CD244 NAIL (NK cell activation-inducing ligand), 2B4, Nmrk, NKR2B4 (natural killer receptor 2B4), SLAM4
Molecule TypeAntigen ExpressionMolecular Weight
Min / Max
Non-lineage Restricted Molecule
Type 1 glycoprotein
NK Cell
Monocyte
T Cell
Dendritic Cell
Basophil
Spleen
Liver
Lung
Small intestine
Testis
Thymocyte
70 / 70

Expression
Human CD244 is expressed on the surface of resting and activated NK cells, g/d T cells, ~50% CD8+ T cells, some CD8+ thymocytes, a small % of CD4+ cells, monocytes and basophils.  In mice, expression is on dendritic epidermal T cells and on all NK and T cells capable of non-MHC-restricted cytotoxicity.  The latter include dendritic epidermal gd T cells and a subset of T cells cultured in IL-2.  CD244 is not expressed on B cells.  CD244 is expressed in spleen, PBL, lung, liver, testis and small intestine.


Structure
MOLECULAR FAMILY NAME: Belongs to the immunoglobulin gene superfamily.

CD244 is a single-pass type-1 370 aa glycoprotein.  It contains 21 aa leader sequence, a 208 aa extracellulardomain which contains an Ig-like V-type and an Ig-like C2-type and 8 potential N-linked glycosylation sites, a 21 aa transmembrane domain and a 120 aa long cytoplasmic tail with 4 tyrosine-based switch motifs (ITSMs, TxYxxV/I) capable of binding several SH2-domain containing proteins including both activating and inhibitory signaling molecules.  The extracellular portion of this Ig domain-containing glycoprotein exhibits several structural features that place it within the CD2 family of the Ig (see CD2), which probably arose from a series of gene duplication events. In addition to CD2 and CD244 this family includes CD48, CD58, CD84 CD229, and CD150.  The human CD244 exhibits about 66% identify with mouse CD244.  The mouse CD244 gene is situated on mouse chromosome 1 near the gene for Ly-17, mouse CD32, placing it close to the CD229 and CD48 loci. 

MOLECULAR MASS
Cell Type Unreduced Reduced Comment
Human polyclonal NK cells 70 kDa 70 kDa In human polyclonal NK a 70 kDa protein was detected in both reducing and nonreducing conditions
Human polyclonal T cells 70 kDa 70 kDa In human polyclonal NK a 70 kDa protein was detected in both reducing and nonreducing conditions
YT cells 63 kDa 63 kDa In YT cells human CD244 is 63 kDa and in transfected BaF3 cells it is 86 kDa suggesting that the degree of glycosylation of human CD244 differs in distict cell types
Mouse NK cells 66 kDa 66 kDa In mouse NK cells a 66 kDa is detected in both reducing and nonreducing gels


POST-TRANSCRIPTIONAL MODIFICATION

CD244 is phosphorylated by src family kinases like lck.  Alternative splicing yields 4 different isoforms.

POST-TRANSLATIONAL MODIFICATION

 The membrane-proximal Ig domain is particularly highly glycosylated.  There are 8 potential N-linked glycoylation sites in human CD244 and 7 in mouse CD244.  About 35% of the Mr corresponds to glycosylation of the protein.  Cytoplasmic tyrosine residues are phosphorylated upon NK cell activation by target cells that express CD4.


Ligands
LIGANDS AND MOLECULES ASSOCIATED WITH CD244

Molecule Comment
CD48 CD244 is the high affinity receptor for CD48
SH2D1A SH2D1A, also called SLAM-associated protein (SAP), associates with tyrosine phosphorylated CD244
SHP-1 SHP-1 was found to associate with CD244 in primary NK cells
SHP-2 SHP-2 associates with tyrosine phosphorylated CD244.  SAP binding to phosphorylated CD244 prevents the association of SHP-2 to CD244
LAT Linker for activation of T cells (LAT) associates with CD244



Function
CD244 plays a role in non-MHC-restricted cytotoxic activity of NK cells and acts as a costimulatory ligand for both NK cell and T cells in vitro.  Treatment with a CD244 mAb activates these cells which augments the non-MHC-restricted cytotoxicity.  CD244 is a NK cell-cell surface receptor which recruits protein tyrosine phosphatase, SHP-2, and the adapter signaling protein, SAP.  CD244 modulates NK cell cytokine production, cytolytic function and extravasation.  It may modulate other receptor-ligand interactions to enhance leukocyte activation.  During CD244-CD48 mediated homotypic interaction of T cells and NK cells or NK-T-cell interactions, CD244 signaling is proposed to induce optimal activation of T cells and NK cells and may serve to increase cell-cell adhesion.  However interaction of CD244 on NK cells with other CD48+ target cells such as tumor cell can lead to inhibition of NK effector functions.  CD244 knockout mice are phenotypically normal but have an increased capacity to clear CD48+ tumor cells in vivo.  Consistent with this finding are the result of cytotoxicity assays performed with CD244-/- splenic NK cells, which demonstrated enhanced killing of CD48+ target cells.  These findings are consistent with CD244 acting as an inhibitory receptor.

BIOCHEMICAL ACTIVITY: No information.

DISEASE RELEVANCE AND FUNCTION OF CD244 IN INTACT ANIMAL

Defective signaling by CD244 and SAP may contribute to the X-linked lymphoproliferative (XLP) disorder that is triggered following EBV infection.  XLP was identified as SLAM associated protein (SAP) and encodes a small SH2 domain containing protein.  CD244 may play a role in autoimmune diseases such as rheumatoid arthritis.  A proportion of CD244+CD8+ T cells in HIV infected individuals increases with disease progression. 

Comments
MOLECULAR INTERACTIONS -
PROTEINS AND DNA ELEMENTS WHICH REGULATE TRANSCRIPTION OF CD244: No information.

SUBSTRATES: No information.

ENZYMES WHICH MODIFY CD244

The Src-family kinases like lck or fyn can phosphorylate CD244.

ADDITIONAL INSIGHTS

CD244 may function as a co-receptor with NKp46, an activating receptor implicated in natural cytotoxicity.  Inhibitory receptors on NK cells can block CD244-mediated NK cell activation and prevent tyrosine phosphorylation of CD244.



Database accession numbers
AnimalPIRSWISSPROTEMGBL/GENBANK
 
HumanEntrezgene51744Q9BZW8
MouseL19057
Antibodies

Revised June 25, 2008


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