{"gene":"ADAM23","run_date":"2026-06-09T22:02:41","timeline":{"discoveries":[{"year":2000,"finding":"The disintegrin-like domain of ADAM23 directly binds αvβ3 integrin via a non-RGD sequence in its putative disintegrin loop, promoting cell adhesion of neural-origin cells (neuroblastoma, astrocytoma, HeLa) in an RGD-independent manner.","method":"Recombinant protein adhesion assay, integrin-binding assay with recombinant disintegrin domain, full-length cDNA transfection in HeLa cells","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro binding assay with recombinant domain, confirmed with full-length transfection, replicated across multiple cell lines","pmids":["10749942"],"is_preprint":false},{"year":2008,"finding":"ADAM23 binds both LGI1 and LGI4 via its ectodomain, establishing it as a receptor for LGI-family secreted proteins alongside ADAM22 and ADAM11.","method":"Quantitative cell-ELISA binding assay, immunoprecipitation and mass spectrometry","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding confirmed by cell-ELISA and co-IP in a single lab with two orthogonal methods","pmids":["18974846"],"is_preprint":false},{"year":2009,"finding":"LGI1 binding to ADAM23 is required for correct neuronal morphology: LGI1 promotes neurite outgrowth from wild-type but not ADAM23-/- neurons, and ADAM23-/- hippocampal CA1 pyramidal neurons show reduced dendritic arborization. ADAM23-/- mice exhibit spontaneous seizures and ADAM23+/- mice have reduced seizure thresholds.","method":"Unbiased LGI1-binding screen (identified ADAM23 as the primary interactor), ADAM23 knockout mouse analysis, neurite outgrowth assay, in vivo seizure monitoring","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined cellular and in vivo phenotypes, unbiased binding screen, multiple orthogonal readouts","pmids":["19796686"],"is_preprint":false},{"year":2009,"finding":"ADAM23 negatively modulates αvβ3 integrin activation: shRNA knockdown of ADAM23 in MDA-MB-435 cells enhances αvβ3 integrin activation by 2–4-fold, increases migration and adhesion to αvβ3 ligands, and enhances pulmonary tumor cell arrest in mice.","method":"shRNA knockdown, integrin activation assay, cell migration and adhesion assay, in vivo pulmonary arrest model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with quantitative integrin activation readout, confirmed in vivo, multiple orthogonal assays in single study","pmids":["19549921"],"is_preprint":false},{"year":2009,"finding":"ADAM23 physically interacts with cellular prion protein (PrPc) at the plasma membrane of hippocampal neurons and neuroblastoma cells; the disintegrin domain of ADAM23 is sufficient for this interaction, and the interaction is glycosylation-independent.","method":"Co-immunoprecipitation, pull-down assay with recombinant proteins (bacterial and eukaryotic), co-localization by immunofluorescence, in vitro binding with tunicamycin-treated cells","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and pull-down in single lab, domain mapping with recombinant proteins, glycosylation control","pmids":["19477226"],"is_preprint":false},{"year":2004,"finding":"ADAM23 is synthesized as a ~100 kDa glycosylated precursor whose maturation to a lower molecular weight form depends on cleavage by furin or a related enzyme; mature ADAM23 is expressed primarily as a cell-surface protein localized to sites of intercellular contact in neurons.","method":"Immunoblotting with anti-ADAM23 disintegrin-domain antibody, furin inhibitor experiments, cell fractionation, tissue distribution analysis","journal":"Journal of neuroscience research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical fractionation and protease inhibitor experiments in a single lab with multiple methods","pmids":["15505805"],"is_preprint":false},{"year":2012,"finding":"LGI3 physically associates with ADAM23 in adipose tissue and 3T3-L1 cells; LGI3 suppresses adipogenesis through ADAM23, as the anti-adipogenic effect of exogenous LGI3 protein is abolished by ADAM23 siRNA knockdown.","method":"Pull-down, co-immunoprecipitation, immunocytochemistry, siRNA knockdown, adipogenesis assay","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and pull-down plus functional rescue experiment in a single lab","pmids":["22405860"],"is_preprint":false},{"year":2014,"finding":"In ADAM23-heterotypic tumor environments, ADAM23-negative cells promote proliferation and invasion of adjacent ADAM23-positive cells through secretion of LGI4 and nitric oxide (NO); ablation of LGI4 and NO in ADAM23-negative cells significantly attenuates ADAM23-positive cell proliferation and invasion.","method":"In vitro co-culture functional assays, LGI4 and NO pathway ablation, in vivo tumor growth/metastasis assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional ablation of LGI4 and NO with defined cellular phenotype readout in single lab, in vitro and in vivo","pmids":["24662834"],"is_preprint":false},{"year":2016,"finding":"ADAM23 expression on dendritic cells (DCs) governs CD4+ T cell activation, proliferation, and cytokine production (IL-2, IFN-γ, IL-4, IL-17) through the αvβ3 integrin receptor; this is independent of DC maturation profile, and neutralizing anti-αvβ3 antibodies phenocopy ADAM23 knockdown.","method":"RNAi knockdown in bone marrow-derived DCs, T cell proliferation assay, cytokine measurement, neutralizing antibody experiments","journal":"Journal of leukocyte biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined T cell readouts, confirmed by neutralizing antibody phenocopy in single lab","pmids":["27317750"],"is_preprint":false},{"year":2016,"finding":"ADAM23 suppresses lung cancer cell colony formation, adhesion, and migration through interaction with αvβ3 integrin via its disintegrin domain; these effects are abolished by anti-ADAM23, anti-αvβ3 antibodies, or ADAM23 disintegrin peptide. ADAM23 expression levels negatively regulate lung metastasis in vivo.","method":"Overexpression and shRNA knockdown, neutralizing antibody/peptide assays, in vivo lung metastasis model","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain and loss-of-function with domain-specific peptide/antibody validation and in vivo confirmation in single lab","pmids":["26800504"],"is_preprint":false},{"year":2016,"finding":"Four secretion-positive ADLTE-causing LGI1 missense mutations (T380A, R407C, S473L, R474Q) significantly impair LGI1 interaction with both ADAM22 and ADAM23 on the cell surface, defining a second loss-of-function mechanism distinct from impaired secretion.","method":"Co-immunoprecipitation, immunofluorescence, cell-surface binding assay, 3D protein modelling","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and immunofluorescence in multiple mutants in a single lab, structural modeling as supporting evidence","pmids":["27760137"],"is_preprint":false},{"year":2018,"finding":"ADAM23 in cardiomyocytes inhibits cardiac hypertrophy by specifically targeting the FAK-AKT signaling cascade; cardiac-specific ADAM23 knockout exacerbates hypertrophy/fibrosis and ADAM23 transgenic overexpression reduces it; FAK inhibitor (PF-562271) reverses the detrimental effects of ADAM23 knockout.","method":"Cardiac-specific conditional knockout, transgenic overexpression, aortic banding model, pharmacologic FAK inhibition, signaling pathway analysis","journal":"Journal of the American Heart