{"gene":"CADM2","run_date":"2026-06-13T19:06:35","timeline":{"discoveries":[{"year":2007,"finding":"Necl-3/SynCAM-2 (CADM2) localizes to myelinated axons at the interface between the axon shaft and the myelin sheath, binds selectively to oligodendrocytes, and engages in homo- and heterophilic interactions with other Necl family members (Necl-1, Necl-2), leading to cell aggregation, establishing it as a bona fide cell adhesion molecule in the nervous system.","method":"Subcellular fractionation/immunolocalization, multiple independent cell adhesion assays (aggregation assays), binding assays with oligodendrocytes","journal":"BMC neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal assays (localization, binding, aggregation) in a single study; not independently replicated","pmids":["17967169"],"is_preprint":false},{"year":2010,"finding":"CADM2a (a defined isoform with its own promoter, mapping to human chromosome 3p12.1) functions as a tumor suppressor in prostate cancer: adenovirus-mediated CADM2a expression suppressed DU145 cell proliferation in vitro and colony formation in soft agar. CADM2a expression is epigenetically silenced by promoter hypermethylation, and treatment with the demethylating agent 5-aza-2'-deoxycytidine alone or combined with the HDAC inhibitor trichostatin A reactivated its expression.","method":"Adenovirus-mediated overexpression with proliferation/colony assays; bisulfite sequencing, methylation-specific PCR; pharmacological demethylation","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional loss-of-function/gain-of-function with defined cellular phenotype plus epigenetic mechanism, single lab, multiple orthogonal methods","pmids":["21062931"],"is_preprint":false},{"year":2013,"finding":"CADM2 functions as a tumor suppressor in renal cell carcinoma: re-expression of CADM2 in the 786-O cancer cell line suppressed tumor cell growth in vitro and in mouse xenografts via G1 phase cell cycle arrest and induction of apoptosis, and inhibited anchorage-independent growth and invasion. Conversely, siRNA-mediated knockdown of endogenous CADM2 induced a tumorigenic phenotype in non-tumorigenic MDCK cells. CADM2 promoter hypermethylation and/or loss of heterozygosity accounts for its silencing.","method":"Lentivirus-mediated overexpression, xenograft mouse model, siRNA knockdown, cell cycle analysis, apoptosis assay, methylation analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with in vitro and in vivo phenotypic readouts, single lab, multiple orthogonal methods","pmids":["23643812"],"is_preprint":false},{"year":2017,"finding":"Cadm2 deletion in obese mice (Cadm2/ob) reduced adiposity, systemic glucose levels, and improved insulin sensitivity, while increasing locomotor activity, energy expenditure rate, and core body temperature, establishing Cadm2 as a regulator of systemic energy homeostasis through the central nervous system. The risk variant rs13078960 was also associated with increased CADM2 expression in the human hypothalamus.","method":"Cadm2 knockout mouse model (loss-of-function), metabolic phenotyping (glucose tolerance, insulin sensitivity, locomotor activity, energy expenditure, core temperature), brain region expression analysis","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout mouse with multiple orthogonal metabolic phenotypic readouts plus human hypothalamic expression data, single lab but rigorous","pmids":["29217450"],"is_preprint":false},{"year":2018,"finding":"CADM2 is a direct target of miR-10b in hepatocellular carcinoma (HCC): miR-10b binds the 3'UTR of CADM2 (confirmed by dual-luciferase reporter assay), and the miR-10b/CADM2 axis modulates EMT, migration, and invasion via the FAK/AKT signaling pathway. Overexpression of CADM2 inhibited EMT and reduced migratory/invasive ability of HCC cells.","method":"Dual-luciferase reporter assay, overexpression of CADM2, wound healing and Transwell migration/invasion assays, Western blotting for FAK/AKT pathway components","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR binding confirmed by luciferase assay plus pathway analysis, single lab, multiple orthogonal methods","pmids":["29506532"],"is_preprint":false},{"year":2018,"finding":"CADM2 overexpression suppresses AKT signaling in esophageal squamous cell carcinoma (ESCC) cells, inhibiting proliferation and inducing apoptosis. CADM2 knockdown reverses the anti-proliferative/pro-apoptotic effect of miR-21-5p downregulation and restores p-AKT levels, placing