{"gene":"CADM1","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2002,"finding":"SynCAM 1 (CADM1) is a brain-specific immunoglobulin domain-containing protein that functions as a homophilic cell adhesion molecule at synapses, binds intracellular PDZ-domain proteins via its cytoplasmic tail, and expression in nonneuronal cells is sufficient to induce functional presynaptic differentiation in cocultured hippocampal neurons. Expression of the isolated cytoplasmic tail in neurons inhibited synapse assembly (dominant-negative effect).","method":"Heterologous cell co-culture synapse induction assay, neuronal dominant-negative overexpression, reconstitution of glutamatergic transmission with coexpressed glutamate receptors","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in nonneuronal cells, functional electrophysiology, dominant-negative mutagenesis, replicated by multiple subsequent studies","pmids":["12202822"],"is_preprint":false},{"year":2005,"finding":"SynCAM 1 (CADM1) and neuroligin-1 (NL1) both specifically induce presynaptic differentiation in co-culture assays; only SynCAM 1 (not NL1) increased synaptic function in immature developing excitatory neurons, and this dominant-positive effect was mediated by its intracellular cytoplasmic tail.","method":"Heterologous cell co-culture synapse induction, electrophysiology, chimeric molecule expression in neurons","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional reconstitution with chimeric molecules and electrophysiology, multiple orthogonal methods","pmids":["15634790"],"is_preprint":false},{"year":2008,"finding":"Two missense mutations in CADM1 (C739A/H246N and A755C/Y251S) located in the third immunoglobulin domain impair trans-active interaction; mutant CADM1 shows reduced high-molecular-weight glycosylated forms, defective trafficking to the cell surface, and increased susceptibility to cleavage/degradation.","method":"Mutant protein expression in cells, Western blot, cell surface trafficking assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based expression with multiple biochemical readouts, single lab","pmids":["18957284"],"is_preprint":false},{"year":2010,"finding":"SynCAM 1 (CADM1) is a target for polysialylation in postnatal mouse brain; polySia is added on N-glycans of the first Ig domain by both ST8SiaII and ST8SiaIV in vitro, and polysialylation of SynCAM 1 completely abolishes its homophilic binding activity.","method":"Glycoproteomics affinity purification from Ncam−/− brain, peptide mass fingerprinting, in vitro polysialylation assay, binding assay after polySia modification","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay plus functional binding readout, identification of specific glycosylation site, replicated in subsequent studies","pmids":["20479255"],"is_preprint":false},{"year":2010,"finding":"SynCAM 1 (CADM1) overexpression in transgenic mice promotes excitatory synapse number; loss of SynCAM 1 results in fewer excitatory synapses. SynCAM 1 also regulates long-term depression (LTD) at mature synapses and affects spatial learning, with knockout mice learning better.","method":"Transgenic overexpression and knockout mice, synapse counting, electrophysiology (LTD), spatial learning behavioral assays","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function in vivo with multiple orthogonal phenotypic readouts, replicated by other labs","pmids":["21145003"],"is_preprint":false},{"year":2010,"finding":"SynCAM 1 (CADM1) localizes to growth cones of developing neurons and is required and sufficient to restrict active filopodia number, negatively regulating growth cone morphological complexity. Focal adhesion kinase (FAK) is a binding partner of SynCAM 1 and is implicated in its morphogenetic activities.","method":"Live imaging of developing neurons, SynCAM 1 overexpression/knockdown, FAK co-immunoprecipitation, filopodia quantification","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct live imaging with gain- and loss-of-function, identified binding partner FAK, multiple methods in one study","pmids":["20368431"],"is_preprint":false},{"year":2010,"finding":"N-glycosylation at specific sites on the SynCAM 1 Ig1 domain (Asn70/Asn104) modulates its adhesive interactions: these N-glycans increase adhesion and are required for synapse induction. In contrast, N-glycosylation of SynCAM 2 at Asn60 reduces adhesion. Sialic acid modification contributes to the glycan-dependent strengthening of SynCAM 1 binding.","method":"Crystallographic analysis of SynCAM 2 Ig1 domain, mass spectrometry of glycosylation sites, site-directed mutagenesis of glycosylation sites, adhesion assays, synapse induction assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus functional assays in one study","pmids":["20739279"],"is_preprint":false},{"year":2011,"finding":"SynCAM 1 (CADM1) self-assembles laterally (cis-oligomerization) via its extracellular membrane-proximal Ig domains 2 and 3, generating oligomers with increased adhesive capacity. Cis assembly promotes adhesive clustering at new axo-dendritic contacts and is required for synaptogenic activity; lateral oligomerization also restricts synaptic size at later stages.","method":"Biochemical characterization of SynCAM oligomers, domain deletion constructs, neuronal overexpression with dominant-negative cis-assembly mutants, synapse induction assays, imaging","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution of cis-oligomerization with domain deletions and mutagenesis plus functional synaptogenesis readouts","pmids":["21926970"],"is_preprint":false},{"year":2009,"finding":"CADM1 interacts with actin-binding protein 4.1B/DAL-1 and scaffold protein MPP3/DLG3. MPP1/p55 and MPP2/DLG2 form a tripartite complex with CADM1 and 4.1B. MPP2 is recruited to the CADM1–4.1B complex during early adhesion. siRNA-mediated suppression of CADM1 disrupts epithelia-like cell structure and mislocalizes 4.1B, MPP2, E-cadherin, and ZO-1 from the membrane.","method":"Co-immunoprecipitation, siRNA knockdown in HEK293 cells, immunofluorescence localization","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, knockdown with multiple localization readouts, single lab","pmids":["19854157"],"is_preprint":false},{"year":2010,"finding":"The cytoplasmic PDZ-binding motif of CADM1 directly interacts with the PDZ domain of Tiam1 (a Rac-specific GEF), inducing lamellipodia formation through Rac activation in HTLV-I-transformed and ATL cell lines, promoting an invasive phenotype.","method":"Co-immunoprecipitation of CADM1 cytoplasmic domain with Tiam1 PDZ domain, Rac activation assay, lamellipodia formation assay in cell lines","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein interaction mapped to specific domains, functional Rac/lamellipodia readout, multiple orthogonal methods","pmids":["20215110"],"is_preprint":false},{"year":2009,"finding":"CADM1 (Necl-2) interacts in cis with the extracellular region of ErbB3 (but not ErbB2), reducing ligand-induced ErbB2-catalyzed tyrosine phosphorylation of ErbB3 and inhibiting subsequent ErbB3-mediated activation of Rac and Akt. These inhibitory effects are mediated by PTPN13, a protein-tyrosine phosphatase that interacts with the cytoplasmic tail of CADM1.","method":"Co-immunoprecipitation (cis interaction), receptor phosphorylation assays, Rac and Akt activity assays, siRNA knockdown, PTPN13 interaction mapping","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, kinase assay, GTPase assay, siRNA), mechanistic pathway placement","pmids":["19561085"],"is_preprint":false},{"year":2013,"finding":"CADM1 (Necl-2) interacts with ErbB4 in parvalbumin-positive GABAergic neurons (co-localizing at excitatory synapses). Knockdown of CADM1 enhances Nrg1-induced ErbB4 phosphorylation. Overexpression of PTPN13, which binds the cytoplasmic tail of CADM1, suppresses Nrg1-induced excitatory synapse development in GABAergic neurons via inhibition of ErbB4 activity.","method":"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, PTPN13 overexpression, ErbB4 phosphorylation assay","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional assays, single lab","pmids":["23769722"],"is_preprint":false},{"year":2006,"finding":"CADM1 (RA175) is expressed at spermatocyte and elongating/elongated spermatid cell junctions in testes. Knockout mice lacking RA175 are male-infertile (oligo-astheno-teratozoospermia): elongating spermatids (steps 9–12) fail to mature and translocate to the adluminal surface and are phagocytosed by Sertoli cells, demonstrating that CADM1-mediated cell junction is necessary for retaining elongating spermatids in Sertoli cell invaginations during maturation.","method":"Gene knockout mice, histology, immunostaining in testes, fertility assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with specific cellular phenotype and immunolocalization, replicated in subsequent studies","pmids":["16382161"],"is_preprint":false},{"year":2007,"finding":"CADM1 (RA175) interacts with Par-3 (a PDZ-domain cell polarity protein) via its cytoplasmic region in testis, and forms a ternary complex with JAM-C via Par-3. In RA175-knockout elongating spermatids, Par-3 is absent and JAM-C is absent or abnormally localized, indicating this ternary complex is required for maintaining specialized adhesion structures in spermatid differentiation.","method":"Co-immunoprecipitation from testis, immunostaining of knockout vs. wildtype testes","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP mapping of ternary complex, supported by KO localization data, single lab","pmids":["18055550"],"is_preprint":false},{"year":2011,"finding":"CADM1 is cleaved by ADAM10 (a disintegrin and metalloprotease) at a membrane-proximal site (identified by LC/MS/MS), and the resulting membrane-bound fragment is subsequently cleaved by γ-secretase to generate a CADM1 intracellular domain (ICD) via regulated intramembrane proteolysis (RIP). ADAM10 mediates endogenous CADM1 shedding as shown by siRNA knockdown.","method":"LC/MS/MS cleavage site mapping, siRNA knockdown of