Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT45FGUX)

DOT Name T-cell surface glycoprotein CD3 zeta chain (CD247)
Synonyms T-cell receptor T3 zeta chain; CD antigen CD247
Gene Name CD247
Related Disease
Immunodeficiency 25 ( )
B-cell lymphoma ( )
Carcinoma ( )
Classic Hodgkin lymphoma ( )
Coeliac disease ( )
Epithelial ovarian cancer ( )
Glioma ( )
Head and neck cancer ( )
Head and neck carcinoma ( )
Hepatitis B virus infection ( )
HIV infectious disease ( )
Hypothyroidism ( )
leukaemia ( )
Leukemia ( )
Lung adenocarcinoma ( )
Myelodysplastic syndrome ( )
Neoplasm ( )
Osteoarthritis ( )
Ovarian cancer ( )
Sarcoma ( )
Small lymphocytic lymphoma ( )
Systemic lupus erythematosus ( )
Adult lymphoma ( )
Gastric cancer ( )
Head-neck squamous cell carcinoma ( )
Immune system disorder ( )
Immunodeficiency ( )
Lymphoma ( )
Pediatric lymphoma ( )
Plasma cell myeloma ( )
Severe combined immunodeficiency ( )
T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta ( )
Gastric neoplasm ( )
Thyroid gland papillary carcinoma ( )
Advanced cancer ( )
Asthma ( )
Autoimmune disease ( )
Bone osteosarcoma ( )
Colorectal carcinoma ( )
Juvenile idiopathic arthritis ( )
Non-insulin dependent diabetes ( )
Osteosarcoma ( )
Rheumatoid arthritis ( )
Stomach cancer ( )
Type-1 diabetes ( )
UniProt ID
CD3Z_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
PDB ID
1TCE; 1YGR; 2HAC; 2OQ1; 3IK5; 3IOZ; 4XZ1; 6JXR; 7FJD; 7FJE; 7FJF; 7PHR; 8ES7; 8ES8; 8ES9
Pfam ID
PF02189 ; PF11628
Sequence
MKWKALFTAAILQAQLPITEAQSFGLLDPKLCYLLDGILFIYGVILTALFLRVKFSRSAD
APAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPQRRKNPQEGLYNELQKDKMA
EAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR
Function
Part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response. When antigen presenting cells (APCs) activate T-cell receptor (TCR), TCR-mediated signals are transmitted across the cell membrane by the CD3 chains CD3D, CD3E, CD3G and CD3Z. All CD3 chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic domain. Upon TCR engagement, these motifs become phosphorylated by Src family protein tyrosine kinases LCK and FYN, resulting in the activation of downstream signaling pathways. CD3Z ITAMs phosphorylation creates multiple docking sites for the protein kinase ZAP70 leading to ZAP70 phosphorylation and its conversion into a catalytically active enzyme. Plays an important role in intrathymic T-cell differentiation. Additionally, participates in the activity-dependent synapse formation of retinal ganglion cells (RGCs) in both the retina and dorsal lateral geniculate nucleus (dLGN).
Tissue Specificity CD3Z is expressed in normal lymphoid tissue and in peripheral blood mononuclear cells (PBMCs) .
KEGG Pathway
.tural killer cell mediated cytotoxicity (hsa04650 )
Th1 and Th2 cell differentiation (hsa04658 )
Th17 cell differentiation (hsa04659 )
T cell receptor sig.ling pathway (hsa04660 )
Chagas disease (hsa05142 )
Epstein-Barr virus infection (hsa05169 )
Human immunodeficiency virus 1 infection (hsa05170 )
PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235 )

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Immunodeficiency 25 DIS6BEGF Definitive Autosomal recessive [1]
B-cell lymphoma DISIH1YQ Strong Biomarker [2]
Carcinoma DISH9F1N Strong Altered Expression [3]
Classic Hodgkin lymphoma DISV1LU6 Strong Altered Expression [4]
Coeliac disease DISIY60C Strong Altered Expression [5]
Epithelial ovarian cancer DIS56MH2 Strong Altered Expression [6]
Glioma DIS5RPEH Strong Biomarker [7]
Head and neck cancer DISBPSQZ Strong Altered Expression [8]
Head and neck carcinoma DISOU1DS Strong Altered Expression [8]
Hepatitis B virus infection DISLQ2XY Strong Genetic Variation [9]
HIV infectious disease DISO97HC Strong Biomarker [10]
Hypothyroidism DISR0H6D Strong Genetic Variation [11]
leukaemia DISS7D1V Strong Biomarker [12]
Leukemia DISNAKFL Strong Biomarker [12]
Lung adenocarcinoma DISD51WR Strong Altered Expression [13]
Myelodysplastic syndrome DISYHNUI Strong Altered Expression [14]
Neoplasm DISZKGEW Strong Biomarker [15]
Osteoarthritis DIS05URM Strong Altered Expression [16]
Ovarian cancer DISZJHAP Strong Altered Expression [6]
Sarcoma DISZDG3U Strong Altered Expression [13]
Small lymphocytic lymphoma DIS30POX Strong Biomarker [17]
Systemic lupus erythematosus DISI1SZ7 Strong Altered Expression [18]
Adult lymphoma DISK8IZR moderate Biomarker [17]
