CD99 MIC2 gene product, E2, CD99R (epitope restricted to subset of CD99 molecules)
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
NK Cell
Thymocyte
Leukocyte
Monocyte
Hematopoietic Cell
Granulocyte
Endothelial Cell
B Cell
Red blood cell
T Cell
Eosinophil
32 / 32

Expression
CD99 is expressed on all leukocyte and hematopoietic cell lines.  It is present at high density on T cells but is absent on fetal B cell lines but is found on some B cells.  Expression is on eosinophils, endothelial cells, granulocytes, and NK cells.  Expression is highest on thymocytes but is reduced on maturation. Expression on CD4+ and CD8+ T cells is bimodal and within the CD4+ population and expression is higher on the CD45RA- subset.  NK cells and monocytes express high levels of CD99.  Expression of CD99 and Xga appears to be linked.  CD99 is highly expressed at the surface of Xg(a+) red blood cells and shows low expression on Xg(a-) red blood cells.  CD99 expression is high on Ewing's tumors.

Structure
MOLECULAR FAMILY NAME: Belongs to the mucin family.

CD99 is a single-pass type-1 185 aa glycoprotein.  It contains a 100 aa extracellular domain which contains 3 EF hand motifs, a proline-rich region and a collagen-like region with 5 (G-X-Y) repeats and is not predicted to have any α helices or β sheets, a 25 aa α helical hydrophobic transmembrane domain and a 35 aa cytoplasmic domain.  The molecule contains a high content of proline and is highly glycosylated with O-linked sugars. CD99 shares a 48% aa identity including conservative changes to Xga antigen, which was originally defined as a blood group polymorphism.  The CD99 gene locus is in the pairing region of the human X and Y chromosomes and was the 1st pseudoautosomal gene to be described in humans.  CD99X escapes X inactivation.  The CD99 gene is closely linked within 10 kb to the Xga gene.

MOLECULAR MASS
Cell Type Unreduced Reduced
Lymphocytes 32 kDa 32 kDa
Tumoral cells (Ewing's sarcoma cells and others 32 kDa 32 kDa

POST-TRANSCRIPTIONAL MODIFICATION

Alternative splicing yields 2 different isoforms.  It is not known whether the restricted expansion of certain epitopes is due to alternative splicing or post-translational modifications.  The isoforms appear to be differentially expressed in a cell type specific manner.  The CD99 type II molecule is a truncated form of CD99 type I and is expressed in varying lower levels than CD99 type I. 

POST-TRANSLATIONAL MODIFICATION

CD99 is heavily O-glycoslated molecule accounting for at least 14 kDa of the final molecular weight with no N-glycosylation site.  It is an intracellular 28 kDa precursor which is not exported to the membrane of red blood cells in Xga-negative females or of neuroblastoma cells.  There is an excision of a 22 residue peptide involved in signaling.  There are indications that in red cells it would form a heterodimer with Xga.


Ligands
LIGANDS AND MOLECULES ASSOCIATED WITH CD99

No other ligand has been identified for CD99 other than itself.

Function
CD99 participates in the positive selection of thymocytes via its ability to act as an adhesin and its ability to induce apoptosis.  CD99 acts as an adhesion molecule and is involved in the transendothelial migration of leukocytes during inflammation, T cell activation and adhesion and binds to cyclophilin A.  The major isoform, CD99 type 1, may also indirectly mediate lymphocyte adhesion adhesion by regulating LFA-1 expression in lymphocytes, whereas the CD99 type II appears to inhibit adhesion via the LFA-1/ICAM-1 pathway.  Activation of a distinct domain of CD99 on T cells induces caspase-independent cell death and is far more potent inducer of cell death than either CD95 or TRAIL.  CD99 mediates TCR/CD3-dependent activation of resting peripheral T cell and induces production of TNF-α and IFN-γ.  All functional events of CD99 are triggered by mAb binding to the O662 epitope, modulation of T cell adhesion especially by the CD2 pathway, induction of homotypic adhesion of corticothymocytes, induction of apoptosis of CD4+CD8+CD3intCD69+ thymocytes.  CD99 on thymocytes and T cells is involved in rosette formation with sheep or human erythrocytes. CD99 mAbs induce homotypic adhesion of CD4+CD8+ thymocytes. 

BIOCHEMICAL ACTIVITY

CD99 induces intracellular protein phosphorylation but as yet it is uncharacterized.

DISEASE RELEVANCE AND FUNCTION OF CD99 IN INTACT ANIMAL

CD99 is a useful marker in differential diagnosis within round cell sarcomas in children with Ewing's positive and neuroblastomas negative and it may be a potential therapeutic target in the Ewing's tumors.  There is increased density in peripheral T cells from HIV positive patients, particularly CD8+ cells.  CD99 regulates the transport of MHC class I molecules from the Golgi complex to the cell surface and is responsible for the important downregulation of MHC class I molecules on the surface of Hodgkin's and Reed-Sternberg cells. 

Comments
MOLECULAR INTERACTIONS-
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD99: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD99: No information.

ADDITIONAL INSIGHTS

CD99 shares close homology with the Xga proteins, whose gene, which was termed PDBA, is located downstream of the CD99 gene (MIC2) and spans the pseudoautosomal boundary.  There is no other significant homology exempt with proteins from the pseudorabies virus which is mostly due to a glycine-rich region of 76-90.


Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene 4267P14209
Antibodies
Tu12   View Reactivity

Revised June 25, 2008


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