CADM2 upstream of AKT in the miR-21-5p/CADM2/AKT axis.","method":"CADM2 overexpression and siRNA knockdown, cell proliferation assays, apoptosis assays, Western blotting for p-AKT","journal":"Chemico-biological interactions","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis (rescue experiment placing CADM2 upstream of AKT), single lab, multiple methods","pmids":["29680210"],"is_preprint":false},{"year":2021,"finding":"CADM1 and CADM2 act as host factors enabling neuropathogenic measles virus (MeV) membrane fusion and transsynaptic spread between neurons. Uniquely, CADM1 and CADM2 interact in cis (on the same cell membrane as the viral attachment protein) with the MeV hemagglutinin (H) protein, triggering hyperfusogenic fusion protein (F)-mediated membrane fusion. Knockdown of CADM1 and CADM2 inhibited syncytium formation and virus transmission between neurons.","method":"siRNA knockdown of CADM1/CADM2, cell-cell fusion assays (syncytium formation), virus transmission assays between neurons, co-localization/interaction studies","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct functional interaction established by loss-of-function (knockdown) with defined mechanistic readout (cis-interaction with viral H protein triggering F protein-mediated fusion), multiple orthogonal assays, replicated in follow-up study","pmids":["33910952"],"is_preprint":false},{"year":2021,"finding":"Only short-stalk isoforms of CADM2 (generated by alternative splicing and predominantly expressed in the brain) induce hyperfusogenic MeV F protein-mediated membrane fusion. These short-stalk isoforms interact in cis with the MeV H protein stalk domain (independently of the head domain), thereby triggering membrane fusion—distinct from conventional receptor-mediated trans interactions.","method":"Splice isoform expression studies, cell-cell fusion assays with isoform-specific constructs, domain-deletion mutants of H protein","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific functional dissection with domain mapping, single lab follow-up study, multiple methods","pmids":["34788082"],"is_preprint":false},{"year":2023,"finding":"Alanine substitutions at positions 171–175 in the stalk region of the MeV H protein abolish CADM1/CADM2-triggered membrane fusion (but not SLAM-triggered fusion), and recombinant hyperfusogenic MeV carrying this H protein mutant cannot spread in primary mouse neurons or cause neurovirulence in suckling hamsters, establishing the H protein stalk region as the molecular interface for CADM1/CADM2-dependent MeV neuropathogenesis in vivo.","method":"Site-directed mutagenesis (alanine substitution of H stalk residues 171–175), primary neuron spreading assay, in vivo neuropathogenicity model (suckling hamsters), cell-cell fusion assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis with defined molecular contact site validated both in vitro and in vivo, mechanistically resolves CADM2-H protein interaction domain","pmids":["37166307"],"is_preprint":false},{"year":2019,"finding":"Overexpression of CADM2 in glioma cells inhibited proliferation in vitro and in vivo, and suppressed migration and invasion. CADM2 overexpression decreased expression of G1/S transition regulators (cyclin D1, cyclin E, CDK2, CDK4) and altered EMT markers (increased E-cadherin, altered β-catenin), placing CADM2 as a regulator of the cell cycle and EMT in glioma.","method":"CADM2 overexpression, in vitro proliferation/migration/invasion assays, in vivo xenograft, Western blotting for cell cycle regulators and EMT markers","journal":"Oncology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with in vitro and in vivo readouts plus molecular pathway analysis, single lab","pmids":["30816549"],"is_preprint":false},{"year":2023,"finding":"In Cadm2 mutant mice (MouseWAS), loss of Cadm2 recapitulated associations found in humans including impulsivity, cognition, and BMI, confirming a direct role for Cadm2 in these behavioral and metabolic phenotypes.","method":"Cadm2 knockout/mutant mouse model with behavioral battery (impulsivity, cognition) and metabolic phenotyping (BMI)","journal":"Translational psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO mouse with defined behavioral and metabolic phenotypes across multiple assays, single lab","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: gene silencing of CADM2 abolished ALC's inhibitory effect on the TLR-MyD88 signaling pathway, thereby reducing suppression of inflammatory