Gastric cancer DISXGOUK moderate Biomarker [19]
Head-neck squamous cell carcinoma DISF7P24 moderate Altered Expression [13]
Immune system disorder DISAEGPH moderate Genetic Variation [20]
Immunodeficiency DIS093I0 moderate Biomarker [21]
Lymphoma DISN6V4S moderate Biomarker [17]
Pediatric lymphoma DIS51BK2 moderate Biomarker [17]
Plasma cell myeloma DIS0DFZ0 moderate Biomarker [22]
Severe combined immunodeficiency DIS6MF4Q moderate Biomarker [23]
T-B+ severe combined immunodeficiency due to CD3delta/CD3epsilon/CD3zeta DISPUD3N Supportive Autosomal recessive [24]
Gastric neoplasm DISOKN4Y Disputed Altered Expression [25]
Thyroid gland papillary carcinoma DIS48YMM Disputed Biomarker [26]
Advanced cancer DISAT1Z9 Limited Altered Expression [27]
Asthma DISW9QNS Limited Genetic Variation [28]
Autoimmune disease DISORMTM Limited Genetic Variation [29]
Bone osteosarcoma DIST1004 Limited Biomarker [30]
Colorectal carcinoma DIS5PYL0 Limited Biomarker [15]
Juvenile idiopathic arthritis DISQZGBV Limited Genetic Variation [31]
Non-insulin dependent diabetes DISK1O5Z Limited Altered Expression [32]
Osteosarcoma DISLQ7E2 Limited Biomarker [30]
Rheumatoid arthritis DISTSB4J Limited Altered Expression [33]
Stomach cancer DISKIJSX Limited Biomarker [19]
Type-1 diabetes DIS7HLUB Limited Genetic Variation [34]
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⏷ Show the Full List of 45 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
2 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the methylation of T-cell surface glycoprotein CD3 zeta chain (CD247). [35]
Fulvestrant DM0YZC6 Approved Fulvestrant increases the methylation of T-cell surface glycoprotein CD3 zeta chain (CD247). [40]
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4 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Tretinoin DM49DUI Approved Tretinoin decreases the expression of T-cell surface glycoprotein CD3 zeta chain (CD247). [36]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of T-cell surface glycoprotein CD3 zeta chain (CD247). [37]
Arsenic DMTL2Y1 Approved Arsenic affects the expression of T-cell surface glycoprotein CD3 zeta chain (CD247). [38]
Methotrexate DM2TEOL Approved Methotrexate decreases the expression of T-cell surface glycoprotein CD3 zeta chain (CD247). [39]
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References

1 Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
2 Effective response and delayed toxicities of refractory advanced diffuse large B-cell lymphoma treated by CD20-directed chimeric antigen receptor-modified T cells.Clin Immunol. 2014 Dec;155(2):160-75. doi: 10.1016/j.clim.2014.10.002. Epub 2014 Oct 16.
3 CD3-zetachain expression of intratumoral lymphocytes is closely related to survival in gastric carcinoma patients.Cancer. 2002 Mar 1;94(5):1437-42. doi: 10.1002/cncr.10346.
4 Expression of signal-transducing zeta chain in peripheral blood T cells and natural killer cells in patients with Hodgkin's disease in different phases of the disease.Leuk Lymphoma. 1999 Nov;35(5-6):545-54. doi: 10.1080/10428199909169619.
5 Expression pattern of T-helper 17 cell signaling pathway and mucosal inflammation in celiac disease.Scand J Gastroenterol. 2014 Feb;49(2):145-56. doi: 10.3109/00365521.2013.863966. Epub 2013 Dec 10.
6 Lymphocyte apoptosis induced by Fas ligand- expressing ovarian carcinoma cells. Implications for altered expression of T cell receptor in tumor-associated lymphocytes.J Clin Invest. 1998 Jun 1;101(11):2579-88. doi: 10.1172/JCI1518.
7 Epigenetic biomarkers of T-cells in human glioma.Epigenetics. 2012 Dec 1;7(12):1391-402. doi: 10.4161/epi.22675. Epub 2012 Oct 29.
8 Change in CD3-chain expression is an independent predictor of disease status in head and neck cancer patients.Int J Cancer. 2016 Jul 1;139(1):122-9. doi: 10.1002/ijc.30046. Epub 2016 Mar 8.
9 CD3Z genetic polymorphism in immune response to hepatitis B vaccination in two independent Chinese populations.PLoS One. 2012;7(4):e35303. doi: 10.1371/journal.pone.0035303. Epub 2012 Apr 18.
10 Long-term in vivo survival of receptor-modified syngeneic T cells in patients with human immunodeficiency virus infection.Blood. 2000 Jul 15;96(2):467-74.
11 Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
12 Upregulated TCR enhances interleukin-2 production in T-cells from patients with CML.DNA Cell Biol. 2012 Nov;31(11):1628-35. doi: 10.1089/dna.2012.1798. Epub 2012 Oct 11.
