Affinage

CADM3

Cell adhesion molecule 3 · UniProt Q8N126

Length
398 aa
Mass
43.3 kDa
Annotated
2026-06-09
28 papers in source corpus 15 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CADM3 (Necl-1/SynCAM3) is a neural immunoglobulin-superfamily cell adhesion molecule that mediates Ca2+-independent intercellular adhesion at axon-glia and synaptic contact sites (PMID:15741237). Its N-terminal Ig-like V domain is sufficient for homophilic trans-dimerization, with Phe82 identified as a key adhesion residue from the dimeric crystal structure (PMID:16467305), and the same ectodomain engages heterophilic partners including Necl-2, nectin-1, nectin-3, and the glial partner Cadm4 (PMID:15741237, PMID:21456004). Its cytoplasmic tail recruits L27-domain MAGUK proteins (Dlg3, Pals2, CASK) but not afadin (PMID:15741237). At peripheral myelinated axons CADM3 is the primary axonal ligand for glial Cadm4, organizing Caspr and Kv1 channel distribution with partial redundancy from Cadm1 and Cadm2 (PMID:33397712), and it negatively regulates Schwann cell myelination by selectively suppressing ErbB3-PI3K/Akt signaling without affecting Mek/Erk (PMID:27658374). In the CNS, CADM3 is required for cone-to-bipolar-cell synapse formation in the retina (PMID:38623325), promotes astrocytic scar formation after spinal cord injury (PMID:35682897), and modulates prefrontal noradrenergic tone to gate emotional behavior (PMID:41308882). Dominant missense variants (Tyr172Cys, Gly368Cys) cause axonal Charcot-Marie-Tooth disease by introducing aberrant disulfide bonds that drive ER retention, reduce cell-surface expression, and impair Cadm4 co-localization at axon-glia contacts (PMID:33889941, PMID:38074074). In glioma, CADM3 is epigenetically silenced through an Sp1/HDAC1 histone-deacetylation mechanism, and its re-expression induces cell cycle arrest, suppresses migration and invasion, and promotes astrocytic differentiation (PMID:19062177, PMID:20078932).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2005 High

    Established that CADM3 is an adhesion molecule with defined homophilic and heterophilic binding partners and a MAGUK-linked cytoplasmic tail, defining its molecular identity and intracellular scaffold.

    Evidence Cell-cell adhesion assays, Co-IP, and domain mapping defining homophilic adhesion, heterophilic binding to Necl-2/nectin-1/nectin-3, and L27-MAGUK binding (Dlg3, Pals2, CASK) but not afadin

    PMID:15741237

    Open questions at the time
    • Functional consequence of MAGUK binding not tested
    • Affinity hierarchy among heterophilic partners not quantified
  2. 2005 High

    Localized CADM3 to non-junctional axon, synaptic, and glial contact sites, predicting roles in synapse formation, axon bundling, and myelination.

    Evidence Immunofluorescence and immunoelectron microscopy of nerve terminals, axons, and myelinated axons

    PMID:15741237

    Open questions at the time
    • Localization is descriptive; functional roles not directly tested
  3. 2006 High

    Defined the structural basis of adhesion, showing the V domain alone drives dimerization and identifying Phe82 as essential, providing a molecular handle for adhesion function.

    Evidence X-ray crystallography at 2.4 A, size-exclusion chromatography, cross-linking, and site-directed mutagenesis

    PMID:16467305

    Open questions at the time
    • Structure of heterophilic complexes (e.g. with Cadm4) not solved
    • In vivo consequence of Phe82 mutation untested
  4. 2008 Medium

    Showed CADM3 is silenced in glioma and acts as a growth/proliferation restraint, framing it as a candidate tumor suppressor in glial tumors.

    Evidence Re-expression in T98G glioma cells with growth curves, flow cytometry, and apoptosis assays; co-culture and synaptosome synapse-formation assays

    PMID:18686604 PMID:18686605

    Open questions at the time
    • Single cell line for tumor phenotype
    • Pathway linking re-expression to arrest/apoptosis not defined
  5. 2009 High

    Identified the epigenetic mechanism of CADM3 silencing in glioma and confirmed tumor-suppressive consequences, linking an Sp1/HDAC1 switch to loss of expression.