Association","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO + transgenic overexpression + pharmacological epistasis rescue in single study with multiple orthogonal methods","pmids":["30371220"],"is_preprint":false},{"year":2018,"finding":"ADAM23 is present in lipid raft membrane microdomains of neuronal cells; the mature 70 kDa form partitions between raft and non-raft domains, while the pro-protein 100 kDa form is mainly in non-raft domains.","method":"Lipid raft fractionation, immunoblotting with monoclonal antibody DL11C8 (targeting cysteine-rich domain), brain region homogenates and primary cultured neurons","journal":"Neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical fractionation across multiple neuronal systems in single lab","pmids":["29792904"],"is_preprint":false},{"year":2019,"finding":"ADAM22 and ADAM23 modulate trafficking of LGI1: they promote its ER export and expression at the neuronal cell surface, and co-transport LGI1 in axonal vesicles to the axon initial segment (AIS). ADLTE-causing LGI1 mutations (S473L, R474Q) prevent association with ADAM22 and enrichment at the AIS.","method":"Live-cell imaging in rat hippocampal neurons, immunofluorescence co-localization, co-transport tracking, LGI1 mutant analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging with functional consequence (AIS enrichment), disease mutant validation in single lab","pmids":["30598502"],"is_preprint":false},{"year":2019,"finding":"ADAM23 negatively regulates Kv1.1 potassium currents and decreases surface expression of Kv1.1 subunits via a clathrin-independent mechanism; this regulation is not reversed by LGI1.","method":"Whole-cell patch-clamp electrophysiology, immunostaining of surface Kv1.1, transfected cultured cells, LGI1-conditioned media treatment","journal":"Neuroscience letters","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct electrophysiology with surface expression quantification in single lab","pmids":["30965109"],"is_preprint":false},{"year":2020,"finding":"ADAM23 undergoes constitutive internalization from the plasma membrane via lipid raft-dependent endocytosis and is recycled back to the plasma membrane through early and recycling endosomes; ADAM23 has longer half-life and higher cell surface stability compared to other ADAMs.","method":"Endocytosis assays, lipid raft disruption, subcellular fractionation, pulse-chase/half-life measurement, immunofluorescence","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple trafficking assays in single lab establishing mechanistic pathway of ADAM23 internalization and recycling","pmids":["33296662"],"is_preprint":false},{"year":2023,"finding":"Axonal ADAM23 is essential for the accumulation and stability of juxtaparanodal Kv1 channel complexes; this function critically depends on ADAM23 interaction with its extracellular ligands LGI2 and LGI3. Juxtaparanodal Kv1 complexes organized via ADAM23 affect the refractory period and enable high-frequency burst firing.","method":"ADAM23 knockout mouse, immunofluorescence at juxtaparanodes, electrophysiology (refractory period measurement), genetic epistasis with LGI2/LGI3","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined structural and electrophysiological phenotypes, ligand interaction epistasis, replicated across multiple methods","pmids":["36828548"],"is_preprint":false},{"year":2023,"finding":"ADAM23 deficiency in astrocytomas induces γ-secretase (GS) complex activity, leading to increased Amyloid-β production/deposition and NICD release, which drives increased cell infiltration; GS inhibition in ADAM23-low astrocytomas reduces invasion.","method":"In vitro and in vivo functional assays, RNA sequencing, GS activity assay, pharmacological GS inhibition","journal":"Neuro-oncology advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with pathway activity readout and pharmacological epistasis in single study","pmids":["38024245"],"is_preprint":false},{"year":2024,"finding":"LGI3 is secreted from oligodendrocytes, enriched at juxtaparanodes, and uses ADAM23 as a receptor (shown by proteomic analysis with epitope-tagged Lgi3 knockin); the LGI3-ADAM23 interaction co-assembles Kv1 channels into juxtaparanodal nanoclusters, and loss of Lgi3 disrupts juxtaparanodal clustering of ADAM23 and Kv1 channels and suppresses Kv1-mediated short-term synaptic plasticity.","method":"Epitope-tagged knockin mouse proteomics, immunofluorescence, Lgi3 knockout mouse, electrophysiology (short-term synaptic plasticity)","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo proteomic identification with knockin, KO phenotype with structural and electrophysiological validation, multiple orthogonal methods","pmids":["38194969"],"is_preprint":false},{"year":2010,"finding":"SP1 binds a specific site (-202/-190) in the proximal ADAM23 promoter; serum deprivation enhances chromatin accessibility at this site, allowing SP1 binding to recruit RNA polymerase II and upregulate ADAM23 expression.","method":"Promoter analysis, chromatin accessibility assay, electrophoretic mobility shift assay/ChIP (SP1 binding), RNA polymerase II recruitment assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP/binding assay with functional promoter readout in single lab","pmids":["20851106"],"is_preprint":false},{"year":2012,"finding":"ADAM23 knockdown in P19 cells promotes G1 arrest and neuronal differentiation (without RA) by upregulating P27KIP1 (and P57KIP2); recombinant GST-ADAM23 disintegrin domain inhibits this differentiation, placing the disintegrin domain as the functional suppressor of differentiation.","method":"RNAi knockdown, cell cycle analysis, recombinant domain rescue, P27KIP1 overexpression","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-specific rescue and epistasis via P27KIP1 overexpression in single lab","pmids":["22973984"],"is_preprint":false},{"year":2025,"finding":"Biallelic loss-of-function LGI1 variants result in reduced LGI1 secretion and impaired ADAM22 binding; residual LGI1 function levels correlate with clinical severity. An ADAM23 variant is associated with lethal neonatal-onset epilepsy and myopathy, genetically linking ADAM23 to the LGI1-ADAM22/23 pathway-related disease spectrum.","method":"Functional secretion assays, ADAM22-binding assays for LGI1 mutants, Lgi1-/- knockout mouse electrophysiology (isolated whole hippocampus), ADAM22-DEE mouse model behavioral analysis","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional variant assays and in vivo mouse electrophysiology in single study, ADAM23 finding based on single variant report","pmids":["40455867"],"is_preprint":false}],"current_model":"ADAM23 is a catalytically inactive transmembrane ADAM-family glycoprotein expressed predominantly in the brain that functions as a cell-adhesion receptor: its disintegrin domain mediates RGD-independent binding to αvβ3 integrin (negatively modulating integrin activation and suppressing metastasis), while its ectodomain serves as a receptor for secreted LGI-family ligands (LGI1, LGI2, LGI3, LGI4); through LGI2/LGI3 interactions, axonal ADAM23 is essential for juxtaparanodal Kv1 potassium channel clustering that regulates the axonal refractory period, and through LGI1 interactions it controls neurite outgrowth, dendritic arborization, and neuronal excitability (loss of ADAM23 causes spontaneous seizures in mice); in cardiomyocytes ADAM23 suppresses hypertrophy via the FAK-AKT cascade; ADAM23 undergoes constitutive lipid-raft-dependent endocytosis with recycling back to the plasma membrane, and its expression is transcriptionally regulated by SP1 and epigenetically silenced by promoter CpG hypermethylation in multiple cancer types."