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CD226
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	6ISA, 6ISC, 6ISB, 6O3O
Identifiers
Aliases	CD226, DNAM-1, DNAM1, PTA1, TLiSA1, CD226 molecule
External IDs	OMIM: 605397; MGI: 3039602; HomoloGene: 4787; GeneCards: CD226; OMA:CD226 - orthologs
Gene location (Human)
Chr.	Chromosome 18 (human)
End	69,961,803 bp
Gene location (Mouse)
Chr.	Chromosome 18 (mouse)
End	89,290,353 bp
RNA expression pattern
	Top expressed in
	monocyte; ; granulocyte; ; blood; ; lymph node; ; gonad; ; testicle; ; spleen; ; appendix; ; sural nerve; ; epithelium of colon;
	Top expressed in
	blood; ; zygote; ; spleen; ; thymus; ; mesenteric lymph nodes; ; embryo; ; bone marrow; ; secondary oocyte; ; subcutaneous adipose tissue; ; esophagus;
	More reference expression data
	More reference expression data
Gene ontology
Molecular function	protein homodimerization activity; protein binding; protein kinase binding; integrin binding; cell adhesion molecule binding;
Cellular component	integral component of plasma membrane; membrane raft; integral component of membrane; membrane; cell surface; external side of plasma membrane; plasma membrane;
Biological process	positive regulation of natural killer cell mediated cytotoxicity directed against tumor cell target; cell adhesion; regulation of immune response; heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules; homophilic cell adhesion via plasma membrane adhesion molecules; positive regulation of Fc receptor mediated stimulatory signaling pathway; cell recognition; cytokine production; positive regulation of immunoglobulin mediated immune response; signal transduction; positive regulation of natural killer cell mediated cytotoxicity; positive regulation of mast cell activation; positive regulation of interferon-gamma production; positive regulation of natural killer cell cytokine production; positive regulation of T cell receptor signaling pathway;
	Sources:Amigo / QuickGO
Orthologs
	10666
	225825
	ENSG00000150637
	ENSMUSG00000034028
	Q15762
	Q8K4F0
	NM_001303618; NM_001303619; NM_006566
	NM_001039148; NM_001039149; NM_178687
	NP_001290547; NP_001290548; NP_006557
	NP_001034238; NP_848802
	Wikidata
View/Edit Human	View/Edit Mouse

CD226 (Cluster of Differentiation 226), PTA1 (outdated term, 'platelet and T cell activation antigen 1')^[5] or DNAM-1 (DNAX Accessory Molecule-1)^[5] is a ~65 kDa immunoglobulin-like transmembrane glycoprotein expressed on the surface of natural killer cells, NK T cell, B cells, dendritic cells, hematopoietic precursor cells, platelets, monocytes and T cells.^[6]

DNAM-1 gene CD226 is conserved between human and mice. In humans the CD226 gene is located on chromosome 18q22.3.^[7] In mice the CD226 gene is located on chromosome 18E4.

Structure

DNAM-1 is composed of three domains: an extracellular domain of 230 amino acids with two immunoglobin-like V-set domains and eight N-glycosylation sites, a transmembrane domain of 28 amino acids and a cytosolic domain of 60 amino acids containing four putative tyrosine residues and one serine residue for phosphorylation.^[8]

Signaling

Upon engagement to its ligand, DNAM-1 is phosphorylated by protein kinase C. Then adhesive molecule LFA-1 crosslinks with DNAM-1 that results in recruitment of DNAM-1 to lipid rafts and promotes association with actin cytoskeleton. Cross-linking with LFA-1 also induce phosphorylation on Tyr¹²⁸ and Tyr¹¹³ by Fyn Src kinase.^[9]

DNAM-1 and CD244 together promotes phosphorylation of SH2 domain of SLP-76. This leads to activation of phospholipase Cγ2, Ca²⁺ influx, cytoskeletal reorganization, degranulation, and secretion.^[8]

Function

DNAM-1 mediates cellular adhesion to other cells bearing its ligands, nectin molecule CD112 and nectin-like protein CD155,^[10]^[11] that are broadly distributed on normal neuronal, epithelial, fibroblastic cells, dendritic cells, monocytes and on infected or transformed cells.

