Details of Drug Off-Target (DOT)

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

• DOT Name: Dual specificity protein phosphatase 14 (DUSP14)
• Synonyms: EC 3.1.3.16; EC 3.1.3.48; MKP-1-like protein tyrosine phosphatase; MKP-L; Mitogen-activated protein kinase phosphatase 6; MAP kinase phosphatase 6; MKP-6
• Gene Name: DUSP14
• Related Disease:
  Tuberculosis
  Autoimmune disease
  Osteoporosis
  Melanoma
  Nervous system inflammation
  Pulmonary tuberculosis
• UniProt ID: DUS14_HUMAN
• PDB ID: 2WGP
• EC Number: 3.1.3.16; 3.1.3.48
• Pfam ID: PF00782
• Sequence:
  MSSRGHSTLPRTLMAPRMISEGDIGGIAQITSSLFLGRGSVASNRHLLQARGITCIVNAT
  IEIPNFNWPQFEYVKVPLADMPHAPIGLYFDTVADKIHSVSRKHGATLVHCAAGVSRSAT
  LCIAYLMKFHNVCLLEAYNWVKARRPVIRPNVGFWRQLIDYERQLFGKSTVKMVQTPYGI
  VPDVYEKESRHLMPYWGI
• Function: Involved in the inactivation of MAP kinases. Dephosphorylates ERK, JNK and p38 MAP-kinases. Plays a negative role in TCR signaling by dephosphorylating MAP3K7 adapter TAB1 leading to its inactivation.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Tuberculosis	DIS2YIMD	Definitive	Biomarker	[1]
Autoimmune disease	DISORMTM	Strong	Altered Expression	[2]
Osteoporosis	DISF2JE0	Strong	Biomarker	[3]
Melanoma	DIS1RRCY	moderate	Genetic Variation	[4]
Nervous system inflammation	DISB3X5A	Limited	Biomarker	[5]
Pulmonary tuberculosis	DIS6FLUM	Limited	Altered Expression	[6]

23 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 Dual specificity protein phosphatase 14 (DUSP14).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Dual specificity protein phosphatase 14 (DUSP14).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dual specificity protein phosphatase 14 (DUSP14).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Dual specificity protein phosphatase 14 (DUSP14).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Dual specificity protein phosphatase 14 (DUSP14).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Dual specificity protein phosphatase 14 (DUSP14).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Dual specificity protein phosphatase 14 (DUSP14).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Dual specificity protein phosphatase 14 (DUSP14).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Dual specificity protein phosphatase 14 (DUSP14).	[16]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Dual specificity protein phosphatase 14 (DUSP14).	[17]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Dual specificity protein phosphatase 14 (DUSP14).	[18]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of Dual specificity protein phosphatase 14 (DUSP14).	[11]
Sertraline	DM0FB1J	Approved	Sertraline increases the expression of Dual specificity protein phosphatase 14 (DUSP14).	[19]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of Dual specificity protein phosphatase 14 (DUSP14).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Dual specificity protein phosphatase 14 (DUSP14).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Dual specificity protein phosphatase 14 (DUSP14).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Dual specificity protein phosphatase 14 (DUSP14).	[22]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Dual specificity protein phosphatase 14 (DUSP14).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Dual specificity protein phosphatase 14 (DUSP14).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Dual specificity protein phosphatase 14 (DUSP14).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Dual specificity protein phosphatase 14 (DUSP14).	[26]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Dual specificity protein phosphatase 14 (DUSP14).	[27]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Dual specificity protein phosphatase 14 (DUSP14).	[28]

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 Dual specificity protein phosphatase 14 (DUSP14).	[12]

References

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• [2] MAP4K Family Kinases and DUSP Family Phosphatases in T-Cell Signaling and Systemic Lupus Erythematosus.Cells. 2019 Nov 13;8(11):1433. doi: 10.3390/cells8111433.
• [3] Activation of Dusp14 protects against osteoclast generation and bone loss by regulating AMPK-dependent manner.Biochem Biophys Res Commun. 2019 Nov 12;519(3):445-452. doi: 10.1016/j.bbrc.2019.07.091. Epub 2019 Sep 13.
• [4] Association between functional polymorphisms in genes involved in the MAPK signaling pathways and cutaneous melanoma risk.Carcinogenesis. 2013 Apr;34(4):885-92. doi: 10.1093/carcin/bgs407. Epub 2013 Jan 4.
• [5] Dual-specificity phosphatase 14 (DUSP14/MKP6) negatively regulates TCR signaling by inhibiting TAB1 activation.J Immunol. 2014 Feb 15;192(4):1547-57. doi: 10.4049/jimmunol.1300989. Epub 2014 Jan 8.
• [6] Influence of the polymorphism of the DUSP14 gene on the expression of immune-related genes and development of pulmonary tuberculosis.Genes Immun. 2016 Jun;17(4):207-12. doi: 10.1038/gene.2016.11. Epub 2016 Mar 3.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [9] 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.
• [10] 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.
• [11] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [12] 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.
• [13] Novel functional view of the crocidolite asbestos-treated A549 human lung epithelial transcriptome reveals an intricate network of pathways with opposing functions. BMC Genomics. 2008 Aug 7;9:376.
• [14] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [15] 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.
• [16] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [17] Inflammation in methotrexate-induced pulmonary toxicity occurs via the p38 MAPK pathway. Toxicology. 2009 Feb 27;256(3):183-90. doi: 10.1016/j.tox.2008.11.016. Epub 2008 Nov 28.
• [18] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [19] 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.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] 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.
• [22] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [23] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [24] 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.
• [25] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [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] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.