Affinage

NCAM1

Neural cell adhesion molecule 1 · UniProt P13591

Length
858 aa
Mass
94.6 kDa
Annotated
2026-06-10
100 papers in source corpus 27 papers cited in narrative 27 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NCAM1 (CD56) is an immunoglobulin-superfamily cell adhesion molecule that mediates homophilic trans-cellular recognition through an antiparallel, cross-shaped dimer formed by its N-terminal Ig domains (PMID:10802736), and that organizes axonal fasciculation, synaptic plasticity, and neuronal migration in the nervous system (PMID:8816705, PMID:9073395). Its adhesive activity is tuned post-translationally by polysialic acid (PSA): polysialylation, catalyzed by the ST8SIA enzymes (PST-1/ST8SIA4 and ST8SIA2) on terminal sialylated N-glycans (PMID:8805371, PMID:17986444), generates steric intermembrane repulsion that overrides homophilic NCAM and cadherin adhesion in a force- and ionic-strength-dependent manner (PMID:15504723, PMID:3281256), and PSA is required for hippocampal LTP and LTD (PMID:8816705). Upon clustering, the NCAM140 isoform signals from lipid rafts through a non-receptor tyrosine kinase cascade—FAK→Fyn→Ras→MEK→ERK1/2→CREB—to drive neurite outgrowth (PMID:10084688, PMID:11980923), a cascade assembled by a βI-spectrin scaffold that bridges PKCβ2 and GAP-43 (PMID:12743109, PMID:17212696) and by RPTPα, which links NCAM to Fyn and is itself activated by CaMKIIα-mediated phosphorylation downstream of NCAM-associated Ca2+ channels (PMID:15623578, PMID:18809727). NCAM also remodels the actin cytoskeleton, activating Pak1→LIMK1→cofilin to promote filopodial actin polymerization (PMID:23303955) and engaging profilin2 to control neural progenitor proliferation and the neuron-versus-glia fate decision during corticogenesis (PMID:31816056). Beyond the nervous system, NCAM1 sustains acute myeloid leukemia stem cells through constitutive MAPK activation, rendering NCAM1+ blasts sensitive to MEK1/2 inhibition (PMID:30814062), promotes NK-cell cytotoxicity by supporting immunological synapse formation and lytic granule exocytosis via Pyk2 phosphorylation (PMID:32510326), and serves as a Zika virus entry receptor (PMID:32753727). Its ectodomain is proteolytically cleaved by KLK8, linking NCAM1 loss to hippocampal neuronal apoptosis (PMID:37076499), and anti-NCAM1 autoantibodies that disrupt its homophilic and Fyn interactions produce schizophrenia-related deficits (PMID:35492247).

Mechanistic history

Synthesis pass · year-by-year structured walk · 27 steps
  1. 1988 High

    Established that NCAM adhesive function is not constitutive but is set by a post-translational modification, defining PSA as a regulatory switch on cell-cell apposition.

    Evidence Cell adhesion assays correlating PSA content with intermembrane repulsion

    PMID:3281256

    Open questions at the time
    • Did not quantify the physical repulsive force
    • Enzymes generating PSA not yet identified
  2. 1996 High

    Resolved how PSA-NCAM is biosynthesized by showing a single recombinant enzyme suffices to polysialylate terminally sialylated N-glycans, defining the acceptor requirement.

    Evidence In vitro reconstitution with recombinant PST-1/ST8SIA4 and incompletely glycosylated NCAM variants

    PMID:8805371

    Open questions at the time
    • In vivo contribution of multiple sialyltransferases not addressed
    • Chain-length determinants unresolved
  3. 1996 High

    Connected PSA-NCAM to functional plasticity, showing PSA is required for activity-dependent LTP/LTD and that NCAM loss degrades plasticity.

    Evidence Enzymatic PSA removal and electrophysiology in NCAM knockout hippocampal slices

    PMID:8816705

    Open questions at the time
    • Downstream signaling linking PSA to plasticity not defined
    • Synaptic versus extrasynaptic site of action unresolved
  4. 1997 High

    Demonstrated an in vivo developmental requirement for NCAM in axonal fasciculation and pathfinding, anchoring its adhesive role in circuit assembly.

    Evidence Histological analysis of mossy fiber tracts in NCAM knockout mice

    PMID:9073395

    Open questions at the time
    • Did not separate homophilic from heterophilic contributions
    • Molecular signaling mechanism not addressed
  5. 2000 High

    Provided the structural basis for homophilic recognition, revealing an antiparallel cross-shaped Ig-domain dimer as the trans-adhesion unit.

    Evidence 1.85 Å X-ray crystallography of the two N-terminal Ig domains

    PMID:10802736

    Open questions at the time
    • Full-length ectodomain trans-zipper geometry not captured
    • Effect of PSA on the binding interface not modeled
  6. 1999 High

    Defined the intracellular signaling consequence of NCAM engagement as a FAK→Fyn→Ras→MAPK→CREB cascade required for neurite outgrowth, converting adhesion into a transcriptional response.

    Evidence NCAM140 clustering, kinase inhibitors, dominant-negatives, and neurite outgrowth assays in cerebellar neurons

    PMID:10084688

    Open questions at the time
    • How clustering reaches FAK/Fyn not yet mechanistically defined
    • Membrane platform for signaling unidentified
  7. 2002 High

    Localized NCAM140 signaling to lipid rafts via palmitoylation and revealed obligatory FGFR co-signaling, explaining where and with which partner the kinase cascade is triggered.

