Details of Drug Off-Target (DOT)

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

• DOT Name: Tetraspanin-15 (TSPAN15)
• Synonyms: Tspan-15; Tetraspan NET-7; Transmembrane 4 superfamily member 15
• Gene Name: TSPAN15
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Neoplasm
  Pulmonary embolism
  Stroke
  Squamous cell carcinoma
• UniProt ID: TSN15_HUMAN
• PDB ID: 7RD5; 7RDB; 8ESV
• Pfam ID: PF00335
• Sequence:
  MPRGDSEQVRYCARFSYLWLKFSLIIYSTVFWLIGALVLSVGIYAEVERQKYKTLESAFL
  APAIILILLGVVMFMVSFIGVLASLRDNLYLLQAFMYILGICLIMELIGGVVALTFRNQT
  IDFLNDNIRRGIENYYDDLDFKNIMDFVQKKFKCCGGEDYRDWSKNQYHDCSAPGPLACG
  VPYTCCIRNTTEVVNTMCGYKTIDKERFSVQDVIYVRGCTNAVIIWFMDNYTIMAGILLG
  ILLPQFLGVLLTLLYITRVEDIIMEHSVTDGLLGPGAKPSVEAAGTGCCLCYPN
• 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 CDH2. Negatively regulates ligand-induced Notch activity probably by regulating ADAM10 activity.
• Reactome Pathway: Amyloid fiber formation (R-HSA-977225)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[2]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Pulmonary embolism	DISJYP9B	Strong	Genetic Variation	[4]
Stroke	DISX6UHX	Strong	Genetic Variation	[4]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Tetraspanin-15 (TSPAN15).	[6]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Tetraspanin-15 (TSPAN15).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Tetraspanin-15 (TSPAN15).	[8]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Tetraspanin-15 (TSPAN15).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Tetraspanin-15 (TSPAN15).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Tetraspanin-15 (TSPAN15).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Tetraspanin-15 (TSPAN15).	[11]

References

• [1] Tspan15 Is a New Stemness-Related Marker in Hepatocellular Carcinoma.Proteomics. 2019 Nov;19(21-22):e1900025. doi: 10.1002/pmic.201900025. Epub 2019 Sep 2.
• [2] In vivo regulation of the A disintegrin and metalloproteinase 10 (ADAM10) by the tetraspanin 15.Cell Mol Life Sci. 2018 Sep;75(17):3251-3267. doi: 10.1007/s00018-018-2791-2. Epub 2018 Mar 8.
• [3] TSPAN15 interacts with BTRC to promote oesophageal squamous cell carcinoma metastasis via activating NF-B signaling.Nat Commun. 2018 Apr 12;9(1):1423. doi: 10.1038/s41467-018-03716-9.
• [4] Genome-wide association analysis of self-reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis.Hum Mol Genet. 2016 May 1;25(9):1867-74. doi: 10.1093/hmg/ddw037. Epub 2016 Feb 9.
• [5] Tspan15 plays a crucial role in metastasis in oral squamous cell carcinoma.Exp Cell Res. 2019 Nov 15;384(2):111622. doi: 10.1016/j.yexcr.2019.111622. Epub 2019 Sep 10.
• [6] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [7] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [8] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [9] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [10] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [11] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [12] 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.