},"narrative":{"mechanistic_narrative":"ADAM23 is a catalytically inactive, furin-matured transmembrane ADAM-family glycoprotein expressed predominantly in the brain that functions as a cell-surface adhesion receptor and ligand-binding hub [PMID:15505805]. Its disintegrin-like domain mediates RGD-independent binding to αvβ3 integrin, promoting adhesion of neural-origin cells while negatively modulating integrin activation; loss of ADAM23 enhances αvβ3 activation, migration, and metastatic colonization, establishing it as a metastasis suppressor [PMID:10749942, PMID:19549921, PMID:26800504]. Through its ectodomain, ADAM23 serves as a receptor for the secreted LGI family of proteins (LGI1, LGI3, LGI4), and these interactions underlie its principal neuronal functions [PMID:18974846, PMID:19796686, PMID:38194969]. LGI1 binding is required for normal neurite outgrowth and dendritic arborization, and ADAM23-null mice develop spontaneous seizures [PMID:19796686]. In axons, ADAM23 acting through LGI2/LGI3 is essential for the accumulation and stability of juxtaparanodal Kv1 potassium channel complexes, co-assembling Kv1 nanoclusters that set the axonal refractory period and support high-frequency firing and short-term synaptic plasticity [PMID:36828548, PMID:38194969]. ADAM23 also independently suppresses surface Kv1.1 currents through a clathrin-independent mechanism [PMID:30965109], and undergoes constitutive lipid-raft-dependent endocytosis with recycling to the plasma membrane, conferring high surface stability [PMID:29792904, PMID:33296662]. Beyond the nervous system, ADAM23 suppresses cardiac hypertrophy via the FAK-AKT cascade [PMID:30371220] and controls dendritic-cell-driven CD4+ T cell activation through αvβ3 integrin [PMID:27317750]. ADAM23 expression is activated by SP1 binding to its proximal promoter [PMID:20851106]. A biallelic ADAM23 variant has been linked to lethal neonatal-onset epilepsy and myopathy within the LGI1-ADAM22/23 disease spectrum [PMID:40455867].","teleology":[{"year":2000,"claim":"Established the molecular basis of ADAM23 adhesive function by showing its disintegrin domain binds a specific integrin partner, addressing how a catalytically inactive ADAM mediates cell adhesion.","evidence":"Recombinant disintegrin-domain adhesion and integrin-binding assays plus full-length transfection across neural cell lines","pmids":["10749942"],"confidence":"High","gaps":["Did not define downstream signaling consequences of αvβ3 engagement","Non-RGD binding motif not resolved at residue level"]},{"year":2004,"claim":"Defined ADAM23 biogenesis, showing maturation depends on furin cleavage and that mature protein localizes to neuronal cell-cell contact sites.","evidence":"Immunoblotting, furin inhibitor experiments and cell fractionation in neurons","pmids":["15505805"],"confidence":"Medium","gaps":["Identity of the maturation protease not definitively shown to be furin","Functional role of contact-site localization untested"]},{"year":2008,"claim":"Identified ADAM23 as a receptor for secreted LGI-family proteins, expanding its role beyond integrin adhesion to ligand recognition.","evidence":"Cell-ELISA binding assay and co-IP/mass spectrometry for LGI1 and LGI4","pmids":["18974846"],"confidence":"Medium","gaps":["Binding affinities and stoichiometry not determined","Functional consequences of LGI binding not addressed in this study"]},{"year":2009,"claim":"Connected ADAM23-LGI1 binding to neuronal morphology and excitability, establishing ADAM23 as a seizure-suppressing receptor in vivo.","evidence":"Unbiased LGI1-binding screen, ADAM23 knockout mouse with neurite/dendrite phenotypes and seizure monitoring","pmids":["19796686"],"confidence":"High","gaps":["Molecular signaling linking LGI1-ADAM23 to neurite outgrowth not resolved","Cell-type contribution to seizures not dissected"]},{"year":2009,"claim":"Showed ADAM23 functions as a metastasis suppressor by restraining αvβ3 integrin activation, linking its adhesion function to tumor cell behavior.","evidence":"shRNA knockdown with integrin activation, migration/adhesion assays and in vivo pulmonary arrest model","pmids":["19549921"],"confidence":"High","gaps":["Mechanism by which ADAM23 dampens integrin activation not defined","Did not establish whether effect is cell-autonomous in patient tumors"]},{"year":2009,"claim":"Added cellular prion protein as a direct membrane partner of the ADAM23 disintegrin domain, broadening its neuronal interaction network.","evidence":"Reciprocal co-IP, recombinant pull-down with domain mapping and glycosylation controls","pmids":["19477226"],"confidence":"Medium","gaps":["Functional consequence of PrPc-ADAM23 interaction unknown","Single-lab interaction without in vivo validation"]},{"year":2010,"claim":"Defined transcriptional control of ADAM23 by identifying an SP1 promoter element regulated by chromatin accessibility.","evidence":"Promoter analysis, EMSA/ChIP for SP1 and RNA Pol II recruitment under serum deprivation","pmids":["20851106"],"confidence":"Medium","gaps":["Physiological signals driving chromatin opening not identified","Relationship to cancer-associated silencing not addressed"]},{"year":2012,"claim":"Extended LGI-ADAM23 signaling to non-neuronal tissue, showing LGI3 acts through ADAM23 to suppress adipogenesis.","evidence":"Pull-down, co-IP and siRNA rescue of LGI3 anti-adipogenic effect in 3T3-L1 cells","pmids":["22405860"],"confidence":"Medium","gaps":["Downstream signaling from ADAM23 in adipocytes not mapped","In vivo relevance not tested"]},{"year":2012,"claim":"Linked the ADAM23 disintegrin domain to cell-cycle and differentiation control, showing it suppresses neuronal differentiation via P27KIP1.","evidence":"RNAi knockdown, cell cycle analysis and recombinant disintegrin-domain rescue in P19 cells","pmids":["22973984"],"confidence":"Medium","gaps":["Receptor mediating the disintegrin effect on differentiation not identified","Mechanism linking domain to P27KIP1 induction unclear"]},{"year":2014,"claim":"Revealed a non-cell-autonomous tumor mechanism whereby ADAM23-negative cells stimulate neighboring ADAM23-positive cells via secreted LGI4 and nitric oxide.","evidence":"Co-culture functional assays with LGI4/NO ablation and in vivo tumor models","pmids":["24662834"],"confidence":"Medium","gaps":["Receptor/signaling integrating LGI4 and NO not defined","Generality across tumor types untested"]},{"year":2016,"claim":"Demonstrated an immune role for ADAM23, controlling dendritic-cell-driven CD4+ T cell responses through αvβ3 integrin.","evidence":"RNAi knockdown in bone-marrow DCs with T cell proliferation/cytokine readouts and anti-αvβ3 neutralizing phenocopy","pmids":["27317750"],"confidence":"Medium","gaps":["Molecular signaling from αvβ3 to T cell outcomes not mapped","In vivo immune consequences not established"]},{"year":2016,"claim":"Confirmed the disintegrin-αvβ3 axis as the basis of ADAM23 tumor suppression in lung cancer using domain-specific antagonists.","evidence":"Gain/loss-of-function with anti-ADAM23, anti-αvβ3 and disintegrin peptide blockade plus in vivo metastasis