factor release. This places CADM2 as a required intermediary between ALC and TLR-MyD88 pathway inhibition in intestinal epithelium.","method":"Gene silencing (knockdown of CADM2), transcriptome sequencing, colitis mouse model (DSS-induced), cytokine measurement","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by gene silencing rescue experiment placing CADM2 in TLR-MyD88 pathway, single lab, multiple methods","pmids":["38369215"],"is_preprint":false},{"year":2024,"finding":"Loss of CADM2 in zebrafish results in excessive sleepiness (hypersomnia phenotype), and this can be rescued by an NPY receptor agonist. In Drosophila, the CADM2 ortholog beat-Ia is required for synaptic elaboration of neuropeptide F (NPF, the fly homolog of NPY) neurites projecting to the suboesophageal zone (SEZ), where they synapse onto GABAergic neurons to stabilize arousal.","method":"CADM2 knockout in zebrafish (loss-of-function sleep phenotyping), Drosophila neuronal knockdown of beat-Ia (sleep phenotyping), brain connectome analysis, NPY receptor agonist pharmacological rescue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — cross-species loss-of-function (fish + fly) with defined circuit mechanism, pharmacological rescue, and connectome evidence; published in peer-reviewed journal","pmids":["41526386"],"is_preprint":false},{"year":2025,"finding":"CADM2 contains a functional recursive splice site (RS1) in its first intron that regulates transcript abundance and isoform usage in neurons. CRISPR-mediated deletion of RS1 in human induced neurons decreased overall CADM2 expression, altered the gradient of RNA abundance across the first intron, changed transcript usage, and globally altered expression of genes involved in neuronal processes (synapse and axon development). Rat models with Cadm2 RS1 deletions showed significant changes in relevant behaviors and functional brain connectivity.","method":"CRISPR modeling of patient deletions in human induced neurons and rats, transcriptome analysis (RNA-seq), behavioral assays, brain connectivity imaging","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR functional validation in human neurons and in vivo rat models with transcriptomic readout; preprint, not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2026,"finding":"DNMT3B binds to the CADM2 promoter and mediates its epigenetic silencing in esophageal squamous cell carcinoma (ESCC). The lncRNA ADAMTS9-AS2 directly binds DNMT3B (confirmed by RIP and ChIP), preventing its occupancy at the CADM2 locus. Rescue experiments confirmed that CADM2 overexpression reversed the oncogenic phenotypes (proliferation, migration, invasion) induced by ADAMTS9-AS2 knockdown, placing DNMT3B-mediated CADM2 methylation downstream of ADAMTS9-AS2 loss.","method":"RIP (RNA immunoprecipitation), ChIP (chromatin immunoprecipitation), pyrosequencing for methylation, CADM2 overexpression rescue experiments, gene knockdown","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct DNMT3B–CADM2 promoter occupancy shown by ChIP, lncRNA-DNMT3B interaction by RIP, functional rescue; single lab","pmids":["41869309"],"is_preprint":false}],"current_model":"CADM2 (also known as Necl-3/SynCAM-2/IGSF4D) is an immunoglobulin superfamily cell adhesion molecule that localizes to myelinated axons and mediates homo- and heterophilic adhesion with other Necl family members and oligodendrocytes; in the brain it regulates synaptic elaboration of neuropeptide Y/NPF circuits controlling arousal (sleep/wakefulness) and energy homeostasis through hypothalamic signaling, with Cadm2 deletion causing hypersomnia and reversing metabolic syndrome features in mice; in cancer contexts it functions as a tumor suppressor (silenced by DNMT3B-mediated promoter hypermethylation) whose re-expression induces G1 arrest, apoptosis, and suppresses EMT via downregulation of FAK/AKT signaling; and it acts as a host cis-acting factor that interacts with the stalk domain of the measles virus hemagglutinin protein to trigger hyperfusogenic fusion-protein-mediated cell–cell membrane fusion enabling transsynaptic MeV spread in neurons and SSPE neuropathogenesis."},"narrative":{"mechanistic_narrative":"Parse failed — see logs","teleology":[],"mechanism_profile":null},"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 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\"Necl-3/SynCAM-2 (CADM2) localizes to myelinated axons at the interface between the axon shaft and the myelin sheath, binds selectively to oligodendrocytes, and engages in homo- and heterophilic interactions with other Necl family members (Necl-1, Necl-2), leading to cell aggregation, establishing it as a bona fide cell adhesion molecule in the nervous system.