    Evidence Luciferase reporter, ChIP, Co-IP, bisulfite sequencing, HDAC assay, and xenograft showing HDAC-mediated silencing, Sp1/HDAC1-to-Sp1/p300 switch, and growth suppression; plus migration/invasion and GFAP differentiation assays

    PMID:19062177 PMID:20078932

    Open questions at the time
    • Upstream trigger of HDAC1 recruitment unknown
    • Differentiation readout limited to GFAP
  6. 2016 High

    Placed CADM3 in the myelination pathway as a negative regulator acting through pathway-selective signaling suppression, resolving how axonal adhesion tunes Schwann cell behavior.

    Evidence Reciprocal shRNA knockdown and overexpression in DRG/Schwann co-cultures with ELISA-based ErbB3/Akt/Erk phosphorylation readouts; PLGA-coating adhesion and sciatic nerve repair models

    PMID:27658374 PMID:27772714

    Open questions at the time
    • Mechanism by which the ectodomain blocks ErbB3 activation unresolved
    • Selectivity for PI3K/Akt over Mek/Erk not mechanistically explained
  7. 2021 High

    Established CADM3 as the primary axonal ligand for glial Cadm4 with redundancy from Cadm1/Cadm2, fixing its position in the axon-glia adhesion hierarchy.

    Evidence Systematic mouse knockout combinations with immunofluorescence for Caspr and Kv1.2 distribution

    PMID:33397712

    Open questions at the time
    • Molecular basis of preferential Cadm3-Cadm4 binding not structurally defined
    • Quantitative contribution of each paralog unresolved
  8. 2021 High

    Demonstrated that a dominant CMT2 variant acts through aberrant disulfide bonding, ER retention, and loss of Cadm4 co-localization, defining the disease mechanism.

    Evidence Mass spectrometry, STORM imaging, ER retention/surface expression assays, and Cadm3Y170C knock-in mice with Kv1.2/Caspr analysis

    PMID:33889941

    Open questions at the time
    • Knock-in mice showed normal conduction, leaving genotype-phenotype gap unresolved
    • Whether loss-of-function or dominant-negative dominates not separated
  9. 2022 Medium

    Revealed a CNS injury role, showing CADM3 promotes reactive-to-scar astrocyte transformation and glial scar formation.

    Evidence SynCAM3 KO mouse spinal cord injury model with single-cell RNA sequencing, qRT-PCR, and immunohistochemistry

    PMID:35682897

    Open questions at the time
    • Direct adhesion partner driving astrocyte transformation not identified
    • Single lab
  10. 2023 Medium

    Extended the CMT2 mechanism to a second variant, generalizing reduced surface expression via cysteine-introducing mutations as the pathogenic principle.

    Evidence Whole exome sequencing, membrane fractionation/Western blot, and structural prediction for Gly368Cys

    PMID:38074074

    Open questions at the time
    • No in vivo model for Gly368Cys
    • Structural change inferred from prediction, not solved
  11. 2024 High

    Demonstrated a CNS synaptic requirement, showing CADM3 is needed for cone-to-OFF-bipolar synapse formation and AMPA receptor positioning in the retina.

    Evidence Immunofluorescence localization, Necl-1 KO mouse analysis, electroretinography, optokinetic testing, and AMPA receptor potentiator rescue

    PMID:38623325

    Open questions at the time
    • Heterophilic partner in the retinal synapse not identified
    • Link between adhesion and AMPA receptor localization mechanistically unresolved
  12. 2025 Medium

    Linked CADM3 to prefrontal noradrenergic regulation of emotional behavior, identifying Adra2a as a downstream effector amenable to pharmacological and genetic rescue.

    Evidence Constitutive KO in rats and mice, mirtazapine/reboxetine pharmacological rescue, AAV regional reconstitution, norepinephrine and dendritic spine measurements

    PMID:41308882

    Open questions at the time
    • Mechanism connecting CADM3 adhesion to Adra2a expression unknown
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CADM3 ectodomain engagement is mechanistically transduced into divergent intracellular outcomes — PI3K/Akt suppression in Schwann cells, AMPA receptor positioning in retina, and noradrenergic tone in cortex — remains unresolved.
  • No unified signaling model links adhesion to downstream effectors
  • MAGUK scaffold function not tied to any in vivo phenotype
  • Structural basis of Cadm3-Cadm4 heterophilic binding undetermined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 4 GO:0060089 molecular transducer activity 1 GO:0060090 molecular adaptor activity 1
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-1266738 Developmental Biology 3 R-HSA-1500931 Cell-Cell communication 2 R-HSA-1643685 Disease 2
Partners
CADM1CADM2CADM4CASKDLG3NECTIN1NECTIN3

