CADM2

CADM2 (also known as Necl-3/SynCAM-2) is a synaptic immunoglobulin-superfamily cell adhesion molecule that mediates axon–oligodendrocyte adhesion through homo- and heterophilic Necl-family interactions, regulates systemic energy homeostasis and arousal through central nervous system signaling, and functions as a tumor suppressor silenced by promoter hypermethylation in multiple cancers (PMID:17967169, PMID:29217450, PMID:21062931). In the brain, CADM2 promotes neural stem cell fate specification and synaptic elaboration of NPY-pathway neurons that stabilize arousal, and its loss in zebrafish causes hypersomnia; a recursive splice site in its first intron regulates expression level and transcript isoform usage, affecting synapse- and axon-development gene programs (PMID:41526386). CADM2 suppresses tumor growth by inducing G1 arrest and apoptosis and by inhibiting AKT/FAK and PI3K/AKT signaling and epithelial-mesenchymal transition, with its expression controlled upstream by miRNAs (miR-10b, miR-21-5p, miR-182) and by the lncRNA ADAMTS9-AS2 that blocks DNMT3B-mediated promoter methylation (PMID:23643812, PMID:29506532, PMID:30816549, PMID:41869309). Short-stalk brain isoforms of CADM2 act as cis-interacting host factors for neuropathogenic measles virus hemagglutinin, triggering hyperfusogenic F-protein-mediated membrane fusion essential for trans-synaptic viral spread and neurovirulence in vivo (PMID:33910952, PMID:34788082, PMID:37166307).

1. 2007 Medium

   The first molecular characterization established that CADM2 localizes to the axon–myelin interface and mediates cell adhesion through homo- and heterophilic Necl-family interactions, defining it as a synaptic adhesion molecule in the nervous system.

   Evidence Immunolocalization on myelinated axons plus multiple independent cell aggregation and heterophilic binding assays

   PMID:17967169

   Open questions at the time

   • No in vivo loss-of-function to confirm axon–oligodendrocyte adhesion requirement
   • Binding affinities and structural basis of Necl interactions not determined
2. 2010 Medium

   The discovery that CADM2 promoter hypermethylation silences its expression in cancer, and that re-expression suppresses prostate cancer cell growth, established CADM2 as an epigenetically regulated tumor suppressor.

   Evidence Two-isoform cloning, bisulfite sequencing showing promoter methylation, adenoviral CADM-2a re-expression suppressing soft-agar colony formation, demethylation rescue with 5-aza-dC/TSA

   PMID:21062931

   Open questions at the time

   • Mechanism by which CADM2 suppresses growth not identified
   • Only one cancer type tested
3. 2013 Medium

   Extension to renal cancer showed CADM2 re-expression induces G1 arrest and apoptosis while loss-of-function converts non-tumorigenic cells to a tumorigenic phenotype, strengthening the tumor-suppressor model with a defined cell-cycle mechanism.

   Evidence Lentiviral overexpression and xenograft assays plus siRNA knockdown in MDCK cells with cell cycle and apoptosis analysis

   PMID:23643812

   Open questions at the time

   • Direct molecular target through which CADM2 enforces G1 arrest unknown
   • No patient cohort validation
4. 2017 High

   Cadm2 knockout mice revealed a metabolic function: CADM2 loss reduces adiposity, improves insulin sensitivity, and increases energy expenditure and locomotor activity, establishing CADM2 as a regulator of systemic energy homeostasis through hypothalamic signaling.

   Evidence Cadm2 knockout mouse model with comprehensive metabolic phenotyping, glucose/insulin tolerance tests, leptin-regulated hypothalamic expression

   PMID:29217450

   Open questions at the time

   • Downstream signaling cascade in hypothalamus not delineated
   • Cell-type specificity of Cadm2 metabolic function not resolved
5. 2018 Medium

   Identification of miR-10b, miR-21-5p, and miR-182 as direct upstream regulators of CADM2, coupled with demonstration that CADM2 suppresses FAK/AKT and PI3K/AKT signaling and EMT, placed CADM2 within defined oncogenic pathways across hepatocellular carcinoma, esophageal, and retinoblastoma contexts.

