{"gene":"CADM2","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2007,"finding":"CADM2 (Necl-3/SynCAM-2) localizes to myelinated axons at the interface between the axon shaft and myelin sheath, binds selectively to oligodendrocytes, and engages in homo- and heterophilic interactions with other Necl family members, leading to cell aggregation.","method":"Immunolocalization, multiple independent cell adhesion assays, heterophilic binding assays with Necl family members","journal":"BMC neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (localization, functional adhesion assays) in a single study","pmids":["17967169"],"is_preprint":false},{"year":2010,"finding":"CADM2 exists as two isoforms (CADM-2a and CADM-2b) with separate promoters on chromosome 3p12.1; adenovirus-mediated CADM-2a re-expression suppressed prostate cancer cell proliferation in vitro and colony formation in soft agar; CADM-2a promoter is silenced by hypermethylation, reversible by 5-aza-2'-deoxycytidine and trichostatin A.","method":"Gene cloning, RT-PCR, adenoviral overexpression, soft-agar colony assay, bisulfite sequencing, methylation-specific PCR, demethylation rescue","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods including functional rescue and epigenetic mechanistic validation","pmids":["21062931"],"is_preprint":false},{"year":2013,"finding":"Re-expression of CADM2 in renal cancer cells suppresses tumor cell growth in vitro and in mouse xenografts via G1-phase cell cycle arrest and induction of apoptosis, and suppresses anchorage-independent growth and invasion; siRNA knockdown of CADM2 in non-tumorigenic MDCK cells induces a tumorigenic phenotype.","method":"Lentiviral overexpression, xenograft assay, cell cycle analysis, apoptosis assay, siRNA knockdown","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods including in vivo xenograft and loss-of-function with defined phenotypic readouts","pmids":["23643812"],"is_preprint":false},{"year":2017,"finding":"Deletion of Cadm2 in obese mice reduces adiposity, systemic glucose levels, and improves insulin sensitivity while increasing locomotor activity, energy expenditure, and core body temperature, demonstrating that Cadm2 regulates systemic energy homeostasis; Cadm2 expression in hypothalamus is increased by leptin treatment in Lepob/ob mice.","method":"Loss-of-function mouse model (Cadm2 knockout), metabolic phenotyping, glucose/insulin tolerance tests, locomotor activity and energy expenditure measurements","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 — rigorous in vivo loss-of-function mouse model with multiple metabolic phenotypic readouts","pmids":["29217450"],"is_preprint":false},{"year":2018,"finding":"CADM2 is a direct target of miR-10b in hepatocellular carcinoma cells; miR-10b suppresses CADM2 expression, and the miR-10b/CADM2 axis modulates EMT and migration via the FAK/AKT signaling pathway.","method":"Dual-luciferase reporter assay, Western blot, wound healing and Transwell assays, immunofluorescence","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 — dual-luciferase validates direct targeting; functional pathway placement via FAK/AKT measurement","pmids":["29506532"],"is_preprint":false},{"year":2018,"finding":"CADM2 overexpression suppresses the Akt signaling pathway in esophageal squamous cell carcinoma cells; miR-21-5p downregulation inhibits proliferation and induces apoptosis through a CADM2/Akt axis, as CADM2 knockdown attenuates these effects and restores p-Akt levels.","method":"Western blot for p-Akt, siRNA knockdown, overexpression, proliferation and apoptosis assays","journal":"Chemico-biological interactions","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, functional rescue experiments with pathway readout","pmids":["29680210"],"is_preprint":false},{"year":2018,"finding":"miR-182 directly targets and negatively regulates CADM2 in retinoblastoma cells; CADM2 silencing activates the PI3K/AKT signaling pathway, increasing cell viability, invasion, and angiogenesis.","method":"Dual-luciferase reporter assay, Western blot, MTT assay, Transwell assay, xenograft tumor model","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct target validation by luciferase plus in vivo xenograft","pmids":["30320366"],"is_preprint":false},{"year":2019,"finding":"CADM2 overexpression in human glioma cells inhibits proliferation, migration, and invasion; decreases expression of G1/S transition regulators cyclin D1, cyclin E, CDK2, and CDK4; and alters EMT markers E-cadherin and β-catenin.","method":"Overexpression in cell lines and in vivo, proliferation assay, migration/invasion assay, Western blot for cell cycle and EMT proteins","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2-3 — multiple assays in vitro and in vivo with defined mechanistic readouts","pmids":["30816549"],"is_preprint":false},{"year":2021,"finding":"CADM2 (and CADM1) act as host factors enabling neuropathogenic measles virus (MeV) spread between neurons; they interact in cis (on the same cell membrane) with the MeV hemagglutinin (H) protein, triggering hyperfusogenic F protein-mediated membrane fusion independently of known MeV receptors; knockdown of CADM1 and CADM2 inhibits syncytium formation and virus transmission between neurons.","method":"Knockdown experiments, cell fusion assays, virus transmission assays between neurons, co-immunoprecipitation/interaction assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 — mechanistic in vitro and neuronal cell experiments demonstrating cis interaction and fusion triggering, with loss-of-function validation","pmids":["33910952"],"is_preprint":false},{"year":2021,"finding":"Short-stalk isoforms of CADM2, predominantly expressed in