Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOZTA1F)

• DOT Name: Mitogen-activated protein kinase kinase kinase 8 (MAP3K8)
• Synonyms: EC 2.7.11.25; Cancer Osaka thyroid oncogene; Proto-oncogene c-Cot; Serine/threonine-protein kinase cot; Tumor progression locus 2; TPL-2
• Gene Name: MAP3K8
• UniProt ID: M3K8_HUMAN
• PDB ID: 4Y83; 4Y85; 5IU2
• EC Number: 2.7.11.25
• Pfam ID: PF00069
• Sequence:
  MEYMSTGSDNKEEIDLLIKHLNVSDVIDIMENLYASEEPAVYEPSLMTMCQDSNQNDERS
  KSLLLSGQEVPWLSSVRYGTVEDLLAFANHISNTAKHFYGQRPQESGILLNMVITPQNGR
  YQIDSDVLLIPWKLTYRNIGSDFIPRGAFGKVYLAQDIKTKKRMACKLIPVDQFKPSDVE
  IQACFRHENIAELYGAVLWGETVHLFMEAGEGGSVLEKLESCGPMREFEIIWVTKHVLKG
  LDFLHSKKVIHHDIKPSNIVFMSTKAVLVDFGLSVQMTEDVYFPKDLRGTEIYMSPEVIL
  CRGHSTKADIYSLGATLIHMQTGTPPWVKRYPRSAYPSYLYIIHKQAPPLEDIADDCSPG
  MRELIEASLERNPNHRPRAADLLKHEALNPPREDQPRCQSLDSALLERKRLLSRKELELP
  ENIADSSCTGSTEESEMLKRQRSLYIDLGALAGYFNLVRGPPTLEYG
• Function: Required for lipopolysaccharide (LPS)-induced, TLR4-mediated activation of the MAPK/ERK pathway in macrophages, thus being critical for production of the pro-inflammatory cytokine TNF-alpha (TNF) during immune responses. Involved in the regulation of T-helper cell differentiation and IFNG expression in T-cells. Involved in mediating host resistance to bacterial infection through negative regulation of type I interferon (IFN) production. In vitro, activates MAPK/ERK pathway in response to IL1 in an IRAK1-independent manner, leading to up-regulation of IL8 and CCL4. Transduces CD40 and TNFRSF1A signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production. May also play a role in the transduction of TNF signals that activate JNK and NF-kappa-B in some cell types. In adipocytes, activates MAPK/ERK pathway in an IKBKB-dependent manner in response to IL1B and TNF, but not insulin, leading to induction of lipolysis. Plays a role in the cell cycle. Isoform 1 shows some transforming activity, although it is much weaker than that of the activated oncogenic variant.
• Tissue Specificity: Expressed in several normal tissues and human tumor-derived cell lines.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Toll-like receptor sig.ling pathway (hsa04620)
  T cell receptor sig.ling pathway (hsa04660)
  TNF sig.ling pathway (hsa04668)
• Reactome Pathway:
  MAP3K8 (TPL2)-dependent MAPK1/3 activation (R-HSA-5684264)
  CD28 dependent PI3K/Akt signaling (R-HSA-389357)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	Mitogen-activated protein kinase kinase kinase 8 (MAP3K8) decreases the response to substance of Afimoxifene.	[32]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[7]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[11]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[15]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[16]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[17]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[18]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[19]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[20]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[21]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[22]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil increases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[7]
Sertraline	DM0FB1J	Approved	Sertraline increases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[17]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[24]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[26]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[27]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[28]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[29]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[30]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Mitogen-activated protein kinase kinase kinase 8 (MAP3K8).	[9]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [8] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [13] 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.
• [14] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [15] Epigenetic regulation of microRNA-370 by interleukin-6 in malignant human cholangiocytes. Oncogene. 2008 Jan 10;27(3):378-86. doi: 10.1038/sj.onc.1210648. Epub 2007 Jul 9.
• [16] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [17] 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.
• [18] Coordinate up-regulation of TMEM97 and cholesterol biosynthesis genes in normal ovarian surface epithelial cells treated with progesterone: implications for pathogenesis of ovarian cancer. BMC Cancer. 2007 Dec 11;7:223.
• [19] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [21] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [22] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [23] Sertraline induces endoplasmic reticulum stress in hepatic cells. Toxicology. 2014 Aug 1;322:78-88. doi: 10.1016/j.tox.2014.05.007. Epub 2014 May 24.
• [24] 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.
• [25] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [26] 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.
• [27] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [28] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [29] Probiotic Bacillus subtilis CW14 reduces disruption of the epithelial barrier and toxicity of ochratoxin A to Caco-2?cells. Food Chem Toxicol. 2019 Apr;126:25-33. doi: 10.1016/j.fct.2019.02.009. Epub 2019 Feb 11.
• [30] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.
• [31] Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.
• [32] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.