Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPLMPG9)

• DOT Name: Dual specificity protein phosphatase 8 (DUSP8)
• Synonyms: EC 3.1.3.16; EC 3.1.3.48; Dual specificity protein phosphatase hVH-5
• Gene Name: DUSP8
• UniProt ID: DUS8_HUMAN
• PDB ID: 4JMK
• EC Number: 3.1.3.16; 3.1.3.48
• Pfam ID: PF00782 ; PF00581
• Sequence:
  MAGDRLPRKVMDAKKLASLLRGGPGGPLVIDSRSFVEYNSWHVLSSVNICCSKLVKRRLQ
  QGKVTIAELIQPAARSQVEATEPQDVVVYDQSTRDASVLAADSFLSILLSKLDGCFDSVA
  ILTGGFATFSSCFPGLCEGKPAALLPMSLSQPCLPVPSVGLTRILPHLYLGSQKDVLNKD
  LMTQNGISYVLNASNSCPKPDFICESRFMRVPINDNYCEKLLPWLDKSIEFIDKAKLSSC
  QVIVHCLAGISRSATIAIAYIMKTMGMSSDDAYRFVKDRRPSISPNFNFLGQLLEYERSL
  KLLAALQGDPGTPSGTPEPPPSPAAGAPLPRLPPPTSESAATGNAAAREGGLSAGGEPPA
  PPTPPATSALQQGLRGLHLSSDRLQDTNRLKRSFSLDIKSAYAPSRRPDGPGPPDPGEAP
  KLCKLDSPSGAALGLSSPSPDSPDAAPEARPRPRRRPRPPAGSPARSPAHSLGLNFGDAA
  RQTPRHGLSALSAPGLPGPGQPAGPGAWAPPLDSPGTPSPDGPWCFSPEGAQGAGGVLFA
  PFGRAGAPGPGGGSDLRRREAARAEPRDARTGWPEEPAPETQFKRRSCQMEFEEGMVEGR
  ARGEELAALGKQASFSGSVEVIEVS
• Function: Has phosphatase activity with synthetic phosphatase substrates and negatively regulates mitogen-activated protein kinase activity, presumably by catalysing their dephosphorylation. Expected to display protein phosphatase activity toward phosphotyrosine, phosphoserine and phosphothreonine residues.
• Tissue Specificity: Abundant in brain, heart and skeletal muscle.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Efferocytosis (hsa04148)
• Reactome Pathway:
  Negative regulation of MAPK pathway (R-HSA-5675221)
  Signaling by MAPK mutants (R-HSA-9652817)
  RAF-independent MAPK1/3 activation (R-HSA-112409)

Molecular Interaction Atlas (MIA) of This DOT

1 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 Dual specificity protein phosphatase 8 (DUSP8).	[1]

17 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 protein phosphatase 8 (DUSP8).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dual specificity protein phosphatase 8 (DUSP8).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Dual specificity protein phosphatase 8 (DUSP8).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Dual specificity protein phosphatase 8 (DUSP8).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Dual specificity protein phosphatase 8 (DUSP8).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Dual specificity protein phosphatase 8 (DUSP8).	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of Dual specificity protein phosphatase 8 (DUSP8).	[8]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Dual specificity protein phosphatase 8 (DUSP8).	[9]
Thalidomide	DM70BU5	Approved	Thalidomide increases the expression of Dual specificity protein phosphatase 8 (DUSP8).	[10]
Sertraline	DM0FB1J	Approved	Sertraline increases the expression of Dual specificity protein phosphatase 8 (DUSP8).	[11]
Febuxostat	DMDEXQ0	Approved	Febuxostat increases the expression of Dual specificity protein phosphatase 8 (DUSP8).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Dual specificity protein phosphatase 8 (DUSP8).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Dual specificity protein phosphatase 8 (DUSP8).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Dual specificity protein phosphatase 8 (DUSP8).	[15]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Dual specificity protein phosphatase 8 (DUSP8).	[16]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Dual specificity protein phosphatase 8 (DUSP8).	[17]
Glyphosate	DM0AFY7	Investigative	Glyphosate affects the expression of Dual specificity protein phosphatase 8 (DUSP8).	[18]

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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [6] Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women. Arch Toxicol. 2017 May;91(5):2067-2078. doi: 10.1007/s00204-016-1879-4. Epub 2016 Nov 12.
• [7] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [8] 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.
• [9] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [10] Polyunsaturated fatty acids synergize with lipid droplet binding thalidomide analogs to induce oxidative stress in cancer cells. Lipids Health Dis. 2010 Jun 2;9:56. doi: 10.1186/1476-511X-9-56.
• [11] 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.
• [12] Febuxostat Increases Ventricular Arrhythmogenesis Through Calcium Handling Dysregulation in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Toxicol Sci. 2022 Sep 24;189(2):216-224. doi: 10.1093/toxsci/kfac073.
• [13] Effects of resveratrol on gene expression in renal cell carcinoma. Cancer Biol Ther. 2004 Sep;3(9):882-8. doi: 10.4161/cbt.3.9.1056. Epub 2004 Sep 21.
• [14] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] 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.
• [17] In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.
• [18] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.