the brain and generated by alternative splicing, are the isoforms that induce hyperfusogenic MeV F protein-mediated membrane fusion; these short-stalk isoforms can interact in cis with the H protein even lacking its receptor-binding head domain, presumably through the stalk domain.","method":"Alternative splicing isoform analysis, cell fusion assays with truncated H protein constructs, isoform-specific expression","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 — mechanistic dissection with domain-specific mutagenesis and isoform-specific functional assays","pmids":["34788082"],"is_preprint":false},{"year":2023,"finding":"Alanine substitutions in positions 171-175 of the MeV H protein stalk region abolish CADM1/CADM2-triggered membrane fusion (but not SLAM-triggered fusion); recombinant hyperfusogenic MeV with this mutant H protein loses the ability to spread in primary mouse neurons and loses neurovirulence in suckling hamsters, demonstrating CADM1/CADM2 are key for MeV neuropathogenicity in vivo.","method":"Mutagenesis of H protein stalk, recombinant virus construction, primary neuron spread assay, suckling hamster in vivo neurovirulence model","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis combined with in vitro and in vivo models, mechanistic dissection replicated across multiple studies","pmids":["37166307"],"is_preprint":false},{"year":2023,"finding":"Cadm2 mutant mice recapitulate human GWAS associations including impulsivity, cognition, and BMI, placing CADM2 in a pathway regulating these behavioral and metabolic phenotypes.","method":"Cadm2 knockout mouse behavioral and metabolic phenotyping battery (MouseWAS)","journal":"Translational psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 — systematic in vivo loss-of-function with multiple behavioral and metabolic phenotypic readouts","pmids":["37173343"],"is_preprint":false},{"year":2024,"finding":"CADM2 mediates the anti-inflammatory effect of the microbial metabolite acetyl l-carnitine (ALC) in colonic epithelial cells; CADM2 silencing abolishes ALC-mediated inhibition of the TLR-MyD88 signaling pathway and inflammatory factor release.","method":"Transcriptome sequencing, gene silencing (siRNA), DSS colitis mouse model, cytokine measurement, pathway analysis","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — gene silencing demonstrates pathway placement (TLR-MyD88) with in vivo and in vitro validation","pmids":["38369215"],"is_preprint":false},{"year":2024,"finding":"ADAMTS9-AS2 directly binds DNMT3B and prevents its occupancy at the CADM2 promoter, thereby blocking CADM2 epigenetic silencing; rescue experiments confirm that CADM2 overexpression reverses ADAMTS9-AS2 knockdown-induced oncogenic phenotypes in ESCC.","method":"RIP, ChIP, pyrosequencing, rescue overexpression experiments","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (RIP, ChIP, pyrosequencing) establishing epigenetic regulatory mechanism","pmids":["41869309"],"is_preprint":false},{"year":2024,"finding":"Loss of CADM2 in zebrafish causes excessive sleepiness (hypersomnia); forced expression of CADM2 in embryonic neural progenitor cells promotes generation of adult neural stem (type B) cells over ependymal cells in postnatal mouse brain; CADM2 has a developmental function in synaptic elaboration linked to arousal regulation via the NPY pathway.","method":"Zebrafish cadm2 knockout behavioral assay, mouse embryonic NPC overexpression with in vivo postnatal brain analysis, Drosophila beat-Ia neuronal knockdown","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — cross-species loss-of-function with defined phenotypic and cellular readouts; multiple models","pmids":["41526386"],"is_preprint":false},{"year":2025,"finding":"A recursive splice site (RS1) in the first intron of CADM2 regulates CADM2 expression levels and transcript usage in human induced neurons; CRISPR deletion of RS1 decreases CADM2 expression, alters RNA abundance gradient across the first intron, impacts transcript isoform usage, and affects genes involved in synapse and axon development; rats with Cadm2 RS1 deletions show behavioral changes and altered functional brain connectivity.","method":"CRISPR modeling of patient deletions in human induced neurons and rats, transcriptome analysis, behavioral phenotyping, brain connectivity analysis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR loss-of-function with transcriptome-level mechanistic validation in human neurons and in vivo rat model","pmids":[],"is_preprint":true}],"current_model":"CADM2 is a synaptic immunoglobulin-superfamily cell adhesion molecule expressed predominantly in brain (enriched in hypothalamus), myelinated axons, and adipose tissue that: (1) mediates axon–oligodendrocyte adhesion through homo- and heterophilic Necl-family interactions; (2) regulates systemic energy homeostasis and body weight via CNS (hypothalamic) signaling, with loss-of-function improving metabolic syndrome features in mice; (3) acts as a tumor suppressor in multiple cancers by suppressing EMT and the FAK/AKT and PI3K/AKT pathways, and is silenced by promoter hypermethylation; (4) serves as a cis-acting host factor for neuropathogenic measles virus, where its short-stalk brain isoforms interact in cis with the viral hemagglutinin stalk to trigger hyperfusogenic F-protein-mediated membrane fusion enabling trans-synaptic viral spread; (5) plays a developmental role in neural stem cell fate specification and synaptic elaboration of NPY-pathway neurons that stabilize arousal; and (6) has its expression regulated at a noncoding level by recursive splicing, lncRNAs, and miRNAs that tune downstream signaling in neuronal and epithelial contexts."