ADAM10, γ-secretase inhibitor, cell-based cleavage assays","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cleavage site identified by MS, specific sheddase identified by siRNA, sequential RIP mechanism validated","pmids":["22172944"],"is_preprint":false},{"year":2012,"finding":"Polysialylation of SynCAM 1 (CADM1) in perinatal brain is exclusively mediated by ST8SiaII (not ST8SiaIV) in vivo. The minimal polypeptide required for ST8SiaII-dependent polysialylation contains both Ig1 (the polySia acceptor site) and Ig2 (a docking site for ST8SiaII); Ig1 alone is insufficient.","method":"Analysis of ST8SiaII and ST8SiaIV single-knockout mice, domain deletion constructs transfected in cell culture, polySia immunoblot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — genetic ablation of specific enzyme in vivo plus domain deletion mapping in vitro","pmids":["22908220"],"is_preprint":false},{"year":2014,"finding":"Trans-homophilic interaction of CADM1 activates PI3K by forming a multi-protein complex with MAGuK family proteins MPP3 and Dlg at the cell periphery; these scaffold proteins connect CADM1 to the p85 regulatory subunit of PI3K. PI3K activation downstream leads to Akt and Rac1 activity, reorganizing the actin cytoskeleton and promoting epithelial cell spreading.","method":"Cell-based CADM1 trans-homophilic spreading assay, chemical inhibitor screen (104 inhibitors), co-immunoprecipitation of CADM1–MPP3–Dlg–p85 complex, Akt and Rac1 activity assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of complex, inhibitor screen, functional spreading assay, single lab","pmids":["24503895"],"is_preprint":false},{"year":2016,"finding":"CADM1 inhibits squamous cell carcinoma proliferation and invasion by forming a complex at the cell surface with HER2 and integrin α6β4 via its extracellular domain, which disrupts downstream STAT3 activity. This effect is dependent on the extracellular domain of CADM1.","method":"Gene transduction (CADM1 overexpression), domain deletion constructs, co-immunoprecipitation of CADM1–HER2–integrin α6β4 complex, STAT3 activity assays, xenograft tumor assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of complex, domain-dependent functional rescue, in vivo xenograft, single lab","pmids":["27035095"],"is_preprint":false},{"year":2005,"finding":"CADM1 (Necl-2) mediates heterotypic cell adhesion with CRTAM (class I-restricted T cell-associated molecule) expressed on activated NK cells and CD8+ T cells. The heterotypic CRTAM–Necl-2 interaction has higher affinity than homotypic Necl-2 interaction and mediates tight heterotypic cell binding without altering cytotoxic function.","method":"Expression-cloning identification of Necl-2 as CRTAM ligand, binding affinity measurements, cell adhesion/aggregation assays, CRTAM-Ig fusion protein blocking","journal":"International immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — expression cloning identification of binding partner, affinity comparison, cell-based adhesion assays","pmids":["16091383"],"is_preprint":false},{"year":2008,"finding":"SynCAM proteins (including SynCAM 1/CADM1) exhibit specific heterophilic adhesion patterns: SynCAM 1 interacts with SynCAM 2, SynCAM 2 interacts with SynCAM 4, and SynCAM 3 interacts with SynCAM 4, as demonstrated by cell overlay experiments using extracellular domains.","method":"Cell overlay adhesion assays with extracellular domain-expressing cells, expression profiling by ISH and immunohistology","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cell overlay assays for adhesion specificity, replicated by subsequent studies on SynCAM family interactions","pmids":["18615557"],"is_preprint":false},{"year":2012,"finding":"CADM1 is a key adhesion receptor in human mast cells mediating homotypic (mast cell–mast cell) adhesion as the sole receptor for MC aggregation; CADM1 isoform SP4 promotes survival via upregulation of pro-survival protein Mcl-1(L). CADM1 downregulation reduces Mcl-1(L) expression and increases caspase-3/7 activity, while SP1 isoform overexpression compromises survival compared to SP4.","method":"Adenoviral CADM1 knockdown, isoform-specific cDNA overexpression, homotypic adhesion assays, Western blot (Mcl-1L, Bcl-2, Bcl-XL), caspase-3/7 activity assay","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with isoform specificity and multiple survival pathway readouts, single lab","pmids":["22438059"],"is_preprint":false},{"year":2013,"finding":"CADM1 (SP4 isoform) is the key receptor mediating human mast cell adhesion to human lung fibroblasts (HLFs) and airway smooth muscle cells (HASMCs). HLFs express both CADM1 and nectin-3 as CADM1 counter-receptors, while HASMCs express only nectin-3. SP4 overexpression specifically increases adhesion to HLFs. CADM1-mediated adhesion accounts for up to 67% of MC adhesion to HLFs.","method":"Adenoviral shRNA knockdown and isoform-specific cDNA overexpression, adhesion assays, counter-receptor expression analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific gain/loss-of-function with quantitative adhesion readouts, counter-receptor identification, single lab","pmids":["23620770"],"is_preprint":false},{"year":2012,"finding":"CADM1 on mast cells promotes heterophilic adhesion to dorsal root ganglion (DRG) neurites via binding to nectin-3 (expressed on DRG neurons). A nectin-3 neutralizing antibody inhibits both mast cell attachment to DRG neurites and subsequent calcium responses in mast cells, demonstrating functional consequence of this heterophilic interaction.","method":"Co-culture adhesion assay, nectin-3 neutralizing antibody blocking, calcium imaging","journal":"Journal of neuroimmunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor blocking with neutralizing antibody, functional calcium response readout, single lab","pmids":["22703826"],"is_preprint":false},{"year":2014,"finding":"CADM1 controls actin cytoskeleton assembly in human mast cells: CADM1 downregulation reduces cortical F-actin polymerization, elongates cortical actin filaments, and increases cell rigidity. CADM1 accounts for ~46% of surface KIT levels and ~31% of F-actin in HMC-1 cells, and regulates phosphotyrosine signaling and KIT tyrosine autophosphorylation.","method":"siRNA/shRNA CADM1 knockdown, flow cytometry (surface KIT), phalloidin staining (F-actin quantification), atomic force microscopy (cell rigidity), phosphotyrosine western blot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods for actin and KIT regulation, single lab","pmids":["24465823"],"is_preprint":false},{"year":2019,"finding":"CADM1-mediated adhesion between mast cells and sensory neurons is necessary and sufficient for enhanced mast cell degranulation and IL-6 secretion in response to neuronal activation and antigen stimulation. A CADM1 blocking peptide or CADM1 knockdown in mast cells significantly decreases mast cell attachment to sensory neurites and abolishes enhanced secretory responses.","method":"Bone marrow-derived mast cell/DRG neuron co-culture, CADM1 blocking peptide, shRNA knockdown, degranulation and cytokine secretion assays","journal":"Frontiers in cellular neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — blocking peptide and knockdown with functional secretion readouts, single lab","pmids":["31275114"],"is_preprint":false},{"year":2019,"finding":"SynCAM 1 (CADM1) in parvalbumin (PV+) interneurons limits visual cortex plasticity: loss of SynCAM 1 selectively reduces thalamocortical inputs onto PV+ interneurons, impairing feedforward inhibition maturation. Brief PV+-cell-specific knockdown of SynCAM 1 in adult visual cortex restores juvenile-like plasticity, demonstrating a cell-autonomous role.","method":"SynCAM 1 knockout mice, conditional PV+-specific AAV-mediated knockdown, synaptic quantification, electrophysiology, ocular dominance plasticity assay","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific loss-of-function with multiple electrophysiology and circuit-level readouts, reciprocal KO and conditional KD","pmids":["30625321"],"is_preprint":false},{"year":2016,"finding":"SynCAM 1 (CADM1) loss reduces the number of excitatory terminals onto parvalbumin-positive interneurons in hippocampal CA3, reduces postsynaptic GluA1 in these interneurons, and impairs mossy fiber refinement and thorny excrescence size in CA3 pyramidal neurons, resulting in CA3 disinhibition and impaired feedforward inhibition.","method":"SynCAM 1 knockout mice, diffusion tensor MRI, immunostaining and synapse quantification, electrophysiology, memory behavioral tasks","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (imaging, immunostaining, electrophysiology, behavior) in knockout model","pmids":["27413156"],"is_preprint":false},{"year":2023,"finding":"Somatic gain-of-function mutations in CADM1 (intramembranous p.Val380Asp or p.Gly379Asp) in aldosterone-producing adenomas cause 10- to 25-fold upregulation of CYP11B2 (aldosterone synthase). Mutant CADM1 inhibits gap junction-permeable dye transfer, and pharmacological gap junction blockade (Gap27) increases CYP11B2 similarly, revealing that CADM1 normally suppresses aldosterone production through promoting gap junction communication.","method":"Whole exome sequencing, H295R cell transduction with mutant/wildtype CADM1, CYP11B2 gene expression, gap junction dye transfer assay, Gap27 pharmacological blockade","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — discovery replicated across independent WES cohorts, functional cell assays, pharmacological mechanistic confirmation, clinical cure by adrenalectomy","pmids":["37291193"],"is_preprint":false},{"year":2018,"finding":"CADM1 and CADM2 act as host factors enabling neuropathogenic measles virus (MeV) to spread between neurons via hyperfusogenic F proteins. CADM1/CADM2 interact in cis (on the same cell membrane) with the MeV attachment protein, triggering the fusion protein and causing membrane fusion — a receptor-mimicking cis-acting mechanism. Knockdown of CADM1 and CADM2 inhibits syncytium formation and virus transmission between neurons.","method":"siRNA