13 A systematic analysis of immune genes and overall survival in cancer patients.BMC Cancer. 2019 Dec 16;19(1):1225. doi: 10.1186/s12885-019-6414-6.
14 Impaired expression of the CD3-zeta chain in peripheral blood T cells of patients with chronic myeloid leukaemia results in an increased susceptibility to apoptosis.Br J Haematol. 2000 Dec;111(3):817-25.
15 Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.J Immunother Cancer. 2017 Mar 21;5:22. doi: 10.1186/s40425-017-0222-9. eCollection 2017.
16 Decreased expression of the CD3zeta chain in T cells infiltrating the synovial membrane of patients with osteoarthritis.Clin Diagn Lab Immunol. 2004 Jan;11(1):195-202. doi: 10.1128/cdli.11.1.195-202.2004.
17 Generation of Potent T-cell Immunotherapy for Cancer Using DAP12-Based, Multichain, Chimeric Immunoreceptors.Cancer Immunol Res. 2015 Jul;3(7):815-26. doi: 10.1158/2326-6066.CIR-15-0054. Epub 2015 May 4.
18 Downregulation of CD3 in NK Cells from Systemic Lupus Erythematosus Patients Confers a Proinflammatory Phenotype.J Immunol. 2018 May 1;200(9):3077-3086. doi: 10.4049/jimmunol.1700588. Epub 2018 Mar 30.
19 Mesothelin is a target of chimeric antigen receptor T cells for treating gastric cancer.J Hematol Oncol. 2019 Feb 18;12(1):18. doi: 10.1186/s13045-019-0704-y.
20 Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci.PLoS Genet. 2011 Feb;7(2):e1002004. doi: 10.1371/journal.pgen.1002004. Epub 2011 Feb 24.
21 Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor-transduced human T cells in solid tumors.Clin Cancer Res. 2014 Aug 15;20(16):4262-73. doi: 10.1158/1078-0432.CCR-13-2627. Epub 2014 Jun 11.
22 B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma.J Clin Invest. 2019 Mar 21;129(6):2210-2221. doi: 10.1172/JCI126397.
23 T Lymphocytes in the Diagnosis of Human T Cell Receptor Immunodeficiencies.Front Immunol. 2015 Jan 29;6:20. doi: 10.3389/fimmu.2015.00020. eCollection 2015.
24 Clinical Practice Guidelines for Rare Diseases: The Orphanet Database. PLoS One. 2017 Jan 18;12(1):e0170365. doi: 10.1371/journal.pone.0170365. eCollection 2017.
25 CD3 zeta expression of regional lymph node and peripheral blood lymphocytes in gastric cancer.Anticancer Res. 2004 May-Jun;24(3b):2123-6.
26 Identification of Biomarkers Based on Differentially Expressed Genes in Papillary Thyroid Carcinoma.Sci Rep. 2018 Jul 2;8(1):9912. doi: 10.1038/s41598-018-28299-9.
27 Myeloid-derived suppressor cells expansion is closely associated with disease severity and progression in HBV-related acute-on-chronic liver failure.J Med Virol. 2019 Aug;91(8):1510-1518. doi: 10.1002/jmv.25466. Epub 2019 Apr 4.
28 Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct.Am J Hum Genet. 2019 Apr 4;104(4):665-684. doi: 10.1016/j.ajhg.2019.02.022. Epub 2019 Mar 28.
29 Association Study of CD226 and CD247 Genes Single Nucleotide Polymorphisms in Iranian Patients with Systemic Sclerosis.Iran J Allergy Asthma Immunol. 2017 Dec;16(6):471-479.
30 Memory T Cells Expressing an NKG2D-CAR Efficiently Target Osteosarcoma Cells.Clin Cancer Res. 2017 Oct 1;23(19):5824-5835. doi: 10.1158/1078-0432.CCR-17-0075. Epub 2017 Jun 28.
31 Investigation of juvenile idiopathic arthritis susceptibility loci: results from a Greek population.Hum Immunol. 2013 Sep;74(9):1194-8. doi: 10.1016/j.humimm.2013.06.018. Epub 2013 Jun 15.
32 CD247, a novel T cell-derived diagnostic and prognostic biomarker for detecting disease progression and severity in patients with type 2 diabetes.Diabetes Care. 2015 Jan;38(1):113-8. doi: 10.2337/dc14-1544. Epub 2014 Nov 3.
33 TCR-CD3 gene polymorphisms and expression profile in rheumatoid arthritis.Autoimmunity. 2016 Nov;49(7):466-471. doi: 10.1080/08916934.2016.1174855. Epub 2016 Apr 26.
34 Association of TCR/CD3, PTPN22, CD28 and ZAP70 gene polymorphisms with type 1 diabetes risk in Tunisian population: family based association study.Immunol Lett. 2015 Jan;163(1):1-7. doi: 10.1016/j.imlet.2014.11.005. Epub 2014 Nov 18.
35 Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
36 Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
37 Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
38 Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
39 The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
40 DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.