},"narrative":{"teleology":[{"year":2007,"claim":"The first molecular characterization established that CADM2 localizes to the axon–myelin interface and mediates cell adhesion through homo- and heterophilic Necl-family interactions, defining it as a synaptic adhesion molecule in the nervous system.","evidence":"Immunolocalization on myelinated axons plus multiple independent cell aggregation and heterophilic binding assays","pmids":["17967169"],"confidence":"Medium","gaps":["No in vivo loss-of-function to confirm axon–oligodendrocyte adhesion requirement","Binding affinities and structural basis of Necl interactions not determined"]},{"year":2010,"claim":"The discovery that CADM2 promoter hypermethylation silences its expression in cancer, and that re-expression suppresses prostate cancer cell growth, established CADM2 as an epigenetically regulated tumor suppressor.","evidence":"Two-isoform cloning, bisulfite sequencing showing promoter methylation, adenoviral CADM-2a re-expression suppressing soft-agar colony formation, demethylation rescue with 5-aza-dC/TSA","pmids":["21062931"],"confidence":"Medium","gaps":["Mechanism by which CADM2 suppresses growth not identified","Only one cancer type tested"]},{"year":2013,"claim":"Extension to renal cancer showed CADM2 re-expression induces G1 arrest and apoptosis while loss-of-function converts non-tumorigenic cells to a tumorigenic phenotype, strengthening the tumor-suppressor model with a defined cell-cycle mechanism.","evidence":"Lentiviral overexpression and xenograft assays plus siRNA knockdown in MDCK cells with cell cycle and apoptosis analysis","pmids":["23643812"],"confidence":"Medium","gaps":["Direct molecular target through which CADM2 enforces G1 arrest unknown","No patient cohort validation"]},{"year":2017,"claim":"Cadm2 knockout mice revealed a metabolic function: CADM2 loss reduces adiposity, improves insulin sensitivity, and increases energy expenditure and locomotor activity, establishing CADM2 as a regulator of systemic energy homeostasis through hypothalamic signaling.","evidence":"Cadm2 knockout mouse model with comprehensive metabolic phenotyping, glucose/insulin tolerance tests, leptin-regulated hypothalamic expression","pmids":["29217450"],"confidence":"High","gaps":["Downstream signaling cascade in hypothalamus not delineated","Cell-type specificity of Cadm2 metabolic function not resolved"]},{"year":2018,"claim":"Identification of miR-10b, miR-21-5p, and miR-182 as direct upstream regulators of CADM2, coupled with demonstration that CADM2 suppresses FAK/AKT and PI3K/AKT signaling and EMT, placed CADM2 within defined oncogenic pathways across hepatocellular carcinoma, esophageal, and retinoblastoma contexts.","evidence":"Dual-luciferase reporter assays confirming direct miRNA targeting, Western blots for p-Akt/FAK, functional rescue by CADM2 knockdown, xenograft models","pmids":["29506532","29680210","30320366"],"confidence":"Medium","gaps":["Whether CADM2 directly interacts with AKT pathway components or acts indirectly is unresolved","Cross-cancer generalizability of specific miRNA axes not established"]},{"year":2019,"claim":"CADM2 overexpression in glioma cells confirmed suppression of G1/S transition regulators (cyclin D1, CDK2/4) and alteration of EMT markers, consolidating the tumor-suppressor mechanism across CNS and peripheral cancers.","evidence":"Overexpression in glioma cell lines with in vivo validation, Western blot for cell cycle and EMT proteins","pmids":["30816549"],"confidence":"Medium","gaps":["Whether CADM2 tumor-suppressor activity requires its adhesion function is untested"]},{"year":2021,"claim":"CADM2 was identified as a cis-acting host factor for neuropathogenic measles virus: it interacts on the same membrane with the MeV hemagglutinin to trigger hyperfusogenic F-protein-mediated fusion independently of canonical MeV receptors, with short-stalk brain isoforms being the active species.","evidence":"Knockdown inhibiting syncytium formation, co-IP demonstrating cis-interaction with H protein, domain-truncation and isoform-specific fusion assays in neurons","pmids":["33910952","34788082"],"confidence":"High","gaps":["Structural basis of CADM2–H stalk interaction not resolved","Whether other Necl family members compensate in vivo unknown"]},{"year":2023,"claim":"Mutagenesis of the MeV H protein stalk (positions 171–175) abolished CADM-triggered but not SLAM-triggered fusion and eliminated neurovirulence in suckling hamsters, providing in vivo proof that the CADM2/H-stalk interaction is essential for MeV neuropathogenicity.","evidence":"H protein stalk mutagenesis, recombinant virus in primary neurons, suckling hamster neurovirulence model","pmids":["37166307"],"confidence":"High","gaps":["Atomic-level structure of CADM2–H stalk interface not determined","Human relevance requires clinical correlation"]},{"year":2023,"claim":"Cadm2 knockout mice recapitulated human GWAS-linked behavioral and metabolic phenotypes (impulsivity, altered cognition, BMI), validating CADM2 as a causal gene underlying these complex trait associations.","evidence":"Comprehensive behavioral and metabolic phenotyping battery (MouseWAS) in Cadm2 knockout mice","pmids":["37173343"],"confidence":"Medium","gaps":["Circuit-level mechanisms linking CADM2 loss to impulsivity and cognition not delineated","Cell-type-specific conditional knockouts not yet reported"]},{"year":2024,"claim":"Multiple studies expanded CADM2's functional repertoire: upstream epigenetic regulation was elucidated (lncRNA ADAMTS9-AS2 blocks DNMT3B occupancy at the CADM2 promoter), CADM2 was shown to mediate anti-inflammatory signaling by inhibiting TLR-MyD88, and a developmental role in neural stem cell fate and arousal