Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT32OZ75)

• DOT Name: Tensin-4 (TNS4)
• Synonyms: C-terminal tensin-like protein
• Gene Name: TNS4
• UniProt ID: TENS4_HUMAN
• Pfam ID: PF08416 ; PF00017
• Sequence:
  MSQVMSSPLLAGGHAVSLAPCDEPRRTLHPAPSPSLPPQCSYYTTEGWGAQALMAPVPCM
  GPPGRLQQAPQVEAKATCFLPSPGEKALGTPEDLDSYIDFSLESLNQMILELDPTFQLLP
  PGTGGSQAELAQSTMSMRKKEESEALDIKYIEVTSARSRCHDGPQHCSSPSVTPPFGSLR
  SGGLLLSRDVPRETRSSSESLIFSGNQGRGHQRPLPPSEGLSPRPPNSPSISIPCMGSKA
  SSPHGLGSPLVASPRLEKRLGGLAPQRGSRISVLSASPVSDVSYMFGSSQSLLHSSNSSH
  QSSSRSLESPANSSSSLHSLGSVSLCTRPSDFQAPRNPTLTMGQPRTPHSPPLAKEHASS
  CPPSITNSMVDIPIVLINGCPEPGSSPPQRTPGHQNSVQPGAASPSNPCPATRSNSQTLS
  DAPFTTCPEGPARDMQPTMKFVMDTSKYWFKPNITREQAIELLRKEEPGAFVIRDSSSYR
  GSFGLALKVQEVPASAQSRPGEDSNDLIRHFLIESSAKGVHLKGADEEPYFGSLSAFVCQ
  HSIMALALPCKLTIPQRELGGADGASDSTDSPASCQKKSAGCHTLYLSSVSVETLTGALA
  VQKAISTTFERDILPTPTVVHFKVTEQGITLTDVQRKVFFRRHYPLTTLRFCGMDPEQRK
  WQKYCKPSWIFGFVAKSQTEPQENVCHLFAEYDMVQPASQVIGLVTALLQDAERM
• Function: Promotes EGF-induced cell migration by displacing tensin TNS3 from the cytoplasmic tail of integrin ITGB1 which results in dissociation of TNS3 from focal adhesions, disassembly of actin stress fibers and initiation of cell migration. Suppresses ligand-induced degradation of EGFR by reducing EGFR ubiquitination in the presence of EGF. Increases MET protein stability by inhibiting MET endocytosis and subsequent lysosomal degradation which leads to increased cell survival, proliferation and migration.
• Tissue Specificity: Expressed at low levels in colon (at protein level) . Expressed in prostate and placenta .
• Reactome Pathway: MET interacts with TNS proteins (R-HSA-8875513)

Molecular Interaction Atlas (MIA) 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 Tensin-4 (TNS4).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Tensin-4 (TNS4).	[11]

11 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 Tensin-4 (TNS4).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tensin-4 (TNS4).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tensin-4 (TNS4).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Tensin-4 (TNS4).	[5]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Tensin-4 (TNS4).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Tensin-4 (TNS4).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Tensin-4 (TNS4).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Tensin-4 (TNS4).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Tensin-4 (TNS4).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Tensin-4 (TNS4).	[12]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Tensin-4 (TNS4).	[13]

References

• [1] 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.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [8] 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.
• [9] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [13] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.