knockdown of CADM1/CADM2 in neurons, co-immunoprecipitation of cis interaction with MeV attachment protein, syncytium formation assay, virus transmission assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown plus Co-IP of cis interaction, single lab, novel mechanism","pmids":["33910952"],"is_preprint":false},{"year":2018,"finding":"CADM1 is upregulated in KSHV-infected PEL cells. Both KSHV oncoproteins vFLIP and vGPCR interact with CADM1, and the PDZ-binding motif at the carboxyl terminus of CADM1 is essential for vGPCR and vFLIP to maintain chronic NF-κB activation. Membrane lipid raft-associated CADM1 interaction with vFLIP is critical for IKK kinase complex initiation and NF-κB activation.","method":"Co-immunoprecipitation of vFLIP/vGPCR with CADM1, PDZ-binding motif deletion mutants, NF-κB reporter assays, lipid raft fractionation, IKK kinase assay","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping and functional NF-κB readout, single lab","pmids":["29698475"],"is_preprint":false},{"year":2016,"finding":"CADM1 regulates the G1/S transition in hepatocellular carcinoma cells; ectopic CADM1 expression increases Retinoblastoma (Rb) protein levels, and CADM1-mediated tumor suppression is associated with the Rb-E2F pathway.","method":"CADM1 overexpression in HCC cell lines, cell cycle analysis (flow cytometry), EdU incorporation, colony formation, in vivo xenograft tumorigenicity, Western blot (Rb protein)","journal":"Hepatobiliary & pancreatic diseases international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with cell cycle and in vivo readouts plus Western blot mechanistic link, single lab","pmids":["27298105"],"is_preprint":false},{"year":2019,"finding":"TWIST1 directly represses CADM1 expression by physically interacting with the CADM1 promoter, as shown by ChIP and promoter assays. Increased CADM1 expression inhibits melanoma cell motility/invasiveness and elicits caspase-independent cell death in non-adherent conditions associated with loss of mitochondrial membrane potential.","method":"Chromatin immunoprecipitation (ChIP), promoter assays, CADM1 overexpression, invasion assay, anoikis assay, mitochondrial membrane potential measurement","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus promoter assay plus functional gain-of-function, single lab","pmids":["30911007"],"is_preprint":false},{"year":2016,"finding":"CADM1 loss in the nucleus accumbens (NAc) reduces excitatory synapse number on medium spiny neurons. Cocaine administration increases stubby spine density in NAc, and maintaining this structural increase requires SynCAM 1. SynCAM 1 knockout mice show altered behavioral responses to acute and repeated cocaine administration.","method":"SynCAM 1 knockout mice, NAc spine morphology analysis, cocaine administration paradigm, behavioral psychostimulant assays","journal":"Neuropsychopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with morphological and behavioral readouts, single lab","pmids":["23169347"],"is_preprint":false},{"year":2014,"finding":"SynCAM 1 (CADM1) and SynCAM 2 engage in heterophilic cis-interactions in addition to homophilic interactions; these cis-interactions modulate SynCAM trans-binding interactions and are required for correct sensory axon pathfinding in vivo in the chick embryo.","method":"In vitro cis-interaction assays (cell aggregation), in ovo SynCAM knockdown in chick embryo, sensory axon pathfinding analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro cis-interaction assays plus in vivo knockdown with axon pathfinding readout","pmids":["25335893"],"is_preprint":false},{"year":2021,"finding":"In the peripheral nervous system, Cadm1 acts redundantly with Cadm2 and Cadm3 as axonal ligands for glial Cadm4. Genetic ablation of all three (Cadm1/2/3 triple KO) phenocopies Cadm4 null abnormalities in Caspr and Kv1 channel distribution. Cadm3 is the main axonal ligand for Cadm4, and its loss can be compensated by combined Cadm2 and Cadm1 action.","method":"Single, double, and triple Cadm knockout mice, immunostaining of Caspr and Kv1 channels at paranodes/juxtaparanodes","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple combinatorial knockouts, systematic phenotypic analysis","pmids":["33397712"],"is_preprint":false},{"year":2023,"finding":"SynCAM 1 (CADM1) controls excitatory synapse number in the prefrontal cortex (PFC) and is upregulated upon LRRTM1 loss. Combined deletion of LRRTM1 and SynCAM 1 reduces PFC dendritic spine number more than the sum of single knockouts (synergistic interaction), reduces Neurexin puncta in PFC, impairs PFC network activity (fMRI/electrophysiology), and causes deficits in social interaction and cognition.","method":"LRRTM1 and SynCAM 1 single and double knockout mice, spine morphology analysis, fMRI, electrophysiology, behavioral testing","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with double KO showing synergistic phenotype, multiple orthogonal methods across synaptic/circuit/behavioral levels","pmids":["36709330"],"is_preprint":false},{"year":2016,"finding":"Extracellular CADM1 interactions in pancreatic β-cells constrain insulin secretion; CADM1 expression decreases after prolonged glucose stimulation. CADM1 promotes assembly of exocytic sites and actin network formation in β-cells, similar to its role in presynaptic assembly. CADM1 also influences insulin secretion in a transcellular (trans-interaction) manner in co-culture.","method":"INS-1 and primary islet β-cell knockdown/overexpression, insulin secretion assays, co-culture transcellular assay, F-actin and exocytic site imaging","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with functional insulin secretion and imaging readouts, single lab","pmids":["27072493"],"is_preprint":false},{"year":2012,"finding":"In tongue cancer cells, CADM1 interacts with BMI1 to inhibit its nuclear translocation. MYCN transcriptionally upregulates miR-21, which directly targets and reduces CADM1 expression, thereby releasing BMI1 to translocate to the nucleus and promote chemo-resistance.","method":"Co-immunoprecipitation of CADM1 with BMI1, nuclear/cytoplasmic fractionation, luciferase reporter assay (miR-21 targeting CADM1 3'UTR), MYCN ChIP at miR-21 promoter","journal":"Journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ChIP plus reporter assay, single lab, novel protein interaction","pmids":["27055844"],"is_preprint":false},{"year":2015,"finding":"PolySia on SynCAM 1 in NG2 cells is confined to the Golgi compartment under basal conditions and is transiently recruited to the cell surface in response to depolarization. The polySia is exclusively on N-glycans and synthesized by ST8SIA2 in NG2 cells. This stimulus-dependent surface translocation indicates polySia-SynCAM 1 is dynamically regulated.","method":"Murine glial cultures, immunostaining with Golgi markers and polySia antibodies, depolarization assay (KCl), glycan analysis (N- vs O-glycan), ST8SiaII/ST8SiaIV knockout cultures","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct imaging of subcellular localization with functional stimulus-dependent redistribution, single lab","pmids":["25752299"],"is_preprint":false}],"current_model":"CADM1 (SynCAM 1) is a trans-membrane immunoglobulin superfamily cell adhesion molecule that drives synapse formation through homophilic and heterophilic trans-interactions and cis-oligomerization via Ig domains 2–3; it recruits PDZ-domain scaffold proteins (MPP2/3, Dlg, Tiam1) and FAK to its cytoplasmic tail to activate PI3K–Akt–Rac1 signaling and actin cytoskeleton remodeling, while its cis-interaction with ErbB3/ErbB4 recruits PTPN13 to suppress receptor tyrosine kinase signaling; site-specific N-glycosylation and polysialylation (by ST8SiaII) of its Ig1 domain dynamically regulate its adhesive capacity; it is proteolytically shed by ADAM10 followed by γ-secretase RIP; in non-neuronal tissues CADM1 mediates mast cell–neuron and mast cell–stromal adhesion, spermatid–Sertoli cell contact required for spermatogenesis, and β-cell exocytic site assembly; somatic gain-of-function intramembranous mutations impair gap junction communication to cause autonomous aldosterone overproduction; and in the nervous system SynCAM 1 cell-autonomously controls thalamocortical synapse maturation onto parvalbumin interneurons to set cortical critical period plasticity."},"narrative":{"mechanistic_narrative":"CADM1 (SynCAM 1, Necl-2/RA175) is an immunoglobulin-superfamily transmembrane cell adhesion molecule that organizes cell-cell contacts and, most prominently, induces presynaptic differentiation through homophilic trans-adhesion coupled to intracellular PDZ-scaffold recruitment [PMID:12202822, PMID:15634790]. Its adhesive output is tuned by its extracellular architecture: membrane-proximal Ig domains 2-3 mediate cis-oligomerization that increases adhesive capacity and is required for synaptogenic activity [PMID:21926970], while site-specific N-glycosylation of the Ig1 domain (Asn70/Asn104) strengthens binding [PMID:20739279] and stimulus-regulated polysialylation of Ig1 by ST8SiaII—using Ig2 as an enzyme docking site—dynamically abolishes homophilic binding [PMID:20479255, PMID:22908220, PMID:25752299]. Through its cytoplasmic PDZ-binding tail CADM1 assembles signaling scaffolds: it binds 4.1B/MPP-family MAGuKs [PMID:19854157] and the Rac-GEF Tiam1 [PMID:20215110], and trans-homophilic engagement nucleates an MPP3-Dlg-p85 complex that activates PI3K-Akt-Rac1 signaling to remodel the actin cytoskeleton and drive cell spreading [PMID:24503895], with FAK contributing to growth-cone morphogenesis [PMID:20368431]. In parallel, cis-association of its extracellular region with ErbB3 or ErbB4 recruits the tyrosine phosphatase PTPN13 to its tail to suppress receptor tyrosine kinase signaling [PMID:19561085, PMID:23769722]. In vivo, SynCAM 1 sets excitatory synapse number and plasticity, cell-autonomously promoting maturation of thalamocortical and excitatory inputs onto parvalbumin interneurons to control cortical critical-period and feedforward