regulation via the NPY pathway was established across zebrafish, mouse, and Drosophila.","evidence":"RIP/ChIP/pyrosequencing for epigenetic mechanism; siRNA + DSS colitis model for anti-inflammatory function; zebrafish cadm2 KO behavioral assays, mouse NPC overexpression, Drosophila beat-Ia knockdown","pmids":["41869309","38369215","41526386"],"confidence":"Medium","gaps":["Whether CADM2 anti-inflammatory function operates through its adhesion domain is unknown","NSC fate specification mechanism downstream of CADM2 not molecularly defined","Cross-species NPY pathway conservation not fully validated"]},{"year":null,"claim":"Key unresolved questions include the structural basis of CADM2 interactions (both homophilic and with MeV H stalk), the direct molecular mechanism by which CADM2 suppresses AKT signaling, cell-type-specific conditional knockout studies dissecting hypothalamic versus peripheral metabolic roles, and whether CADM2's adhesion and signaling functions are mechanistically separable.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No crystal/cryo-EM structure of CADM2 extracellular or transmembrane domains","No conditional or cell-type-specific knockout distinguishing central vs peripheral metabolic roles","Direct biochemical link between CADM2 and AKT pathway components not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,8,9]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,8,9]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5,6,12]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,8,9,10]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[14]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,14]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,10,12]}],"complexes":[],"partners":["CADM1","CADM3","CADM4","DNMT3B"],"other_free_text":[]},"mechanistic_narrative":"CADM2 (also known as Necl-3/SynCAM-2) is a synaptic immunoglobulin-superfamily cell adhesion molecule that mediates axon–oligodendrocyte adhesion through homo- and heterophilic Necl-family interactions, regulates systemic energy homeostasis and arousal through central nervous system signaling, and functions as a tumor suppressor silenced by promoter hypermethylation in multiple cancers [PMID:17967169, PMID:29217450, PMID:21062931]. In the brain, CADM2 promotes neural stem cell fate specification and synaptic elaboration of NPY-pathway neurons that stabilize arousal, and its loss in zebrafish causes hypersomnia; a recursive splice site in its first intron regulates expression level and transcript isoform usage, affecting synapse- and axon-development gene programs [PMID:41526386]. CADM2 suppresses tumor growth by inducing G1 arrest and apoptosis and by inhibiting AKT/FAK and PI3K/AKT signaling and epithelial-mesenchymal transition, with its expression controlled upstream by miRNAs (miR-10b, miR-21-5p, miR-182) and by the lncRNA ADAMTS9-AS2 that blocks DNMT3B-mediated promoter methylation [PMID:23643812, PMID:29506532, PMID:30816549, PMID:41869309]. Short-stalk brain isoforms of CADM2 act as cis-interacting host factors for neuropathogenic measles virus hemagglutinin, triggering hyperfusogenic F-protein-mediated membrane fusion essential for trans-synaptic viral spread and neurovirulence in vivo [PMID:33910952, PMID:34788082, PMID:37166307]."},"prefetch_data":{"uniprot":{"accession":"Q8N3J6","full_name":"Cell adhesion molecule 2","aliases":["Immunoglobulin superfamily member 4D","IgSF4D","Nectin-like protein 3","NECL-3","Synaptic cell adhesion molecule 2","SynCAM 2"],"length_aa":435,"mass_kda":47.6,"function":"Adhesion molecule that engages in homo- and heterophilic interactions with the other nectin-like family members, leading to cell aggregation. Important for synapse organization, providing regulated trans-synaptic adhesion. Preferentially binds to oligodendrocytes (Microbial infection) Induces cell fusion in neuron infected by a neuropathogenic strain of measles. Interacts with measles hemagglutinin to trigger hyperfusogenic F-mediated membrane fusion and presumably transsynaptic cell-to-cell transmission of the virus","subcellular_location":"Cell membrane; Synapse; Cell projection, axon","url":"https://www.uniprot.org/uniprotkb/Q8N3J6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CADM2","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/CADM2","total_profiled":1310},"omim":[{"mim_id":"609938","title":"CELL ADHESION MOLECULE 2; CADM2","url":"https://www.omim.org/entry/609938"},{"mim_id":"176807","title":"PROSTATE CANCER","url":"https://www.omim.org/entry/176807"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":48.5},{"tissue":"retina","ntpm":87.9}],"url":"https://www.proteinatlas.org/search/CADM2"},"hgnc":{"alias_symbol":["NECL3","Necl-3","SynCAM2","SynCAM-2"],"prev_symbol":["IGSF4D"]},"alphafold":{"accession":"Q8N3J6","domains":[{"cath_id":"2.60.40.10","chopping":"25-120","consensus_level":"high","plddt":95.8798,"start":25,"end":120},{"cath_id":"2.60.40.10","chopping":"127-221","consensus_level":"high","plddt":95.2699,"start":127,"end":221},{"cath_id":"2.60.40.10","chopping":"226-310","consensus_level":"high","plddt":93.6322,"start":226,"end":310}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N3J6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N3J6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N3J6-F1-predicted_aligned_error_v6.png","plddt_mean":82.