Details of Drug Off-Target (DOT)

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

• DOT Name: Tetraspanin-5 (TSPAN5)
• Synonyms: Tspan-5; Tetraspan NET-4; Transmembrane 4 superfamily member 9
• Gene Name: TSPAN5
• Related Disease:
  Major depressive disorder
  Rheumatoid arthritis
  Neuroblastoma
  Osteoporosis
  Type-1 diabetes
• UniProt ID: TSN5_HUMAN
• Pfam ID: PF00335
• Sequence:
  MSGKHYKGPEVSCCIKYFIFGFNVIFWFLGITFLGIGLWAWNEKGVLSNISSITDLGGFD
  PVWLFLVVGGVMFILGFAGCIGALRENTFLLKFFSVFLGIIFFLELTAGVLAFVFKDWIK
  DQLYFFINNNIRAYRDDIDLQNLIDFTQEYWQCCGAFGADDWNLNIYFNCTDSNASRERC
  GVPFSCCTKDPAEDVINTQCGYDARQKPEVDQQIVIYTKGCVPQFEKWLQDNLTIVAGIF
  IGIALLQIFGICLAQNLVSDIEAVRASW
• Function: Part of TspanC8 subgroup, composed of 6 members that interact with the transmembrane metalloprotease ADAM10. This interaction is required for ADAM10 exit from the endoplasmic reticulum and for enzymatic maturation and trafficking to the cell surface as well as substrate specificity. Different TspanC8/ADAM10 complexes have distinct substrates. Promotes ADAM10-mediated cleavage of CD44. Seems to regulate VE-cadherin expression in endothelial cells probably through interaction with ADAM10, promoting leukocyte transmigration.
• Reactome Pathway: Amyloid fiber formation (R-HSA-977225)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[1]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[2]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[3]
Osteoporosis	DISF2JE0	Limited	Biomarker	[4]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[4]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Tetraspanin-5 (TSPAN5).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Tetraspanin-5 (TSPAN5).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Tetraspanin-5 (TSPAN5).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Tetraspanin-5 (TSPAN5).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tetraspanin-5 (TSPAN5).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tetraspanin-5 (TSPAN5).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Tetraspanin-5 (TSPAN5).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Tetraspanin-5 (TSPAN5).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tetraspanin-5 (TSPAN5).	[11]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Tetraspanin-5 (TSPAN5).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Tetraspanin-5 (TSPAN5).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Tetraspanin-5 (TSPAN5).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Tetraspanin-5 (TSPAN5).	[16]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Tetraspanin-5 (TSPAN5).	[17]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Tetraspanin-5 (TSPAN5).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Tetraspanin-5 (TSPAN5).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Tetraspanin-5 (TSPAN5).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Tetraspanin-5 (TSPAN5).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Tetraspanin-5 (TSPAN5).	[22]

References

• [1] Pharmacogenomics-Driven Prediction of Antidepressant Treatment Outcomes: A Machine-Learning Approach With Multi-trial Replication.Clin Pharmacol Ther. 2019 Oct;106(4):855-865. doi: 10.1002/cpt.1482. Epub 2019 Jun 29.
• [2] Genome-wide association analysis implicates the involvement of eight loci with response to tocilizumab for the treatment of rheumatoid arthritis.Pharmacogenomics J. 2013 Jun;13(3):235-41. doi: 10.1038/tpj.2012.8. Epub 2012 Apr 10.
• [3] TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: pharmacometabolomics-informed pharmacogenomics.Mol Psychiatry. 2016 Dec;21(12):1717-1725. doi: 10.1038/mp.2016.6. Epub 2016 Feb 23.
• [4] Screening of differentially expressed genes in male idiopathic osteoporosis via RNA sequencing.Mol Med Rep. 2018 Jul;18(1):67-76. doi: 10.3892/mmr.2018.8985. Epub 2018 May 7.
• [5] 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.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [8] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [9] 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.
• [10] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [11] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [12] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [13] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [16] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [20] 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.
• [21] 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.
• [22] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.