Affinage

NCAM2

Neural cell adhesion molecule 2 · UniProt O15394

Length
837 aa
Mass
93.0 kDa
Annotated
2026-06-10
18 papers in source corpus 11 papers cited in narrative 11 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

NCAM2 is an immunoglobulin superfamily cell adhesion molecule of the neuronal surface that organizes dendritic and axonal architecture, glutamatergic synapse stability, and amyloidogenic trafficking (PMID:9226371, PMID:26611261, PMID:32043120). Its N-terminal Ig1 domain mediates homophilic binding through reciprocal swapping of two N-terminal beta-strands between monomers, while its rigid FnIII1-2 double domain binds and activates FGFR to drive Ras-MAPK-dependent neurite outgrowth (PMID:18706912, PMID:29895898). At the cytoskeletal interface, NCAM2 forms a complex with MAP2 and 14-3-3 proteins that stabilizes the microtubule network and supports dendritic arborization, neuronal polarization, and cortical migration; its loss destabilizes microtubules and disrupts these processes in vivo (PMID:32043120, PMID:34299022). NCAM2 couples surface adhesion to endosomal trafficking: it forms a complex with APP through its extracellular domain and with the Rab11 adaptor Rab11-FIP5 through its intracellular domain, channeling APP into BACE1-containing Rab11-positive recycling endosomes and thereby promoting amyloidogenic APP processing, an interaction enhanced by Abeta oligomers and synaptic NMDA receptor activation (PMID:40721030). NCAM2 is itself a BACE1 substrate; cleavage liberates a C-terminal fragment that associates with BACE1 and helps target the protease to recycling endosomes, so that NCAM2 deficiency redistributes BACE1 to the cell surface and lowers axonal BACE1 levels (PMID:36251052, PMID:37522285). In Alzheimer-relevant settings, Abeta binds NCAM2 directly and triggers its BACE1-mediated removal from synapses, and the resulting extracellular fragment drives disassembly of GluR1-containing glutamatergic synapses, linking NCAM2 cleavage to synapse loss (PMID:26611261).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1997 Medium

    Established NCAM2's molecular identity, defining it as an Ig-superfamily cell adhesion molecule with a defined domain architecture and chromosomal locus.

    Evidence cDNA cloning from human fetal brain and sequence/chromosomal mapping

    PMID:9226371

    Open questions at the time
    • No functional assay beyond structural prediction
    • Binding partners and adhesion mode unknown at this stage
  2. 2008 High

    Resolved the molecular basis of NCAM2 homophilic adhesion by showing the Ig1 domain dimerizes via N-terminal beta-strand swapping.

    Evidence X-ray crystallography at 2.7 A and gel-filtration chromatography of the Ig1 domain

    PMID:18706912

    Open questions at the time
    • Adhesion demonstrated for an isolated domain, not full-length cell-cell contacts
    • Functional consequence of homophilic binding not tested
  3. 2015 High

    Connected NCAM2 cleavage to synapse loss, showing Abeta binds NCAM2 and BACE1 cleavage of its extracellular region disassembles glutamatergic synapses.

    Evidence Abeta-NCAM2 binding assays, knockdown and cleavage-resistant mutant in hippocampal neurons, AD hippocampus tissue analysis

    PMID:26611261

    Open questions at the time
    • Synaptic adhesion partners of NCAM2 not fully defined
    • Intracellular signaling downstream of NCAM2 loss at synapses unresolved
  4. 2018 High

    Identified an FGFR-activating, growth-promoting function distinct from NCAM1, defining the rigid FnIII1-2 domains as the FGFR-binding module driving neurite outgrowth.

    Evidence NMR and SAXS structural analysis, ATP-binding test, in vitro FGFR binding, neurite outgrowth with FGFR/Ras-MAPK inhibitors

    PMID:29895898

    Open questions at the time
    • Direct FGFR contact residues not mapped
    • In vivo relevance of FGFR activation not established
  5. 2019 High

    Revealed a signaling role in dendritic maturation, where NCAM2 modulates L-type VGCC Ca2+ spikes via c-Src to control spine conversion and synapse maturation.

    Evidence Overexpression in mouse cortical neurons, live Ca2+ imaging, VGCC and c-Src pharmacological inhibition, synaptic vesicle recycling assays

    PMID:29522129

    Open questions at the time
    • Mechanism linking NCAM2 to VGCC/c-Src activation unclear
    • Loss-of-function effect on Ca2+ spikes not tested
  6. 2020 High

    Linked NCAM2 to the cytoskeleton, showing a MAP2/14-3-3 complex through which NCAM2 stabilizes microtubules and supports dendritic and migratory architecture.