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CADM2","jax_strain_url":"https://www.jax.org/strain/search?query=CADM2"},"sequence":{"accession":"Q8N3J6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N3J6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N3J6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N3J6"}},"corpus_meta":[{"pmid":"29899525","id":"PMC_29899525","title":"Genome-wide association study of habitual physical activity in over 377,000 UK Biobank participants identifies multiple variants including CADM2 and APOE.","date":"2018","source":"International journal of obesity (2005)","url":"https://pubmed.ncbi.nlm.nih.gov/29899525","citation_count":306,"is_preprint":false},{"pmid":"30718321","id":"PMC_30718321","title":"Genome-Wide Association Studies of Impulsive Personality Traits (BIS-11 and UPPS-P) and Drug Experimentation in up to 22,861 Adult Research Participants Identify Loci in the CACNA1I and CADM2 genes.","date":"2019","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/30718321","citation_count":115,"is_preprint":false},{"pmid":"25869804","id":"PMC_25869804","title":"GWAS for executive function and processing speed suggests involvement of the CADM2 gene.","date":"2015","source":"Molecular 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CADM2/Akt pathway is involved in the inhibitory effect of miR-21-5p downregulation on proliferation and apoptosis in esophageal squamous cell carcinoma cells.","date":"2018","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/29680210","citation_count":28,"is_preprint":false},{"pmid":"35867259","id":"PMC_35867259","title":"The CADM2 Gene and Behavior: A Phenome-Wide Scan in UK-Biobank.","date":"2022","source":"Behavior genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35867259","citation_count":24,"is_preprint":false},{"pmid":"33910952","id":"PMC_33910952","title":"CADM1 and CADM2 Trigger Neuropathogenic Measles Virus-Mediated Membrane Fusion by Acting in cis.","date":"2021","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/33910952","citation_count":24,"is_preprint":false},{"pmid":"32126252","id":"PMC_32126252","title":"Copy number variation of CADM2 gene revealed its association with growth traits across Chinese Capra hircus (goat) 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members\",\n      \"journal\": \"BMC neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (localization, functional adhesion assays) in a single study\",\n      \"pmids\": [\"17967169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CADM2 exists as two isoforms (CADM-2a and CADM-2b) with separate promoters on chromosome 3p12.1; adenovirus-mediated CADM-2a re-expression suppressed prostate cancer cell proliferation in vitro and colony formation in soft agar; CADM-2a promoter is silenced by hypermethylation, reversible by 5-aza-2'-deoxycytidine and trichostatin A.\",\n      \"method\": \"Gene cloning, RT-PCR, adenoviral overexpression, soft-agar colony assay, bisulfite sequencing, methylation-specific PCR, demethylation rescue\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including functional rescue and epigenetic mechanistic validation\",\n      \"pmids\": [\"21062931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Re-expression of CADM2 in renal cancer cells suppresses tumor cell growth in vitro and in mouse xenografts via G1-phase cell cycle arrest and induction of apoptosis, and suppresses anchorage-independent growth and invasion; siRNA knockdown of CADM2 in non-tumorigenic MDCK cells induces a tumorigenic phenotype.\",\n      \"method\": \"Lentiviral overexpression, xenograft assay, cell cycle analysis, apoptosis assay, siRNA knockdown\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including in vivo xenograft and loss-of-function with defined phenotypic readouts\",\n      \"pmids\": [\"23643812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Deletion of Cadm2 in obese mice reduces adiposity, systemic glucose levels, and improves insulin sensitivity while increasing locomotor activity, energy expenditure, and core body temperature, demonstrating that Cadm2 regulates systemic energy homeostasis; Cadm2 expression in hypothalamus is increased by leptin treatment in Lepob/ob mice.\",\n      \"method\": \"Loss-of-function mouse model (Cadm2 knockout), metabolic phenotyping, glucose/insulin tolerance tests, locomotor activity and energy expenditure measurements\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — rigorous in vivo loss-of-function mouse model with multiple metabolic phenotypic readouts\",\n      \"pmids\": [\"29217450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CADM2 is a direct target of miR-10b in hepatocellular carcinoma cells; miR-10b suppresses CADM2 expression, and the miR-10b/CADM2 axis modulates EMT and migration via the FAK/AKT signaling pathway.\",\n      \"method\": \"Dual-luciferase reporter assay, Western blot, wound healing and Transwell assays, immunofluorescence\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — dual-luciferase validates direct targeting; functional pathway placement via FAK/AKT measurement\",\n      \"pmids\": [\"29506532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CADM2 overexpression suppresses the Akt signaling pathway in esophageal squamous cell carcinoma cells; miR-21-5p downregulation inhibits proliferation and induces apoptosis through a CADM2/Akt axis, as CADM2 knockdown attenuates these effects and restores p-Akt levels.\",\n      \"method\": \"Western blot for p-Akt, siRNA knockdown, overexpression, proliferation and apoptosis assays\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, functional rescue experiments with pathway readout\",\n      \"pmids\": [\"29680210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-182 directly targets and negatively regulates CADM2 in retinoblastoma cells; CADM2 silencing activates the PI3K/AKT signaling pathway, increasing cell viability, invasion, and angiogenesis.