model","pmids":["26800504"],"confidence":"Medium","gaps":["Did not resolve intracellular signaling downstream of integrin modulation","Clinical correlation limited"]},{"year":2016,"claim":"Linked disease-causing LGI1 missense mutations to loss of ADAM22/ADAM23 binding, defining a binding-deficient mechanism of epilepsy distinct from secretion failure.","evidence":"Co-IP, immunofluorescence and surface-binding assays of ADLTE mutants with structural modeling","pmids":["27760137"],"confidence":"Medium","gaps":["Relative contribution of ADAM23 versus ADAM22 binding not separated","Structural model not experimentally determined"]},{"year":2018,"claim":"Defined a cardiac function for ADAM23, showing it suppresses hypertrophy through the FAK-AKT cascade.","evidence":"Cardiac-specific knockout, transgenic overexpression, aortic banding and pharmacologic FAK inhibition rescue","pmids":["30371220"],"confidence":"High","gaps":["Upstream receptor/ligand triggering FAK-AKT regulation in cardiomyocytes not identified","Whether integrin or LGI ligands mediate this is unknown"]},{"year":2018,"claim":"Placed ADAM23 in lipid-raft microdomains and showed its mature form partitions between raft and non-raft domains, providing membrane-organization context.","evidence":"Lipid raft fractionation and immunoblotting across brain regions and primary neurons","pmids":["29792904"],"confidence":"Medium","gaps":["Functional importance of raft partitioning not directly tested here","Raft residency relationship to ligand binding unknown"]},{"year":2019,"claim":"Showed ADAM22/ADAM23 chaperone LGI1 trafficking, promoting ER export and axonal co-transport to the axon initial segment.","evidence":"Live-cell imaging and co-transport tracking in hippocampal neurons with disease-mutant analysis","pmids":["30598502"],"confidence":"Medium","gaps":["Relative roles of ADAM22 versus ADAM23 in trafficking not fully separated","Structural basis of co-transport vesicle loading unknown"]},{"year":2019,"claim":"Demonstrated direct ADAM23 regulation of Kv1.1 surface expression and current through a clathrin-independent, LGI1-independent mechanism.","evidence":"Whole-cell patch-clamp and surface Kv1.1 immunostaining in transfected cells","pmids":["30965109"],"confidence":"Medium","gaps":["Molecular pathway of clathrin-independent Kv1.1 internalization unresolved","Reconciliation with juxtaparanodal clustering role not addressed"]},{"year":2023,"claim":"Established axonal ADAM23 as essential for juxtaparanodal Kv1 channel clustering through LGI2/LGI3, defining its role in setting the refractory period and burst firing.","evidence":"ADAM23 knockout mouse with juxtaparanodal immunofluorescence, electrophysiology and LGI2/LGI3 genetic epistasis","pmids":["36828548"],"confidence":"High","gaps":["Molecular bridge between ADAM23 and Kv1 channel scaffolding not defined","Reconciliation with ADAM23's negative Kv1.1 regulation unresolved"]},{"year":2023,"claim":"Identified a γ-secretase-dependent invasion mechanism unleashed by ADAM23 loss in astrocytoma, linking ADAM23 deficiency to Aβ and NICD-driven infiltration.","evidence":"In vitro/in vivo functional assays, RNA-seq, γ-secretase activity assay and pharmacologic inhibition","pmids":["38024245"],"confidence":"Medium","gaps":["Mechanism by which ADAM23 restrains γ-secretase activity unknown","Clinical translatability of GS inhibition untested"]},{"year":2024,"claim":"Defined oligodendrocyte-derived LGI3 as a juxtaparanodal ligand that uses ADAM23 to co-assemble Kv1 nanoclusters and support short-term synaptic plasticity.","evidence":"Epitope-tagged Lgi3 knockin proteomics, Lgi3 knockout immunofluorescence and electrophysiology","pmids":["38194969"],"confidence":"High","gaps":["Stoichiometry of the LGI3-ADAM23-Kv1 assembly not resolved","Glia-axon directionality of complex assembly not fully mapped"]},{"year":2025,"claim":"Genetically linked ADAM23 to human disease, associating a biallelic variant with lethal neonatal-onset epilepsy and myopathy within the LGI1-ADAM22/23 spectrum.","evidence":"Functional variant assays plus Lgi1-/- and ADAM22-DEE mouse models","pmids":["40455867"],"confidence":"Medium","gaps":["ADAM23 finding rests on a single variant report","Functional consequence of the ADAM23 variant not directly characterized"]},{"year":null,"claim":"The molecular scaffold linking ADAM23 to Kv1 channels and reconciling its dual roles as a Kv1.1 negative regulator and a juxtaparanodal Kv1-clustering factor remains undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the ADAM23-LGI-Kv1 complex","Downstream signaling from αvβ3 integrin modulation in different tissues not unified","Direct functional characterization of disease-associated ADAM23 variants lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[1,2,6,18]},{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,14,16]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[4,5,12,15]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[15]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[13]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[2,16,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[17,21]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8]}],"complexes":["juxtaparanodal Kv1 channel complex"],"partners":["ITGAV","ITGB3","LGI1","LGI2","LGI3","LGI4","PRNP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75077","full_name":"Disintegrin and metalloproteinase domain-containing protein 23","aliases":["Metalloproteinase-like, disintegrin-like, and cysteine-rich protein 3","MDC-3"],"length_aa":832,"mass_kda":91.9,"function":"May play a role in cell-cell and cell-matrix interactions. This is a non-catalytic metalloprotease-like protein","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/O75077/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ADAM23","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":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ADAM23","total_profiled":1310},"omim":[{"mim_id":"621475","title":"DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 121; DEE121","url":"https://www.omim.org/entry/621475"},{"mim_id":"618510","title":"DYSTROTELIN; DYTN","url":"https://www.omim.org/entry/618510"},{"mim_id":"608302","title":"LEUCINE-RICH GENE, GLIOMA-INACTIVATED, 3; LGI3","url":"https://www.omim.org/entry/608302"},{"mim_id":"604619","title":"LEUCINE-RICH GENE, GLIOMA-INACTIVATED, 1; LGI1","url":"https://www.omim.org/entry/604619"},{"mim_id":"603710","title":"A DISINTEGRIN AND METALLOPROTEINASE DOMAIN 23; ADAM23","url":"https://www.omim.org/entry/603710"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":31.5},{"tissue":"parathyroid gland","ntpm":77.8}],"url":"https://www.proteinatlas.org/search/ADAM23"},"hgnc":{"alias_symbol":["MDC3"],"prev_symbol":[]},"alphafold":{"accession":"O75077","domains":[{"cath_id":"3.40.390.10","chopping":"111-137_144-256_294-485","consensus_level":"medium","plddt":87.8795,"start":111,"end":485},{"cath_id":"4.10.70.10","chopping":"521-582","consensus_level":"medium","plddt":85.5156,"start":521,"end":582},{"cath_id":"-","chopping":"589-727","consensus_level":"high","plddt":94.8164,"start":589,"end":727},{"cath_id":"2.10.25","chopping":"734-774","consensus_level":"medium","plddt":90.3939,"start":734,"end":774}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75077","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75077-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75077-F1-predicted_aligned_error_v6.png","plddt_mean":76.