    Evidence Palmitoylation mutagenesis, raft disruption, FGFR inhibition, and neurite outgrowth in NCAM-deficient neurons

    PMID:11980923

    Open questions at the time
    • Molecular link between rafts and FAK/Fyn activation not yet specified
    • Stoichiometry of NCAM-FGFR engagement unresolved
  8. 2002 Medium

    Showed NCAM140 also restrains cell motility through Fyn and through heterophilic engagement of heparan sulfate proteoglycans, broadening its role beyond promotion of outgrowth.

    Evidence Motility/adhesion assays and domain-deletion constructs in transfected cells

    PMID:11839780

    Open questions at the time
    • Single-lab functional assays
    • In vivo relevance of the paracrine motility inhibition not tested
  9. 2003 High

    Identified βI spectrin as the scaffold that physically bridges NCAM to PKCβ2 and recruits the complex to rafts, providing the structural organizer of the signaling assembly.

    Evidence Reciprocal co-IP, raft fractionation, dominant-negative spectrin, and neurite outgrowth assays

    PMID:12743109

    Open questions at the time
    • How spectrin coordinates with the Fyn arm not fully resolved
    • Isoform-specific scaffolding differences only partly defined
  10. 2004 High

    Resolved how NCAM activates Fyn by identifying RPTPα as the phosphatase bridge required for Fyn association and activation, filling the gap between clustering and kinase activity.

    Evidence Co-IP, RPTPα-deficient neurons, dominant-negative RPTPα, and neurite outgrowth assays

    PMID:15623578

    Open questions at the time
    • Trigger for RPTPα phosphatase activation not yet identified
    • Cis versus trans engagement requirement unresolved
  11. 2004 High

    Quantitatively demonstrated that polysialylation generates a direct repulsive force sufficient to override both NCAM and cadherin adhesion, providing the biophysical mechanism for PSA-dependent de-adhesion.

    Evidence Surface force apparatus measurements on membrane-bound NCAM ± PSA

    PMID:15504723

    Open questions at the time
    • In vivo membrane-context validation limited
    • Effect on heterophilic ligands beyond cadherin not measured
  12. 2006 Medium

    Defined GAP-43 as a molecular switch directing signaling between the NCAM180/spectrin and NCAM140/Fyn pathways, explaining isoform-specific routing of the outgrowth signal.

    Evidence Isoform and phosphorylation-mutant overexpression, co-IP, and neurite outgrowth in PC12E2 cells and neurons

    PMID:17212696

    Open questions at the time
    • Single-lab data
    • Physiological context selecting one pathway over the other not defined
  13. 2008 High

    Identified the activation trigger for RPTPα as a Ca2+/CaMKIIα circuit, showing NCAM-associated Ca2+ channels phosphorylate RPTPα to enhance its phosphatase activity.

    Evidence Ca2+ channel blockers, CaMKIIα inhibitors, RPTPα Ser180/Ser204 mutagenesis, and neurite outgrowth assays

    PMID:18809727

    Open questions at the time
    • Identity and gating of the NCAM-associated channels not fully defined
    • Spatial coupling of channels to the signaling complex unresolved
  14. 2009 High

    Connected neuronal depolarization to NCAM isoform choice via a chromatin/elongation kinetic-coupling mechanism, revealing activity-dependent regulation of NCAM exon 18 splicing.

    Evidence Depolarization, slow RNAP II mutant, ChIP for H3K9ac/H3K36me3, and HDAC inhibition with RT-PCR

    PMID:19251664

    Open questions at the time
    • Functional consequence of the spliced isoform not tested here
    • Upstream signal linking depolarization to chromatin marks not defined
  15. 2009 Medium

    Showed NCAM140 promotes neurogenic proliferation in vivo through heterophilic, PSA-independent interactions, mapping the activity to the FnIII repeats and Ig domain 5.

    Evidence In vivo viral overexpression with domain-deletion mutants and BrdU/doublecortin counting

    PMID:19788570

    Open questions at the time
    • Heterophilic partner not identified
    • Single-lab in vivo evidence
  16. 2013 High

    Linked NCAM signaling to direct actin remodeling by identifying Pak1 as a partner driving LIMK1/cofilin-dependent actin polymerization in growth cones.

    Evidence Yeast two-hybrid, co-IP in growth cones, NCAM-deficient brains, Pak1 gain/loss constructs, and actin/neurite assays

    PMID:23303955

    Open questions at the time
    • Coordination between Pak1 and the FAK/Fyn cascade unresolved
    • Direct binding interface not mapped
  17. 2020 High

    Extended NCAM cytoskeletal control to cell-fate decisions, showing NCAM-profilin2 interaction tunes actin polymerization to set the timing of cortical neurogenesis versus gliogenesis.

    Evidence NPC-specific conditional knockout, NCAM-profilin2 co-IP, binding-site mutagenesis, and cortical layer/lineage analysis

    PMID:31816056

    Open questions at the time
    • Signal upstream of profilin2 engagement not defined
    • Relationship to PSA regulation in NPCs unclear
  18. 2017 High

    Demonstrated NCAM acts in functional opposition to GFRα1 during Purkinje cell migration, establishing genetic epistasis between an adhesion molecule and a GDNF co-receptor.

    Evidence Gfra1/Ncam mutant epistasis, GFRα1-NCAM co-IP, and cis/trans migration assays

    PMID:28076782

    Open questions at the time
    • Downstream effectors of the GFRα1-NCAM interaction not defined
    • Whether intracellular signaling is engaged unresolved
  19. 2017 Medium

    Implicated NCAM1 in cardiac pathology, showing TGFβ1 induces NCAM1 via p38 to cause intercalated-disc adhesion defects.