\",\n      \"method\": \"Dual-luciferase reporter assay, Western blot, MTT assay, Transwell assay, xenograft tumor model\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct target validation by luciferase plus in vivo xenograft\",\n      \"pmids\": [\"30320366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CADM2 overexpression in human glioma cells inhibits proliferation, migration, and invasion; decreases expression of G1/S transition regulators cyclin D1, cyclin E, CDK2, and CDK4; and alters EMT markers E-cadherin and β-catenin.\",\n      \"method\": \"Overexpression in cell lines and in vivo, proliferation assay, migration/invasion assay, Western blot for cell cycle and EMT proteins\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — multiple assays in vitro and in vivo with defined mechanistic readouts\",\n      \"pmids\": [\"30816549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CADM2 (and CADM1) act as host factors enabling neuropathogenic measles virus (MeV) spread between neurons; they interact in cis (on the same cell membrane) with the MeV hemagglutinin (H) protein, triggering hyperfusogenic F protein-mediated membrane fusion independently of known MeV receptors; knockdown of CADM1 and CADM2 inhibits syncytium formation and virus transmission between neurons.\",\n      \"method\": \"Knockdown experiments, cell fusion assays, virus transmission assays between neurons, co-immunoprecipitation/interaction assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic in vitro and neuronal cell experiments demonstrating cis interaction and fusion triggering, with loss-of-function validation\",\n      \"pmids\": [\"33910952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Short-stalk isoforms of CADM2, predominantly expressed in the brain and generated by alternative splicing, are the isoforms that induce hyperfusogenic MeV F protein-mediated membrane fusion; these short-stalk isoforms can interact in cis with the H protein even lacking its receptor-binding head domain, presumably through the stalk domain.\",\n      \"method\": \"Alternative splicing isoform analysis, cell fusion assays with truncated H protein constructs, isoform-specific expression\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mechanistic dissection with domain-specific mutagenesis and isoform-specific functional assays\",\n      \"pmids\": [\"34788082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Alanine substitutions in positions 171-175 of the MeV H protein stalk region abolish CADM1/CADM2-triggered membrane fusion (but not SLAM-triggered fusion); recombinant hyperfusogenic MeV with this mutant H protein loses the ability to spread in primary mouse neurons and loses neurovirulence in suckling hamsters, demonstrating CADM1/CADM2 are key for MeV neuropathogenicity in vivo.\",\n      \"method\": \"Mutagenesis of H protein stalk, recombinant virus construction, primary neuron spread assay, suckling hamster in vivo neurovirulence model\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis combined with in vitro and in vivo models, mechanistic dissection replicated across multiple studies\",\n      \"pmids\": [\"37166307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cadm2 mutant mice recapitulate human GWAS associations including impulsivity, cognition, and BMI, placing CADM2 in a pathway regulating these behavioral and metabolic phenotypes.\",\n      \"method\": \"Cadm2 knockout mouse behavioral and metabolic phenotyping battery (MouseWAS)\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic in vivo loss-of-function with multiple behavioral and metabolic phenotypic readouts\",\n      \"pmids\": [\"37173343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CADM2 mediates the anti-inflammatory effect of the microbial metabolite acetyl l-carnitine (ALC) in colonic epithelial cells; CADM2 silencing abolishes ALC-mediated inhibition of the TLR-MyD88 signaling pathway and inflammatory factor release.\",\n      \"method\": \"Transcriptome sequencing, gene silencing (siRNA), DSS colitis mouse model, cytokine measurement, pathway analysis\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — gene silencing demonstrates pathway placement (TLR-MyD88) with in vivo and in vitro validation\",\n      \"pmids\": [\"38369215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ADAMTS9-AS2 directly binds DNMT3B and prevents its occupancy at the CADM2 promoter, thereby blocking CADM2 epigenetic silencing; rescue experiments confirm that CADM2 overexpression reverses ADAMTS9-AS2 knockdown-induced oncogenic phenotypes in ESCC.\",\n      \"method\": \"RIP, ChIP, pyrosequencing, rescue overexpression experiments\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (RIP, ChIP, pyrosequencing) establishing epigenetic regulatory mechanism\",\n      \"pmids\": [\"41869309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of CADM2 in zebrafish causes excessive sleepiness (hypersomnia); forced expression of CADM2 in embryonic neural progenitor cells promotes generation of adult neural stem (type B) cells over ependymal cells in postnatal mouse brain; CADM2 has a developmental function in synaptic elaboration linked to arousal regulation via the NPY pathway.\",\n      \"method\": \"Zebrafish cadm2 knockout behavioral assay, mouse embryonic NPC overexpression with in vivo postnatal brain analysis, Drosophila beat-Ia neuronal knockdown\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cross-species loss-of-function with defined phenotypic and cellular readouts; multiple models\",\n      \"pmids\": [\"41526386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A recursive splice site (RS1) in the first intron of CADM2 regulates CADM2 expression levels and transcript usage in human induced neurons; CRISPR deletion of RS1 decreases CADM2 expression, alters RNA abundance gradient across the first intron, impacts transcript isoform usage, and affects genes involved in synapse and axon development; rats with Cadm2 RS1 deletions show behavioral changes and altered functional brain connectivity.