inhibition [PMID:21145003, PMID:30625321, PMID:27413156], and acting synergistically with LRRTM1 in prefrontal circuit assembly [PMID:36709330]. Beyond the brain, CADM1 is required for spermatid-Sertoli junctions during spermatogenesis via a Par-3/JAM-C ternary complex [PMID:16382161, PMID:18055550], mediates mast cell adhesion to neurons and stromal cells to potentiate degranulation [PMID:22703826, PMID:31275114], constrains beta-cell insulin secretion by organizing exocytic sites [PMID:27072493], and is processed by ADAM10 followed by gamma-secretase to release an intracellular domain [PMID:22172944]. Somatic intramembranous gain-of-function mutations (p.Val380Asp, p.Gly379Asp) in aldosterone-producing adenomas impair gap-junction communication and drive aldosterone overproduction, establishing that CADM1 normally suppresses aldosterone synthesis [PMID:37291193].","teleology":[{"year":2002,"claim":"Establishing that a single adhesion molecule can instruct presynaptic assembly answered whether trans-cellular adhesion alone organizes synapses; SynCAM 1 was shown sufficient and its cytoplasmic tail necessary.","evidence":"Heterologous cell-neuron co-culture synapse induction, dominant-negative tail expression, reconstituted glutamatergic transmission","pmids":["12202822"],"confidence":"High","gaps":["Did not identify the intracellular scaffolds bound by the tail","Did not resolve the trans-adhesive interface structurally"]},{"year":2005,"claim":"Comparing SynCAM 1 to neuroligin-1 distinguished synapse formation from synapse function, showing SynCAM 1 uniquely promotes functional maturation of immature excitatory synapses via its cytoplasmic tail.","evidence":"Co-culture induction, chimeric molecule expression in neurons, electrophysiology","pmids":["15634790"],"confidence":"High","gaps":["Downstream effectors of the dominant-positive tail not defined"]},{"year":2006,"claim":"Knockout phenotyping in testis extended CADM1 function beyond brain, showing its adhesion is required to retain maturing spermatids at Sertoli cell junctions.","evidence":"RA175 knockout mice, testis histology and immunostaining, fertility assays","pmids":["16382161"],"confidence":"High","gaps":["Counter-receptor on Sertoli cells not identified in this study","Intracellular junction machinery not yet mapped"]},{"year":2008,"claim":"Mapping CADM1's adhesive interface to Ig3 and linking trans-binding to surface trafficking and cleavage susceptibility connected extracellular structure to protein stability.","evidence":"Missense mutant expression, Western blot, cell surface trafficking assays","pmids":["18957284"],"confidence":"Medium","gaps":["Single lab","No structural confirmation of the Ig3 interaction interface"]},{"year":2010,"claim":"Multiple studies established how glycosylation tunes CADM1 adhesion and how the cytoplasmic tail couples to actin signaling, defining the molecule as a dynamically regulated adhesion-signaling hub.","evidence":"Crystallography of SynCAM 2 Ig1, MS glycosite mapping and mutagenesis, in vitro polysialylation, FAK and Tiam1 Co-IP, Rac assays, neuronal imaging, transgenic/knockout mice","pmids":["20739279","20479255","20368431","20215110","21145003","19561085"],"confidence":"High","gaps":["How glycan-state switching is regulated in vivo","Quantitative contribution of each scaffold to synaptogenesis unresolved"]},{"year":2011,"claim":"Demonstrating cis-oligomerization via Ig2-3 and regulated intramembrane proteolysis by ADAM10/gamma-secretase revealed two layers of post-assembly control over CADM1 adhesion.","evidence":"Oligomer biochemistry, domain deletions, dominant-negative cis mutants, synapse induction; LC/MS/MS cleavage mapping, ADAM10 siRNA, gamma-secretase inhibition","pmids":["21926970","22172944"],"confidence":"High","gaps":["Function of the released intracellular domain not established","Triggers of shedding in vivo unknown"]},{"year":2013,"claim":"Linking CADM1-PTPN13 to ErbB4 suppression in parvalbumin interneurons placed CADM1 in inhibitory-circuit control of neuregulin signaling.","evidence":"Co-IP, co-localization, siRNA, PTPN13 overexpression, ErbB4 phosphorylation assay","pmids":["23769722"],"confidence":"Medium","gaps":["Single lab","In vivo requirement for the CADM1-PTPN13-ErbB4 axis not tested genetically here"]},{"year":2014,"claim":"Identifying the MPP3-Dlg-p85 scaffold linking trans-homophilic CADM1 to PI3K-Akt-Rac1 provided the signaling route from adhesion to actin reorganization, and cis-interactions with SynCAM 2 were shown to guide axon pathfinding and actin assembly in mast cells.","evidence":"Spreading assays, inhibitor screen, complex Co-IP, Akt/Rac assays; chick in ovo knockdown; mast cell knockdown with AFM and phalloidin","pmids":["24503895","25335893","24465823"],"confidence":"Medium","gaps":["Single labs for each finding","Direct demonstration that PI3K activation drives in vivo synaptogenesis missing"]},{"year":2019,"claim":"Cell-type-specific manipulation showed SynCAM 1 in parvalbumin interneurons gates cortical critical-period plasticity, and CADM1 adhesion was shown necessary for mast cell-neuron functional coupling.","evidence":"Knockout and PV-specific AAV knockdown, electrophysiology, ocular dominance plasticity; mast cell-DRG co-culture with blocking peptide and secretion assays","pmids":["30625321","31275114"],"confidence":"High","gaps":["Molecular link between PV-cell SynCAM 1 and plasticity machinery incomplete","Mast cell intracellular signaling from CADM1 not fully resolved"]},{"year":2023,"claim":"Discovery of somatic intramembranous gain-of-function CADM1 mutations in aldosterone-producing adenomas established a Mendelian-type disease mechanism in which CADM1 normally suppresses aldosterone via gap-junction communication.","evidence":"Whole exome sequencing across cohorts, mutant expression in H295R cells, CYP11B2 expression, gap-junction dye transfer, Gap27 blockade","pmids":["37291193"],"confidence":"High","gaps":["How an intramembranous adhesion molecule controls connexin function molecularly unresolved","Whether the same mechanism operates in non-adrenal tissue unknown"]},{"year":null,"claim":"It remains unresolved how CADM1's glycan-state, cis/trans adhesion, proteolytic processing, and scaffold recruitment are integrated into a single regulatory logic that selects among its divergent tissue-specific outputs.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified structural model coupling adhesion state to intracellular signaling output","Function of the released ICD undetermined","Mechanism connecting CADM1 to gap-junction regulation unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[0,7,18,19,34]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[16,10,0]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8,9,16]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,7,16,29]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[38]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,4,25,26]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[16,10]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[0,18,34]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[12,33]}],"complexes":["CADM1-4.1B-MPP2/MPP3 scaffold complex","CADM1-Par-3-JAM-C ternary complex","CADM1-HER2-integrin alpha6beta4 complex"],"partners":["MPP3","TIAM1","PTPN13","ERBB3","ERBB4","FAK","CRTAM","PAR-3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BY67","full_name":"Cell adhesion molecule 1","aliases":["Immunoglobulin superfamily member 4","IgSF4","Nectin-like protein 2","NECL-2","Spermatogenic immunoglobulin superfamily","SgIgSF","Synaptic cell adhesion molecule","SynCAM","Tumor suppressor in lung cancer 1","TSLC-1"],"length_aa":442,"mass_kda":48.5,"function":"Mediates homophilic cell-cell adhesion in a Ca(2+)-independent manner (PubMed:12050160, PubMed:22438059). Also mediates heterophilic cell-cell adhesion with CADM3 and NECTIN3 in a Ca(2+)-independent manner (By similarity). Interaction with CRTAM promotes natural killer (NK) cell cytotoxicity and interferon-gamma (IFN-gamma) secretion by CD8+ cells in vitro as well as NK cell-mediated rejection of tumors expressing CADM1 in vivo (PubMed:15811952). In mast cells, may mediate attachment to and promote communication with nerves (PubMed:15905536). CADM1, together with MITF, is essential for development and survival of mast cells in vivo (PubMed:22438059). By interacting with CRTAM and thus promoting the adhesion between CD8+ T-cells and CD8+ dendritic cells, regulates the retention of activated CD8+ T-cell within the draining lymph node (By similarity). Required for the intestinal retention of intraepithelial CD4+ CD8+ T-cells and, to a lesser extent, intraepithelial and lamina propria CD8+ T-cells and CD4+ T-cells (By similarity). Interaction with CRTAM promotes the adhesion to gut-associated CD103+ dendritic cells, which may facilitate the expression of gut-homing and adhesion molecules on T-cells and the conversion of CD4+ T-cells into CD4+ CD8+ T-cells (By similarity). Acts as a synaptic cell adhesion molecule and plays a role in the formation of dendritic spines and in synapse assembly (By similarity). May be involved in neuronal migration, axon growth, pathfinding, and fasciculation on the axons of differentiating neurons (By similarity). May play diverse roles in the spermatogenesis including in the adhesion of spermatocytes and spermatids to Sertoli cells and for their normal differentiation into mature spermatozoa (By similarity). Acts as a tumor suppressor in non-small-cell lung cancer (NSCLC) cells (PubMed:11279526, PubMed:12234973). May contribute to the less invasive phenotypes of lepidic growth tumor cells (PubMed:12920246) (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","url":"https://www.uniprot.org/uniprotkb/Q9BY67/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CADM1","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/CADM1","total_profiled":1310},"omim":[{"mim_id":"605686","title":"CELL ADHESION MOLECULE 1; CADM1","url":"https://www.omim.org/entry/605686"},{"mim_id":"604873","title":"MYELIN PROTEIN ZERO-LIKE 2; MPZL2","url":"https://www.omim.org/entry/604873"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"retina","ntpm":266.5}],"url":"https://www.proteinatlas.org/search/CADM1"},"hgnc":{"alias_symbol":["NECL2","ST17","BL2","SYNCAM","IGSF4A","Necl-2","SYNCAM1","RA175"],"prev_symbol":["TSLC1","IGSF4"]},"alphafold":{"accession":"Q9BY67","domains":[{"cath_id":"2.60.40.10","chopping":"46-140","consensus_level":"high","plddt":95.5193,"start":46,"end":140},{"cath_id":"2.60.40.10","chopping":"144-230","consensus_level":"high","plddt":94.2078,"start":144,"end":230},{"cath_id":"2.60.40.10","chopping":"242-327","consensus_level":"high","plddt":94.2262,"start":242,"end":327}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BY67","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BY67-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BY67-F1-predicted_aligned_error_v6.png","plddt_mean":80.