\",\n      \"method\": \"Subcellular fractionation/immunolocalization, multiple independent cell adhesion assays (aggregation assays), binding assays with oligodendrocytes\",\n      \"journal\": \"BMC neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal assays (localization, binding, aggregation) in a single study; not independently replicated\",\n      \"pmids\": [\"17967169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CADM2a (a defined isoform with its own promoter, mapping to human chromosome 3p12.1) functions as a tumor suppressor in prostate cancer: adenovirus-mediated CADM2a expression suppressed DU145 cell proliferation in vitro and colony formation in soft agar. CADM2a expression is epigenetically silenced by promoter hypermethylation, and treatment with the demethylating agent 5-aza-2'-deoxycytidine alone or combined with the HDAC inhibitor trichostatin A reactivated its expression.\",\n      \"method\": \"Adenovirus-mediated overexpression with proliferation/colony assays; bisulfite sequencing, methylation-specific PCR; pharmacological demethylation\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional loss-of-function/gain-of-function with defined cellular phenotype plus epigenetic mechanism, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"21062931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CADM2 functions as a tumor suppressor in renal cell carcinoma: re-expression of CADM2 in the 786-O cancer cell line suppressed tumor cell growth in vitro and in mouse xenografts via G1 phase cell cycle arrest and induction of apoptosis, and inhibited anchorage-independent growth and invasion. Conversely, siRNA-mediated knockdown of endogenous CADM2 induced a tumorigenic phenotype in non-tumorigenic MDCK cells. CADM2 promoter hypermethylation and/or loss of heterozygosity accounts for its silencing.\",\n      \"method\": \"Lentivirus-mediated overexpression, xenograft mouse model, siRNA knockdown, cell cycle analysis, apoptosis assay, methylation analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with in vitro and in vivo phenotypic readouts, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"23643812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cadm2 deletion in obese mice (Cadm2/ob) reduced adiposity, systemic glucose levels, and improved insulin sensitivity, while increasing locomotor activity, energy expenditure rate, and core body temperature, establishing Cadm2 as a regulator of systemic energy homeostasis through the central nervous system. The risk variant rs13078960 was also associated with increased CADM2 expression in the human hypothalamus.\",\n      \"method\": \"Cadm2 knockout mouse model (loss-of-function), metabolic phenotyping (glucose tolerance, insulin sensitivity, locomotor activity, energy expenditure, core temperature), brain region expression analysis\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout mouse with multiple orthogonal metabolic phenotypic readouts plus human hypothalamic expression data, single lab but rigorous\",\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 (HCC): miR-10b binds the 3'UTR of CADM2 (confirmed by dual-luciferase reporter assay), and the miR-10b/CADM2 axis modulates EMT, migration, and invasion via the FAK/AKT signaling pathway. Overexpression of CADM2 inhibited EMT and reduced migratory/invasive ability of HCC cells.\",\n      \"method\": \"Dual-luciferase reporter assay, overexpression of CADM2, wound healing and Transwell migration/invasion assays, Western blotting for FAK/AKT pathway components\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR binding confirmed by luciferase assay plus pathway analysis, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"29506532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CADM2 overexpression suppresses AKT signaling in esophageal squamous cell carcinoma (ESCC) cells, inhibiting proliferation and inducing apoptosis. CADM2 knockdown reverses the anti-proliferative/pro-apoptotic effect of miR-21-5p downregulation and restores p-AKT levels, placing CADM2 upstream of AKT in the miR-21-5p/CADM2/AKT axis.