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ADAM23","jax_strain_url":"https://www.jax.org/strain/search?query=ADAM23"},"sequence":{"accession":"O75077","fasta_url":"https://rest.uniprot.org/uniprotkb/O75077.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75077/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75077"}},"corpus_meta":[{"pmid":"10749942","id":"PMC_10749942","title":"ADAM 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domain of ADAM23 directly binds αvβ3 integrin via a non-RGD sequence in its putative disintegrin loop, promoting cell adhesion of neural-origin cells (neuroblastoma, astrocytoma, HeLa) in an RGD-independent manner.\",\n      \"method\": \"Recombinant protein adhesion assay, integrin-binding assay with recombinant disintegrin domain, full-length cDNA transfection in HeLa cells\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro binding assay with recombinant domain, confirmed with full-length transfection, replicated across multiple cell lines\",\n      \"pmids\": [\"10749942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ADAM23 binds both LGI1 and LGI4 via its ectodomain, establishing it as a receptor for LGI-family secreted proteins alongside ADAM22 and ADAM11.\",\n      \"method\": \"Quantitative cell-ELISA binding assay, immunoprecipitation and mass spectrometry\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding confirmed by cell-ELISA and co-IP in a single lab with two orthogonal methods\",\n      \"pmids\": [\"18974846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"LGI1 binding to ADAM23 is required for correct neuronal morphology: LGI1 promotes neurite outgrowth from wild-type but not ADAM23-/- neurons, and ADAM23-/- hippocampal CA1 pyramidal neurons show reduced dendritic arborization. ADAM23-/- mice exhibit spontaneous seizures and ADAM23+/- mice have reduced seizure thresholds.\",\n      \"method\": \"Unbiased LGI1-binding screen (identified ADAM23 as the primary interactor), ADAM23 knockout mouse analysis, neurite outgrowth assay, in vivo seizure monitoring\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined cellular and in vivo phenotypes, unbiased binding screen, multiple orthogonal readouts\",\n      \"pmids\": [\"19796686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ADAM23 negatively modulates αvβ3 integrin activation: shRNA knockdown of ADAM23 in MDA-MB-435 cells enhances αvβ3 integrin activation by 2–4-fold, increases migration and adhesion to αvβ3 ligands, and enhances pulmonary tumor cell arrest in mice.\",\n      \"method\": \"shRNA knockdown, integrin activation assay, cell migration and adhesion assay, in vivo pulmonary arrest model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with quantitative integrin activation readout, confirmed in vivo, multiple orthogonal assays in single study\",\n      \"pmids\": [\"19549921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ADAM23 physically interacts with cellular prion protein (PrPc) at the plasma membrane of hippocampal neurons and neuroblastoma cells; the disintegrin domain of ADAM23 is sufficient for this interaction, and the interaction is glycosylation-independent.\",\n      \"method\": \"Co-immunoprecipitation, pull-down assay with recombinant proteins (bacterial and eukaryotic), co-localization by immunofluorescence, in vitro binding with tunicamycin-treated cells\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and pull-down in single lab, domain mapping with recombinant proteins, glycosylation control\",\n      \"pmids\": [\"19477226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ADAM23 is synthesized as a ~100 kDa glycosylated precursor whose maturation to a lower molecular weight form depends on cleavage by furin or a related enzyme; mature ADAM23 is expressed primarily as a cell-surface protein localized to sites of intercellular contact in neurons.\",\n      \"method\": \"Immunoblotting with anti-ADAM23 disintegrin-domain antibody, furin inhibitor experiments, cell fractionation, tissue distribution analysis\",\n      \"journal\": \"Journal of neuroscience research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical fractionation and protease inhibitor experiments in a single lab with multiple methods\",\n      \"pmids\": [\"15505805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LGI3 physically associates with ADAM23 in adipose tissue and 3T3-L1 cells; LGI3 suppresses adipogenesis through ADAM23, as the anti-adipogenic effect of exogenous LGI3 protein is abolished by ADAM23 siRNA knockdown.\",\n      \"method\": \"Pull-down, co-immunoprecipitation, immunocytochemistry, siRNA knockdown, adipogenesis assay\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and pull-down plus functional rescue experiment in a single lab\",\n      \"pmids\": [\"22405860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In ADAM23-heterotypic tumor environments, ADAM23-negative cells promote proliferation and invasion of adjacent ADAM23-positive cells through secretion of LGI4 and nitric oxide (NO); ablation of LGI4 and NO in ADAM23-negative cells significantly attenuates ADAM23-positive cell proliferation and invasion.\",\n      \"method\": \"In vitro co-culture functional assays, LGI4 and NO pathway ablation, in vivo tumor growth/metastasis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional ablation of LGI4 and NO with defined cellular phenotype readout in single lab, in vitro and in vivo\",\n      \"pmids\": [\"24662834\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ADAM23 expression on dendritic cells (DCs) governs CD4+ T cell activation, proliferation, and cytokine production (IL-2, IFN-γ, IL-4, IL-17) through the αvβ3 integrin receptor; this is independent of DC maturation profile, and neutralizing anti-αvβ3 antibodies phenocopy ADAM23 knockdown.\",\n      \"method\": \"RNAi knockdown in bone marrow-derived DCs, T cell proliferation assay, cytokine measurement, neutralizing antibody experiments\",\n      \"journal\": \"Journal of leukocyte biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined T cell readouts, confirmed by neutralizing antibody phenocopy in single lab\",\n      \"pmids\": [\"27317750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ADAM23 suppresses lung cancer cell colony formation, adhesion, and migration through interaction with αvβ3 integrin via its disintegrin domain; these effects are abolished by anti-ADAM23, anti-αvβ3 antibodies, or ADAM23 disintegrin peptide. ADAM23 expression levels negatively regulate lung metastasis in vivo.\",\n      \"method\": \"Overexpression and shRNA knockdown, neutralizing antibody/peptide assays, in vivo lung metastasis model\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain and loss-of-function with domain-specific peptide/antibody validation and in vivo confirmation in single lab\",\n      \"pmids\": [\"26800504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Four secretion-positive ADLTE-causing LGI1 missense mutations (T380A, R407C, S473L, R474Q) significantly impair LGI1 interaction with both ADAM22 and ADAM23 on the cell surface, defining a second loss-of-function mechanism distinct from impaired secretion.