Details of Drug Off-Target (DOT)

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

• DOT Name: CD81 antigen (CD81)
• Synonyms: 26 kDa cell surface protein TAPA-1; Target of the antiproliferative antibody 1; Tetraspanin-28; Tspan-28; CD antigen CD81
• Gene Name: CD81
• Related Disease:
  Bone osteosarcoma
  Breast cancer
  Colorectal carcinoma
  Osteosarcoma
  Acute myelogenous leukaemia
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  B-cell lymphoma
  B-cell neoplasm
  Benign prostatic hyperplasia
  Breast carcinoma
  Burkitt lymphoma
  Colon cancer
  Colon carcinoma
  Depression
  Gastric cancer
  Gastric neoplasm
  Hepatitis
  Hepatitis A virus infection
  Hepatocellular carcinoma
  Influenza
  Major depressive disorder
  Neoplasm
  Non-insulin dependent diabetes
  Obesity
  Plasma cell myeloma
  Prostate cancer
  Prostate carcinoma
  Pulmonary tuberculosis
  Skin cancer
  Stomach cancer
  Lymphoproliferative syndrome
  Melanoma
  Meningioma
  Metastatic malignant neoplasm
  Common variable immunodeficiency
  Advanced cancer
  Bladder cancer
  Cataract
  Chronic obstructive pulmonary disease
  Epstein barr virus infection
  Immune system disorder
  Immunodeficiency, common variable, 6
  Periodontitis
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: CD81_HUMAN
• PDB ID: 1G8Q; 1IV5; 3X0E; 5DFV; 5DFW; 5M2C; 5M33; 5M3D; 5M3T; 5M4R; 5TCX; 6EJG; 6EJM; 6EK2; 6U9S; 7JIC
• Pfam ID: PF00335
• Sequence:
  MGVEGCTKCIKYLLFVFNFVFWLAGGVILGVALWLRHDPQTTNLLYLELGDKPAPNTFYV
  GIYILIAVGAVMMFVGFLGCYGAIQESQCLLGTFFTCLVILFACEVAAGIWGFVNKDQIA
  KDVKQFYDQALQQAVVDDDANNAKAVVKTFHETLDCCGSSTLTALTTSVLKNNLCPSGSN
  IISNLFKEDCHQKIDDLFSGKLYLIGIAAIVVAVIMIFEMILSMVLCCGIRNSSVY
• Function: Structural component of specialized membrane microdomains known as tetraspanin-enriched microdomains (TERMs), which act as platforms for receptor clustering and signaling. Essential for trafficking and compartmentalization of CD19 receptor on the surface of activated B cells. Upon initial encounter with microbial pathogens, enables the assembly of CD19-CR2/CD21 and B cell receptor (BCR) complexes at signaling TERMs, lowering the threshold dose of antigen required to trigger B cell clonal expansion and antibody production. In T cells, facilitates the localization of CD247/CD3 zeta at antigen-induced synapses with B cells, providing for costimulation and polarization toward T helper type 2 phenotype. Present in MHC class II compartments, may also play a role in antigen presentation. Can act both as positive and negative regulator of homotypic or heterotypic cell-cell fusion processes. Positively regulates sperm-egg fusion and may be involved in acrosome reaction. In myoblasts, associates with CD9 and PTGFRN and inhibits myotube fusion during muscle regeneration. In macrophages, associates with CD9 and beta-1 and beta-2 integrins, and prevents macrophage fusion into multinucleated giant cells specialized in ingesting complement-opsonized large particles. Also prevents the fusion of mononuclear cell progenitors into osteoclasts in charge of bone resorption. May regulate the compartmentalization of enzymatic activities. In T cells, defines the subcellular localization of dNTPase SAMHD1 and permits its degradation by the proteasome, thereby controlling intracellular dNTP levels. Also involved in cell adhesion and motility. Positively regulates integrin-mediated adhesion of macrophages, particularly relevant for the inflammatory response in the lung; (Microbial infection) Acts as a receptor for hepatitis C virus (HCV) in hepatocytes. Association with CLDN1 and the CLDN1-CD81 receptor complex is essential for HCV entry into host cell; (Microbial infection) Involved in SAMHD1-dependent restriction of HIV-1 replication. May support early replication of both R5- and X4-tropic HIV-1 viruses in T cells, likely via proteasome-dependent degradation of SAMHD1; (Microbial infection) Specifically required for Plasmodium falciparum infectivity of hepatocytes, controlling sporozoite entry into hepatocytes via the parasitophorous vacuole and subsequent parasite differentiation to exoerythrocytic forms.
• Tissue Specificity: Expressed on B cells (at protein level) . Expressed in hepatocytes (at protein level) . Expressed in monocytes/macrophages (at protein level) . Expressed on both naive and memory CD4-positive T cells (at protein level) .
• KEGG Pathway:
  B cell receptor sig.ling pathway (hsa04662)
  Malaria (hsa05144)
  Hepatitis C (hsa05160)
• Reactome Pathway:
  Regulation of Complement cascade (R-HSA-977606)
  Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DOT