\",\n      \"method\": \"CADM2 overexpression and siRNA knockdown, cell proliferation assays, apoptosis assays, Western blotting for p-AKT\",\n      \"journal\": \"Chemico-biological interactions\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis (rescue experiment placing CADM2 upstream of AKT), single lab, multiple methods\",\n      \"pmids\": [\"29680210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CADM1 and CADM2 act as host factors enabling neuropathogenic measles virus (MeV) membrane fusion and transsynaptic spread between neurons. Uniquely, CADM1 and CADM2 interact in cis (on the same cell membrane as the viral attachment protein) with the MeV hemagglutinin (H) protein, triggering hyperfusogenic fusion protein (F)-mediated membrane fusion. Knockdown of CADM1 and CADM2 inhibited syncytium formation and virus transmission between neurons.\",\n      \"method\": \"siRNA knockdown of CADM1/CADM2, cell-cell fusion assays (syncytium formation), virus transmission assays between neurons, co-localization/interaction studies\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct functional interaction established by loss-of-function (knockdown) with defined mechanistic readout (cis-interaction with viral H protein triggering F protein-mediated fusion), multiple orthogonal assays, replicated in follow-up study\",\n      \"pmids\": [\"33910952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Only short-stalk isoforms of CADM2 (generated by alternative splicing and predominantly expressed in the brain) induce hyperfusogenic MeV F protein-mediated membrane fusion. These short-stalk isoforms interact in cis with the MeV H protein stalk domain (independently of the head domain), thereby triggering membrane fusion—distinct from conventional receptor-mediated trans interactions.\",\n      \"method\": \"Splice isoform expression studies, cell-cell fusion assays with isoform-specific constructs, domain-deletion mutants of H protein\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific functional dissection with domain mapping, single lab follow-up study, multiple methods\",\n      \"pmids\": [\"34788082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Alanine substitutions at positions 171–175 in the stalk region of the MeV H protein abolish CADM1/CADM2-triggered membrane fusion (but not SLAM-triggered fusion), and recombinant hyperfusogenic MeV carrying this H protein mutant cannot spread in primary mouse neurons or cause neurovirulence in suckling hamsters, establishing the H protein stalk region as the molecular interface for CADM1/CADM2-dependent MeV neuropathogenesis in vivo.\",\n      \"method\": \"Site-directed mutagenesis (alanine substitution of H stalk residues 171–175), primary neuron spreading assay, in vivo neuropathogenicity model (suckling hamsters), cell-cell fusion assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis with defined molecular contact site validated both in vitro and in vivo, mechanistically resolves CADM2-H protein interaction domain\",\n      \"pmids\": [\"37166307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Overexpression of CADM2 in glioma cells inhibited proliferation in vitro and in vivo, and suppressed migration and invasion. CADM2 overexpression decreased expression of G1/S transition regulators (cyclin D1, cyclin E, CDK2, CDK4) and altered EMT markers (increased E-cadherin, altered β-catenin), placing CADM2 as a regulator of the cell cycle and EMT in glioma.\",\n      \"method\": \"CADM2 overexpression, in vitro proliferation/migration/invasion assays, in vivo xenograft, Western blotting for cell cycle regulators and EMT markers\",\n      \"journal\": \"Oncology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with in vitro and in vivo readouts plus molecular pathway analysis, single lab\",\n      \"pmids\": [\"30816549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In Cadm2 mutant mice (MouseWAS), loss of Cadm2 recapitulated associations found in humans including impulsivity, cognition, and BMI, confirming a direct role for Cadm2 in these behavioral and metabolic phenotypes.\",\n      \"method\": \"Cadm2 knockout/mutant mouse model with behavioral battery (impulsivity, cognition) and metabolic phenotyping (BMI)\",\n      \"journal\": \"Translational psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO mouse with defined behavioral and metabolic phenotypes across multiple assays, single lab\",\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: gene silencing of CADM2 abolished ALC's inhibitory effect on the TLR-MyD88 signaling pathway, thereby reducing suppression of inflammatory factor release. This places CADM2 as a required intermediary between ALC and TLR-MyD88 pathway inhibition in intestinal epithelium.