| NCAM1 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | NCAM1, CD56, MSK39, NCAM, neural cell adhesion molecule 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM:116930;MGI:97281;HomoloGene:40754;GeneCards:NCAM1;OMA:NCAM1 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Neural cell adhesion molecule (NCAM), also calledCD56, is a homophilic binding glycoprotein expressed on the surface ofneurons,glia andskeletal 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, thehematopoietic system. Here, the expression of CD56 is mostly associated with, but not limited to,natural killer cells. CD56 has been detected on other lymphoid cells, includinggamma delta (γδ) Τ cells and activatedCD8+ T cells, as well as on dendritic cells.[5] NCAM has been implicated as having a role in cell–cell adhesion,[6] neurite outgrowth, synaptic plasticity, and learning and memory.
NCAM is a glycoprotein of Immunoglobulin (Ig) superfamily.At least 27 alternatively spliced NCAM mRNAs are produced, giving a wide diversity of NCAM isoforms.[7] The three main isoforms of NCAM vary only in theircytoplasmic domain:
The extracellular domain of NCAM consists of fiveimmunoglobulin-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 signalling 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- andcis-. Current models suggesttrans- 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. Bothcis- andtrans- 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:
NCAM exhibitsglycoforms as it can be posttranslationally modified by the addition ofpolysialic 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 enzymeendoneuraminidase (EndoN) has been shown to abolishlong-term potentiation (LTP) andlong-term depression (LTD).[9][10][11]
The neural cell adhesion molecule NCAM1 appears on earlyembryonic cells and is important in the formation ofcell collectives and their boundaries at sites ofmorphogenesis.
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.
NCAM is thought to signal to induce neurite outgrowth via thefibroblast growth factor receptor (FGFR) and act upon the p59Fyn signaling pathway.
In nerves, NCAM1 regulates homophilic (like-like) interactions between neurons and between neurons and muscle; it associates withfibroblast growth factor receptor (FGFR) and stimulatestyrosine kinase activity of receptor to induceneurite outgrowth. Whenneural crest cells stop makingN-CAM andN-cadherin, and start displayingintegrin receptors, cells separate and migrate.
Duringhematopoiesis, CD56 is the prototypic marker ofNK cells, also present on subset ofCD4+ T cells andCD8+ T cells.
Incell adhesion, CD56 contributes tocell-cell adhesion orcell-matrix adhesion duringembryonic development.
Inanatomic pathology, pathologists make use of CD56immunohistochemistry to recognize certain tumors.
A member of the NCAM superfamily, NCAM2 gene has been observed progressively downregulated inhuman papillomavirus-positiveneoplastic keratinocytes derived from uterine cervical preneoplastic lesions at different levels of malignancy.[12] For this reason, NCAM2 is likely to be associated with tumorigenesis and may be a potential prognostic marker for uterine cervicalpreneoplastic lesions progression.[12]
NCAM2 is found in lower levels in hippocampal synapses of Alzheimer's disease sufferers and is found to be broken down bybeta-amyloid.[13]
NCAM has been identified as one of the target proteins for the rabies virus, allowing entry into the cell.[14]
NCAM has been used as a target molecule for experimental antibody-based immunotherapy. Successful radio-immunolocalisation of metastases was demonstrated after giving injections of NCAM-binding 123J-UJ13a or 131J-UJ13a radio-immunoconjugates to children with neuroblastoma. Patients with small cell lung cancer were treated with the anti-NCAM immunotoxin huN901-DM1 in two different clinical studies, revealing acceptable toxicity and signs of clinical response.[15]
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