Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP72P0F)

• DOT Name: Tensin-2 (TNS2)
• Synonyms: EC 3.1.3.48; C1 domain-containing phosphatase and tensin homolog; C1-TEN; Tensin-like C1 domain-containing phosphatase
• Gene Name: TNS2
• Related Disease:
  Adult glioblastoma
  Diabetic kidney disease
  Glioblastoma multiforme
  Nephrotic syndrome
  Pierson syndrome
  Colon cancer
  Colon carcinoma
  Lung cancer
• UniProt ID: TENS2_HUMAN
• PDB ID: 2DKQ; 2KNO; 2L6K; 2LOZ; 3HQC
• EC Number: 3.1.3.48
• Pfam ID: PF00130 ; PF08416 ; PF10409 ; PF00017
• Sequence:
  MKSSGPVERLLRALGRRDSSRAASRPRKAEPHSFREKVFRKKPPVCAVCKVTIDGTGVSC
  RVCKVATHRKCEAKVTSACQALPPVELRRNTAPVRRIEHLGSTKSLNHSKQRSTLPRSFS
  LDPLMERRWDLDLTYVTERILAAAFPARPDEQRHRGHLRELAHVLQSKHRDKYLLFNLSE
  KRHDLTRLNPKVQDFGWPELHAPPLDKLCSICKAMETWLSADPQHVVVLYCKGNKGKLGV
  IVSAYMHYSKISAGADQALATLTMRKFCEDKVATELQPSQRRYISYFSGLLSGSIRMNSS
  PLFLHYVLIPMLPAFEPGTGFQPFLKIYQSMQLVYTSGVYHIAGPGPQQLCISLEPALLL
  KGDVMVTCYHKGGRGTDRTLVFRVQFHTCTIHGPQLTFPKDQLDEAWTDERFPFQASVEF
  VFSSSPEKIKGSTPRNDPSVSVDYNTTEPAVRWDSYENFNQHHEDSVDGSLTHTRGPLDG
  SPYAQVQRPPRQTPPAPSPEPPPPPMLSVSSDSGHSSTLTTEPAAESPGRPPPTAAERQE
  LDRLLGGCGVASGGRGAGRETAILDDEEQPTVGGGPHLGVYPGHRPGLSRHCSCRQGYRE
  PCGVPNGGYYRPEGTLERRRLAYGGYEGSPQGYAEASMEKRRLCRSLSEGLYPYPPEMGK
  PATGDFGYRAPGYREVVILEDPGLPALYPCPACEEKLALPTAALYGLRLEREAGEGWASE
  AGKPLLHPVRPGHPLPLLLPACGHHHAPMPDYSCLKPPKAGEEGHEGCSYTMCPEGRYGH
  PGYPALVTYSYGGAVPSYCPAYGRVPHSCGSPGEGRGYPSPGAHSPRAGSISPGSPPYPQ
  SRKLSYEIPTEEGGDRYPLPGHLASAGPLASAESLEPVSWREGPSGHSTLPRSPRDAPCS
  ASSELSGPSTPLHTSSPVQGKESTRRQDTRSPTSAPTQRLSPGEALPPVSQAGTGKAPEL
  PSGSGPEPLAPSPVSPTFPPSSPSDWPQERSPGGHSDGASPRSPVPTTLPGLRHAPWQGP
  RGPPDSPDGSPLTPVPSQMPWLVASPEPPQSSPTPAFPLAASYDTNGLSQPPLPEKRHLP
  GPGQQPGPWGPEQASSPARGISHHVTFAPLLSDNVPQTPEPPTQESQSNVKFVQDTSKFW
  YKPHLSRDQAIALLKDKDPGAFLIRDSHSFQGAYGLALKVATPPPSAQPWKGDPVEQLVR
  HFLIETGPKGVKIKGCPSEPYFGSLSALVSQHSISPISLPCCLRIPSKDPLEETPEAPVP
  TNMSTAADLLRQGAACSVLYLTSVETESLTGPQAVARASSAALSCSPRPTPAVVHFKVSA
  QGITLTDNQRKLFFRRHYPVNSITFSSTDPQDRRWTNPDGTTSKIFGFVAKKPGSPWENV
  CHLFAELDPDQPAGAIVTFITKVLLGQRK
• Function: Tyrosine-protein phosphatase which regulates cell motility, proliferation and muscle-response to insulin. Phosphatase activity is mediated by binding to phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P3) via the SH2 domain. In muscles and under catabolic conditions, dephosphorylates IRS1 leading to its degradation and muscle atrophy. Negatively regulates PI3K-AKT pathway activation. Dephosphorylates nephrin NPHS1 in podocytes which regulates activity of the mTORC1 complex. Under normal glucose conditions, NPHS1 outcompetes IRS1 for binding to phosphatidylinositol 3-kinase (PI3K) which balances mTORC1 activity but high glucose conditions lead to up-regulation of TNS2, increased NPHS1 dephosphorylation and activation of mTORC1, contributing to podocyte hypertrophy and proteinuria. Required for correct podocyte morphology, podocyte-glomerular basement membrane interaction and integrity of the glomerular filtration barrier. Enhances RHOA activation in the presence of DLC1. Plays a role in promoting DLC1-dependent remodeling of the extracellular matrix.
• Tissue Specificity: Detected in heart, kidney, brain, thymus, spleen, liver, placenta, lung, skeletal muscle and small intestine.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[2]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Nephrotic syndrome	DISSPSC2	Strong	Biomarker	[3]
Pierson syndrome	DIS0DF3C	Strong	Biomarker	[4]
Colon cancer	DISVC52G	Limited	Altered Expression	[5]
Colon carcinoma	DISJYKUO	Limited	Altered Expression	[5]
Lung cancer	DISCM4YA	Limited	Altered Expression	[5]

