Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT42FF0Z)

• DOT Name: Dual specificity testis-specific protein kinase 1 (TESK1)
• Synonyms: EC 2.7.12.1; Testicular protein kinase 1
• Gene Name: TESK1
• UniProt ID: TESK1_HUMAN
• EC Number: 2.7.12.1
• Pfam ID: PF07714
• Sequence:
  MAGERPPLRGPGPGPGEVPGEGPPGPGGTGGGPGRGRPSSYRALRSAVSSLARVDDFHCA
  EKIGAGFFSEVYKVRHRQSGQVMVLKMNKLPSNRGNTLREVQLMNRLRHPNILRFMGVCV
  HQGQLHALTEYMNGGTLEQLLSSPEPLSWPVRLHLALDIARGLRYLHSKGVFHRDLTSKN
  CLVRREDRGFTAVVGDFGLAEKIPVYREGARKEPLAVVGSPYWMAPEVLRGELYDEKADV
  FAFGIVLCELIARVPADPDYLPRTEDFGLDVPAFRTLVGDDCPLPFLLLAIHCCNLEPST
  RAPFTEITQHLEWILEQLPEPAPLTRTALTHNQGSVARGGPSATLPRPDPRLSRSRSDLF
  LPPSPESPPNWGDNLTRVNPFSLREDLRGGKIKLLDTPSKPVLPLVPPSPFPSTQLPLVT
  TPETLVQPGTPARRCRSLPSSPELPRRMETALPGPGPPAVGPSAEEKMECEGSSPEPEPP
  GPAPQLPLAVATDNFISTCSSASQPWSPRSGPVLNNNPPAVVVNSPQGWAGEPWNRAQHS
  LPRAAALERTEPSPPPSAPREPDEGLPCPGCCLGPFSFGFLSMCPRPTPAVARYRNLNCE
  AGSLLCHRGHHAKPPTPSLQLPGARS
• Function: Dual specificity protein kinase activity catalyzing autophosphorylation and phosphorylation of exogenous substrates on both serine/threonine and tyrosine residues. Regulates the cellular cytoskeleton by enhancing actin stress fiber formation via phosphorylation of cofilin and by preventing microtubule breakdown via inhibition of TAOK1/MARKK kinase activity. Inhibits podocyte motility via regulation of actin cytoskeletal dynamics and phosphorylation of CFL1. Positively regulates integrin-mediated cell spreading, via phosphorylation of cofilin. Suppresses ciliogenesis via multiple pathways; phosphorylation of CFL1, suppression of ciliary vesicle directional trafficking to the ciliary base, and by facilitating YAP1 nuclear localization where it acts as a transcriptional corepressor of the TEAD4 target genes AURKA and PLK1. Probably plays a central role at and after the meiotic phase of spermatogenesis.
• Tissue Specificity: Expressed in podocytes and renal tubular cells in the kidney (at protein level).
• Reactome Pathway: Regulation of cytoskeletal remodeling and cell spreading by IPP complex components (R-HSA-446388)

Molecular Interaction Atlas (MIA) of This DOT

10 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 Dual specificity testis-specific protein kinase 1 (TESK1).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dual specificity testis-specific protein kinase 1 (TESK1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dual specificity testis-specific protein kinase 1 (TESK1).	[3]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Dual specificity testis-specific protein kinase 1 (TESK1).	[4]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Dual specificity testis-specific protein kinase 1 (TESK1).	[5]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Dual specificity testis-specific protein kinase 1 (TESK1).	[6]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Dual specificity testis-specific protein kinase 1 (TESK1).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dual specificity testis-specific protein kinase 1 (TESK1).	[9]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 increases the expression of Dual specificity testis-specific protein kinase 1 (TESK1).	[10]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Dual specificity testis-specific protein kinase 1 (TESK1).	[11]

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 affects the methylation of Dual specificity testis-specific protein kinase 1 (TESK1).	[8]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [5] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [6] 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.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [8] 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.
• [9] 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.
• [10] Global expression profiling of theophylline response genes in macrophages: evidence of airway anti-inflammatory regulation. Respir Res. 2005 Aug 8;6(1):89. doi: 10.1186/1465-9921-6-89.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.