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CADM1","jax_strain_url":"https://www.jax.org/strain/search?query=CADM1"},"sequence":{"accession":"Q9BY67","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BY67.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BY67/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BY67"}},"corpus_meta":[{"pmid":"12202822","id":"PMC_12202822","title":"SynCAM, 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Expression of the isolated cytoplasmic tail in neurons inhibited synapse assembly (dominant-negative effect).\",\n      \"method\": \"Heterologous cell co-culture synapse induction assay, neuronal dominant-negative overexpression, reconstitution of glutamatergic transmission with coexpressed glutamate receptors\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in nonneuronal cells, functional electrophysiology, dominant-negative mutagenesis, replicated by multiple subsequent studies\",\n      \"pmids\": [\"12202822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SynCAM 1 (CADM1) and neuroligin-1 (NL1) both specifically induce presynaptic differentiation in co-culture assays; only SynCAM 1 (not NL1) increased synaptic function in immature developing excitatory neurons, and this dominant-positive effect was mediated by its intracellular cytoplasmic tail.\",\n      \"method\": \"Heterologous cell co-culture synapse induction, electrophysiology, chimeric molecule expression in neurons\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional reconstitution with chimeric molecules and electrophysiology, multiple orthogonal methods\",\n      \"pmids\": [\"15634790\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Two missense mutations in CADM1 (C739A/H246N and A755C/Y251S) located in the third immunoglobulin domain impair trans-active interaction; mutant CADM1 shows reduced high-molecular-weight glycosylated forms, defective trafficking to the cell surface, and increased susceptibility to cleavage/degradation.\",\n      \"method\": \"Mutant protein expression in cells, Western blot, cell surface trafficking assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based expression with multiple biochemical readouts, single lab\",\n      \"pmids\": [\"18957284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SynCAM 1 (CADM1) is a target for polysialylation in postnatal mouse brain; polySia is added on N-glycans of the first Ig domain by both ST8SiaII and ST8SiaIV in vitro, and polysialylation of SynCAM 1 completely abolishes its homophilic binding activity.\",\n      \"method\": \"Glycoproteomics affinity purification from Ncam−/− brain, peptide mass fingerprinting, in vitro polysialylation assay, binding assay after polySia modification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay plus functional binding readout, identification of specific glycosylation site, replicated in subsequent studies\",\n      \"pmids\": [\"20479255\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SynCAM 1 (CADM1) overexpression in transgenic mice promotes excitatory synapse number; loss of SynCAM 1 results in fewer excitatory synapses. SynCAM 1 also regulates long-term depression (LTD) at mature synapses and affects spatial learning, with knockout mice learning better.\",\n      \"method\": \"Transgenic overexpression and knockout mice, synapse counting, electrophysiology (LTD), spatial learning behavioral assays\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function in vivo with multiple orthogonal phenotypic readouts, replicated by other labs\",\n      \"pmids\": [\"21145003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SynCAM 1 (CADM1) localizes to growth cones of developing neurons and is required and sufficient to restrict active filopodia number, negatively regulating growth cone morphological complexity. Focal adhesion kinase (FAK) is a binding partner of SynCAM 1 and is implicated in its morphogenetic activities.\",\n      \"method\": \"Live imaging of developing neurons, SynCAM 1 overexpression/knockdown, FAK co-immunoprecipitation, filopodia quantification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct live imaging with gain- and loss-of-function, identified binding partner FAK, multiple methods in one study\",\n      \"pmids\": [\"20368431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"N-glycosylation at specific sites on the SynCAM 1 Ig1 domain (Asn70/Asn104) modulates its adhesive interactions: these N-glycans increase adhesion and are required for synapse induction. In contrast, N-glycosylation of SynCAM 2 at Asn60 reduces adhesion. Sialic acid modification contributes to the glycan-dependent strengthening of SynCAM 1 binding.\",\n      \"method\": \"Crystallographic analysis of SynCAM 2 Ig1 domain, mass spectrometry of glycosylation sites, site-directed mutagenesis of glycosylation sites, adhesion assays, synapse induction assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus functional assays in one study\",\n      \"pmids\": [\"20739279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SynCAM 1 (CADM1) self-assembles laterally (cis-oligomerization) via its extracellular membrane-proximal Ig domains 2 and 3, generating oligomers with increased adhesive capacity. Cis assembly promotes adhesive clustering at new axo-dendritic contacts and is required for synaptogenic activity; lateral oligomerization also restricts synaptic size at later stages.\",\n      \"method\": \"Biochemical characterization of SynCAM oligomers, domain deletion constructs, neuronal overexpression with dominant-negative cis-assembly mutants, synapse induction assays, imaging\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution of cis-oligomerization with domain deletions and mutagenesis plus functional synaptogenesis readouts\",\n      \"pmids\": [\"21926970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CADM1 interacts with actin-binding protein 4.1B/DAL-1 and scaffold protein MPP3/DLG3. MPP1/p55 and MPP2/DLG2 form a tripartite complex with CADM1 and 4.1B. MPP2 is recruited to the CADM1–4.1B complex during early adhesion. siRNA-mediated suppression of CADM1 disrupts epithelia-like cell structure and mislocalizes 4.1B, MPP2, E-cadherin, and ZO-1 from the membrane.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown in HEK293 cells, immunofluorescence localization\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, knockdown with multiple localization readouts, single lab\",\n      \"pmids\": [\"19854157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The cytoplasmic PDZ-binding motif of CADM1 directly interacts with the PDZ domain of Tiam1 (a Rac-specific GEF), inducing lamellipodia formation through Rac activation in HTLV-I-transformed and ATL cell lines, promoting an invasive phenotype.\",\n      \"method\": \"Co-immunoprecipitation of CADM1 cytoplasmic domain with Tiam1 PDZ domain, Rac activation assay, lamellipodia formation assay in cell lines\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein interaction mapped to specific domains, functional Rac/lamellipodia readout, multiple orthogonal methods\",\n      \"pmids\": [\"20215110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CADM1 (Necl-2) interacts in cis with the extracellular region of ErbB3 (but not ErbB2), reducing ligand-induced ErbB2-catalyzed tyrosine phosphorylation of ErbB3 and inhibiting subsequent ErbB3-mediated activation of Rac and Akt. These inhibitory effects are mediated by PTPN13, a protein-tyrosine phosphatase that interacts with the cytoplasmic tail of CADM1.\",\n      \"method\": \"Co-immunoprecipitation (cis interaction), receptor phosphorylation assays, Rac and Akt activity assays, siRNA knockdown, PTPN13 interaction mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, kinase assay, GTPase assay, siRNA), mechanistic pathway placement\",\n      \"pmids\": [\"19561085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CADM1 (Necl-2) interacts with ErbB4 in parvalbumin-positive GABAergic neurons (co-localizing at excitatory synapses). Knockdown of CADM1 enhances Nrg1-induced ErbB4 phosphorylation. Overexpression of PTPN13, which binds the cytoplasmic tail of CADM1, suppresses Nrg1-induced excitatory synapse development in GABAergic neurons via inhibition of ErbB4 activity.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, PTPN13 overexpression, ErbB4 phosphorylation assay\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional assays, single lab\",\n      \"pmids\": [\"23769722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CADM1 (RA175) is expressed at spermatocyte and elongating/elongated spermatid cell junctions in testes. Knockout mice lacking RA175 are male-infertile (oligo-astheno-teratozoospermia): elongating spermatids (steps 9–12) fail to mature and translocate to the adluminal surface and are phagocytosed by Sertoli cells, demonstrating that CADM1-mediated cell junction is necessary for retaining elongating spermatids in Sertoli cell invaginations during maturation.