    Evidence Cardiac TGFβ1 transgenic mice, p38 inhibition, NCAM1 siRNA knockdown, and rescue in cardiomyocytes

    PMID:28870505

    Open questions at the time
    • Single-lab study
    • Mechanism by which NCAM1 disrupts disc adhesion not defined
  20. 2018 Medium

    Extended NCAM1's plasticity role to disease by showing injury-induced NCAM1 turnover mediates cortical spine reorganization and behavioral sensitization in neuropathic pain.

    Evidence Nerve injury model, protein turnover and spine morphology analysis, and ACC NCAM1 manipulation with behavioral tests

    PMID:29346771

    Open questions at the time
    • Molecular signaling driving spine changes not defined
    • Single-lab study
  21. 2019 High

    Established a non-neural pathogenic role, showing NCAM1 maintains AML leukemic stem cells through constitutive MAPK activation and confers a MEK-inhibitor vulnerability.

    Evidence CRISPR/shRNA depletion, phosphoproteomics, serial transplantation in murine AML, and MEK1/2 inhibition

    PMID:30814062

    Open questions at the time
    • How NCAM1 constitutively engages MAPK in leukemia not defined
    • Ligand/clustering requirement in AML unresolved
  22. 2020 High

    Defined a mechanism for NCAM1 in immune cytotoxicity, showing CD56 supports immunological synapse formation and lytic granule exocytosis through Pyk2 phosphorylation.

    Evidence CRISPR knockout with rescue in NK92 cells, synapse imaging, exocytosis assays, and Pyk2 phosphorylation

    PMID:32510326

    Open questions at the time
    • Upstream link from CD56 engagement to Pyk2 not defined
    • Homophilic versus heterophilic trigger in NK cells unresolved
  23. 2020 High

    Identified NCAM1 as a Zika virus entry receptor, assigning it a role in viral internalization in neural and other cell types.

    Evidence Photo-crosslinking chemical proteomics with NCAM1 overexpression, knockout, and inhibition in cell lines

    PMID:32753727

    Open questions at the time
    • Viral domain engaging NCAM1 not mapped
    • Internalization machinery downstream of NCAM1 binding unresolved
  24. 2022 Medium

    Connected NCAM1 to schizophrenia, showing patient autoantibodies disrupt homophilic, GDNF, and Fyn interactions, suppress FAK/MEK/ERK signaling, and reduce synapse density to produce disease-related behavior.

    Evidence Patient antibody detection and CSF injection in mice with phosphorylation, spine/synapse, and behavioral readouts

    PMID:35492247

    Open questions at the time
    • Single-lab study partly dependent on patient material
    • Causal role of autoantibodies in patients not established
  25. 2023 Medium

    Identified KLK8 as a protease that cleaves the NCAM1 ectodomain and linked this cleavage to hippocampal neuronal apoptosis in a depression model.

    Evidence In vitro cleavage assay, KLK8 overexpression, transgenic/knockout mice, and NCAM1 rescue in CUMS models

    PMID:37076499

    Open questions at the time
    • Cleavage site and fate of cleaved fragments not defined
    • Single-lab study
  26. 2007 High

    Resolved the in vivo division of labor between polysialyltransferases, showing ST8SiaIV is the major regulator and that ST8SiaII/IV act synergistically to build long polySia chains at specific N-glycan sites.

    Evidence Single and double sialyltransferase knockout mice with glycan fine-structure analysis of brain polySia-NCAM

    PMID:17986444

    Open questions at the time
    • Regulation of enzyme expression/activity not addressed
    • Functional consequence of differential chain length unresolved
  27. 2001 Medium

    Identified transcriptional control of NCAM expression through cooperative LEF-1/Alx4 binding at the NCAM promoter, with Alx4 repressing endogenous NCAM in stromal cells.

    Evidence Co-IP/GST pulldown, EMSA, promoter reporter assays, and endogenous protein measurement

    PMID:11696550

    Open questions at the time
    • Tissue contexts using this regulation not broadly defined
    • Single-lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse NCAM-engaging signals (homophilic, heterophilic, viral, autoantibody, constitutive in leukemia) are differentially routed into the shared FAK/Fyn/RPTPα/MAPK and actin machinery to produce context-specific outcomes remains unresolved.
  • Mechanism of constitutive MAPK engagement in AML undefined
  • Heterophilic partners for neurogenic and migration roles not all identified
  • How PSA status integrates with intracellular signaling not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098631 cell adhesion mediator activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0060090 molecular adaptor activity 2 GO:0001618 virus receptor activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005856 cytoskeleton 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 3 R-HSA-112316 Neuronal System 2 R-HSA-1500931 Cell-Cell communication 2 R-HSA-168256 Immune System 1
Partners
FYNGAP43GFRA1KLK8PAK1PFN2PTPRASPTB

