Neural cell adhesion molecule

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NCAM1
Protein NCAM1 PDB 1epf.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases NCAM1, CD56, MSK39, NCAM, neural cell adhesion molecule 1
External IDs OMIM: 116930 MGI: 97281 HomoloGene: 40754 GeneCards: 4684
RNA expression pattern
PBB GE NCAM1 209968 s at tn.png

PBB GE NCAM1 212843 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
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
View/Edit Human View/Edit Mouse

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,[1] neurite outgrowth, synaptic plasticity, and learning and memory.

Forms, domains and homophilic binding[edit]

NCAM is a glycoprotein of Immunoglobulin (Ig) superfamily. At least 27 alternatively spliced NCAM mRNAs are produced, giving a wide diversity of NCAM isoforms.[2] 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[edit]

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.[3] 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.[3]

Posttranslational modification[edit]

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).[4][5][6]

Expression in normal cells[edit]

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[edit]

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[edit]

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

Alzheimers[edit]

NCAM2 is found in lower levels in synapses in the hippocampuses of Alzheimers sufferers and is found to be broken down by beta-amyloid[7]

Anti-NCAM therapy[edit]

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.[8]

References[edit]

  1. ^ Pathology Outlines
  2. ^ Reyes AA, Small SJ, Akeson R (Mar 1991). "At least 27 alternatively spliced forms of the neural cell adhesion molecule mRNA are expressed during rat heart development". Molecular and Cellular Biology 11 (3): 1654–61. PMC 369464. PMID 1996115. 
  3. ^ a b Suzuki M, Angata K, Nakayama J, Fukuda M (Dec 2003). "Polysialic acid and mucin type o-glycans on the neural cell adhesion molecule differentially regulate myoblast fusion". The Journal of Biological Chemistry 278 (49): 49459–68. doi:10.1074/jbc.M308316200. PMID 13679364. 
  4. ^ Becker CG, Artola A, Gerardy-Schahn R, Becker T, Welzl H, Schachner M (Jul 1996). "The polysialic acid modification of the neural cell adhesion molecule is involved in spatial learning and hippocampal long-term potentiation". Journal of Neuroscience Research 45 (2): 143–52. doi:10.1002/(SICI)1097-4547(19960715)45:2<143::AID-JNR6>3.0.CO;2-A. PMID 8843031. 
  5. ^ Stoenica L, Senkov O, Gerardy-Schahn R, Weinhold B, Schachner M, Dityatev A (May 2006). "In vivo synaptic plasticity in the dentate gyrus of mice deficient in the neural cell adhesion molecule NCAM or its polysialic acid". The European Journal of Neuroscience 23 (9): 2255–64. doi:10.1111/j.1460-9568.2006.04771.x. PMID 16706834. 
  6. ^ Senkov O, Sun M, Weinhold B, Gerardy-Schahn R, Schachner M, Dityatev A (Oct 2006). "Polysialylated neural cell adhesion molecule is involved in induction of long-term potentiation and memory acquisition and consolidation in a fear-conditioning paradigm". The Journal of Neuroscience 26 (42): 10888–109898. doi:10.1523/JNEUROSCI.0878-06.2006. PMID 17050727. 
  7. ^ Leshchyns'ka I, Liew HT, Shepherd C, Halliday GM, Stevens CH, Ke YD, Ittner LM, Sytnyk V (2015). "Aβ-dependent reduction of NCAM2-mediated synaptic adhesion contributes to synapse loss in Alzheimer's disease". Nature Communications 6: 8836. doi:10.1038/ncomms9836. PMID 26611261. 
  8. ^ Jensen M, Berthold F (Dec 2007). "Targeting the neural cell adhesion molecule in cancer". Cancer Letters 258 (1): 9–21. doi:10.1016/j.canlet.2007.09.004. PMID 17949897. 

External links[edit]