\",\n      \"method\": \"Gene knockout mice, histology, immunostaining in testes, fertility assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with specific cellular phenotype and immunolocalization, replicated in subsequent studies\",\n      \"pmids\": [\"16382161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"CADM1 (RA175) interacts with Par-3 (a PDZ-domain cell polarity protein) via its cytoplasmic region in testis, and forms a ternary complex with JAM-C via Par-3. In RA175-knockout elongating spermatids, Par-3 is absent and JAM-C is absent or abnormally localized, indicating this ternary complex is required for maintaining specialized adhesion structures in spermatid differentiation.\",\n      \"method\": \"Co-immunoprecipitation from testis, immunostaining of knockout vs. wildtype testes\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP mapping of ternary complex, supported by KO localization data, single lab\",\n      \"pmids\": [\"18055550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CADM1 is cleaved by ADAM10 (a disintegrin and metalloprotease) at a membrane-proximal site (identified by LC/MS/MS), and the resulting membrane-bound fragment is subsequently cleaved by γ-secretase to generate a CADM1 intracellular domain (ICD) via regulated intramembrane proteolysis (RIP). ADAM10 mediates endogenous CADM1 shedding as shown by siRNA knockdown.\",\n      \"method\": \"LC/MS/MS cleavage site mapping, siRNA knockdown of ADAM10, γ-secretase inhibitor, cell-based cleavage assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cleavage site identified by MS, specific sheddase identified by siRNA, sequential RIP mechanism validated\",\n      \"pmids\": [\"22172944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Polysialylation of SynCAM 1 (CADM1) in perinatal brain is exclusively mediated by ST8SiaII (not ST8SiaIV) in vivo. The minimal polypeptide required for ST8SiaII-dependent polysialylation contains both Ig1 (the polySia acceptor site) and Ig2 (a docking site for ST8SiaII); Ig1 alone is insufficient.\",\n      \"method\": \"Analysis of ST8SiaII and ST8SiaIV single-knockout mice, domain deletion constructs transfected in cell culture, polySia immunoblot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genetic ablation of specific enzyme in vivo plus domain deletion mapping in vitro\",\n      \"pmids\": [\"22908220\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Trans-homophilic interaction of CADM1 activates PI3K by forming a multi-protein complex with MAGuK family proteins MPP3 and Dlg at the cell periphery; these scaffold proteins connect CADM1 to the p85 regulatory subunit of PI3K. PI3K activation downstream leads to Akt and Rac1 activity, reorganizing the actin cytoskeleton and promoting epithelial cell spreading.\",\n      \"method\": \"Cell-based CADM1 trans-homophilic spreading assay, chemical inhibitor screen (104 inhibitors), co-immunoprecipitation of CADM1–MPP3–Dlg–p85 complex, Akt and Rac1 activity assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of complex, inhibitor screen, functional spreading assay, single lab\",\n      \"pmids\": [\"24503895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CADM1 inhibits squamous cell carcinoma proliferation and invasion by forming a complex at the cell surface with HER2 and integrin α6β4 via its extracellular domain, which disrupts downstream STAT3 activity. This effect is dependent on the extracellular domain of CADM1.\",\n      \"method\": \"Gene transduction (CADM1 overexpression), domain deletion constructs, co-immunoprecipitation of CADM1–HER2–integrin α6β4 complex, STAT3 activity assays, xenograft tumor assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of complex, domain-dependent functional rescue, in vivo xenograft, single lab\",\n      \"pmids\": [\"27035095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CADM1 (Necl-2) mediates heterotypic cell adhesion with CRTAM (class I-restricted T cell-associated molecule) expressed on activated NK cells and CD8+ T cells. The heterotypic CRTAM–Necl-2 interaction has higher affinity than homotypic Necl-2 interaction and mediates tight heterotypic cell binding without altering cytotoxic function.\",\n      \"method\": \"Expression-cloning identification of Necl-2 as CRTAM ligand, binding affinity measurements, cell adhesion/aggregation assays, CRTAM-Ig fusion protein blocking\",\n      \"journal\": \"International immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — expression cloning identification of binding partner, affinity comparison, cell-based adhesion assays\",\n      \"pmids\": [\"16091383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SynCAM proteins (including SynCAM 1/CADM1) exhibit specific heterophilic adhesion patterns: SynCAM 1 interacts with SynCAM 2, SynCAM 2 interacts with SynCAM 4, and SynCAM 3 interacts with SynCAM 4, as demonstrated by cell overlay experiments using extracellular domains.\",\n      \"method\": \"Cell overlay adhesion assays with extracellular domain-expressing cells, expression profiling by ISH and immunohistology\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cell overlay assays for adhesion specificity, replicated by subsequent studies on SynCAM family interactions\",\n      \"pmids\": [\"18615557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CADM1 is a key adhesion receptor in human mast cells mediating homotypic (mast cell–mast cell) adhesion as the sole receptor for MC aggregation; CADM1 isoform SP4 promotes survival via upregulation of pro-survival protein Mcl-1(L). CADM1 downregulation reduces Mcl-1(L) expression and increases caspase-3/7 activity, while SP1 isoform overexpression compromises survival compared to SP4.\",\n      \"method\": \"Adenoviral CADM1 knockdown, isoform-specific cDNA overexpression, homotypic adhesion assays, Western blot (Mcl-1L, Bcl-2, Bcl-XL), caspase-3/7 activity assay\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with isoform specificity and multiple survival pathway readouts, single lab\",\n      \"pmids\": [\"22438059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CADM1 (SP4 isoform) is the key receptor mediating human mast cell adhesion to human lung fibroblasts (HLFs) and airway smooth muscle cells (HASMCs). HLFs express both CADM1 and nectin-3 as CADM1 counter-receptors, while HASMCs express only nectin-3. SP4 overexpression specifically increases adhesion to HLFs. CADM1-mediated adhesion accounts for up to 67% of MC adhesion to HLFs.\",\n      \"method\": \"Adenoviral shRNA knockdown and isoform-specific cDNA overexpression, adhesion assays, counter-receptor expression analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific gain/loss-of-function with quantitative adhesion readouts, counter-receptor identification, single lab\",\n      \"pmids\": [\"23620770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CADM1 on mast cells promotes heterophilic adhesion to dorsal root ganglion (DRG) neurites via binding to nectin-3 (expressed on DRG neurons). A nectin-3 neutralizing antibody inhibits both mast cell attachment to DRG neurites and subsequent calcium responses in mast cells, demonstrating functional consequence of this heterophilic interaction.\",\n      \"method\": \"Co-culture adhesion assay, nectin-3 neutralizing antibody blocking, calcium imaging\",\n      \"journal\": \"Journal of neuroimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor blocking with neutralizing antibody, functional calcium response readout, single lab\",\n      \"pmids\": [\"22703826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CADM1 controls actin cytoskeleton assembly in human mast cells: CADM1 downregulation reduces cortical F-actin polymerization, elongates cortical actin filaments, and increases cell rigidity. CADM1 accounts for ~46% of surface KIT levels and ~31% of F-actin in HMC-1 cells, and regulates phosphotyrosine signaling and KIT tyrosine autophosphorylation.\",\n      \"method\": \"siRNA/shRNA CADM1 knockdown, flow cytometry (surface KIT), phalloidin staining (F-actin quantification), atomic force microscopy (cell rigidity), phosphotyrosine western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods for actin and KIT regulation, single lab\",\n      \"pmids\": [\"24465823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CADM1-mediated adhesion between mast cells and sensory neurons is necessary and sufficient for enhanced mast cell degranulation and IL-6 secretion in response to neuronal activation and antigen stimulation. A CADM1 blocking peptide or CADM1 knockdown in mast cells significantly decreases mast cell attachment to sensory neurites and abolishes enhanced secretory responses.\",\n      \"method\": \"Bone marrow-derived mast cell/DRG neuron co-culture, CADM1 blocking peptide, shRNA knockdown, degranulation and cytokine secretion assays\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — blocking peptide and knockdown with functional secretion readouts, single lab\",\n      \"pmids\": [\"31275114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SynCAM 1 (CADM1) in parvalbumin (PV+) interneurons limits visual cortex plasticity: loss of SynCAM 1 selectively reduces thalamocortical inputs onto PV+ interneurons, impairing feedforward inhibition maturation. Brief PV+-cell-specific knockdown of SynCAM 1 in adult visual cortex restores juvenile-like plasticity, demonstrating a cell-autonomous role.\",\n      \"method\": \"SynCAM 1 knockout mice, conditional PV+-specific AAV-mediated knockdown, synaptic quantification, electrophysiology, ocular dominance plasticity assay\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific loss-of-function with multiple electrophysiology and circuit-level readouts, reciprocal KO and conditional KD\",\n      \"pmids\": [\"30625321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SynCAM 1 (CADM1) loss reduces the number of excitatory terminals onto parvalbumin-positive interneurons in hippocampal CA3, reduces postsynaptic GluA1 in these interneurons, and impairs mossy fiber refinement and thorny excrescence size in CA3 pyramidal neurons, resulting in CA3 disinhibition and impaired feedforward inhibition.