47 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Definitive	Altered Expression	[1]
Breast cancer	DIS7DPX1	Definitive	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Definitive	Biomarker	[3]
Osteosarcoma	DISLQ7E2	Definitive	Altered Expression	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[4]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[5]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[6]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[6]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[7]
B-cell neoplasm	DISVY326	Strong	Biomarker	[8]
Benign prostatic hyperplasia	DISI3CW2	Strong	Genetic Variation	[9]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Burkitt lymphoma	DIS9D5XU	Strong	Altered Expression	[10]
Colon cancer	DISVC52G	Strong	Altered Expression	[11]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[11]
Depression	DIS3XJ69	Strong	Biomarker	[12]
Gastric cancer	DISXGOUK	Strong	Biomarker	[13]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[13]
Hepatitis	DISXXX35	Strong	Genetic Variation	[14]
Hepatitis A virus infection	DISUMFQV	Strong	Genetic Variation	[14]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[15]
Influenza	DIS3PNU3	Strong	Biomarker	[16]
Major depressive disorder	DIS4CL3X	Strong	Altered Expression	[12]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[17]
Obesity	DIS47Y1K	Strong	Altered Expression	[18]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[19]
Prostate cancer	DISF190Y	Strong	Biomarker	[9]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[9]
Pulmonary tuberculosis	DIS6FLUM	Strong	Altered Expression	[20]
Skin cancer	DISTM18U	Strong	Altered Expression	[21]
Stomach cancer	DISKIJSX	Strong	Biomarker	[13]
Lymphoproliferative syndrome	DISMVL8O	moderate	Biomarker	[15]
Melanoma	DIS1RRCY	moderate	Biomarker	[22]
Meningioma	DISPT4TG	moderate	Altered Expression	[23]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[24]
Common variable immunodeficiency	DISHE7JQ	Supportive	Autosomal dominant	[25]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[26]
Bladder cancer	DISUHNM0	Limited	Altered Expression	[27]
Cataract	DISUD7SL	Limited	Biomarker	[28]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Biomarker	[28]
Epstein barr virus infection	DISOO0WT	Limited	Altered Expression	[29]
Immune system disorder	DISAEGPH	Limited	Biomarker	[30]
Immunodeficiency, common variable, 6	DISA7XXW	Limited	Autosomal recessive	[31]
Periodontitis	DISI9JOI	Limited	Altered Expression	[32]
Urinary bladder cancer	DISDV4T7	Limited	Altered Expression	[27]
Urinary bladder neoplasm	DIS7HACE	Limited	Altered Expression	[27]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cocaine	DMSOX7I	Approved	CD81 antigen (CD81) increases the response to substance of Cocaine.	[52]

4 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 CD81 antigen (CD81).	[33]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of CD81 antigen (CD81).	[40]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of CD81 antigen (CD81).	[46]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of CD81 antigen (CD81).	[40]

17 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of CD81 antigen (CD81).	[34]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of CD81 antigen (CD81).	[35]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of CD81 antigen (CD81).	[36]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of CD81 antigen (CD81).	[37]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of CD81 antigen (CD81).	[38]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of CD81 antigen (CD81).	[39]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of CD81 antigen (CD81).	[41]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of CD81 antigen (CD81).	[42]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of CD81 antigen (CD81).	[43]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline decreases the expression of CD81 antigen (CD81).	[44]
APR-246	DMNFADH	Phase 2	APR-246 increases the expression of CD81 antigen (CD81).	[45]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of CD81 antigen (CD81).	[47]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of CD81 antigen (CD81).	[48]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of CD81 antigen (CD81).	[49]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of CD81 antigen (CD81).	[50]
Rutin	DMEHRAJ	Investigative	Rutin increases the expression of CD81 antigen (CD81).	[51]
CATECHIN	DMY38SB	Investigative	CATECHIN increases the expression of CD81 antigen (CD81).	[51]