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1988 NCAM polysialic acid (PSA) content regulates cell-cell adhesion by steric hindrance: high PSA content increases intermembrane repulsion and inhibits membrane apposition, while low PSA content promotes adhesion and triggers contact-dependent intercellular events. Cell adhesion assays, biochemical analysis of PSA content Science High 3281256
1996 PSA-NCAM is required for activity-induced synaptic plasticity (LTP and LTD) in hippocampal slices; enzymatic removal of PSA with endoneuraminidase-N completely prevented LTP and LTD induction, and recovery of PSA immunoreactivity correlated with full recovery of plasticity. NCAM-deficient mice also showed decaying LTP. Enzymatic PSA removal (endoneuraminidase-N), hippocampal organotypic slice cultures, electrophysiology in NCAM knockout mice Neuron High 8816705
1997 NCAM is essential for axonal fasciculation and pathfinding of hippocampal mossy fibers in vivo; NCAM-null mice show strongly disrupted fasciculation, pathfinding, and altered distribution of mossy fiber terminals, with a more severe phenotype in adults than young animals. NCAM knockout mice (gene targeting), histological and immunofluorescence analysis of hippocampal mossy fiber tract Molecular and cellular neurosciences High 9073395
1999 NCAM140 clustering activates a signaling cascade: p125FAK → p59Fyn → Ras → MEK → ERK1/2 (MAPK) activation, leading to CREB phosphorylation at Ser133. This pathway is required for NCAM-stimulated neurite outgrowth in cerebellar neurons. NCAM clustering assay, phosphorylation assays (Western blot), kinase inhibitors, dominant-negative constructs, neurite outgrowth assay Journal of neurobiology High 10084688
2000 Crystal structure (1.85 Å) of the two N-terminal extracellular Ig domains of NCAM reveals a cross-shaped antiparallel dimer as the structural basis for homophilic trans-cellular recognition and adhesion. X-ray crystallography Nature structural biology High 10802736
2002 Lipid raft association of NCAM140 is required for activation of the non-receptor tyrosine kinase pathway (FAK and ERK1/2) and neurite outgrowth. Mutation of NCAM140 palmitoylation sites or lipid raft disruption abolishes tyrosine kinase activation and neurite outgrowth. Additionally, FGF receptor co-signaling is also required, as a specific FGFR inhibitor completely blocks NCAM-triggered neurite outgrowth. Transfection of NCAM-deficient hippocampal neurons, palmitoylation site mutagenesis, lipid raft disruption (methyl-β-cyclodextrin), FGFR-specific inhibitor, kinase phosphorylation assays, neurite outgrowth assay The Journal of cell biology High 11980923
2002 NCAM140 reduces cell motility by interfering with fibronectin substratum attachment and through its cytoplasmic domain via interaction with p59Fyn. The extracellular domain of NCAM also acts as a paracrine inhibitor of NCAM-negative cell locomotion via heterophilic interaction with heparan sulfate proteoglycans (through the two N-terminal Ig modules). NCAM transfection, motility assays, fibronectin adhesion assay, domain deletion constructs, heparin-binding assays Journal of cell science Medium 11839780
2003 NCAM120, NCAM140, and NCAM180 form detergent-insoluble complexes with βI spectrin in hippocampal neurons. βI spectrin binds directly to the intracellular domain of NCAM180 and to NCAM140. PKCβ2 forms complexes with NCAM140/NCAM180 via spectrin as a bridge. NCAM activation promotes redistribution of the NCAM-spectrin-PKCβ2 complex to lipid rafts, and disruption of spectrin binding (by dominant-negative βI spectrin fragments) impairs neurite outgrowth. Co-immunoprecipitation, subcellular fractionation (Triton X-100 insoluble complexes/lipid rafts), dominant-negative constructs, methyl-β-cyclodextrin treatment, neurite outgrowth assay The Journal of cell biology High 12743109
2004 NCAM140 directly interacts with the intracellular domain of RPTPα (receptor-like protein tyrosine phosphatase alpha) in a Ca2+-independent manner. This NCAM-RPTPα complex is bridged by spectrin and redistributes to lipid rafts upon NCAM activation. RPTPα is required to link NCAM to p59Fyn kinase activation; in RPTPα-deficient neurons, NCAM-Fyn association and Fyn activation are abolished, and NCAM-dependent neurite outgrowth is blocked. Co-immunoprecipitation, RPTPα-deficient mouse neurons, dominant-negative RPTPα mutants, kinase activation assays, neurite outgrowth assay The Journal of cell biology High 15623578
2004 NCAM polysialylation directly increases intermembrane repulsion (measured by molecular force measurements), sufficient to overwhelm homophilic NCAM adhesion and cadherin-mediated adhesion. The steric repulsion is ionic strength-dependent, and PSA-dependent attenuation of cadherin adhesion increases with PSA-NCAM:cadherin ratio. Molecular force measurements (surface force apparatus) using membrane-bound NCAM with and without PSA The Journal of biological chemistry High 15504723