\",\n      \"method\": \"SynCAM 1 knockout mice, diffusion tensor MRI, immunostaining and synapse quantification, electrophysiology, memory behavioral tasks\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (imaging, immunostaining, electrophysiology, behavior) in knockout model\",\n      \"pmids\": [\"27413156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Somatic gain-of-function mutations in CADM1 (intramembranous p.Val380Asp or p.Gly379Asp) in aldosterone-producing adenomas cause 10- to 25-fold upregulation of CYP11B2 (aldosterone synthase). Mutant CADM1 inhibits gap junction-permeable dye transfer, and pharmacological gap junction blockade (Gap27) increases CYP11B2 similarly, revealing that CADM1 normally suppresses aldosterone production through promoting gap junction communication.\",\n      \"method\": \"Whole exome sequencing, H295R cell transduction with mutant/wildtype CADM1, CYP11B2 gene expression, gap junction dye transfer assay, Gap27 pharmacological blockade\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — discovery replicated across independent WES cohorts, functional cell assays, pharmacological mechanistic confirmation, clinical cure by adrenalectomy\",\n      \"pmids\": [\"37291193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CADM1 and CADM2 act as host factors enabling neuropathogenic measles virus (MeV) to spread between neurons via hyperfusogenic F proteins. CADM1/CADM2 interact in cis (on the same cell membrane) with the MeV attachment protein, triggering the fusion protein and causing membrane fusion — a receptor-mimicking cis-acting mechanism. Knockdown of CADM1 and CADM2 inhibits syncytium formation and virus transmission between neurons.\",\n      \"method\": \"siRNA knockdown of CADM1/CADM2 in neurons, co-immunoprecipitation of cis interaction with MeV attachment protein, syncytium formation assay, virus transmission assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown plus Co-IP of cis interaction, single lab, novel mechanism\",\n      \"pmids\": [\"33910952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CADM1 is upregulated in KSHV-infected PEL cells. Both KSHV oncoproteins vFLIP and vGPCR interact with CADM1, and the PDZ-binding motif at the carboxyl terminus of CADM1 is essential for vGPCR and vFLIP to maintain chronic NF-κB activation. Membrane lipid raft-associated CADM1 interaction with vFLIP is critical for IKK kinase complex initiation and NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation of vFLIP/vGPCR with CADM1, PDZ-binding motif deletion mutants, NF-κB reporter assays, lipid raft fractionation, IKK kinase assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping and functional NF-κB readout, single lab\",\n      \"pmids\": [\"29698475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CADM1 regulates the G1/S transition in hepatocellular carcinoma cells; ectopic CADM1 expression increases Retinoblastoma (Rb) protein levels, and CADM1-mediated tumor suppression is associated with the Rb-E2F pathway.\",\n      \"method\": \"CADM1 overexpression in HCC cell lines, cell cycle analysis (flow cytometry), EdU incorporation, colony formation, in vivo xenograft tumorigenicity, Western blot (Rb protein)\",\n      \"journal\": \"Hepatobiliary & pancreatic diseases international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with cell cycle and in vivo readouts plus Western blot mechanistic link, single lab\",\n      \"pmids\": [\"27298105\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TWIST1 directly represses CADM1 expression by physically interacting with the CADM1 promoter, as shown by ChIP and promoter assays. Increased CADM1 expression inhibits melanoma cell motility/invasiveness and elicits caspase-independent cell death in non-adherent conditions associated with loss of mitochondrial membrane potential.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), promoter assays, CADM1 overexpression, invasion assay, anoikis assay, mitochondrial membrane potential measurement\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus promoter assay plus functional gain-of-function, single lab\",\n      \"pmids\": [\"30911007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CADM1 loss in the nucleus accumbens (NAc) reduces excitatory synapse number on medium spiny neurons. Cocaine administration increases stubby spine density in NAc, and maintaining this structural increase requires SynCAM 1. SynCAM 1 knockout mice show altered behavioral responses to acute and repeated cocaine administration.\",\n      \"method\": \"SynCAM 1 knockout mice, NAc spine morphology analysis, cocaine administration paradigm, behavioral psychostimulant assays\",\n      \"journal\": \"Neuropsychopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with morphological and behavioral readouts, single lab\",\n      \"pmids\": [\"23169347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SynCAM 1 (CADM1) and SynCAM 2 engage in heterophilic cis-interactions in addition to homophilic interactions; these cis-interactions modulate SynCAM trans-binding interactions and are required for correct sensory axon pathfinding in vivo in the chick embryo.\",\n      \"method\": \"In vitro cis-interaction assays (cell aggregation), in ovo SynCAM knockdown in chick embryo, sensory axon pathfinding analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro cis-interaction assays plus in vivo knockdown with axon pathfinding readout\",\n      \"pmids\": [\"25335893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In the peripheral nervous system, Cadm1 acts redundantly with Cadm2 and Cadm3 as axonal ligands for glial Cadm4. Genetic ablation of all three (Cadm1/2/3 triple KO) phenocopies Cadm4 null abnormalities in Caspr and Kv1 channel distribution. Cadm3 is the main axonal ligand for Cadm4, and its loss can be compensated by combined Cadm2 and Cadm1 action.\",\n      \"method\": \"Single, double, and triple Cadm knockout mice, immunostaining of Caspr and Kv1 channels at paranodes/juxtaparanodes\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple combinatorial knockouts, systematic phenotypic analysis\",\n      \"pmids\": [\"33397712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SynCAM 1 (CADM1) controls excitatory synapse number in the prefrontal cortex (PFC) and is upregulated upon LRRTM1 loss. Combined deletion of LRRTM1 and SynCAM 1 reduces PFC dendritic spine number more than the sum of single knockouts (synergistic interaction), reduces Neurexin puncta in PFC, impairs PFC network activity (fMRI/electrophysiology), and causes deficits in social interaction and cognition.\",\n      \"method\": \"LRRTM1 and SynCAM 1 single and double knockout mice, spine morphology analysis, fMRI, electrophysiology, behavioral testing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with double KO showing synergistic phenotype, multiple orthogonal methods across synaptic/circuit/behavioral levels\",\n      \"pmids\": [\"36709330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Extracellular CADM1 interactions in pancreatic β-cells constrain insulin secretion; CADM1 expression decreases after prolonged glucose stimulation. CADM1 promotes assembly of exocytic sites and actin network formation in β-cells, similar to its role in presynaptic assembly. CADM1 also influences insulin secretion in a transcellular (trans-interaction) manner in co-culture.\",\n      \"method\": \"INS-1 and primary islet β-cell knockdown/overexpression, insulin secretion assays, co-culture transcellular assay, F-actin and exocytic site imaging\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with functional insulin secretion and imaging readouts, single lab\",\n      \"pmids\": [\"27072493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"In tongue cancer cells, CADM1 interacts with BMI1 to inhibit its nuclear translocation. MYCN transcriptionally upregulates miR-21, which directly targets and reduces CADM1 expression, thereby releasing BMI1 to translocate to the nucleus and promote chemo-resistance.\",\n      \"method\": \"Co-immunoprecipitation of CADM1 with BMI1, nuclear/cytoplasmic fractionation, luciferase reporter assay (miR-21 targeting CADM1 3'UTR), MYCN ChIP at miR-21 promoter\",\n      \"journal\": \"Journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ChIP plus reporter assay, single lab, novel protein interaction\",\n      \"pmids\": [\"27055844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PolySia on SynCAM 1 in NG2 cells is confined to the Golgi compartment under basal conditions and is transiently recruited to the cell surface in response to depolarization. The polySia is exclusively on N-glycans and synthesized by ST8SIA2 in NG2 cells. This stimulus-dependent surface translocation indicates polySia-SynCAM 1 is dynamically regulated.