    Evidence Protein complex identification, NCAM2 knockdown in neurons and in vivo, MAP2 immunofluorescence, in utero electroporation for cortical migration

    PMID:32043120

    Open questions at the time
    • Direct versus indirect MAP2/14-3-3 binding not fully resolved
    • How surface NCAM2 transmits signals to microtubules unknown
  7. 2021 Medium

    Expanded the NCAM2 interactome, identifying >100 candidate partners including neurofilaments, CaMKIIalpha, actin, and Nogo with predicted phospho-regulated binding.

    Evidence Co-IP mass spectrometry from mouse cerebral cortex, validation co-IP, in silico phosphosite analysis

    PMID:34299022

    Open questions at the time
    • Functional consequences of most interactions not established
    • Phosphorylation sites predicted, not experimentally mapped
  8. 2022 High

    Showed NCAM2 controls BACE1 subcellular distribution: a BACE1-generated NCAM2 CTF associates with BACE1 and targets it to Rab11 recycling endosomes.

    Evidence Overexpression/knockdown in neurons and CHO cells, Rab11 co-localization, BACE1 shedding ELISA in KO mice, Sez6 cleavage assay

    PMID:36251052

    Open questions at the time
    • Motifs in the NCAM2 CTF mediating BACE1 targeting not defined
    • Direct versus adaptor-mediated NCAM2-BACE1 association unresolved
  9. 2023 Medium

    Established an in vivo axonal role, with NCAM2 deficiency lowering axonal BACE1, shortening the mossy fiber infrapyramidal bundle, and impairing spatial memory.

    Evidence NCAM2-deficient mice, BACE1 immunofluorescence in mossy fibers, bundle morphometry, behavioral testing

    PMID:37522285

    Open questions at the time
    • Causal link between axonal BACE1 changes and behavior not isolated
    • Sex-differential phenotype mechanism unexplained
  10. 2023 Medium

    Demonstrated a stage-specific developmental role, where elevated NCAM2 arrests radial glial progenitors and causes transient migratory deficits.

    Evidence Viral Ncam2 overexpression in adult mice, BrdU/EdU lineage tracing, RGP marker immunofluorescence, in utero electroporation

    PMID:37724425

    Open questions at the time
    • Molecular pathway driving RGP arrest not defined
    • Loss-of-function effect on adult neurogenesis not reported
  11. 2025 High

    Defined NCAM2 as a trafficking scaffold for amyloidogenesis, bridging APP (extracellular) to Rab11-FIP5 (intracellular) to deliver APP into BACE1-positive recycling endosomes.

    Evidence Reciprocal Co-IP for NCAM2-APP and NCAM2-Rab11-FIP5, overexpression and KO neurons, endosome fractionation/imaging, BACE1 product quantification, Abeta oligomer and NMDA receptor activation

