CD56 NCAM (neural cell adhesion molecule), NKH-1 antigen
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
NK Cell
Hematopoietic Cell
Peripheral blood
Tumor Cell
Spleen
Leukemia cell
Carcinoma Cell
T Cell
Liver
Muscle Cell
Brain
Lung
Neural Cell
Myeloma
120 / 120
140 / 140
180 / 180

Expression
CD56 is expressed in hemopoietic cells, which is restricted to NK cells and a subset of T cells.  The prototypic marker of human NK cells is also present on a subset of CD4+ and CD8+ T cells in peripheral blood, and is variably expressed on in vitro cultured T cell clones.  The level of CD56 expression  defines the subsets of NK cells such that the highest expression is by NK cells of the liver and decidua, and CD56 dim cells are found in the peripheral blood and spleen.  CD56+ T cells are concentrated in the liver.  CD56 is present on the brain in the cerebellum and cortex and at neuromuscular junctions and is also present on certain LGL leukemias, small cell lung carcinomas, neural-derived tumors, myelomas, and myeloid leukemias.  Expression is on neural cells, muscle cells and embroyonic tissues and tumors.   


Structure
MOLECULAR FAMILY NAME: Belongs to the immunoglobulin supergene family.

CD56 is a single-pass type-1 glycoprotein.  It contains a 689 aa extracellular domain which contains 5 Ig-like C2-type domains, 2 fibronectin type-3 domains and 6 potential N-glycosylation sites, a transmembrane domains and a cytoplasmic domain that is divided into a large 180 kDa form, a hemopoietic shorter 140 kDa form and a GPI-linked 120 kDa form found in muscle.  All 5 Ig-like C-type domains are required for homotypic binding with domain 1 binds domain 5, domain 2 binds domain 4 and domain 3 binds domain 3.  The three dimensional structure of the N terminal Ig-like C-type domain has a similarity to domain 1 of CD106 (VCAM-1).  CD56 includes soluble and GPI-anchored ioforms, which arise by alternative splicing from a single gene, and are post-translationally modified by glycosylation, acylation, sulfation and phosphorylation.   Electron microscopy of the purified protein suggests that these domains are tandemly arranged to form a flexible rod-like structure projecting from the cell surface. 

MOLECULAR MASS
Cell Type Unreduced Reduced Comment
NK cells and T cells 175-220 kDa

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 3 different isoforms.  Soluble, transmembrane-anchored, and GPI-anchored glycoproteins have been identified in different tissues.  The predominant isoform is NK and T cells is in the transmembrane-anchored glycoprotein.

POST-TRANSLATIONAL MODIFICATION

There are 6 potential sites for N-linked glycosylation.  CD56 on NK and T cells is extensively modified with polysialic acid and migrates as a diffuse band of high molecular weight on SDA-Page gels.  After treatment with neuraminidase to remove sialic acid, the predominant glycoprotein is ~140 kDa.

Ligands
CD56 has a clear function in homotypic binding to CD56 molecules on other cells.  All 5 IgSF domains appear to be involved, and these pair up in an anti-parallel alignment such that domain 1 binds to domain 5, domain 2 to 4, and domain 3 with itself.  CD56 on neuronal cells can bind to chondroitin sulfate (CS) proteoglycans of the cell matrix.  The result of this interaction is the inhibition of neurite outgrowth.  CD56 cis-interactions with other molecules have not been defined, although indirect evidence suggests a potential association of  CD56 with the related neural cell adhesion molecule L1, and with the fibroblast growth factor receptor through which CD56 may transduce signals.

LIGANDS AND MOLECULES ASSOCIATED WITH CD56
Molecule Comment
NCAM-1 CD56 (NCAM) mediates homophilic adhesion in certain cell types
Heparin sulfate
Chondroutun sulphate proteoglycans
Another putative ligand




Function
The significance of CD56 expression on NK cells is not clear and remains controversial.  However, the role of CD56 as a homophilic and heterophilic cell adhesion molecule on neuronal cells has been well studied.  In vitro data suggest that CD56 functions in the control of neuronal development by regulating cell migration, neurite outgrowth, selective fasciculation and axon sorting, target recognition, and synaptic plasticity.  Binding to chondroitin sulphate proteoglycans of the cell matrix inhibits outgrowth of neuronal cells.  CD56 regulates interactions between neurons and between neurons and muscle.  In vitro data suggest that CD56 functions in the control of neuronal development by regulating cell migration, neurite outgrowth, selective fasciculation and axon sorting, target recognition, and synaptic plasticity.  The function on T cells and NK cells is not known although there is some evidence that CD56 is involved in homophilic adhesion of these cells.  CD56 knockout mice appear  normal in NK- and T-cell development, but do have abnormalities in neurologic guidance and connectivity.  Moreover, these animals exhibit deficient spatial learning which implicates CD56 in synaptic plasticity.  CD56 gene targeting to produce mice that express only a secreted CD56 results in a dominant embryonic lethality.  This suggests a role for CD56 in heterophilic interactions, in addition to its relatively well characterized function in homotypic adhesion.  The capacity of CD56 for cell adhesion can be down modulated by post-translational attachment of a large polysialic acid (PSA) moiety to the 5th IgSF domain.  PSA expression is regulated by neuronal activity at the synapse and is required for the induction of synaptic plasticity by CD56.

In the nervous system, there is evidence for both homophilic and heterophilic adhesion by CD56.  It is implicated in neural development. This has not been convincingly demonstrated with hematopoietic cells. No consensus has emerged on the role of CD56 in T or NK cell function, although there have been reports for involvement in homophilic adhesion.  CD56 exists in lipid microdomains and transduces cell signaling via regulation the activation of signal transduction molecules.

BIOCHEMICAL ACTIVITY: No information.

DISEASE RELEVANCE AND FUNCTION OF CD56 IN INTACT ANIMAL

Some CD56 antibodies inhibit NK-target cell inteactions in certain systems but knockout mice show neurologic abnormalities but NK-and T-cell development appear normal.  CD56 is significant in identification of human growth and spreading of solid tumors.


Comments
NCAM is highly conserved between species, the murine homologue sharing a 24% aa and a 26% aa identity with the insect and mollusc orthologues, respectively.  The Drosophila orthologue, fasciclin 2 functions in selective fasciculation and axon sorting, and the mollusc Aplysia orthologue apCAM has a role in synaptic plasticity.

MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD56: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD56: No information.

ADDITIONAL INSIGHTS

While NCAM is expressed in the brain of humans and rodents, NCAM is present on human NK cells but is not found on mouse or rat NK cells. T and NK cell development and function appear normal in mice with disrupted NCAM genes.

Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
ChickenA25435P13590M15861
DrosophilaB41054P34082M77166
HumanEntrezgene 4684P13591
MouseA29673P13595Y00051
RatS00846P13596X06564
XenopusS09600P16170M25696
Antibodies
B159   View Reactivity
C5.9   View Reactivity
ERIC-1   View Reactivity
MEM-188   View Reactivity
MOC-1   View Reactivity
MY31   View Reactivity
NCAM16.2   View Reactivity
NK1   View Reactivity
T199   View Reactivity

Revised June 25, 2008


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