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, cell-surface binding assay, 3D protein modelling\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and immunofluorescence in multiple mutants in a single lab, structural modeling as supporting evidence\",\n      \"pmids\": [\"27760137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ADAM23 in cardiomyocytes inhibits cardiac hypertrophy by specifically targeting the FAK-AKT signaling cascade; cardiac-specific ADAM23 knockout exacerbates hypertrophy/fibrosis and ADAM23 transgenic overexpression reduces it; FAK inhibitor (PF-562271) reverses the detrimental effects of ADAM23 knockout.\",\n      \"method\": \"Cardiac-specific conditional knockout, transgenic overexpression, aortic banding model, pharmacologic FAK inhibition, signaling pathway analysis\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO + transgenic overexpression + pharmacological epistasis rescue in single study with multiple orthogonal methods\",\n      \"pmids\": [\"30371220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ADAM23 is present in lipid raft membrane microdomains of neuronal cells; the mature 70 kDa form partitions between raft and non-raft domains, while the pro-protein 100 kDa form is mainly in non-raft domains.\",\n      \"method\": \"Lipid raft fractionation, immunoblotting with monoclonal antibody DL11C8 (targeting cysteine-rich domain), brain region homogenates and primary cultured neurons\",\n      \"journal\": \"Neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical fractionation across multiple neuronal systems in single lab\",\n      \"pmids\": [\"29792904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADAM22 and ADAM23 modulate trafficking of LGI1: they promote its ER export and expression at the neuronal cell surface, and co-transport LGI1 in axonal vesicles to the axon initial segment (AIS). ADLTE-causing LGI1 mutations (S473L, R474Q) prevent association with ADAM22 and enrichment at the AIS.\",\n      \"method\": \"Live-cell imaging in rat hippocampal neurons, immunofluorescence co-localization, co-transport tracking, LGI1 mutant analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging with functional consequence (AIS enrichment), disease mutant validation in single lab\",\n      \"pmids\": [\"30598502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ADAM23 negatively regulates Kv1.1 potassium currents and decreases surface expression of Kv1.1 subunits via a clathrin-independent mechanism; this regulation is not reversed by LGI1.\",\n      \"method\": \"Whole-cell patch-clamp electrophysiology, immunostaining of surface Kv1.1, transfected cultured cells, LGI1-conditioned media treatment\",\n      \"journal\": \"Neuroscience letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct electrophysiology with surface expression quantification in single lab\",\n      \"pmids\": [\"30965109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ADAM23 undergoes constitutive internalization from the plasma membrane via lipid raft-dependent endocytosis and is recycled back to the plasma membrane through early and recycling endosomes; ADAM23 has longer half-life and higher cell surface stability compared to other ADAMs.\",\n      \"method\": \"Endocytosis assays, lipid raft disruption, subcellular fractionation, pulse-chase/half-life measurement, immunofluorescence\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple trafficking assays in single lab establishing mechanistic pathway of ADAM23 internalization and recycling\",\n      \"pmids\": [\"33296662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Axonal ADAM23 is essential for the accumulation and stability of juxtaparanodal Kv1 channel complexes; this function critically depends on ADAM23 interaction with its extracellular ligands LGI2 and LGI3. Juxtaparanodal Kv1 complexes organized via ADAM23 affect the refractory period and enable high-frequency burst firing.\",\n      \"method\": \"ADAM23 knockout mouse, immunofluorescence at juxtaparanodes, electrophysiology (refractory period measurement), genetic epistasis with LGI2/LGI3\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined structural and electrophysiological phenotypes, ligand interaction epistasis, replicated across multiple methods\",\n      \"pmids\": [\"36828548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ADAM23 deficiency in astrocytomas induces γ-secretase (GS) complex activity, leading to increased Amyloid-β production/deposition and NICD release, which drives increased cell infiltration; GS inhibition in ADAM23-low astrocytomas reduces invasion.\",\n      \"method\": \"In vitro and in vivo functional assays, RNA sequencing, GS activity assay, pharmacological GS inhibition\",\n      \"journal\": \"Neuro-oncology advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with pathway activity readout and pharmacological epistasis in single study\",\n      \"pmids\": [\"38024245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LGI3 is secreted from oligodendrocytes, enriched at juxtaparanodes, and uses ADAM23 as a receptor (shown by proteomic analysis with epitope-tagged Lgi3 knockin); the LGI3-ADAM23 interaction co-assembles Kv1 channels into juxtaparanodal nanoclusters, and loss of Lgi3 disrupts juxtaparanodal clustering of ADAM23 and Kv1 channels and suppresses Kv1-mediated short-term synaptic plasticity.\",\n      \"method\": \"Epitope-tagged knockin mouse proteomics, immunofluorescence, Lgi3 knockout mouse, electrophysiology (short-term synaptic plasticity)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo proteomic identification with knockin, KO phenotype with structural and electrophysiological validation, multiple orthogonal methods\",\n      \"pmids\": [\"38194969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SP1 binds a specific site (-202/-190) in the proximal ADAM23 promoter; serum deprivation enhances chromatin accessibility at this site, allowing SP1 binding to recruit RNA polymerase II and upregulate ADAM23 expression.\",\n      \"method\": \"Promoter analysis, chromatin accessibility assay, electrophoretic mobility shift assay/ChIP (SP1 binding), RNA polymerase II recruitment assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP/binding assay with functional promoter readout in single lab\",\n      \"pmids\": [\"20851106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ADAM23 knockdown in P19 cells promotes G1 arrest and neuronal differentiation (without RA) by upregulating P27KIP1 (and P57KIP2); recombinant GST-ADAM23 disintegrin domain inhibits this differentiation, placing the disintegrin domain as the functional suppressor of differentiation.\",\n      \"method\": \"RNAi knockdown, cell cycle analysis, recombinant domain rescue, P27KIP1 overexpression\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific rescue and epistasis via P27KIP1 overexpression in single lab\",\n      \"pmids\": [\"22973984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Biallelic loss-of-function LGI1 variants result in reduced LGI1 secretion and impaired ADAM22 binding; residual LGI1 function levels correlate with clinical severity. An ADAM23 variant is associated with lethal neonatal-onset epilepsy and myopathy, genetically linking ADAM23 to the LGI1-ADAM22/23 pathway-related disease spectrum.