DNAM-1 promotes lymphocyte signaling, lymphokine secretion and cytotoxicity of NK cells and cytotoxic CD8+ T lymphocytes.^[6] Cross-linking of DNAM-1 with antibodies causes cellular activation.^[7]

DNAM-1 participates on platelets activation and aggregation.^[8]

DNAM-1 possibly plays a role in trans-endothelial migration of NK cells because it was shown that monoclonal antibodies against DNAM-1 or CD155 inhibit this process.^[9]

DNAM-1 interaction with its ligands promotes killing of immature and mature dendritic cells, is involved in the crosstalk between NK cells and T lymphocytes and can lyse activated T lymphocytes during graft versus host disease (GvHD).^[8]^[9]

DNAM-1 also participates in the immunological synapse where is colocalized with LFA-1.^[9]

DNAM-1 regulation

DNAM-1 expression on NK cells can be regulated by cell-cell interaction and by soluble factors. In human, IL-2 and IL-15 up-regulate DNAM-1 expression, whereas TGF-β, indolamine 2,3-dioxygenase and chronic exposure to CD155 can down-regulate DNAM-1 expression on NK cells.^[9]

DNAM-1 and NK cells

DNAM is involved in NK cell education, differentiation, cytokine production and immune synapse formation. DNAM-1 exerts synergistic roles in NK cells regulation with three molecules that are TIGIT, CD96 and CRTAM.^[9]

Cytotoxic response of NK cells might require synergistic activation from specific pairs of receptors. DNAM-1 could synergize with SLAM family member 2B4 (CD244) or with other receptors to induce full NK cell activation.^[8]

DNAM-1 in cancer

The role of DNAM-1 in tumor environment was firstly described in vivo using RMA lymphoma model. In this model, enforced expression of DNAM-1 ligands CD155 and CD112 increased tumor rejection. CD155 and CD112 are expressed on the surface of a wide number of tumor cells in solid and lymphoid malignances such as lung carcinoma, primary human leukemia, myeloma, melanoma, neuroblastoma, ovarian cancer, colorectal carcinoma, and Ewing sarcoma cells.^[9]

The role of DNAM-1 in the killing of tumor cells was supported with DNAM-/- mice model that was more susceptible to formation of spontaneous fibrosarcoma.^[8]

It was shown that NK cells can kill leukemia and neuroblastoma cells expressing CD155 and block of CD155 or DNAM-1 results in inhibition of tumor cells lysis.^[9]

In vivo, tumor cells are capable of evading DNAM-1 tumor suppressing mechanisms. Tumor cells can downregulate CD155 or CD112 to disable recognition of these DNAM-1 ligands. The other mechanism is a downregulation of DNAM-1 from the effector NK cell surface due to the chronic ligand (CD155) exposure.^[9]

DNAM-1 was also used in T lymphocytes with a chimeric antigen receptors (CAR) for the treatment of cancer.^[12]

DNAM-1 and infections

DNAM-1 has a relevant role in the process of recognizing virus-infected cells during early infection for example in case of cytomegalovirus infection by NK cells. DNAM-1 ligands are also expressed in antigen-presenting cells activated by toll-like receptors and CD155 might be activated by DNA-damage response as was demonstrated for human immunodeficiency virus (HIV).^[8]

DNAM-1 functionality during infections may be impaired by viral immune evasion mechanisms. Viruses can downregulate production of surface CD112 and CD155 and thus avoid recognition of DNAM-1 expressed on NK cells. The other way is downregulation of DNAM-1 expressions that may occur during chronic infections.^[8]

NK cells activated with interferon α can kill HCV-infected cells in a DNAM-1 dependent manner.^[13]

During the bacterial infection interaction between DNAM-1 and its ligands helps to mediate the migration of leukocytes from the blood to secondary lymphoid organs or into inflamed tissues.^[9]

Soluble DNAM-1

It is suggested that soluble DNAM-1 is a prognostic marker in some types of cancer and in graft-versus-host-disease and that soluble DNAM-1 might play role in pathogenesis of some autoimmune diseases such as systemic lupus erythematosus, systemic sclerosis and rheumatoid arthritis.^[14]