2006 GAP-43 phosphorylation (by PKC and CKII) potentiates NCAM-induced neurite outgrowth. In the presence of GAP-43, NCAM-180/spectrin/GAP-43 functional association is required for neurite outgrowth; in the absence of GAP-43, the NCAM-140/Fyn signaling pathway is predominant. GAP-43 thus acts as a molecular switch between NCAM-180 and NCAM-140 signaling. Overexpression and phosphorylation mutants in PC12E2 cells and hippocampal neurons, neurite outgrowth assay, co-immunoprecipitation Journal of neurochemistry Medium 17212696
2008 NCAM clustering induces Ca2+ influx via T- and L-type voltage-dependent Ca2+ channels associated with NCAM, activating CaMKIIα which phosphorylates RPTPα at Ser180 and Ser204, enhancing RPTPα phosphatase activity. Overexpression of RPTPα with mutated Ser180/Ser204 inhibits NCAM-induced neurite outgrowth. Co-immunoprecipitation, Ca2+ channel blockers, CaMKIIα inhibitors, phosphorylation assays, RPTPα serine mutagenesis, neurite outgrowth assay The Journal of cell biology High 18809727
2009 Neuronal membrane depolarization triggers skipping of NCAM exon 18 independently of the CaMKIV pathway, through a kinetic coupling mechanism: H3K9 hyper-acetylation is induced in an intragenic region surrounding the alternative exon (without promoter acetylation), associated with chromatin relaxation and H3K36 tri-methylation, which accelerates RNA Pol II elongation and promotes exon skipping. Depolarization of neuronal cells, slow RNAP II mutant, chromatin immunoprecipitation (H3K9ac, H3K36me3), HDAC inhibitor trichostatin A, RT-PCR for alternative splicing Proceedings of the National Academy of Sciences of the United States of America High 19251664
2009 Ectopic expression of NCAM140 in radial glia and type C cells in vivo induces increased cell proliferation and generation of additional neuronal type A cells in the rostral migratory stream. This neurogenic effect requires only the fibronectin type III repeats and Ig-domain 5 of NCAM and is independent of polysialylation (as transgenic NCAM in these cells is not polysialylated), implicating heterophilic NCAM interactions. In vivo retroviral/lentiviral overexpression in postnatal mouse brain, domain deletion mutants, PSA immunostaining, cell counting (BrdU/doublecortin) The European journal of neuroscience Medium 19788570
2013 NCAM directly interacts with p21-activated kinase 1 (Pak1) in growth cones (identified by yeast two-hybrid and confirmed in neurons). NCAM activation enhances Pak1 autophosphorylation/activity, promotes Pak1 membrane association, and activates downstream LIMK1 and cofilin phosphorylation, increasing filamentous actin and filopodium mobility. Pak1 is required for NCAM-dependent neurite outgrowth. Yeast two-hybrid screen, co-immunoprecipitation in growth cones, NCAM-deficient mouse brains, dominant-negative and constitutively active Pak1 constructs, actin polymerization assay, neurite outgrowth assay The Journal of neuroscience High 23303955
2017 TGFβ1 induces NCAM1 expression in cardiomyocytes via a p38-dependent pathway. NCAM1 upregulation mediates TGFβ1-induced cell-cell adhesion defects at intercalated discs; selective targeting of NCAM1 rescues the cell adhesion defect caused by TGFβ1 treatment. Cardiac-specific TGFβ1 transgenic mice, electron microscopy, immunostaining, p38 inhibition, siRNA knockdown of NCAM1, rescue assay in cardiomyocytes Journal of molecular and cellular cardiology Medium 28870505
2017 GFRα1 counteracts NCAM function during Purkinje cell migration: GFRα1 directly interacts with NCAM in embryonic Purkinje cells, and genetic reduction of NCAM enhances wild-type Purkinje cell migration and restores migration in Gfra1 mutants. GFRα1 can act both in cis and trans to limit NCAM-mediated restriction of Purkinje cell migration. Gfra1 and Ncam knockout/heterozygous mice, co-immunoprecipitation of GFRα1 and NCAM, in vitro migration assays with cis/trans GFRα1 constructs Cell reports High 28076782
2018 Peripheral nerve injury increases NCAM1 turnover in the anterior cingulate cortex (ACC), and NCAM1 mediates spine reorganization in ACC neurons contributing to behavioral sensitization (neuropathic pain). This mechanism parallels NMDA-receptor- and protein-synthesis-dependent LTP maintenance. Peripheral nerve injury model, protein turnover assays, spine morphology analysis, behavioral sensitization tests, NCAM1 manipulation in ACC Cell reports Medium 29346771