    PMID:40721030

    Open questions at the time
    • Structural basis of NCAM2-APP and NCAM2-Rab11-FIP5 binding unknown
    • Whether this pathway is therapeutically targetable not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NCAM2's adhesion, FGFR-signaling, cytoskeletal, and APP/BACE1 trafficking functions are integrated and differentially deployed across neuronal compartments remains unresolved.
  • No unified model linking surface adhesion to endosomal trafficking control
  • Splice-isoform-specific functions not dissected
  • No human disease-causing mutation defined in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2 GO:0060089 molecular transducer activity 2 GO:0060090 molecular adaptor activity 2 GO:0098631 cell adhesion mediator activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005768 endosome 2
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2 R-HSA-9609507 Protein localization 2
Partners
APPBACE1CAMK2AFGFRMAP2RAB11FIP5YWHAGYWHAZ
Complex memberships
NCAM2-APP-Rab11-FIP5 complexNCAM2-MAP2-14-3-3 complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 NCAM2 encodes a 837-amino acid protein containing five immunoglobulin-like domains, two fibronectin type III domains, a transmembrane domain, and a cytoplasmic domain, establishing its structural classification as a member of the immunoglobulin superfamily of cell adhesion molecules. cDNA cloning from human fetal brain library, sequence analysis, chromosomal mapping via somatic cell hybrids and radiation hybrid mapping Genomics Medium 9226371
2008 The crystal structure of NCAM2 Ig1 domain at 2.7 Å resolution revealed domain swapping of the two N-terminal beta-strands between two Ig1 monomers, and gel-filtration chromatography confirmed that NCAM2 Ig1 forms dimers in solution, suggesting beta-strand swapping as the molecular mechanism of NCAM2 homophilic binding. X-ray crystallography (2.7 Å resolution) and gel-filtration chromatography Journal of molecular biology High 18706912
2015 Aβ binds directly to NCAM2 at the cell surface of hippocampal neurons and induces removal of NCAM2 from synapses. BACE1-mediated cleavage of the membrane-proximal external region of NCAM2 is increased in AD hippocampus, generating soluble extracellular fragments (NCAM2-ED). Knockdown of NCAM2 or incubation with NCAM2-ED causes disassembly of GluR1-containing glutamatergic synapses. A cleavage-resistant NCAM2 mutant inhibits Aβ-dependent synapse disassembly. Co-incubation binding assay (Aβ–NCAM2 at cell surface), NCAM2 knockdown in cultured hippocampal neurons, overexpression of cleavage-resistant NCAM2 mutant, immunofluorescence of synaptic markers, human AD hippocampus tissue analysis Nature communications High 26611261
2018 The NCAM2 FnIII1-2 double domain adopts a rigid structure (low flexibility by SAXS), does not bind ATP (unlike NCAM1, whose Walker A motif in FnIII2 binds ATP), and binds FGFR in vitro. The FnIII1-2 double domain induces neurite outgrowth in a concentration-dependent manner through activation of FGFR, and the most potent NCAM2-derived peptide stimulates neurite outgrowth via FGFR-dependent activation of the Ras-MAPK pathway. NMR spectroscopy (structural model of FnIII2), SAXS (domain flexibility), ATP analogue titration, in vitro FGFR binding assay, neurite outgrowth assay with FGFR inhibitors, Ras-MAPK pathway readout Scientific reports High 29895898
2019 Elevated NCAM2 levels in cortical neurons increase the frequency of L-type voltage-gated Ca2+ channel-dependent submembrane Ca2+ spikes in dendritic protrusions and promote their propagation along dendrites via c-Src protein tyrosine kinase. This Ca2+ spike propagation increases instability of dendritic protrusions, reduces conversion to dendritic spines, and inhibits synapse maturation (increased GAP43, reduced activity-dependent synaptic vesicle recycling). NCAM2 overexpression in mouse cortical neurons, live Ca2+ imaging, pharmacological inhibition of L-type VGCCs and c-Src, dendritic protrusion dynamics tracking, synaptic vesicle recycling assay Cerebral cortex High 29522129
2020 NCAM2 interacts physically with the cytoskeletal-associated proteins MAP2 and 14-3-3γ and ζ, forming a protein complex. NCAM2 depletion destabilizes the microtubular network and reduces MAP2 signal, compromising dendritic architecture (shorter trees, retraction, somatic neurites) and causing deficits in neuronal polarization and cortical migration in vivo. Proteomic/cell biology experiments (protein complex identification), NCAM2 knockdown in hippocampal neurons and in vivo, immunofluorescence for MAP2, dendritic morphology analysis, in utero electroporation for cortical migration Cerebral cortex High 32043120
2021 Mass spectrometry-based interactome analysis of NCAM2 in mouse postnatal cerebral cortex identified >100 interacting proteins; validated partners include Neurofilaments (NEFs), MAP2, CaMKIIα, Actin, and Nogo. In silico analysis of the NCAM2.1 cytosolic tail revealed phosphorylation site motifs with predicted affinity for these interactors. Co-immunoprecipitation followed by mass spectrometry (MS), validation by additional co-IP/pulldown, in silico phosphorylation site analysis International journal of molecular sciences Medium 34299022
2022 BACE1 cleaves NCAM2 in cultured hippocampal neurons and NCAM2-transfected CHO cells, generating a C-terminal fragment (CTF) comprising the intracellular domain and a small portion of the extracellular domain. This NCAM2-CTF associates with BACE1 (interaction that precedes endocytosis) and both co-localize in Rab11-positive recycling endosomes. Overexpression of full-length NCAM2 or the transmembrane/intracellular fragment increases BACE1 in recycling endosomes; in NCAM2-deficient neurons, BACE1 accumulates at the cell surface and is reduced intracellularly, correlating with increased BACE1 shedding and reduced cleavage of the BACE1-exclusive substrate Sez6. Overexpression and knockdown in hippocampal neurons and CHO cells, co-localization imaging with Rab11 marker, BACE1 inhibition experiments, NCAM2-deficient mouse brains (ELISA for shed BACE1), Sez6 cleavage assay Cellular and molecular life sciences High 36251052
2023 NCAM2 deficiency in mice reduces axonal BACE1 levels in hippocampal mossy fiber projections and shortens the infrapyramidal bundle, demonstrating that NCAM2 regulates axonal BACE1 levels and hippocampal axonal organization. This is associated with impaired short-term spatial memory and cognitive flexibility, and sex-differential behavioral phenotypes including increased self-grooming. NCAM2-deficient mouse analysis, immunofluorescence of BACE1 in mossy fibers, morphometric measurement of infrapyramidal bundle, behavioral testing (Morris water maze, Y-maze, self-grooming, rearing, digging) Cerebral cortex Medium 37522285
2023 NCAM2 overexpression in adult mice arrests radial glial progenitors (RGPs) in an RGP-like state, impairing normal progression of young-adult neurogenesis in the hippocampal dentate gyrus. Changes in NCAM2 levels during corticogenesis cause transient migratory deficits without affecting RGP survival or proliferation, indicating a stage-specific role. Ncam2 overexpression by viral vector in adult mice, BrdU/EdU lineage tracing, immunofluorescence of RGP markers, in utero electroporation for corticogenesis studies Cerebral cortex Medium 37724425
2025 APP binds to the extracellular domain of NCAM2, and the intracellular domain of NCAM2 binds the Rab11 adaptor protein Rab11-FIP5. The NCAM2/APP complex is endocytosed from the cell surface and targeted to BACE1-containing Rab11-positive recycling endosomes where APP is processed. NCAM2 expression increases convergence of APP with BACE1 and elevates amyloidogenic APP cleavage products. In NCAM2-deficient neurons, APP accumulates at the cell surface and in early endosomes, with reduced APP in recycling endosomes. Binding of NCAM2 to APP is increased by Aβ oligomers and activation of synaptic NMDA receptors. Co-immunoprecipitation (NCAM2-APP and NCAM2-Rab11-FIP5), overexpression in CHO cells and neurons, NCAM2-deficient neurons (loss-of-function), endosome fractionation/imaging, BACE1 cleavage product quantification, Aβ oligomer treatment, NMDA receptor activation Progress in neurobiology High 40721030