\",\n      \"method\": \"Functional secretion assays, ADAM22-binding assays for LGI1 mutants, Lgi1-/- knockout mouse electrophysiology (isolated whole hippocampus), ADAM22-DEE mouse model behavioral analysis\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional variant assays and in vivo mouse electrophysiology in single study, ADAM23 finding based on single variant report\",\n      \"pmids\": [\"40455867\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ADAM23 is a catalytically inactive transmembrane ADAM-family glycoprotein expressed predominantly in the brain that functions as a cell-adhesion receptor: its disintegrin domain mediates RGD-independent binding to αvβ3 integrin (negatively modulating integrin activation and suppressing metastasis), while its ectodomain serves as a receptor for secreted LGI-family ligands (LGI1, LGI2, LGI3, LGI4); through LGI2/LGI3 interactions, axonal ADAM23 is essential for juxtaparanodal Kv1 potassium channel clustering that regulates the axonal refractory period, and through LGI1 interactions it controls neurite outgrowth, dendritic arborization, and neuronal excitability (loss of ADAM23 causes spontaneous seizures in mice); in cardiomyocytes ADAM23 suppresses hypertrophy via the FAK-AKT cascade; ADAM23 undergoes constitutive lipid-raft-dependent endocytosis with recycling back to the plasma membrane, and its expression is transcriptionally regulated by SP1 and epigenetically silenced by promoter CpG hypermethylation in multiple cancer types.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ADAM23 is a catalytically inactive, furin-matured transmembrane ADAM-family glycoprotein expressed predominantly in the brain that functions as a cell-surface adhesion receptor and ligand-binding hub [#5]. Its disintegrin-like domain mediates RGD-independent binding to αvβ3 integrin, promoting adhesion of neural-origin cells while negatively modulating integrin activation; loss of ADAM23 enhances αvβ3 activation, migration, and metastatic colonization, establishing it as a metastasis suppressor [#0, #3, #9]. Through its ectodomain, ADAM23 serves as a receptor for the secreted LGI family of proteins (LGI1, LGI3, LGI4), and these interactions underlie its principal neuronal functions [#1, #2, #18]. LGI1 binding is required for normal neurite outgrowth and dendritic arborization, and ADAM23-null mice develop spontaneous seizures [#2]. In axons, ADAM23 acting through LGI2/LGI3 is essential for the accumulation and stability of juxtaparanodal Kv1 potassium channel complexes, co-assembling Kv1 nanoclusters that set the axonal refractory period and support high-frequency firing and short-term synaptic plasticity [#16, #18]. ADAM23 also independently suppresses surface Kv1.1 currents through a clathrin-independent mechanism [#14], and undergoes constitutive lipid-raft-dependent endocytosis with recycling to the plasma membrane, conferring high surface stability [#12, #15]. Beyond the nervous system, ADAM23 suppresses cardiac hypertrophy via the FAK-AKT cascade [#11] and controls dendritic-cell-driven CD4+ T cell activation through αvβ3 integrin [#8]. ADAM23 expression is activated by SP1 binding to its proximal promoter [#19]. A biallelic ADAM23 variant has been linked to lethal neonatal-onset epilepsy and myopathy within the LGI1-ADAM22/23 disease spectrum [#21].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the molecular basis of ADAM23 adhesive function by showing its disintegrin domain binds a specific integrin partner, addressing how a catalytically inactive ADAM mediates cell adhesion.\",\n      \"evidence\": \"Recombinant disintegrin-domain adhesion and integrin-binding assays plus full-length transfection across neural cell lines\",\n      \"pmids\": [\"10749942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define downstream signaling consequences of αvβ3 engagement\", \"Non-RGD binding motif not resolved at residue level\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined ADAM23 biogenesis, showing maturation depends on furin cleavage and that mature protein localizes to neuronal cell-cell contact sites.\",\n      \"evidence\": \"Immunoblotting, furin inhibitor experiments and cell fractionation in neurons\",\n      \"pmids\": [\"15505805\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the maturation protease not definitively shown to be furin\", \"Functional role of contact-site localization untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified ADAM23 as a receptor for secreted LGI-family proteins, expanding its role beyond integrin adhesion to ligand recognition.\",\n      \"evidence\": \"Cell-ELISA binding assay and co-IP/mass spectrometry for LGI1 and LGI4\",\n      \"pmids\": [\"18974846\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding affinities and stoichiometry not determined\", \"Functional consequences of LGI binding not addressed in this study\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Connected ADAM23-LGI1 binding to neuronal morphology and excitability, establishing ADAM23 as a seizure-suppressing receptor in vivo.\",\n      \"evidence\": \"Unbiased LGI1-binding screen, ADAM23 knockout mouse with neurite/dendrite phenotypes and seizure monitoring\",\n      \"pmids\": [\"19796686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular signaling linking LGI1-ADAM23 to neurite outgrowth not resolved\", \"Cell-type contribution to seizures not dissected\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed ADAM23 functions as a metastasis suppressor by restraining αvβ3 integrin activation, linking its adhesion function to tumor cell behavior.\",\n      \"evidence\": \"shRNA knockdown with integrin activation, migration/adhesion assays and in vivo pulmonary arrest model\",\n      \"pmids\": [\"19549921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which ADAM23 dampens integrin activation not defined\", \"Did not establish whether effect is cell-autonomous in patient tumors\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Added cellular prion protein as a direct membrane partner of the ADAM23 disintegrin domain, broadening its neuronal interaction network.\",\n      \"evidence\": \"Reciprocal co-IP, recombinant pull-down with domain mapping and glycosylation controls\",\n      \"pmids\": [\"19477226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of PrPc-ADAM23 interaction unknown\", \"Single-lab interaction without in vivo validation\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined transcriptional control of ADAM23 by identifying an SP1 promoter element regulated by chromatin accessibility.\",\n      \"evidence\": \"Promoter analysis, EMSA/ChIP for SP1 and RNA Pol II recruitment under serum deprivation\",\n      \"pmids\": [\"20851106\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological signals driving chromatin opening not identified\", \"Relationship to cancer-associated silencing not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended LGI-ADAM23 signaling to non-neuronal tissue, showing LGI3 acts through ADAM23 to suppress adipogenesis.\",\n      \"evidence\": \"Pull-down, co-IP and siRNA rescue of LGI3 anti-adipogenic effect in 3T3-L1 cells\",\n      \"pmids\": [\"22405860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling from ADAM23 in adipocytes not mapped\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked the ADAM23 disintegrin domain to cell-cycle and differentiation control, showing it suppresses neuronal differentiation via P27KIP1.