Neural cell adhesion molecule
Neural cell adhesion molecule (NCAM), also called CD56, is a homophilic binding glycoprotein expressed on the surface of neurons, glia and skeletal muscle. Although CD56 is often considered a marker of neural lineage commitment due to its discovery site, CD56 expression is also found in, among others, the hematopoietic system. Here, the expression of CD56 is most stringently associated with, but certainly not limited to, natural killer cells. CD56 has been detected on other lymphoid cells, including gamma delta (γδ) Τ cells and activated CD8+ T cells, as well as on dendritic cells. NCAM has been implicated as having a role in cell–cell adhesion, 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. 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.
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. 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.
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).
Expression in normal cells
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.
In nerves, NCAM1 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.
- 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.
NCAM2 is found in lower levels in synapses in the hippocampuses of Alzheimers sufferers and is found to be broken down by beta-amyloid
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.
- Van Acker HH, Capsomidis A, Smits EL, Van Tendeloo VF (2017). "CD56 in the Immune System: More Than a Marker for Cytotoxicity?". Frontiers in Immunology. 8: 892. doi:10.3389/fimmu.2017.00892. PMC 5522883. PMID 28791027.
- Pathology Outlines
- Reyes AA, Small SJ, Akeson R (March 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. doi:10.1128/mcb.11.3.1654. PMC 369464. PMID 1996115.
- Suzuki M, Angata K, Nakayama J, Fukuda M (December 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.
- Becker CG, Artola A, Gerardy-Schahn R, Becker T, Welzl H, Schachner M (July 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.
- 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.
- Senkov O, Sun M, Weinhold B, Gerardy-Schahn R, Schachner M, Dityatev A (October 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.
- Leshchyns'ka I, Liew HT, Shepherd C, Halliday GM, Stevens CH, Ke YD, Ittner LM, Sytnyk V (November 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. PMC 4674770. PMID 26611261.
- Jensen M, Berthold F (December 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.