Disease relevance of CD226

• Natural killer cell-mediated killing of freshly isolated neuroblastoma cells: critical role of DNAX accessory molecule-1-poliovirus receptor interaction [1].
• Accordingly, NK-mediated lysis of these leukemias was dependent on DNAM-1 but not NKG2D [2].
• We conclude that CD226 may be involved in the immune response to HIV infection and that further experiments are needed to find the function of CD226 in the pathogenesis of HIV infection [3].
• Prognostic and predictive relevance of DNAM-1, SOCS6 and CADH-7 genes on chromosome 18q in colorectal cancer [4].
• Four patients had PTA 1 to 4 months before undergoing CABG with IMA grafts, because of either asymptomatic supraclavicular murmurs or neurologic symptoms [5].

High impact information on CD226

• Whereas ligation of the DNAM-1 adhesion molecule triggers cytotoxicity mediated by normal NK and T cells, this function was defective in NK cell clones from leukocyte adhesion deficiency syndrome [6].
• Further studies demonstrated that LFA-1 physically associates with DNAM-1 in NK cells and anti-CD3 mAb stimulated T cells, for which serine phosphorylation of DNAM-1 plays a critical role [6].
• DNAM-1 is a 65 kDa transmembrane glycoprotein consisting of 318 aa including two immunoglobulin-like domains [7].
• In addition, DNAM-1 is a tyrosine-phosphorylated signal-transducing molecule that participates in primary adhesion during cytotoxic T lymphocyte (CTL)-mediated cytotoxicity [7].
• Altogether, our results demonstrate that DNAM-1 regulates monocyte extravasation via its interaction with PVR expressed at endothelial junctions on normal cells [8].

Biological context of CD226

• We also demonstrated that platelet activation with thrombin induces tyrosine phosphorylation of CD226 as well as CD226-mediated platelet adhesion [9].
• CD226 expression deficiency causes high sensitivity to apoptosis in NK T cells from patients with systemic lupus erythematosus [10].
• CD226 mediates platelet and megakaryocytic cell adhesion to vascular endothelial cells [9].
• Bioinformatics analysis shows that, within this CD226 gene region, there are putative binding sites for transcription factors AP-1, Sp1, PEA3, and Ets-1 [11].
• CD226 MoAb or LFA-1 MoAb or CD226 MoAb plus LFA-1 MoAbs did not increase the ploidy of the generated megakaryocytes from fetus-derived CD34(+) cells [12].

Anatomical context of CD226

• DNAX accessory molecule 1 (DNAM-1; CD226) is a transmembrane glycoprotein involved in T cell and natural killer (NK) cell cytotoxicity [8].
• CD226 synergizes with FcepsilonRI on mast cells, and its engagement augments degranulation through a pathway involving Fyn, linker of activation of T-cells, phospholipase C gamma2, and CD18 [13].
• This binding was almost completely abrogated by anti-PVR monoclonal antibodies (mAbs), but not modified by anti-Nectin-2 mAbs, which demonstrates that PVR is the major DNAM-1 ligand on endothelial cells [8].
• Because DNAM-1 is highly expressed on leukocytes, we investigated the role of the DNAM-1-PVR interaction during the monocyte transendothelial migration process [8].
• In vitro, both anti-DNAM-1 and anti-PVR mAbs strongly blocked the transmigration of monocytes through the endothelium [8].

Associations of CD226 with chemical compounds

• Moreover, experiments using mutant transfectants suggested that the tyrosine at residue 322 of CD226 plays an important role for its adhesive function [9].
• Requirement of the serine at residue 329 for lipid raft recruitment of DNAM-1 (CD226) [14].
• CONCLUSIONS: Loss of Dnam-1 gene copy number and retention of Cadh-7 might be indicators of worse prognosis, and Dnam-1 deletion might predict for a beneficial response to adjuvant 5-FU-based chemotherapy in patients with CRC [4].

Regulatory relationships of CD226

• We show that the carboxyl-terminal peptide of PTA-1 also can bind human discs large and that the presence or absence of this peptide greatly influences binding between PTA-1 and different isoforms of 4.1G [15].
• CD226 was not expressed on erythroid progenitor cells and erythroblasts and most cells of granulocytic lineage although G-CSF induced a significant increase of the expression of CD226 on CD34(+) cells in early period of time [12].
• TGF beta down-regulates TLiSA1 expression and inhibits the differentiation of precursor lymphocytes into CTL and LAK cells [16].

Other interactions of CD226

• CD226 is one of the main activating receptors on natural killer cells, and it can induce cytotoxicity to target cells through interaction with its ligands CD155 or CD112 [11].
• The activating NK receptors NKp30, NKG2D, and DNAM-1 represented the major receptors responsible for the induction of NK-mediated cytotoxicity against MSCs [17].
• We here review current knowledge on these receptors, CD226, CD96 and CRTAM, and their role in tumor immunosurveillance [18].
• The TCR-mediated signal also induces the formation of the immunological synapse (IS), in which lipid raft-associated molecules, including LFA-1, DNAM-1, protein kinase C, Fyn and others, are recruited, resulting in efficient signal transduction for T cell activation [14].
• Antibody to TGF beta reversed the inhibitory effect of the cytokine on differentiation and on TLiSA1 expression [16].

Analytical, diagnostic and therapeutic context of CD226

• We also demonstrate that ligation of CD226 and LFA-1 with their respective ligands cooperates in triggering cytotoxicity and cytokine secretion by T and NK cells [19].
• Both immunohistochemical analysis and confocal microscopy revealed expression of DNAM-1 ligands by DCs in lymph nodes in which they were localized in the parafollicular T-cell region and surrounded the high endothelial venules [20].
• This fusion protein was used as a probe in the investigation of CD226 ligand by immunohistochemistry [21].
• An enzymelinked immunosorbent assay (ELISA) was used to detect the level of soluble CD226 in the plasma of HIV-infected patients and normal controls and in the supernatant of HIV-1SF33-infected cells [3].
• About 130g CD226/Ig fusion protein could be obtained from 100mL COS-7 culture supernatants by anti-CD226 affinity chromatography purification [21].

References