\",\n      \"method\": \"Murine glial cultures, immunostaining with Golgi markers and polySia antibodies, depolarization assay (KCl), glycan analysis (N- vs O-glycan), ST8SiaII/ST8SiaIV knockout cultures\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct imaging of subcellular localization with functional stimulus-dependent redistribution, single lab\",\n      \"pmids\": [\"25752299\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CADM1 (SynCAM 1) is a trans-membrane immunoglobulin superfamily cell adhesion molecule that drives synapse formation through homophilic and heterophilic trans-interactions and cis-oligomerization via Ig domains 2–3; it recruits PDZ-domain scaffold proteins (MPP2/3, Dlg, Tiam1) and FAK to its cytoplasmic tail to activate PI3K–Akt–Rac1 signaling and actin cytoskeleton remodeling, while its cis-interaction with ErbB3/ErbB4 recruits PTPN13 to suppress receptor tyrosine kinase signaling; site-specific N-glycosylation and polysialylation (by ST8SiaII) of its Ig1 domain dynamically regulate its adhesive capacity; it is proteolytically shed by ADAM10 followed by γ-secretase RIP; in non-neuronal tissues CADM1 mediates mast cell–neuron and mast cell–stromal adhesion, spermatid–Sertoli cell contact required for spermatogenesis, and β-cell exocytic site assembly; somatic gain-of-function intramembranous mutations impair gap junction communication to cause autonomous aldosterone overproduction; and in the nervous system SynCAM 1 cell-autonomously controls thalamocortical synapse maturation onto parvalbumin interneurons to set cortical critical period plasticity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CADM1 (SynCAM 1, Necl-2/RA175) is an immunoglobulin-superfamily transmembrane cell adhesion molecule that organizes cell-cell contacts and, most prominently, induces presynaptic differentiation through homophilic trans-adhesion coupled to intracellular PDZ-scaffold recruitment [#0, #1]. Its adhesive output is tuned by its extracellular architecture: membrane-proximal Ig domains 2-3 mediate cis-oligomerization that increases adhesive capacity and is required for synaptogenic activity [#7], while site-specific N-glycosylation of the Ig1 domain (Asn70/Asn104) strengthens binding [#6] and stimulus-regulated polysialylation of Ig1 by ST8SiaII—using Ig2 as an enzyme docking site—dynamically abolishes homophilic binding [#3, #15, #38]. Through its cytoplasmic PDZ-binding tail CADM1 assembles signaling scaffolds: it binds 4.1B/MPP-family MAGuKs [#8] and the Rac-GEF Tiam1 [#9], and trans-homophilic engagement nucleates an MPP3-Dlg-p85 complex that activates PI3K-Akt-Rac1 signaling to remodel the actin cytoskeleton and drive cell spreading [#16], with FAK contributing to growth-cone morphogenesis [#5]. In parallel, cis-association of its extracellular region with ErbB3 or ErbB4 recruits the tyrosine phosphatase PTPN13 to its tail to suppress receptor tyrosine kinase signaling [#10, #11]. In vivo, SynCAM 1 sets excitatory synapse number and plasticity, cell-autonomously promoting maturation of thalamocortical and excitatory inputs onto parvalbumin interneurons to control cortical critical-period and feedforward inhibition [#4, #25, #26], and acting synergistically with LRRTM1 in prefrontal circuit assembly [#35]. Beyond the brain, CADM1 is required for spermatid-Sertoli junctions during spermatogenesis via a Par-3/JAM-C ternary complex [#12, #13], mediates mast cell adhesion to neurons and stromal cells to potentiate degranulation [#22, #24], constrains beta-cell insulin secretion by organizing exocytic sites [#36], and is processed by ADAM10 followed by gamma-secretase to release an intracellular domain [#14]. Somatic intramembranous gain-of-function mutations (p.Val380Asp, p.Gly379Asp) in aldosterone-producing adenomas impair gap-junction communication and drive aldosterone overproduction, establishing that CADM1 normally suppresses aldosterone synthesis [#27].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing that a single adhesion molecule can instruct presynaptic assembly answered whether trans-cellular adhesion alone organizes synapses; SynCAM 1 was shown sufficient and its cytoplasmic tail necessary.\",\n      \"evidence\": \"Heterologous cell-neuron co-culture synapse induction, dominant-negative tail expression, reconstituted glutamatergic transmission\",\n      \"pmids\": [\"12202822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the intracellular scaffolds bound by the tail\", \"Did not resolve the trans-adhesive interface structurally\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Comparing SynCAM 1 to neuroligin-1 distinguished synapse formation from synapse function, showing SynCAM 1 uniquely promotes functional maturation of immature excitatory synapses via its cytoplasmic tail.\",\n      \"evidence\": \"Co-culture induction, chimeric molecule expression in neurons, electrophysiology\",\n      \"pmids\": [\"15634790\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of the dominant-positive tail not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Knockout phenotyping in testis extended CADM1 function beyond brain, showing its adhesion is required to retain maturing spermatids at Sertoli cell junctions.\",\n      \"evidence\": \"RA175 knockout mice, testis histology and immunostaining, fertility assays\",\n      \"pmids\": [\"16382161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Counter-receptor on Sertoli cells not identified in this study\", \"Intracellular junction machinery not yet mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapping CADM1's adhesive interface to Ig3 and linking trans-binding to surface trafficking and cleavage susceptibility connected extracellular structure to protein stability.\",\n      \"evidence\": \"Missense mutant expression, Western blot, cell surface trafficking assays\",\n      \"pmids\": [\"18957284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"No structural confirmation of the Ig3 interaction interface\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Multiple studies established how glycosylation tunes CADM1 adhesion and how the cytoplasmic tail couples to actin signaling, defining the molecule as a dynamically regulated adhesion-signaling hub.\",\n      \"evidence\": \"Crystallography of SynCAM 2 Ig1, MS glycosite mapping and mutagenesis, in vitro polysialylation, FAK and Tiam1 Co-IP, Rac assays, neuronal imaging, transgenic/knockout mice\",\n      \"pmids\": [\"20739279\", \"20479255\", \"20368431\", \"20215110\", \"21145003\", \"19561085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How glycan-state switching is regulated in vivo\", \"Quantitative contribution of each scaffold to synaptogenesis unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating cis-oligomerization via Ig2-3 and regulated intramembrane proteolysis by ADAM10/gamma-secretase revealed two layers of post-assembly control over CADM1 adhesion.\",\n      \"evidence\": \"Oligomer biochemistry, domain deletions, dominant-negative cis mutants, synapse induction; LC/MS/MS cleavage mapping, ADAM10 siRNA, gamma-secretase inhibition\",\n      \"pmids\": [\"21926970\", \"22172944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Function of the released intracellular domain not established\", \"Triggers of shedding in vivo unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linking CADM1-PTPN13 to ErbB4 suppression in parvalbumin interneurons placed CADM1 in inhibitory-circuit control of neuregulin signaling.\",\n      \"evidence\": \"Co-IP, co-localization, siRNA, PTPN13 overexpression, ErbB4 phosphorylation assay\",\n      \"pmids\": [\"23769722\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"In vivo requirement for the CADM1-PTPN13-ErbB4 axis not tested genetically here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying the MPP3-Dlg-p85 scaffold linking trans-homophilic CADM1 to PI3K-Akt-Rac1 provided the signaling route from adhesion to actin reorganization, and cis-interactions with SynCAM 2 were shown to guide axon pathfinding and actin assembly in mast cells.\",\n      \"evidence\": \"Spreading assays, inhibitor screen, complex Co-IP, Akt/Rac assays; chick in ovo knockdown; mast cell knockdown with AFM and phalloidin\",\n      \"pmids\": [\"24503895\", \"25335893\", \"24465823\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single labs for each finding\", \"Direct demonstration that PI3K activation drives in vivo synaptogenesis missing\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Cell-type-specific manipulation showed SynCAM 1 in parvalbumin interneurons gates cortical critical-period plasticity, and CADM1 adhesion was shown necessary for mast cell-neuron functional coupling.\",\n      \"evidence\": \"Knockout and PV-specific AAV knockdown, electrophysiology, ocular dominance plasticity; mast cell-DRG co-culture with blocking peptide and secretion assays\",\n      \"pmids\": [\"30625321\", \"31275114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between PV-cell SynCAM 1 and plasticity machinery incomplete\", \"Mast cell intracellular signaling from CADM1 not fully resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery of somatic intramembranous gain-of-function CADM1 mutations in aldosterone-producing adenomas established a Mendelian-type disease mechanism in which CADM1 normally suppresses aldosterone via gap-junction communication.\",\n      \"evidence\": \"Whole exome sequencing across cohorts, mutant expression in H295R cells, CYP11B2 expression, gap-junction dye transfer, Gap27 blockade\",\n      \"pmids\": [\"37291193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How an intramembranous adhesion molecule controls connexin function molecularly unresolved\", \"Whether the same mechanism operates in non-adrenal tissue unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how CADM1's glycan-state, cis/trans adhesion, proteolytic processing, and scaffold recruitment are integrated into a single regulatory logic that selects among its divergent tissue-specific outputs.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified structural model coupling adhesion state to intracellular signaling output\", \"Function of the released ICD undetermined\", \"Mechanism connecting CADM1 to gap-junction regulation unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [0, 7, 18, 19, 34]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [16, 10, 0]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 9, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 7, 16, 29]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [38]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 4, 25, 26]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16, 10]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [0, 18, 34]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [12, 33]}\n    ],\n    \"complexes\": [\n      \"CADM1-4.1B-MPP2/MPP3 scaffold complex\",\n      \"CADM1-Par-3-JAM-C ternary complex\",\n      \"CADM1-HER2-integrin alpha6beta4 complex\"\n    ],\n    \"partners\": [\n      \"MPP3\",\n      \"Tiam1\",\n      \"PTPN13\",\n      \"ErbB3\",\n      \"ErbB4\",\n      \"FAK\",\n      \"CRTAM\",\n      \"Par-3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}