   Evidence Dual-luciferase reporter assays confirming direct miRNA targeting, Western blots for p-Akt/FAK, functional rescue by CADM2 knockdown, xenograft models

   PMID:29506532 PMID:29680210 PMID:30320366

   Open questions at the time

   • Whether CADM2 directly interacts with AKT pathway components or acts indirectly is unresolved
   • Cross-cancer generalizability of specific miRNA axes not established
6. 2019 Medium

   CADM2 overexpression in glioma cells confirmed suppression of G1/S transition regulators (cyclin D1, CDK2/4) and alteration of EMT markers, consolidating the tumor-suppressor mechanism across CNS and peripheral cancers.

   Evidence Overexpression in glioma cell lines with in vivo validation, Western blot for cell cycle and EMT proteins

   PMID:30816549

   Open questions at the time

   • Whether CADM2 tumor-suppressor activity requires its adhesion function is untested
7. 2021 High

   CADM2 was identified as a cis-acting host factor for neuropathogenic measles virus: it interacts on the same membrane with the MeV hemagglutinin to trigger hyperfusogenic F-protein-mediated fusion independently of canonical MeV receptors, with short-stalk brain isoforms being the active species.

   Evidence Knockdown inhibiting syncytium formation, co-IP demonstrating cis-interaction with H protein, domain-truncation and isoform-specific fusion assays in neurons

   PMID:33910952 PMID:34788082

   Open questions at the time

   • Structural basis of CADM2–H stalk interaction not resolved
   • Whether other Necl family members compensate in vivo unknown
8. 2023 High

   Mutagenesis of the MeV H protein stalk (positions 171–175) abolished CADM-triggered but not SLAM-triggered fusion and eliminated neurovirulence in suckling hamsters, providing in vivo proof that the CADM2/H-stalk interaction is essential for MeV neuropathogenicity.

   Evidence H protein stalk mutagenesis, recombinant virus in primary neurons, suckling hamster neurovirulence model

   PMID:37166307

   Open questions at the time

   • Atomic-level structure of CADM2–H stalk interface not determined
   • Human relevance requires clinical correlation
9. 2023 Medium

   Cadm2 knockout mice recapitulated human GWAS-linked behavioral and metabolic phenotypes (impulsivity, altered cognition, BMI), validating CADM2 as a causal gene underlying these complex trait associations.

   Evidence Comprehensive behavioral and metabolic phenotyping battery (MouseWAS) in Cadm2 knockout mice

   PMID:37173343

   Open questions at the time

   • Circuit-level mechanisms linking CADM2 loss to impulsivity and cognition not delineated
   • Cell-type-specific conditional knockouts not yet reported
10. 2024 Medium

    Multiple studies expanded CADM2's functional repertoire: upstream epigenetic regulation was elucidated (lncRNA ADAMTS9-AS2 blocks DNMT3B occupancy at the CADM2 promoter), CADM2 was shown to mediate anti-inflammatory signaling by inhibiting TLR-MyD88, and a developmental role in neural stem cell fate and arousal regulation via the NPY pathway was established across zebrafish, mouse, and Drosophila.

    Evidence RIP/ChIP/pyrosequencing for epigenetic mechanism; siRNA + DSS colitis model for anti-inflammatory function; zebrafish cadm2 KO behavioral assays, mouse NPC overexpression, Drosophila beat-Ia knockdown

    PMID:38369215 PMID:41526386 PMID:41869309

    Open questions at the time

    • Whether CADM2 anti-inflammatory function operates through its adhesion domain is unknown
    • NSC fate specification mechanism downstream of CADM2 not molecularly defined
    • Cross-species NPY pathway conservation not fully validated

• Key unresolved questions include the structural basis of CADM2 interactions (both homophilic and with MeV H stalk), the direct molecular mechanism by which CADM2 suppresses AKT signaling, cell-type-specific conditional knockout studies dissecting hypothalamic versus peripheral metabolic roles, and whether CADM2's adhesion and signaling functions are mechanistically separable.
• No crystal/cryo-EM structure of CADM2 extracellular or transmembrane domains
• No conditional or cell-type-specific knockout distinguishing central vs peripheral metabolic roles
• Direct biochemical link between CADM2 and AKT pathway components not established