References

• [1] The tetraspanin CD81 mediates the growth and metastases of human osteosarcoma.Cell Oncol (Dordr). 2019 Dec;42(6):861-871. doi: 10.1007/s13402-019-00472-w. Epub 2019 Sep 7.
• [2] Systems-level Analysis Reveals Multiple Modulators of Epithelial-mesenchymal Transition and Identifies DNAJB4 and CD81 as Novel Metastasis Inducers in Breast Cancer.Mol Cell Proteomics. 2019 Sep;18(9):1756-1771. doi: 10.1074/mcp.RA119.001446. Epub 2019 Jun 20.
• [3] Exosomes secreted from human colorectal cancer cell lines contain mRNAs, microRNAs and natural antisense RNAs, that can transfer into the human hepatoma HepG2 and lung cancer A549 cell lines.Oncol Rep. 2012 Nov;28(5):1551-8. doi: 10.3892/or.2012.1967. Epub 2012 Aug 10.
• [4] Tetraspanin CD81 is an adverse prognostic marker in acute myeloid leukemia.Oncotarget. 2016 Sep 20;7(38):62377-62385. doi: 10.18632/oncotarget.11481.
• [5] High complement levels in astrocyte-derived exosomes of Alzheimer disease.Ann Neurol. 2018 Mar;83(3):544-552. doi: 10.1002/ana.25172. Epub 2018 Mar 10.
• [6] Erratum to "Magnetic Resonance Imaging of Atherosclerosis Using CD81-Targeted Microparticles of Iron Oxide in Mice".Biomed Res Int. 2018 Oct 18;2018:8093438. doi: 10.1155/2018/8093438. eCollection 2018.
• [7] Splenic large B-cell lymphoma in patients with hepatitis C virus infection.Hum Pathol. 2005 Aug;36(8):878-85. doi: 10.1016/j.humpath.2005.06.005.
• [8] CD81 as target for B cell lymphomas.J Exp Med. 2019 Jul 1;216(7):1469-1470. doi: 10.1084/jem.20190733. Epub 2019 Jun 6.
• [9] Nanoscale flow cytometry to distinguish subpopulations of prostate extracellular vesicles in patient plasma.Prostate. 2019 May;79(6):592-603. doi: 10.1002/pros.23764. Epub 2019 Jan 24.
• [10] The importance of CD39, CD43, CD81, and CD95 expression for differentiating B cell lymphoma by flow cytometry.Cytometry B Clin Cytom. 2018 May;94(3):451-458. doi: 10.1002/cyto.b.21533. Epub 2017 May 24.
• [11] Colon cancer cells secrete exosomes to promote self-proliferation by shortening mitosis duration and activation of STAT3 in a hypoxic environment.Cell Biosci. 2019 Aug 6;9:62. doi: 10.1186/s13578-019-0325-8. eCollection 2019.
• [12] Neuron-related blood inflammatory markers as an objective evaluation tool for major depressive disorder: An exploratory pilot case-control study.J Affect Disord. 2018 Nov;240:88-98. doi: 10.1016/j.jad.2018.07.040. Epub 2018 Jul 17.
• [13] CD81 is a candidate tumor suppressor gene in human gastric cancer.Cell Oncol (Dordr). 2013 Apr;36(2):141-53. doi: 10.1007/s13402-012-0119-z. Epub 2012 Dec 21.
• [14] CD81 nucleotide mutation in hepatocellular carcinoma and lack of CD81 polymorphism in patients at stages of hepatitis C virus infection.J Med Virol. 2001 Jan;63(1):22-8.
• [15] CD81(+) Exosomes Play a Pivotal Role in the Establishment of Hepatitis C Persistent Infection and Contribute Toward the Progression of Hepatocellular Carcinoma.Viral Immunol. 2019 Dec;32(10):453-462. doi: 10.1089/vim.2019.0077. Epub 2019 Nov 22.
• [16] Dual function of CD81 in influenza virus uncoating and budding.PLoS Pathog. 2013;9(10):e1003701. doi: 10.1371/journal.ppat.1003701. Epub 2013 Oct 10.
• [17] Genetics of Type 2 Diabetes in U.S. Hispanic/Latino Individuals: Results From the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).Diabetes. 2017 May;66(5):1419-1425. doi: 10.2337/db16-1150. Epub 2017 Mar 2.
• [18] Putative targets of CNS melanocortin receptor activity.Ann N Y Acad Sci. 2003 Jun;994:211-7. doi: 10.1111/j.1749-6632.2003.tb03182.x.
• [19] Expression of CD81 and CD117 in plasma cell myeloma and the relationship to prognosis.Cancer Med. 2018 Dec;7(12):5920-5927. doi: 10.1002/cam4.1840. Epub 2018 Oct 24.
• [20] Gene expression profiles of bronchoalveolar cells in pulmonary TB.Tuberculosis (Edinb). 2008 Jan;88(1):39-51. doi: 10.1016/j.tube.2007.07.003. Epub 2007 Oct 24.