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Necl-1/CADM3 exhibits Ca2+-independent homophilic cell-cell adhesion activity, and Ca2+-independent heterophilic adhesion with Necl-2/SynCAM1, nectin-1, and nectin-3, but not with Necl-5 or nectin-2. Its C-terminal cytoplasmic region binds membrane-associated guanylate kinase (MAGUK) subfamily members containing the L27 domain (Dlg3, Pals2, and CASK), but does not bind afadin. Cell-cell adhesion assays, co-immunoprecipitation, domain mapping Journal of cell science High 15741237
2005 Necl-1/CADM3 localizes at non-junctional contact sites of presynaptic nerve terminals, axons, and glial cell processes (axon bundles and myelinated axons) as determined by immunofluorescence and immunoelectron microscopy, consistent with roles in synapse formation, axon bundling, and myelination. Immunofluorescence microscopy, immunoelectron microscopy Journal of cell science High 15741237
2006 The N-terminal Ig-like V domain of Necl-1/CADM3 is sufficient for homophilic interaction; the protein crystallizes as a dimer confirmed by size-exclusion chromatography and chemical cross-linking. Mutagenesis identified Phe82 as a key residue for adhesion activity. X-ray crystallography (2.4 Å resolution), size-exclusion chromatography, chemical cross-linking, site-directed mutagenesis The Journal of biological chemistry High 16467305
2009 Loss of NECL1/CADM3 expression in glioma is caused at least partly by histone deacetylation (not CpG methylation). HDAC inhibitor TSA reactivates NECL1 expression. Sp1 binds HDAC1 at the NECL1 promoter in untreated glioma cells, and switches to binding p300/CBP after TSA treatment. Re-expression of NECL1 in glioma cells induces cell cycle arrest and suppresses proliferation in vitro and tumor growth in vivo. Luciferase reporter assay, chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP), DNA bisulfite sequencing, HDAC activity assay, xenograft model Glia High 19062177
2009 NECL1/CADM3 expression in glioma cells inhibits migration and invasion (scratch and Transwell assays), reduces extracellular metalloproteinase activities, and promotes potential differentiation toward an astrocyte phenotype with upregulation of GFAP. Scratch assay, Transwell assay, metalloproteinase activity measurement, Western blot for GFAP Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae Medium 20078932
2008 Re-expression of NECL1/CADM3 in the NECL1-silent T98G glioma cell line decreases cell growth rate and increases apoptosis, establishing a role in restraining glioma cell proliferation. Cell growth curve, flow cytometry, Hoechst staining Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae Medium 18686605
2008 Overexpression of Necl1/CADM3 in HEK293 cells induces synapse formation when co-cultured with neurons. Ectopic expression of Necl1 in primary neurons increases synapse density. Necl1 partially localizes to synaptosomes. Co-culture synapse formation assay, immunofluorescence, Western blot, synaptosome fractionation Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae Medium 18686604
2011 Zebrafish cadm3 and cadm2a bind heterophilically: in vitro binding assays show cadm3 preferentially binds cadm4, while cadm2a preferentially binds cadm1, mirroring tetrapod binding preferences. In vitro binding assay with subtype-specific antibodies The Journal of comparative neurology Medium 21456004
2016 shRNA-mediated knockdown of axonal Cadm3 promotes Schwann cell myelination in DRG neuron/Schwann cell co-cultures, while overexpression of Cadm3 nearly abolishes myelin segment formation. SCG neurons (which do not support myelination) express higher Cadm3 than DRG neurons; Cadm3 knockdown in SCG neurons enables myelination. The extracellular domain of Cadm3 interferes dose-dependently with activation of ErbB3 and the PI3K/Akt pro-myelinating pathway but does not affect the Mek/Erk1/2 pathway. shRNA knockdown, overexpression in vitro myelinating co-culture, ELISA-based signaling assay (ErbB3, Akt, Erk1/2 phosphorylation) Glia High 27658374
