Neural cell adhesion molecule

NCAM1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2E3V, 2HAZ, 2VKW, 2VKX, 3MTR, 5AEA
Identifiers
Aliases	NCAM1, CD56, MSK39, NCAM, neural cell adhesion molecule 1
External IDs	OMIM: 116930 MGI: 97281 HomoloGene: 40754 GeneCards: NCAM1
Gene ontology Molecular function • virus receptor activity • identical protein binding • Ras guanyl-nucleotide exchange factor activity Cellular component • cytoplasm • integral component of membrane • membrane • Golgi membrane • plasma membrane • extracellular region • cell surface • anchored component of membrane • extracellular exosome • external side of plasma membrane Biological process • interferon-gamma-mediated signaling pathway • MAPK cascade • regulation of synaptic plasticity • axon guidance • cell adhesion • viral entry into host cell • viral process • neuron projection development • positive regulation of GTPase activity Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4684	17967
Ensembl	ENSG00000149294	ENSMUSG00000039542
UniProt	P13591	P13595
RefSeq (mRNA)	NM_181351 NM_000615 NM_001076682 NM_001242607 NM_001242608	NM_001081445 NM_001113204 NM_010875 NM_001311065
RefSeq (protein)	NP_000606.3 NP_001070150.1 NP_001229537.1 NP_851996.2	NP_001074914.1 NP_001106675.1 NP_035005.2 NP_001297994.1
Location (UCSC)	Chr 11: 112.96 – 113.28 Mb	Chr 9: 49.5 – 49.8 Mb
PubMed search	[1]	[2]
Wikidata

Neural cell adhesion molecule (NCAM), also called CD56, is a homophilic binding glycoprotein expressed on the surface of neurons, glia, skeletal muscle and natural killer cells. NCAM has been implicated as having a role in cell–cell adhesion,^[3] neurite outgrowth, synaptic plasticity, and learning and memory.

Forms, domains and homophilic binding

NCAM is a glycoprotein of Immunoglobulin (Ig) superfamily. At least 27 alternatively spliced NCAM mRNAs are produced, giving a wide diversity of NCAM isoforms.^[4] The three main isoforms of NCAM vary only in their cytoplasmic domain:

• NCAM-120kDa (GPI anchored)
• NCAM-140kDa (short cytoplasmic domain)
• NCAM-180kDa (long cytoplasmic domain)

The extracellular domain of NCAM consists of five immunoglobulin-like (Ig) domains followed by two fibronectin type III (FNIII) domains. The different domains of NCAM have been shown to have different roles, with the Ig domains being involved in homophilic binding to NCAM, and the FNIII domains being involved signaling leading to neurite outgrowth.

Homophilic binding occurs between NCAM molecules on opposing surfaces (trans-) and NCAM molecules on the same surface (cis-)1. There is much controversy as to how exactly NCAM homophilic binding is arranged both in trans- and cis-. Current models suggest trans- homophilic binding occurs between two NCAM molecules binding antiparallel between all five Ig domains or just IgI and IgII. cis- homophilic binding is thought to occur by interactions between both IgI and IgII, and IgI and IgIII, forming a higher order NCAM multimer. Both cis- and trans- NCAM homophilic binding have been shown to be important in NCAM “activation” leading to neurite outgrowth.

Minor exons

Another layer of complexity is created by the insertion of other "minor" exons in the NCAM transcript. The two most notable are:

• the VASE (VAriable domain Spliced Exon) exon which is thought to correlate with an inhibition of the neurite outgrowth promoting properties of NCAM.
• the MSD (Muscle Specific Domain), which is thought to play a positive role in myoblast fusion.^[5] In skeletal muscle it is found in all three NCAM isoforms, increasing their MW, giving NCAM-125, NCAM-145, and NCAM-185 isoforms, but is most commonly found in the NCAM-125 isoform.^[5]

Posttranslational modification

NCAM exhibits glycoforms as it can be posttranslationally modified by the addition of polysialic acid (PSA) to the fifth Ig domain, which is thought to abrogate its homophilic binding properties and can lead to reduced cell adhesion important in cell migration and invasion. PSA has been shown to be critical in learning and memory. Removal of PSA from NCAM by the enzyme endoneuraminidase (EndoN) has been shown to abolish long-term potentiation (LTP) and long-term depression (LTD).^[6][7][8]

Expression in normal cells

The neural cell adhesion molecule NCAM1 appears on early embryonic cells and is important in the formation of cell collectives and their boundaries at sites of morphogenesis.

Later in development, NCAM1 (CD56) expression is found on various differentiated tissues and is a major CAM mediating adhesion among neurons and between neurons and muscle.

Function

NCAM is thought to signal to induce neurite outgrowth via the fibroblast growth factor receptor (FGFR) and act upon the p59Fyn signaling pathway.

In nerves, NCMA1 regulates homophilic (like-like) interactions between neurons and between neurons and muscle; it associates with fibroblast growth factor receptor (FGFR) and stimulates tyrosine kinase activity of receptor to induce neurite outgrowth. When neural crest cells stop making N-CAM and N-cadherin, and start displaying integrin receptors, cells separate and migrate.

During hematopoiesis, CD56 is the prototypic marker of NK cells, also present on subset of CD4+ T cells and CD8+ T cells.

In cell adhesion, CD56 contributes to cell-cell adhesion or cell-matrix adhesion during embryonic development.

Pathology

In anatomic pathology, pathologists make use of CD56 immunohistochemistry to recognize certain tumors.

• Normal cells that stain positively for CD56 include NK cells, activated T cells, the brain and cerebellum, and neuroendocrine tissues.
• Tumors that are CD56-positive are myeloma, myeloid leukemia, neuroendocrine tumors, Wilms' tumor, neuroblastoma, NK/T cell lymphomas, pancreatic acinar cell carcinoma, pheochromocytoma, paraganglioma, small cell lung carcinoma, and the Ewing's sarcoma family of tumors.

Alzheimers

NCAM2 is found in lower levels in synapses in the hippocampuses of Alzheimers sufferers and is found to be broken down by beta-amyloid^[9]

Anti-NCAM therapy

NCAM has been used as a target molecule for experimental antibody-based immunotherapy. Successful radioimmunolocalisation of metastases was demonstrated after giving injections of NCAM-binding 123J-UJ13a or 131J-UJ13a radioimmunoconjugates to children with neuroblastoma. Patients with small cell lung cancer were treated with the anti-NCAM immunotoxine huN901-DM1 in two different clinical studies, revealing acceptable toxicity and signs of clinical response.^[10]

References

External links

• Neural Cell Adhesion Molecule at the US National Library of Medicine Medical Subject Headings (MeSH)

PDB gallery
1epf: CRYSTAL STRUCTURE OF THE TWO N-TERMINAL IMMUNOGLOBULIN DOMAINS OF THE NEURAL CELL ADHESION MOLECULE (NCAM)  1lwr: Solution structure of the NCAM fibronectin type III module 2  1qz1: Crystal Structure of the Ig 1-2-3 fragment of NCAM  2e3v: Crystal structure of the first fibronectin type III domain of neural cell adhesion molecule splicing isoform from human muscle culture lambda-4.4  2haz: Crystal structure of the first fibronectin domain of human NCAM1  2ncm: NEURAL CELL ADHESION MOLECULE, NMR, 20 STRUCTURES  3ncm: NEURAL CELL ADHESION MOLECULE, MODULE 2, NMR, 20 STRUCTURES