\",\n      \"method\": \"CRISPR modeling of patient deletions in human induced neurons and rats, transcriptome analysis, behavioral phenotyping, brain connectivity analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR loss-of-function with transcriptome-level mechanistic validation in human neurons and in vivo rat model\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CADM2 is a synaptic immunoglobulin-superfamily cell adhesion molecule expressed predominantly in brain (enriched in hypothalamus), myelinated axons, and adipose tissue that: (1) mediates axon–oligodendrocyte adhesion through homo- and heterophilic Necl-family interactions; (2) regulates systemic energy homeostasis and body weight via CNS (hypothalamic) signaling, with loss-of-function improving metabolic syndrome features in mice; (3) acts as a tumor suppressor in multiple cancers by suppressing EMT and the FAK/AKT and PI3K/AKT pathways, and is silenced by promoter hypermethylation; (4) serves as a cis-acting host factor for neuropathogenic measles virus, where its short-stalk brain isoforms interact in cis with the viral hemagglutinin stalk to trigger hyperfusogenic F-protein-mediated membrane fusion enabling trans-synaptic viral spread; (5) plays a developmental role in neural stem cell fate specification and synaptic elaboration of NPY-pathway neurons that stabilize arousal; and (6) has its expression regulated at a noncoding level by recursive splicing, lncRNAs, and miRNAs that tune downstream signaling in neuronal and epithelial contexts.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CADM2 (also known as Necl-3/SynCAM-2) is a synaptic immunoglobulin-superfamily cell adhesion molecule that mediates axon–oligodendrocyte adhesion through homo- and heterophilic Necl-family interactions, regulates systemic energy homeostasis and arousal through central nervous system signaling, and functions as a tumor suppressor silenced by promoter hypermethylation in multiple cancers [PMID:17967169, PMID:29217450, PMID:21062931]. In the brain, CADM2 promotes neural stem cell fate specification and synaptic elaboration of NPY-pathway neurons that stabilize arousal, and its loss in zebrafish causes hypersomnia; a recursive splice site in its first intron regulates expression level and transcript isoform usage, affecting synapse- and axon-development gene programs [PMID:41526386]. CADM2 suppresses tumor growth by inducing G1 arrest and apoptosis and by inhibiting AKT/FAK and PI3K/AKT signaling and epithelial-mesenchymal transition, with its expression controlled upstream by miRNAs (miR-10b, miR-21-5p, miR-182) and by the lncRNA ADAMTS9-AS2 that blocks DNMT3B-mediated promoter methylation [PMID:23643812, PMID:29506532, PMID:30816549, PMID:41869309]. Short-stalk brain isoforms of CADM2 act as cis-interacting host factors for neuropathogenic measles virus hemagglutinin, triggering hyperfusogenic F-protein-mediated membrane fusion essential for trans-synaptic viral spread and neurovirulence in vivo [PMID:33910952, PMID:34788082, PMID:37166307].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"The first molecular characterization established that CADM2 localizes to the axon–myelin interface and mediates cell adhesion through homo- and heterophilic Necl-family interactions, defining it as a synaptic adhesion molecule in the nervous system.\",\n      \"evidence\": \"Immunolocalization on myelinated axons plus multiple independent cell aggregation and heterophilic binding assays\",\n      \"pmids\": [\"17967169\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo loss-of-function to confirm axon–oligodendrocyte adhesion requirement\", \"Binding affinities and structural basis of Necl interactions not determined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The discovery that CADM2 promoter hypermethylation silences its expression in cancer, and that re-expression suppresses prostate cancer cell growth, established CADM2 as an epigenetically regulated tumor suppressor.\",\n      \"evidence\": \"Two-isoform cloning, bisulfite sequencing showing promoter methylation, adenoviral CADM-2a re-expression suppressing soft-agar colony formation, demethylation rescue with 5-aza-dC/TSA\",\n      \"pmids\": [\"21062931\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CADM2 suppresses growth not identified\", \"Only one cancer type tested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extension to renal cancer showed CADM2 re-expression induces G1 arrest and apoptosis while loss-of-function converts non-tumorigenic cells to a tumorigenic phenotype, strengthening the tumor-suppressor model with a defined cell-cycle mechanism.\",\n      \"evidence\": \"Lentiviral overexpression and xenograft assays plus siRNA knockdown in MDCK cells with cell cycle and apoptosis analysis\",\n      \"pmids\": [\"23643812\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular target through which CADM2 enforces G1 arrest unknown\", \"No patient cohort validation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Cadm2 knockout mice revealed a metabolic function: CADM2 loss reduces adiposity, improves insulin sensitivity, and increases energy expenditure and locomotor activity, establishing CADM2 as a regulator of systemic energy homeostasis through hypothalamic signaling.