2016 NECL1/CADM3-coated PLGA surfaces enhance Schwann cell adhesion and proliferation, and NECL1-coated PLGA conduits implanted to bridge sciatic nerve defects improve Schwann cell aggregation and functional nerve regeneration in vivo, demonstrating that CADM3 on axon surfaces mediates Schwann cell adhesion. In vitro cell culture on coated surfaces, in vivo sciatic nerve repair model, MTT, RT-PCR, immunohistochemistry Materials science & engineering. C Medium 27772714
2021 Genetic ablation of all three axonal Cadms (Cadm1, Cadm2, Cadm3) in mice phenocopies the Cadm4-null abnormalities (aberrant Caspr and Kv1 channel distribution). Double knockout of Cadm3 with Cadm2 or Cadm1 also replicates the Cadm4-null phenotype, but Cadm1/Cadm2 double KO does not. Cadm3 heterozygosity combined with loss of the other two Cadms causes detectable defects, establishing Cadm3 as the primary axonal ligand for glial Cadm4 with partial functional redundancy from Cadm1 and Cadm2. Genetic epistasis — multiple mouse knockout combinations, immunofluorescence for Caspr and Kv1.2 channel distribution The Journal of neuroscience High 33397712
2021 A dominant missense variant in CADM3 (Tyr172Cys) causes autosomal dominant axonal CMT2. Mass spectrometry detected a novel disulfide bond in the mutant protein. The mutant CADM3 is retained in the endoplasmic reticulum with reduced cell surface expression. STORM imaging revealed decreased co-localization of mutant CADM3 with CADM4 at intercellular contact sites. Cadm3Y170C knock-in mice show normal nerve conduction but abnormal distribution of Kv1.2 channels and Caspr along myelinated axons. High-resolution mass spectrometry, immunofluorescence/STORM imaging, ER retention assay, knock-in mouse model with axonal organization analysis Brain High 33889941
2022 SynCAM3/CADM3 knockout mice subjected to spinal cord injury show reduced astrocytic scar formation compared to wild-type, with prevention of reactive astrocyte-to-scar-forming astrocyte transformation and improved ECM reconstitution, indicating CADM3 promotes glial scar formation after CNS injury. SynCAM3 KO mouse model, single-cell RNA sequencing, qRT-PCR, immunohistochemistry International journal of molecular sciences Medium 35682897
2023 A second pathogenic CADM3 variant (Gly368Cys) causes dominant axonal CMT2. Functional analysis showed significantly decreased CADM3-Gly368Cys protein levels at the cell membrane and major predicted structural changes, consistent with the disease mechanism of reduced surface expression established for the Tyr172Cys variant. Whole exome sequencing, cell membrane fractionation/Western blot, structural prediction Brain communications Medium 38074074
2024 Necl-1/CADM3 is localized at S- and S/M-opsin-containing cones and at dendrites of type 4 OFF cone bipolar cells in mouse retina. Necl-1 knockout mice show dislocated cone-to-type 4 OFF CBC synapses, abnormal horizontal cell distribution, mislocalized AMPA receptors, and aberrant short-wavelength signal transmission rescued by AMPA receptor potentiation, establishing CADM3 as required for cone synapse formation mediating OFF pathways. Immunofluorescence localization, Necl-1 KO mouse analysis, electroretinography, optokinetic response testing, AMPA receptor potentiator rescue experiment iScience High 38623325
2025 Necl1/CADM3 deficiency in rats causes prefrontal cortex-specific noradrenergic dysfunction: norepinephrine depletion, dendritic spine loss, and upregulation of adrenergic receptor α2A (Adra2a). Adra2a antagonism (mirtazapine) rescues depressive phenotypes in KO rats; prefrontal-targeted Necl1 reconstitution rescues depressive behavior and normalizes Adra2a expression, establishing Necl1 as a synaptic-noradrenergic integrator in emotional processing. Constitutive KO in rats and mice, pharmacological rescue (mirtazapine, reboxetine), AAV-mediated regional reconstitution, norepinephrine measurement, dendritic spine analysis, adrenergic receptor expression analysis Journal of affective disorders Medium 41308882