2019 NCAM1 promotes leukemogenesis and confers drug resistance in AML by constitutively activating the MAPK signaling pathway. NCAM1 perturbation induces cell death or differentiation and sensitizes leukemic blasts to genotoxic agents in vitro and in vivo. In a murine AML model, Ncam1 deletion prolonged disease latency and reduced leukemia-initiating cells. Pharmacological MEK1/2 inhibition specifically inhibits NCAM1+ AML cell proliferation. CRISPR/Cas9 knockout and shRNA knockdown, phosphoproteomics, transcriptomics, serial transplantation in murine AML model, MEK1/2 inhibitor treatment, in vitro and in vivo drug sensitivity assays Blood High 30814062
2020 NCAM1 functions as an entry receptor for Zika virus (ZIKV): chemical proteomics with photo-crosslinking identified NCAM1 as a ZIKV-interacting protein in living cells, and overexpression, knockout, and inhibition of NCAM1 in Vero cells and human glioblastoma cells validated its role in ZIKV internalization. Time-resolved chemical proteomics (photocrosslinking + biotin enrichment + mass spectrometry), NCAM1 overexpression, CRISPR knockout, inhibition in cell lines Nature communications High 32753727
2020 CD56 (NCAM1) regulates NK cell cytotoxicity through Pyk2: CD56 deletion in NK92 cells impairs immunological synapse formation, lytic granule polarization and exocytosis, and reduces Pyk2 phosphorylation at Tyr402. Reintroduction of CD56 rescues cytotoxicity, granule exocytosis, and Pyk2 phosphorylation. CRISPR/Cas9 CD56 knockout in NK92 cells, rescue by CD56 reintroduction, lytic granule exocytosis assay, immunological synapse imaging, Pyk2 phosphorylation assay eLife High 32510326
2020 NCAM regulates temporal specification of neural progenitor cells (NPCs) during corticogenesis by interacting with profilin2 to enhance actin polymerization. NPC-specific NCAM deletion reduces NPC proliferation, delays cortical neuron production, and advances gliogenesis. Mutations in the profilin2-binding site of NCAM abolish these regulatory effects. NPC-specific NCAM conditional knockout mice, co-immunoprecipitation of NCAM-profilin2, actin polymerization assay, profilin2-binding site mutagenesis, BrdU/EdU labeling, cortical layer marker immunostaining The Journal of cell biology High 31816056
2022 Anti-NCAM1 autoantibodies from schizophrenia patients disrupt NCAM1-NCAM1 homophilic interactions, NCAM1-GDNF interactions, and the NCAM1-Fyn interaction; they inhibit FAK, MEK1, and ERK1 phosphorylation when introduced into mouse cerebrospinal fluid, reduce spine and synapse density in frontal cortex, and induce schizophrenia-related behavior (deficient pre-pulse inhibition and cognitive impairment). Cell-based assay and ELISA for autoantibody detection; purified patient antibody injection into mouse CSF; spine/synapse counting by immunofluorescence; behavioral tests (PPI, cognitive tasks); phosphorylation assays Cell reports. Medicine Medium 35492247
2023 KLK8 (kallikrein-related peptidase 8) proteolytically cleaves the extracellular domain of NCAM1. KLK8-mediated NCAM1 cleavage contributes to hippocampal neuronal apoptosis in CUMS-induced depression. Overexpression of NCAM1 or NCAM1 mimetic peptide rescues neurons from KLK8-induced apoptosis. Co-immunoprecipitation, in vitro cleavage assay, adenovirus-mediated KLK8 overexpression in hippocampal neurons, KLK8 transgenic and knockout mice, NCAM1 overexpression rescue, CUMS mouse/rat models, immunofluorescence Cell death & disease Medium 37076499
1996 Polysialylation of NCAM is catalyzed by a single enzyme (PST-1/ST8SIA4) acting on terminal sialylated N-glycans on NCAM; reconstitution in vitro using incompletely glycosylated NCAM variants and soluble recombinant PST-1 demonstrated that a single enzyme is sufficient and that terminal sialylation of the N-glycan core (via either α2,3 or α2,6 linkage to galactose) generates the PSA acceptor site. In vitro reconstitution with recombinant PST-1, incompletely glycosylated NCAM variants, glycosyltransferase assay Current biology High 8805371
2001 LEF-1 and Alx4 can bind simultaneously to adjacent sites on the NCAM promoter (through Alx4's proline-rich N-terminal domain interacting with LEF-1's HMG-box), and this binding alters NCAM promoter activity. Alx4 expression in primary mammary stromal cells decreases endogenous NCAM protein levels. Protein interaction assays (co-immunoprecipitation/GST pulldown), EMSA on NCAM promoter, promoter reporter assay, endogenous NCAM protein measurement in Alx4-transfected stromal cells The Journal of biological chemistry Medium 11696550
2007 ST8SiaIV (PST) is the major regulator of NCAM polysialylation in vivo based on differential mRNA expression correlating with PSA levels; ST8SiaII and ST8SiaIV both polysialylate N-glycosylation sites 5 and 6 of NCAM but produce polySia chains of different lengths, with synergistic action required for synthesis of long polySia chains at site 5. ST8SiaII and ST8SiaIV knockout mice; isolation and tryptic digestion of polySia-NCAM from mouse brains; glycan structural analysis of polysialylated glycopeptides The Journal of biological chemistry High 17986444