• [21] The tetraspanin CD81 protein increases melanoma cell motility by up-regulating metalloproteinase MT1-MMP expression through the pro-oncogenic Akt-dependent Sp1 activation signaling pathways.J Biol Chem. 2014 May 30;289(22):15691-704. doi: 10.1074/jbc.M113.534206. Epub 2014 Apr 14.
• [22] EWI-2 negatively regulates TGF- signaling leading to altered melanoma growth and metastasis.Cell Res. 2015 Mar;25(3):370-85. doi: 10.1038/cr.2015.17. Epub 2015 Feb 6.
• [23] The protein expression profile of meningioma cells is associated with distinct cytogenetic tumour subgroups.Neuropathol Appl Neurobiol. 2015 Apr;41(3):319-32. doi: 10.1111/nan.12127.
• [24] CD81 Promotes a Migratory Phenotype in Neuronal-Like Cells.Microsc Microanal. 2019 Feb;25(1):229-235. doi: 10.1017/S1431927618015532. Epub 2019 Feb 4.
• [25] "A rose is a rose is a rose," but CVID is Not CVID common variable immune deficiency (CVID), what do we know in 2011?. Adv Immunol. 2011;111:47-107. doi: 10.1016/B978-0-12-385991-4.00002-7.
• [26] Electrochemical immunosensing of nanovesicles as biomarkers for breast cancer.Biosens Bioelectron. 2020 Feb 15;150:111882. doi: 10.1016/j.bios.2019.111882. Epub 2019 Nov 13.
• [27] Suppression of CD81 promotes bladder cancer cell invasion through increased matrix metalloproteinase expression via extracellular signal-regulated kinase phosphorylation.Investig Clin Urol. 2019 Sep;60(5):396-404. doi: 10.4111/icu.2019.60.5.396. Epub 2019 Jul 17.
• [28] Double deletion of tetraspanins CD9 and CD81 in mice leads to a syndrome resembling accelerated aging.Sci Rep. 2018 Mar 23;8(1):5145. doi: 10.1038/s41598-018-23338-x.
• [29] Pre-stimulation of CD81 expression by resting B cells increases proliferation following EBV infection, but the overexpression of CD81 induces the apoptosis of EBV-transformed B cells.Int J Mol Med. 2015 Dec;36(6):1464-78. doi: 10.3892/ijmm.2015.2372. Epub 2015 Oct 13.
• [30] A monoclonal antibody recognizing a new epitope on CD81 inhibits T-cell migration without inducing cytokine production.J Biochem. 2020 Apr 1;167(4):399-409. doi: 10.1093/jb/mvz103.
• [31] 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.
• [32] Decreased salivary concentration of CD9 and CD81 exosome-related tetraspanins may be associated with the periodontal clinical status.J Clin Periodontol. 2019 Apr;46(4):470-480. doi: 10.1111/jcpe.13099. Epub 2019 Apr 15.
• [33] 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.
• [34] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [35] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [36] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [37] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [38] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [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.
• [41] Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. Front Physiol. 2016 Nov 24;7:559. doi: 10.3389/fphys.2016.00559. eCollection 2016.
• [42] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [43] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [44] Controlled diesel exhaust and allergen coexposure modulates microRNA and gene expression in humans: Effects on inflammatory lung markers. J Allergy Clin Immunol. 2016 Dec;138(6):1690-1700. doi: 10.1016/j.jaci.2016.02.038. Epub 2016 Apr 24.
• [45] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [46] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [47] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [48] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [49] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [50] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
• [51] Epicatechin and a cocoa polyphenolic extract modulate gene expression in human Caco-2 cells. J Nutr. 2004 Oct;134(10):2509-16.
• [52] In vivo gene silencing of CD81 by lentiviral expression of small interference RNAs suppresses cocaine-induced behaviour. J Neurochem. 2005 Mar;92(5):1243-55. doi: 10.1111/j.1471-4159.2004.02961.x.