\",\n      \"evidence\": \"RNAi knockdown, cell cycle analysis and recombinant disintegrin-domain rescue in P19 cells\",\n      \"pmids\": [\"22973984\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating the disintegrin effect on differentiation not identified\", \"Mechanism linking domain to P27KIP1 induction unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed a non-cell-autonomous tumor mechanism whereby ADAM23-negative cells stimulate neighboring ADAM23-positive cells via secreted LGI4 and nitric oxide.\",\n      \"evidence\": \"Co-culture functional assays with LGI4/NO ablation and in vivo tumor models\",\n      \"pmids\": [\"24662834\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor/signaling integrating LGI4 and NO not defined\", \"Generality across tumor types untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated an immune role for ADAM23, controlling dendritic-cell-driven CD4+ T cell responses through αvβ3 integrin.\",\n      \"evidence\": \"RNAi knockdown in bone-marrow DCs with T cell proliferation/cytokine readouts and anti-αvβ3 neutralizing phenocopy\",\n      \"pmids\": [\"27317750\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular signaling from αvβ3 to T cell outcomes not mapped\", \"In vivo immune consequences not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Confirmed the disintegrin-αvβ3 axis as the basis of ADAM23 tumor suppression in lung cancer using domain-specific antagonists.\",\n      \"evidence\": \"Gain/loss-of-function with anti-ADAM23, anti-αvβ3 and disintegrin peptide blockade plus in vivo metastasis model\",\n      \"pmids\": [\"26800504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not resolve intracellular signaling downstream of integrin modulation\", \"Clinical correlation limited\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked disease-causing LGI1 missense mutations to loss of ADAM22/ADAM23 binding, defining a binding-deficient mechanism of epilepsy distinct from secretion failure.\",\n      \"evidence\": \"Co-IP, immunofluorescence and surface-binding assays of ADLTE mutants with structural modeling\",\n      \"pmids\": [\"27760137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of ADAM23 versus ADAM22 binding not separated\", \"Structural model not experimentally determined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined a cardiac function for ADAM23, showing it suppresses hypertrophy through the FAK-AKT cascade.\",\n      \"evidence\": \"Cardiac-specific knockout, transgenic overexpression, aortic banding and pharmacologic FAK inhibition rescue\",\n      \"pmids\": [\"30371220\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream receptor/ligand triggering FAK-AKT regulation in cardiomyocytes not identified\", \"Whether integrin or LGI ligands mediate this is unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed ADAM23 in lipid-raft microdomains and showed its mature form partitions between raft and non-raft domains, providing membrane-organization context.\",\n      \"evidence\": \"Lipid raft fractionation and immunoblotting across brain regions and primary neurons\",\n      \"pmids\": [\"29792904\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional importance of raft partitioning not directly tested here\", \"Raft residency relationship to ligand binding unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed ADAM22/ADAM23 chaperone LGI1 trafficking, promoting ER export and axonal co-transport to the axon initial segment.\",\n      \"evidence\": \"Live-cell imaging and co-transport tracking in hippocampal neurons with disease-mutant analysis\",\n      \"pmids\": [\"30598502\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative roles of ADAM22 versus ADAM23 in trafficking not fully separated\", \"Structural basis of co-transport vesicle loading unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated direct ADAM23 regulation of Kv1.1 surface expression and current through a clathrin-independent, LGI1-independent mechanism.\",\n      \"evidence\": \"Whole-cell patch-clamp and surface Kv1.1 immunostaining in transfected cells\",\n      \"pmids\": [\"30965109\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular pathway of clathrin-independent Kv1.1 internalization unresolved\", \"Reconciliation with juxtaparanodal clustering role not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established axonal ADAM23 as essential for juxtaparanodal Kv1 channel clustering through LGI2/LGI3, defining its role in setting the refractory period and burst firing.\",\n      \"evidence\": \"ADAM23 knockout mouse with juxtaparanodal immunofluorescence, electrophysiology and LGI2/LGI3 genetic epistasis\",\n      \"pmids\": [\"36828548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular bridge between ADAM23 and Kv1 channel scaffolding not defined\", \"Reconciliation with ADAM23's negative Kv1.1 regulation unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a γ-secretase-dependent invasion mechanism unleashed by ADAM23 loss in astrocytoma, linking ADAM23 deficiency to Aβ and NICD-driven infiltration.\",\n      \"evidence\": \"In vitro/in vivo functional assays, RNA-seq, γ-secretase activity assay and pharmacologic inhibition\",\n      \"pmids\": [\"38024245\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ADAM23 restrains γ-secretase activity unknown\", \"Clinical translatability of GS inhibition untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined oligodendrocyte-derived LGI3 as a juxtaparanodal ligand that uses ADAM23 to co-assemble Kv1 nanoclusters and support short-term synaptic plasticity.\",\n      \"evidence\": \"Epitope-tagged Lgi3 knockin proteomics, Lgi3 knockout immunofluorescence and electrophysiology\",\n      \"pmids\": [\"38194969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the LGI3-ADAM23-Kv1 assembly not resolved\", \"Glia-axon directionality of complex assembly not fully mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Genetically linked ADAM23 to human disease, associating a biallelic variant with lethal neonatal-onset epilepsy and myopathy within the LGI1-ADAM22/23 spectrum.\",\n      \"evidence\": \"Functional variant assays plus Lgi1-/- and ADAM22-DEE mouse models\",\n      \"pmids\": [\"40455867\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ADAM23 finding rests on a single variant report\", \"Functional consequence of the ADAM23 variant not directly characterized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular scaffold linking ADAM23 to Kv1 channels and reconciling its dual roles as a Kv1.1 negative regulator and a juxtaparanodal Kv1-clustering factor remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the ADAM23-LGI-Kv1 complex\", \"Downstream signaling from αvβ3 integrin modulation in different tissues not unified\", \"Direct functional characterization of disease-associated ADAM23 variants lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [1, 2, 6, 18]},\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 14, 16]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [4, 5, 12, 15]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [2, 16, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [17, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\"juxtaparanodal Kv1 channel complex\"],\n    \"partners\": [\"ITGAV\", \"ITGB3\", \"LGI1\", \"LGI2\", \"LGI3\", \"LGI4\", \"PRNP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}