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1988 The neural cell adhesion molecule (NCAM) as a regulator of cell-cell interactions. Science (New York, N.Y.) 758 3281256
1996 PSA-NCAM is required for activity-induced synaptic plasticity. Neuron 515 8816705
1989 Identity of Leu-19 (CD56) leukocyte differentiation antigen and neural cell adhesion molecule. The Journal of experimental medicine 468 2471777
2006 PSA-NCAM in mammalian structural plasticity and neurogenesis. Progress in neurobiology 355 17029752
2002 Clinical and biologic features of CD4(+)CD56(+) malignancies. Blood 318 11861268
1997 NCAM is essential for axonal growth and fasciculation in the hippocampus. Molecular and cellular neurosciences 245 9073395
2002 Cosignaling of NCAM via lipid rafts and the FGF receptor is required for neuritogenesis. The Journal of cell biology 228 11980923
2009 Neuronal cell depolarization induces intragenic chromatin modifications affecting NCAM alternative splicing. Proceedings of the National Academy of Sciences of the United States of America 224 19251664
1999 NCAM stimulates the Ras-MAPK pathway and CREB phosphorylation in neuronal cells. Journal of neurobiology 190 10084688
2004 Direct evidence that neural cell adhesion molecule (NCAM) polysialylation increases intermembrane repulsion and abrogates adhesion. The Journal of biological chemistry 182 15504723
2004 Zippers make signals: NCAM-mediated molecular interactions and signal transduction. Neurochemical research 164 15662836
1998 The neural cell adhesion molecule (NCAM) in development and plasticity of the nervous system. Experimental gerontology 162 9951628
2006 Haplotype spanning TTC12 and ANKK1, flanked by the DRD2 and NCAM1 loci, is strongly associated to nicotine dependence in two distinct American populations. Human molecular genetics 157 17085484
1998 Neural cell adhesion molecules (NCAM) and NCAM-PSA expression in neuroendocrine lung tumors. The American journal of surgical pathology 145 9777989
1990 Enhanced myogenesis in NCAM-transfected mouse myoblasts. Nature 140 2179732
2003 What is CD4+CD56+ malignancy and how should it be treated? Bone marrow transplantation 138 13130309
1994 High expression of CD56 (N-CAM) in a patient with cutaneous CD4-positive lymphoma. American journal of hematology 137 7526680
2005 Structural biology of NCAM homophilic binding and activation of FGFR. Journal of neurochemistry 136 16045455
2008 NCAM-induced intracellular signaling revisited. Journal of neuroscience research 127 17975827
2007 CD4+/CD56+ hematodermic tumor: the features of an evolving entity and its relationship to dendritic cells. American journal of clinical pathology 116 17439829
2007 Dissecting polysialic acid and NCAM functions in brain development. Journal of neurochemistry 115 17986140
2001 Revisiting the function of PSA-NCAM in the nervous system. Molecular neurobiology 115 11831554
2007 The unexpected effect of cyclosporin A on CD56+CD16- and CD56+CD16+ natural killer cell subpopulations. Blood 113 17495133
2003 Neural cell adhesion molecule (NCAM) association with PKCbeta2 via betaI spectrin is implicated in NCAM-mediated neurite outgrowth. The Journal of cell biology 112 12743109
1992 NCAM: structural diversity, function and regulation of expression. Seminars in cell biology 111 1623208
2000 PSA-NCAM: an important regulator of hippocampal plasticity. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 104 10715576
2007 NCAM1 association study of bipolar disorder and schizophrenia: polymorphisms and alternatively spliced isoforms lead to similarities and differences. Psychiatric genetics 103 17413444
2000 Structural basis of cell-cell adhesion by NCAM. Nature structural biology 102 10802736
1991 Expression of cytoadhesion molecules (CD56, CD54, CD18 and CD29) by myeloma plasma cells. British journal of haematology 99 1721526
2004 RPTPalpha is essential for NCAM-mediated p59fyn activation and neurite elongation. The Journal of cell biology 96 15623578
2013 Polysialic acid: versatile modification of NCAM, SynCAM 1 and neuropilin-2. Neurochemical research 90 23354723
2002 NCAM regulates cell motility. Journal of cell science 87 11839780
2002 Differential expression of CD56 and CD44 in the evolution of extramedullary myeloma. British journal of haematology 85 11841427
2008 Neural cell adhesion molecule (NCAM) marks adult myogenic cells committed to differentiation. Experimental cell research 83 18308302
2008 Haplotypic variants in DRD2, ANKK1, TTC12, and NCAM1 are associated with comorbid alcohol and drug dependence. Alcoholism, clinical and experimental research 82 18828801
2019 NCAM1 (CD56) promotes leukemogenesis and confers drug resistance in AML. Blood 80 30814062
2004 Molecular mechanisms of NCAM function. Frontiers in bioscience : a journal and virtual library 74 15353284
2006 NCAM1 and neurocognition in schizophrenia. Biological psychiatry 71 17161382
1996 Polysialylation of NCAM by a single enzyme. Current biology : CB 66 8805371
2006 GAP-43 regulates NCAM-180-mediated neurite outgrowth. Journal of neurochemistry 61 17212696
2013 ANKK1, TTC12, and NCAM1 polymorphisms and heroin dependence: importance of considering drug exposure. JAMA psychiatry 58 23303482
1993 Neural cell adhesion molecule (NCAM) and perineural invasion in bile duct cancer. Journal of surgical oncology 57 8501910
2003 NCAM(CD56) and RUNX1(AML1) are up-regulated in human ischemic cardiomyopathy and a rat model of chronic cardiac ischemia. The American journal of pathology 55 12937148
2002 Cadherins and NCAM as potential targets in metal toxicity. Toxicology and applied pharmacology 55 12183105
2007 Enzyme-dependent variations in the polysialylation of the neural cell adhesion molecule (NCAM) in vivo. The Journal of biological chemistry 54 17986444
2004 NCAM mimetic peptides: Pharmacological and therapeutic potential. Journal of molecular neuroscience : MN 54 14742908
1995 Neural cell adhesion molecule (NCAM) as a quantitative marker in synaptic remodeling. Neurochemical research 54 7643959
1991 Expression of the neural cell adhesion molecule (CD56) by human myeloma cells. Clinical and experimental immunology 54 1706237
2023 Identification of human exTreg cells as CD16+CD56+ cytotoxic CD4+ T cells. Nature immunology 53 37563308
2015 L1-CAM and N-CAM: From Adhesion Proteins to Pharmacological Targets. Trends in pharmacological sciences 53 26478212
2020 CD56 regulates human NK cell cytotoxicity through Pyk2. eLife 51 32510326
