":"PMC_40169805","title":"Mettl3 regulates the pathogenesis of Alzheimer's disease via fine-tuning Lingo2.","date":"2025","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/40169805","citation_count":8,"is_preprint":false},{"pmid":"38888423","id":"PMC_38888423","title":"Variations in the LINGO2 and GLIS3 Genes and Gene-Environment Interactions Increase Gestational Diabetes Mellitus Risk in Chinese Women.","date":"2024","source":"Environmental science & technology","url":"https://pubmed.ncbi.nlm.nih.gov/38888423","citation_count":7,"is_preprint":false},{"pmid":"22123311","id":"PMC_22123311","title":"LINGO-2 polymorphism and the risk of Parkinson's disease in Taiwan.","date":"2011","source":"Parkinsonism & related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/22123311","citation_count":7,"is_preprint":false},{"pmid":"39443477","id":"PMC_39443477","title":"Soluble form of Lingo2, an autism spectrum disorder-associated molecule, functions as an excitatory synapse organizer in neurons.","date":"2024","source":"Translational psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/39443477","citation_count":4,"is_preprint":false},{"pmid":"37935323","id":"PMC_37935323","title":"Delayed recanalization reduced neuronal apoptosis and neurological deficits by enhancing liver-derived trefoil factor 3-mediated neuroprotection via LINGO2/EGFR/Src signaling pathway after middle cerebral artery occlusion in rats.","date":"2023","source":"Experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/37935323","citation_count":3,"is_preprint":false},{"pmid":"38336020","id":"PMC_38336020","title":"A Trefoil factor 3-Lingo2 axis restrains proliferative expansion of type-1 T helper cells during GI nematode infection.","date":"2024","source":"Mucosal immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38336020","citation_count":3,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.07.26.605344","title":"Whole genome sequencing of 76 Mexican Indigenous reveals recent selection signatures linked to pathogens and diet adaptation","date":"2024-07-29","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.26.605344","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.11.22.624040","title":"CNV-Finder: Streamlining Copy Number Variation Discovery","date":"2024-11-23","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.22.624040","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.12.19.629410","title":"Genome-wide association analyses in dairy heifers highlight genes overlapping with mouse and human fertility and human health traits","date":"2024-12-21","source":"bioRxiv","url":"https://doi.org/10.1101/2024.12.19.629410","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11383,"output_tokens":2202,"usd":0.03359,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9226,"output_tokens":2900,"usd":0.059315,"stage2_stop_reason":"end_turn"},"total_usd":0.092905,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"LINGO2 physically interacts with TFF3 (Trefoil factor 3) by co-immunoprecipitation, co-localizes with TFF3 on the intestinal epithelial cell membrane, and forms an inhibitory complex with EGFR. TFF3 binding to LINGO2 disrupts LINGO2-EGFR complexes, thereby de-repressing EGFR signaling and allowing TFF3 to block apoptosis and promote wound healing.\",\n      \"method\": \"Co-immunoprecipitation, co-localization imaging, Lingo2-deficient mouse model with colitis/helminth phenotypic readouts, apoptosis assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, co-localization, genetic knockout model with multiple orthogonal phenotypic readouts across barrier integrity, apoptosis, and infection paradigms\",\n      \"pmids\": [\"31562318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In rat stroke (MCAO) model, liver-derived TFF3 co-immunoprecipitates with LINGO2 in the brain; LINGO2 siRNA knockdown or EGFR inhibition reversed TFF3-mediated increases in p-EGFR, p-Src, and Bcl-2, and worsened neuronal apoptosis and neurological deficits, establishing a LINGO2/EGFR/Src signaling axis mediating TFF3 neuroprotection.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown (intracerebroventricular), western blot, EGFR inhibitor pharmacology, immunofluorescence, behavioral assays in rats\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with defined pathway readouts and pharmacological validation in a single lab, consistent with the intestinal LINGO2-EGFR mechanism\",\n      \"pmids\": [\"37935323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A soluble ectodomain form of Lingo2 (sLingo2) is produced by proteolytic cleavage mediated by the transmembrane metalloprotease ADAM10, and sLingo2 acts as an excitatory synapse organizer, inducing excitatory synapse formation in mouse and human neurons and increasing miniature excitatory postsynaptic current frequency.