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 Tensin-2 (TNS2).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Tensin-2 (TNS2).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Tensin-2 (TNS2).	[17]

11 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 Tensin-2 (TNS2).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tensin-2 (TNS2).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tensin-2 (TNS2).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of Tensin-2 (TNS2).	[10]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Tensin-2 (TNS2).	[11]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Tensin-2 (TNS2).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Tensin-2 (TNS2).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Tensin-2 (TNS2).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Tensin-2 (TNS2).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Tensin-2 (TNS2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Tensin-2 (TNS2).	[18]

References

• [1] Transcriptional profiling of human glioblastoma vessels indicates a key role of VEGF-A and TGF2 in vascular abnormalization.J Pathol. 2012 Nov;228(3):378-90. doi: 10.1002/path.4072. Epub 2012 Aug 31.
• [2] C1-Ten is a PTPase of nephrin, regulating podocyte hypertrophy through mTORC1 activation.Sci Rep. 2017 Sep 27;7(1):12346. doi: 10.1038/s41598-017-12382-8.
• [3] Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment. Nat Commun. 2018 May 17;9(1):1960. doi: 10.1038/s41467-018-04193-w.
• [4] Deficiency of the tensin2 gene in the ICGN mouse: an animal model for congenital nephrotic syndrome.Mamm Genome. 2006 May;17(5):407-16. doi: 10.1007/s00335-005-0167-z.
• [5] Down-regulation of tensin2 enhances tumorigenicity and is associated with a variety of cancers.Oncotarget. 2016 Jun 21;7(25):38143-38153. doi: 10.18632/oncotarget.9411.
• [6] 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.
• [7] 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.
• [8] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [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] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [11] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [12] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [13] 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.
• [14] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] 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.
• [17] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [18] Transcriptomic?pathway?and?benchmark dose analysis of Bisphenol A, Bisphenol S, Bisphenol F, and 3,3',5,5'-Tetrabromobisphenol A in H9 human embryonic stem cells. Toxicol In Vitro. 2021 Apr;72:105097. doi: 10.1016/j.tiv.2021.105097. Epub 2021 Jan 18.