\",\n      \"method\": \"Gene silencing (knockdown of CADM2), transcriptome sequencing, colitis mouse model (DSS-induced), cytokine measurement\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by gene silencing rescue experiment placing CADM2 in TLR-MyD88 pathway, single lab, multiple methods\",\n      \"pmids\": [\"38369215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of CADM2 in zebrafish results in excessive sleepiness (hypersomnia phenotype), and this can be rescued by an NPY receptor agonist. In Drosophila, the CADM2 ortholog beat-Ia is required for synaptic elaboration of neuropeptide F (NPF, the fly homolog of NPY) neurites projecting to the suboesophageal zone (SEZ), where they synapse onto GABAergic neurons to stabilize arousal.\",\n      \"method\": \"CADM2 knockout in zebrafish (loss-of-function sleep phenotyping), Drosophila neuronal knockdown of beat-Ia (sleep phenotyping), brain connectome analysis, NPY receptor agonist pharmacological rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cross-species loss-of-function (fish + fly) with defined circuit mechanism, pharmacological rescue, and connectome evidence; published in peer-reviewed journal\",\n      \"pmids\": [\"41526386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CADM2 contains a functional recursive splice site (RS1) in its first intron that regulates transcript abundance and isoform usage in neurons. CRISPR-mediated deletion of RS1 in human induced neurons decreased overall CADM2 expression, altered the gradient of RNA abundance across the first intron, changed transcript usage, and globally altered expression of genes involved in neuronal processes (synapse and axon development). Rat models with Cadm2 RS1 deletions showed significant changes in relevant behaviors and functional brain connectivity.\",\n      \"method\": \"CRISPR modeling of patient deletions in human induced neurons and rats, transcriptome analysis (RNA-seq), behavioral assays, brain connectivity imaging\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR functional validation in human neurons and in vivo rat models with transcriptomic readout; preprint, not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DNMT3B binds to the CADM2 promoter and mediates its epigenetic silencing in esophageal squamous cell carcinoma (ESCC). The lncRNA ADAMTS9-AS2 directly binds DNMT3B (confirmed by RIP and ChIP), preventing its occupancy at the CADM2 locus. Rescue experiments confirmed that CADM2 overexpression reversed the oncogenic phenotypes (proliferation, migration, invasion) induced by ADAMTS9-AS2 knockdown, placing DNMT3B-mediated CADM2 methylation downstream of ADAMTS9-AS2 loss.\",\n      \"method\": \"RIP (RNA immunoprecipitation), ChIP (chromatin immunoprecipitation), pyrosequencing for methylation, CADM2 overexpression rescue experiments, gene knockdown\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct DNMT3B–CADM2 promoter occupancy shown by ChIP, lncRNA-DNMT3B interaction by RIP, functional rescue; single lab\",\n      \"pmids\": [\"41869309\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CADM2 (also known as Necl-3/SynCAM-2/IGSF4D) is an immunoglobulin superfamily cell adhesion molecule that localizes to myelinated axons and mediates homo- and heterophilic adhesion with other Necl family members and oligodendrocytes; in the brain it regulates synaptic elaboration of neuropeptide Y/NPF circuits controlling arousal (sleep/wakefulness) and energy homeostasis through hypothalamic signaling, with Cadm2 deletion causing hypersomnia and reversing metabolic syndrome features in mice; in cancer contexts it functions as a tumor suppressor (silenced by DNMT3B-mediated promoter hypermethylation) whose re-expression induces G1 arrest, apoptosis, and suppresses EMT via downregulation of FAK/AKT signaling; and it acts as a host cis-acting factor that interacts with the stalk domain of the measles virus hemagglutinin protein to trigger hyperfusogenic fusion-protein-mediated cell–cell membrane fusion enabling transsynaptic MeV spread in neurons and SSPE neuropathogenesis.\"\n}\n```","stage2_raw":"","audit_flag":{"gene":"CADM2","tier":"BEHAVIOR","verdict":"Model-behavior concern","subtype":"model_safety_refusal","uniprot_band":"medium","rules_fired":"R10","issue":"R10: API stop_reason='refusal' at stage2"},"evaluation":null}