2020 Chemical proteomics tracks virus entry and uncovers NCAM1 as Zika virus receptor. Nature communications 49 32753727
2005 CD56/NCAM-positive Langerhans cell sarcoma: a clinicopathologic study of 4 cases. International journal of hematology 48 15914364
1991 Characterization of NCAM expression and function in BT4C and BT4Cn glioma cells. International journal of cancer 48 1985868
1993 NCAM expression by subsets of taste cells is dependent upon innervation. The Journal of comparative neurology 46 8245222
2001 Alx4 binding to LEF-1 regulates N-CAM promoter activity. The Journal of biological chemistry 45 11696550
2018 Rapid Turnover of Cortical NCAM1 Regulates Synaptic Reorganization after Peripheral Nerve Injury. Cell reports 44 29346771
2004 Clinicobiological, immunophenotypic, and molecular characteristics of monoclonal CD56-/+dim chronic natural killer cell large granular lymphocytosis. The American journal of pathology 43 15466379
1994 NCAM and lung cancer. International journal of cancer. Supplement = Journal international du cancer. Supplement 40 8194895
1993 NCAM (CD56)-positive malignant lymphoma. Leukemia & lymphoma 40 7512851
2008 Expression of CD56 and WT1 in ovarian stroma and ovarian stromal tumors. The American journal of surgical pathology 39 18425046
2008 Neural cell adhesion molecule (NCAM) isoform expression is associated with neuroblastoma differentiation status. Pediatric blood & cancer 38 18213713
2008 NCAM induces CaMKIIalpha-mediated RPTPalpha phosphorylation to enhance its catalytic activity and neurite outgrowth. The Journal of cell biology 38 18809727
2004 Ex vivo expansion of CD8+CD56+ and CD8+CD56- natural killer T cells specific for MUC1 mucin. Cancer research 37 14871854
2002 The role of NCAM in remyelination. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 37 11976973
2005 Mycosis fungoides with a CD56+ immunophenotype. Journal of the American Academy of Dermatology 36 15965442
2004 CD56(+dim) and CD56(+bright) cell activation and apoptosis in hepatitis C virus infection. Clinical and experimental immunology 36 15270860
2000 Neural cell adhesion molecule (NCAM) and myoblast fusion. Developmental biology 36 10772795
2013 The neural cell adhesion molecule (NCAM) associates with and signals through p21-activated kinase 1 (Pak1). The Journal of neuroscience : the official journal of the Society for Neuroscience 35 23303955
2000 Control of NCAM polysialylation by the differential expression of polysialyltransferases ST8SiaII and ST8SiaIV. European journal of cell biology 35 11089916
2022 NCAM1 and GDF15 are biomarkers of Charcot-Marie-Tooth disease in patients and mice. Brain : a journal of neurology 33 35148379
2020 Upregulation of Neural Cell Adhesion Molecule 1 (NCAM1) by hsa-miR-141-3p Suppresses Ameloblastoma Cell Migration. Medical science monitor : international medical journal of experimental and clinical research 33 32269209
2023 Upregulation of KLK8 contributes to CUMS-induced hippocampal neuronal apoptosis by cleaving NCAM1. Cell death & disease 32 37076499
1995 Expression of N-CAM (CD56) on acute leukemia cells: relationship with disease characteristics and outcome. Leukemia & lymphoma 32 8535222
1991 Expression of neural cell adhesion molecule (NCAM) isoforms in neuroblastoma. Journal of clinical pathology 32 1856291
2005 SNPs in the neural cell adhesion molecule 1 gene (NCAM1) may be associated with human neural tube defects. Human genetics 31 15883837
2001 Significance of cell adhesion molecules, CD56/NCAM in particular, in human tumor growth and spreading. Folia histochemica et cytobiologica 31 11820619
2022 Autoantibodies against NCAM1 from patients with schizophrenia cause schizophrenia-related behavior and changes in synapses in mice. Cell reports. Medicine 30 35492247
2020 Deep phenotypical characterization of human CD3+ CD56+ T cells by mass cytometry. European journal of immunology 30 33231295
1997 NCAM and schizophrenia: genetic studies. Molecular psychiatry 30 9154219
1994 CD56 (NCAM)-positive malignant lymphoma. Leukemia & lymphoma 30 7522719
2017 TGF-β1 affects cell-cell adhesion in the heart in an NCAM1-dependent mechanism. Journal of molecular and cellular cardiology 29 28870505
2001 CD2- CD4+ CD56+ hematodermic/hematolymphoid malignancy. Journal of the American Academy of Dermatology 29 11174380
2014 Characterisation of genetic variation in ST8SIA2 and its interaction region in NCAM1 in patients with bipolar disorder. PloS one 28 24651862
2008 Clinicopathological correlates of plasma cell CD56 (NCAM) expression in multiple myeloma. Leukemia & lymphoma 27 18231917
1990 NCAM in the organ of Corti of the developing mouse. Journal of neurocytology 26 2292721
2016 NCAM1 Polysialylation: The Prion Protein's Elusive Reason for Being? ASN neuro 25 27879349
2006 Correlation between expression of CD56/NCAM and severe leukostasis in hyperleukocytic acute myelomonocytic leukaemia. European journal of haematology 25 16519701
2016 Pharmacological approach for targeting dysfunctional brain plasticity: Focus on neural cell adhesion molecule (NCAM). Pharmacological research 24 27095082
2009 NCAM expression induces neurogenesis in vivo. The European journal of neuroscience 24 19788570
2004 CD56+ lymphoma with skin involvement: clinicopathologic features and classification. Archives of dermatology 24 15096371
1993 Expression of NCAM mRNA and polypeptides in aging rat brain. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience 24 8488756
2022 Human NK cells responses are enhanced by CD56 engagement. European journal of immunology 23 35775327
2014 NCAM1-TTC12-ANKK1-DRD2 variants and smoking motives as intermediate phenotypes for nicotine dependence. Psychopharmacology 23 25273375
2012 Human natural killer cell maturation defect supports in vivo CD56(bright) to CD56(dim) lineage development. PloS one 23 23240056
2011 Immunophenotypic characteristics and clinical relevance of CD56+ and CD56- extranodal nasal-type natural killer/T-cell lymphoma. Leukemia & lymphoma 23 21323521
2020 NCAM regulates temporal specification of neural progenitor cells via profilin2 during corticogenesis. The Journal of cell biology 22 31816056
2020 The Drosophila NCAM homolog Fas2 signals independently of adhesion. Development (Cambridge, England) 22 31862845
2017 GFRα1 Regulates Purkinje Cell Migration by Counteracting NCAM Function. Cell reports 22 28076782
2017 Reduction in CD16/CD56 and CD16/CD3/CD56 Natural Killer Cells in Coronary Artery Disease. Immunological investigations 21 28414590

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