Source papers

Stage 0 corpus · 18 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 Aβ-dependent reduction of NCAM2-mediated synaptic adhesion contributes to synapse loss in Alzheimer's disease. Nature communications 76 26611261
1997 Cloning of a novel human neural cell adhesion molecule gene (NCAM2) that maps to chromosome region 21q21 and is potentially involved in Down syndrome. Genomics 58 9226371
2011 NCAM2/OCAM/RNCAM: cell adhesion molecule with a role in neuronal compartmentalization. The international journal of biochemistry & cell biology 42 22155300
2021 The Hidden Side of NCAM Family: NCAM2, a Key Cytoskeleton Organization Molecule Regulating Multiple Neural Functions. International journal of molecular sciences 33 34576185
2020 NCAM2 Regulates Dendritic and Axonal Differentiation through the Cytoskeletal Proteins MAP2 and 14-3-3. Cerebral cortex (New York, N.Y. : 1991) 31 32043120
2014 21q21 deletion involving NCAM2: report of 3 cases with neurodevelopmental disorders. European journal of medical genetics 29 25464110
2019 Neural Cell Adhesion Molecule 2 (NCAM2)-Induced c-Src-Dependent Propagation of Submembrane Ca2+ Spikes Along Dendrites Inhibits Synapse Maturation. Cerebral cortex (New York, N.Y. : 1991) 19 29522129
2018 NCAM2 Fibronectin type-III domains form a rigid structure that binds and activates the Fibroblast Growth Factor Receptor. Scientific reports 17 29895898
2016 NCAM2 deletion in a boy with macrocephaly and autism: Cause, association or predisposition? European journal of medical genetics 13 27596683
2021 New Partners Identified by Mass Spectrometry Assay Reveal Functions of NCAM2 in Neural Cytoskeleton Organization. International journal of molecular sciences 9 34299022
2022 circ-Ncam2 (mmu_circ_0006413) Participates in LPS-Induced Microglia Activation and Neuronal Apoptosis via the TLR4/NF-κB Pathway. Journal of molecular neuroscience : MN 8 35687299
2008 Crystal structure of the Ig1 domain of the neural cell adhesion molecule NCAM2 displays domain swapping. Journal of molecular biology 6 18706912
2023 Regulation of young-adult neurogenesis and neuronal differentiation by neural cell adhesion molecule 2 (NCAM2). Cerebral cortex (New York, N.Y. : 1991) 5 37724425
2022 The BACE1-generated C-terminal fragment of the neural cell adhesion molecule 2 (NCAM2) promotes BACE1 targeting to Rab11-positive endosomes. Cellular and molecular life sciences : CMLS 5 36251052
2023 Deficiency in the neural cell adhesion molecule 2 (NCAM2) reduces axonal levels of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), affects axonal organization in the hippocampus, and leads to behavioral deficits. Cerebral cortex (New York, N.Y. : 1991) 4 37522285
2020 A molecular marker of milk composition traits in NCAM2 gene of Chinese Holstein. Animal biotechnology 3 33314987
2025 NCAM2 promotes targeting of APP from the cell surface to BACE1-containing recycling endosomes. Progress in neurobiology 1 40721030
2008 WITHDRAWN: The Neural Cell Adhesion Molecule NCAM2/OCAM/RNCAM, a Close Relative to NCAM. Neurochemical research 1 18368488

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