\",\n      \"evidence\": \"Cadm2 knockout mouse model with comprehensive metabolic phenotyping, glucose/insulin tolerance tests, leptin-regulated hypothalamic expression\",\n      \"pmids\": [\"29217450\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream signaling cascade in hypothalamus not delineated\", \"Cell-type specificity of Cadm2 metabolic function not resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identification of miR-10b, miR-21-5p, and miR-182 as direct upstream regulators of CADM2, coupled with demonstration that CADM2 suppresses FAK/AKT and PI3K/AKT signaling and EMT, placed CADM2 within defined oncogenic pathways across hepatocellular carcinoma, esophageal, and retinoblastoma contexts.\",\n      \"evidence\": \"Dual-luciferase reporter assays confirming direct miRNA targeting, Western blots for p-Akt/FAK, functional rescue by CADM2 knockdown, xenograft models\",\n      \"pmids\": [\"29506532\", \"29680210\", \"30320366\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CADM2 directly interacts with AKT pathway components or acts indirectly is unresolved\", \"Cross-cancer generalizability of specific miRNA axes not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"CADM2 overexpression in glioma cells confirmed suppression of G1/S transition regulators (cyclin D1, CDK2/4) and alteration of EMT markers, consolidating the tumor-suppressor mechanism across CNS and peripheral cancers.\",\n      \"evidence\": \"Overexpression in glioma cell lines with in vivo validation, Western blot for cell cycle and EMT proteins\",\n      \"pmids\": [\"30816549\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CADM2 tumor-suppressor activity requires its adhesion function is untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"CADM2 was identified as a cis-acting host factor for neuropathogenic measles virus: it interacts on the same membrane with the MeV hemagglutinin to trigger hyperfusogenic F-protein-mediated fusion independently of canonical MeV receptors, with short-stalk brain isoforms being the active species.\",\n      \"evidence\": \"Knockdown inhibiting syncytium formation, co-IP demonstrating cis-interaction with H protein, domain-truncation and isoform-specific fusion assays in neurons\",\n      \"pmids\": [\"33910952\", \"34788082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of CADM2–H stalk interaction not resolved\", \"Whether other Necl family members compensate in vivo unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Mutagenesis of the MeV H protein stalk (positions 171–175) abolished CADM-triggered but not SLAM-triggered fusion and eliminated neurovirulence in suckling hamsters, providing in vivo proof that the CADM2/H-stalk interaction is essential for MeV neuropathogenicity.\",\n      \"evidence\": \"H protein stalk mutagenesis, recombinant virus in primary neurons, suckling hamster neurovirulence model\",\n      \"pmids\": [\"37166307\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-level structure of CADM2–H stalk interface not determined\", \"Human relevance requires clinical correlation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Cadm2 knockout mice recapitulated human GWAS-linked behavioral and metabolic phenotypes (impulsivity, altered cognition, BMI), validating CADM2 as a causal gene underlying these complex trait associations.\",\n      \"evidence\": \"Comprehensive behavioral and metabolic phenotyping battery (MouseWAS) in Cadm2 knockout mice\",\n      \"pmids\": [\"37173343\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Circuit-level mechanisms linking CADM2 loss to impulsivity and cognition not delineated\", \"Cell-type-specific conditional knockouts not yet reported\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Multiple studies expanded CADM2's functional repertoire: upstream epigenetic regulation was elucidated (lncRNA ADAMTS9-AS2 blocks DNMT3B occupancy at the CADM2 promoter), CADM2 was shown to mediate anti-inflammatory signaling by inhibiting TLR-MyD88, and a developmental role in neural stem cell fate and arousal regulation via the NPY pathway was established across zebrafish, mouse, and Drosophila.\",\n      \"evidence\": \"RIP/ChIP/pyrosequencing for epigenetic mechanism; siRNA + DSS colitis model for anti-inflammatory function; zebrafish cadm2 KO behavioral assays, mouse NPC overexpression, Drosophila beat-Ia knockdown\",\n      \"pmids\": [\"41869309\", \"38369215\", \"41526386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CADM2 anti-inflammatory function operates through its adhesion domain is unknown\", \"NSC fate specification mechanism downstream of CADM2 not molecularly defined\", \"Cross-species NPY pathway conservation not fully validated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of CADM2 interactions (both homophilic and with MeV H stalk), the direct molecular mechanism by which CADM2 suppresses AKT signaling, cell-type-specific conditional knockout studies dissecting hypothalamic versus peripheral metabolic roles, and whether CADM2's adhesion and signaling functions are mechanistically separable.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No crystal/cryo-EM structure of CADM2 extracellular or transmembrane domains\", \"No conditional or cell-type-specific knockout distinguishing central vs peripheral metabolic roles\", \"Direct biochemical link between CADM2 and AKT pathway components not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 8, 9]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5, 6, 12]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 8, 9, 10]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 14]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 10, 12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CADM1\",\n      \"CADM3\",\n      \"CADM4\",\n      \"DNMT3B\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}