Source papers

Stage 0 corpus · 28 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Nectin-like molecule-1/TSLL1/SynCAM3: a neural tissue-specific immunoglobulin-like cell-cell adhesion molecule localizing at non-junctional contact sites of presynaptic nerve terminals, axons and glia cell processes. Journal of cell science 110 15741237
2011 Plant pathogenic bacteria utilize biofilm growth-associated repressor (BigR), a novel winged-helix redox switch, to control hydrogen sulfide detoxification under hypoxia. The Journal of biological chemistry 67 21632538
2001 Isolation of the TSLL1 and TSLL2 genes, members of the tumor suppressor TSLC1 gene family encoding transmembrane proteins. Oncogene 61 11536053
2006 Crystal structure of the V domain of human Nectin-like molecule-1/Syncam3/Tsll1/Igsf4b, a neural tissue-specific immunoglobulin-like cell-cell adhesion molecule. The Journal of biological chemistry 40 16467305
2009 Loss of NECL1, a novel tumor suppressor, can be restored in glioma by HDAC inhibitor-Trichostatin A through Sp1 binding site. Glia 39 19062177
2007 BigR, a transcriptional repressor from plant-associated bacteria, regulates an operon implicated in biofilm growth. Journal of bacteriology 35 17586627
2021 Differential Contribution of Cadm1-Cadm3 Cell Adhesion Molecules to Peripheral Myelinated Axons. The Journal of neuroscience : the official journal of the Society for Neuroscience 25 33397712
2018 BigR is a sulfide sensor that regulates a sulfur transferase/dioxygenase required for aerobic respiration of plant bacteria under sulfide stress. Scientific reports 23 29472641
2011 Localization of Cadm2a and Cadm3 proteins during development of the zebrafish nervous system. The Journal of comparative neurology 23 21456004
2018 miR-140-5p suppresses retinoblastoma cell proliferation, migration, and invasion by targeting CEMIP and CADM3. Cellular and molecular biology (Noisy-le-Grand, France) 20 29808799
2016 Cadm3 (Necl-1) interferes with the activation of the PI3 kinase/Akt signaling cascade and inhibits Schwann cell myelination in vitro. Glia 20 27658374
2016 NECL1 coated PLGA as favorable conduits for repair of injured peripheral nerve. Materials science & engineering. C, Materials for biological applications 18 27772714
2021 A CADM3 variant causes Charcot-Marie-Tooth disease with marked upper limb involvement. Brain : a journal of neurology 16 33889941
2022 The Sulfide-Responsive SqrR/BigR Homologous Regulator YgaV of Escherichia coli Controls Expression of Anaerobic Respiratory Genes and Antibiotic Tolerance. Antioxidants (Basel, Switzerland) 13 36552568
2009 A novel method for isolating Schwann cells using the extracellular domain of Necl1. Journal of neuroscience research 12 19125407
2003 Isolation of the mouse Tsll1 and Tsll2 genes, orthologues of the human TSLC1-like genes 1 and 2 (TSLL1 and TSLL2). Gene 12 14659875
2022 Synaptic Cell Adhesion Molecule 3 (SynCAM3) Deletion Promotes Recovery from Spinal Cord Injury by Limiting Glial Scar Formation. International journal of molecular sciences 10 35682897
2007 Crystallization and preliminary X-ray analysis of BigR, a transcription repressor from Xylella fastidiosa involved in biofilm formation. Acta crystallographica. Section F, Structural biology and crystallization communications 9 17620720
2023 GRIK5 stimulates colon cancer growth and metastasis through cAMP/PKA/CADM3 signaling. Cell biology international 8 36959746
2022 Circ004463 promotes fibroblast proliferation and collagen I synthesis by sponging miR-23b and regulating CADM3/MAP4K4 via activation of AKT/ERK pathways. International journal of biological macromolecules 8 36502948
2022 Usefulness of SynCAM3 and cyclin D1 immunohistochemistry in distinguishing superficial CD34-positive fibroblastic tumor from its histological mimics. Medical molecular morphology 6 36344703
2024 Clinical significance of low expression of CADM3 in breast cancer and preliminary exploration of related mechanisms. BMC cancer 3 38515057
2023 Novel variant in CADM3 causes Charcot-Marie-Tooth disease. Brain communications 3 38074074
2024 Necl-1/CADM3 regulates cone synapse formation in the mouse retina. iScience 2 38623325
2009 [Neural adhesion molecule NECL1 inhibits migration, invasion, and potentially induces differentiation of glioma cell]. Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae 1 20078932
2008 [Role of cell adhesion molecules Necl1 in synaptogenesis in primary cultured rat neurons]. Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae 1 18686604
2008 [Effect of NECL1 on the proliferation of T98G glioma cell line]. Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae 1 18686605
2025 Necl1 deficiency induces noradrenergic dysfunction and depressive-like states in rodents: A cross-species model validated by pharmacological intervention. Journal of affective disorders 0 41308882

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