\",\n      \"method\": \"Quantitative secretome analysis, ADAM10 metalloprotease identification, in vitro synaptogenesis assays with mouse and human neurons, whole-cell electrophysiology (mEPSC recording)\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical identification of the sheddase (ADAM10), functional synaptogenesis assay in two neuronal systems with electrophysiological validation, single lab\",\n      \"pmids\": [\"39443477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Downregulation of LINGO2 in cultured APPV717I (familial Alzheimer's disease) iPSC-derived neurons rescued neurite outgrowth deficits and reversed AD-associated transcriptional changes related to synaptic function, apoptosis, and cellular senescence, implicating LINGO2 as a downstream mediator of APP-driven neurodegeneration.\",\n      \"method\": \"LINGO2 knockdown in iPSC-derived APPV717I neurons, neurite outgrowth assay, single-nucleus RNA-sequencing, xenograft mouse model\",\n      \"journal\": \"Acta neuropathologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined cellular phenotype (neurite outgrowth) and transcriptomic rescue in isogenic human iPSC-derived neurons, single lab\",\n      \"pmids\": [\"38918213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mettl3-mediated m6A modification of Lingo2 mRNA recruits the m6A reader Ythdf2 to promote Lingo2 mRNA degradation, reducing Lingo2 protein levels; decreased Lingo2 enhances interaction between APP and Bace1, increasing Aβ production. Restoration of Lingo2 or Mettl3 inhibition reduced Aβ plaques and behavioral deficits in 5xFAD mice.\",\n      \"method\": \"m6A-seq/MeRIP, Ythdf2 binding assay, co-immunoprecipitation of APP and Bace1, heterozygous Mettl3 neuronal knockout and knock-in mouse models, ectopic Lingo2 overexpression, Mettl3 inhibitor (STM2457) treatment, behavioral assays\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — m6A epitranscriptomic writing (Mettl3), reader (Ythdf2) binding established biochemically, APP-Bace1 co-IP as functional consequence, multiple genetic models with orthogonal pharmacological validation in a single study\",\n      \"pmids\": [\"40169805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"T cell-specific deletion of Lingo2 (the TFF3 receptor) impairs TH2 cell commitment and allows proliferative expansion of IFNγ+ CD4+ TH1 cells during Trichuris muris infection, blocking worm expulsion through an IFNγ-dependent mechanism, demonstrating that TFF3-LINGO2 signaling in T cells restrains TH1 expansion and promotes type-2 immunity.\",\n      \"method\": \"T cell-specific Lingo2 conditional knockout mice, helminth infection model, flow cytometry for TH1/TH2 subset analysis, IFNγ blockade epistasis\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific genetic knockout with defined cellular phenotype (TH1/TH2 balance) and epistasis (IFNγ-dependent mechanism) in an infection model\",\n      \"pmids\": [\"38336020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LINGO2 silencing in gastric cancer cells reduced AKT/ERK/MEK phosphorylation and decreased EMT markers (N-Cadherin, Vimentin) and stemness markers (OCT4, IHH), while decreasing the CD44+ cancer stem cell population, indicating LINGO2 promotes pro-tumorigenic signaling through these kinase pathways.\",\n      \"method\": \"siRNA-mediated LINGO2 knockdown in gastric cancer cell lines, western blot for phospho-kinases and EMT markers, flow cytometry (CD44), cell motility and tumorigenicity assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function with multiple downstream readouts (kinase phosphorylation, EMT markers, stemness markers) but no upstream binding partner or direct mechanism established, single lab\",\n      \"pmids\": [\"30696080\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LINGO2 is a transmembrane leucine-rich repeat/Ig-domain protein that (1) forms an inhibitory complex with EGFR on epithelial and neuronal cell surfaces, which is de-repressed when TFF3 binds LINGO2, activating EGFR/Src signaling to drive wound healing, anti-helminth immunity (via TH1/TH2 balance), and neuroprotection; (2) has its ectodomain shed by ADAM10 to generate a soluble form that organizes excitatory synapses; and (3) in neurons is post-transcriptionally regulated by Mettl3-mediated m6A modification that recruits Ythdf2 to degrade Lingo2 mRNA, with reduced Lingo2 enhancing APP–Bace1 interaction and Aβ production in Alzheimer's disease models.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LINGO2 is a transmembrane leucine-rich repeat/Ig-domain cell-surface receptor that couples the trefoil factor TFF3 to EGFR-dependent cytoprotective signaling and that independently shapes neuronal synapse biology and neurodegenerative pathology [#0, #2, #4]. At epithelial surfaces LINGO2 forms an inhibitory complex with EGFR; TFF3 binding to LINGO2 disrupts this complex, de-repressing EGFR signaling to block apoptosis and promote wound healing [#0], and the same TFF3-LINGO2 axis drives EGFR/Src activation and Bcl-2 induction to confer neuroprotection in ischemic brain [#1]. In T cells the TFF3-LINGO2 interaction restrains IFN\\u03b3+ TH1 expansion and favors TH2 commitment, enabling type-2 immunity and helminth clearance [#5]. Beyond receptor signaling, LINGO2 contributes to neuronal connectivity: its ectodomain is shed by ADAM10 to yield a soluble fragment (sLingo2) that organizes excitatory synapses and increases excitatory transmission [#2]. In Alzheimer's disease models LINGO2 levels are set post-transcriptionally by Mettl3-mediated m6A modification, which recruits Ythdf2 to degrade Lingo2 mRNA; reduced LINGO2 enhances APP\\u2013Bace1 interaction and A\\u03b2 production, and loss of LINGO2 mediates APP-driven neurite and transcriptional deficits [#3, #4]. In gastric cancer LINGO2 promotes AKT/ERK/MEK signaling, EMT, and a CD44+ stem-like population [#6].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Established LINGO2 as a TFF3 receptor that gates EGFR signaling, answering how the secreted trefoil factor TFF3 transduces a cytoprotective signal at the epithelial surface.\",\n      \"evidence\": \"Reciprocal co-IP, co-localization, and Lingo2-deficient mice with colitis/helminth and apoptosis readouts in intestinal epithelium\",\n      \"pmids\": [\"31562318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the LINGO2-EGFR inhibitory complex unresolved\", \"Stoichiometry and direct vs. indirect nature of LINGO2-EGFR contact not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed LINGO2 drives pro-tumorigenic kinase signaling, extending its functional reach beyond epithelial repair into cancer.\",\n      \"evidence\": \"siRNA knockdown in gastric cancer cell lines with phospho-kinase, EMT/stemness marker, and tumorigenicity readouts\",\n      \"pmids\": [\"30696080\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No upstream binding partner or direct mechanism linking LINGO2 to AKT/ERK/MEK established\", \"Relationship to the EGFR axis not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Generalized the TFF3-LINGO2-EGFR axis to the CNS, showing it mediates TFF3 neuroprotection after ischemic stroke.\",\n      \"evidence\": \"Co-IP, intracerebroventricular siRNA knockdown, EGFR inhibitor pharmacology, and behavioral assays in a rat MCAO model\",\n      \"pmids\": [\"37935323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab pharmacology and knockdown\", \"Cell types in brain mediating the axis not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a distinct LINGO2 function in synapse formation via regulated ectodomain shedding, separating its receptor role from a secreted synaptogenic role.\",\n      \"evidence\": \"Secretome analysis, ADAM10 sheddase identification, synaptogenesis assays in mouse and human neurons, and mEPSC electrophysiology\",\n      \"pmids\": [\"39443477\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Postsynaptic receptor/partner for sLingo2 unknown\", \"Relationship between shedding and EGFR signaling not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated LINGO2 as a downstream effector of APP-driven neurodegeneration, showing its loss rescues familial AD neuronal phenotypes.\",\n      \"evidence\": \"LINGO2 knockdown in isogenic APPV717I iPSC-derived neurons with neurite outgrowth, snRNA-seq rescue, and xenograft models\",\n      \"pmids\": [\"38918213\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking APP to LINGO2 not defined in this study\", \"Direction of effect appears opposite to the m6A study and is not reconciled\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated a cell-autonomous role for LINGO2 in T cells, showing TFF3-LINGO2 signaling restrains TH1 expansion to permit type-2 immunity.\",\n      \"evidence\": \"T cell-specific conditional Lingo2 knockout in Trichuris muris infection with TH1/TH2 flow cytometry and IFN\\u03b3 blockade epistasis\",\n      \"pmids\": [\"38336020\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling in T cells (EGFR involvement) not shown\", \"Direct TFF3-LINGO2 binding in T cells not biochemically confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established epitranscriptomic control of LINGO2 and connected its levels to amyloid processing, answering how LINGO2 abundance is regulated and how it modulates A\\u03b2 production.\",\n      \"evidence\": \"m6A-seq/MeRIP, Ythdf2 binding, APP-Bace1 co-IP, Mettl3 knockout/knock-in mice, Lingo2 overexpression, and STM2457 in 5xFAD mice\",\n      \"pmids\": [\"40169805\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which LINGO2 restrains APP-Bace1 interaction unknown\", \"Apparent contradiction with iPSC study where LINGO2 loss is protective not reconciled\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether LINGO2's epithelial/T-cell receptor role, its synaptogenic shed-ectodomain role, and its amyloid-modulating role share a unifying biochemical mechanism remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of LINGO2 or its complexes\", \"Opposing directionality of LINGO2 effects across AD models unresolved\", \"Whether EGFR signaling underlies the synaptic and neurodegenerative phenotypes untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [\"LINGO2-EGFR inhibitory complex\"],\n    \"partners\": [\"TFF3\", \"EGFR\", \"ADAM10\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}