Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDDNF3Q)

• DOT Name: Mitogen-activated protein kinase 6 (MAPK6)
• Synonyms: MAP kinase 6; MAPK 6; EC 2.7.11.24; Extracellular signal-regulated kinase 3; ERK-3; MAP kinase isoform p97; p97-MAPK
• Gene Name: MAPK6
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Carcinoma
  Cervical cancer
  Cervical carcinoma
  Gout
  Head and neck neoplasm
  Intrahepatic cholangiocarcinoma
  Neuralgia
  Squamous cell carcinoma
  Colon cancer
  Colon carcinoma
  Hyperplasia
  Metastatic malignant neoplasm
  Neoplasm
  Carcinoma of liver and intrahepatic biliary tract
  Fetal growth restriction
  Head and neck cancer
  Head and neck carcinoma
  Liver cancer
  Lung cancer
  Lung carcinoma
  Melanoma
• UniProt ID: MK06_HUMAN
• PDB ID: 6YKY; 6YLC; 6YLL; 7AQB
• EC Number: 2.7.11.24
• Pfam ID: PF00069
• Sequence:
  MAEKFESLMNIHGFDLGSRYMDLKPLGCGGNGLVFSAVDNDCDKRVAIKKIVLTDPQSVK
  HALREIKIIRRLDHDNIVKVFEILGPSGSQLTDDVGSLTELNSVYIVQEYMETDLANVLE
  QGPLLEEHARLFMYQLLRGLKYIHSANVLHRDLKPANLFINTEDLVLKIGDFGLARIMDP
  HYSHKGHLSEGLVTKWYRSPRLLLSPNNYTKAIDMWAAGCIFAEMLTGKTLFAGAHELEQ
  MQLILESIPVVHEEDRQELLSVIPVYIRNDMTEPHKPLTQLLPGISREALDFLEQILTFS
  PMDRLTAEEALSHPYMSIYSFPMDEPISSHPFHIEDEVDDILLMDETHSHIYNWERYHDC
  QFSEHDWPVHNNFDIDEVQLDPRALSDVTDEEEVQVDPRKYLDGDREKYLEDPAFDTNYS
  TEPCWQYSDHHENKYCDLECSHTCNYKTRSSSYLDNLVWRESEVNHYYEPKLIIDLSNWK
  EQSKEKSDKKGKSKCERNGLVKAQIALEEASQQLAGKEREKNQGFDFDSFIAGTIQLSSQ
  HEPTDVVDKLNDLNSSVSQLELKSLISKSVSQEKQEKGMANLAQLEALYQSSWDSQFVSG
  GEDCFFINQFCEVRKDEQVEKENTYTSYLDKFFSRKEDTEMLETEPVEDGKLGERGHEEG
  FLNNSGEFLFNKQLESIGIPQFHSPVGSPLKSIQATLTPSAMKSSPQIPHQTYSSILKHL
  N
• Function: Atypical MAPK protein. Phosphorylates microtubule-associated protein 2 (MAP2) and MAPKAPK5. The precise role of the complex formed with MAPKAPK5 is still unclear, but the complex follows a complex set of phosphorylation events: upon interaction with atypical MAPKAPK5, ERK3/MAPK6 is phosphorylated at Ser-189 and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK3/MAPK6. May promote entry in the cell cycle.
• Tissue Specificity: Highest expression in the skeletal muscle, followed by the brain. Also found in heart, placenta, lung, liver, pancreas, kidney and skin fibroblasts.
• KEGG Pathway: IL-17 sig.ling pathway (hsa04657)
• Reactome Pathway: MAPK6/MAPK4 signaling (R-HSA-5687128)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Carcinoma	DISH9F1N	Strong	Altered Expression	[3]
Cervical cancer	DISFSHPF	Strong	Biomarker	[4]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[4]
Gout	DISHC0U7	Strong	Genetic Variation	[5]
Head and neck neoplasm	DIS1OB2G	Strong	Altered Expression	[6]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Biomarker	[7]
Neuralgia	DISWO58J	Strong	Biomarker	[8]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[9]
Colon cancer	DISVC52G	moderate	Genetic Variation	[10]
Colon carcinoma	DISJYKUO	moderate	Genetic Variation	[10]
Hyperplasia	DISK4DFB	moderate	Biomarker	[11]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[10]
Neoplasm	DISZKGEW	moderate	Biomarker	[7]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Altered Expression	[12]
Fetal growth restriction	DIS5WEJ5	Limited	Genetic Variation	[13]
Head and neck cancer	DISBPSQZ	Limited	Biomarker	[14]
Head and neck carcinoma	DISOU1DS	Limited	Biomarker	[14]
Liver cancer	DISDE4BI	Limited	Altered Expression	[12]
Lung cancer	DISCM4YA	Limited	Altered Expression	[14]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[14]
Melanoma	DIS1RRCY	Limited	Altered Expression	[14]

12 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 6 (MAPK6).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mitogen-activated protein kinase 6 (MAPK6).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitogen-activated protein kinase 6 (MAPK6).	[17]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Mitogen-activated protein kinase 6 (MAPK6).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Mitogen-activated protein kinase 6 (MAPK6).	[19]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Mitogen-activated protein kinase 6 (MAPK6).	[20]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Mitogen-activated protein kinase 6 (MAPK6).	[21]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Mitogen-activated protein kinase 6 (MAPK6).	[22]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Mitogen-activated protein kinase 6 (MAPK6).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mitogen-activated protein kinase 6 (MAPK6).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Mitogen-activated protein kinase 6 (MAPK6).	[25]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of Mitogen-activated protein kinase 6 (MAPK6).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Mitogen-activated protein kinase 6 (MAPK6).	[26]

References

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• [2] Long non-coding RNA SNHG6 enhances cell proliferation, migration and invasion by regulating miR-26a-5p/MAPK6 in breast cancer.Biomed Pharmacother. 2019 Feb;110:294-301. doi: 10.1016/j.biopha.2018.11.016. Epub 2018 Dec 3.
• [3] ERK3 signals through SRC-3 coactivator to promote human lung cancer cell invasion.J Clin Invest. 2012 May;122(5):1869-80. doi: 10.1172/JCI61492. Epub 2012 Apr 16.
• [4] MiR-144-3p: a novel tumor suppressor targeting MAPK6 in cervical cancer.J Physiol Biochem. 2019 Jun;75(2):143-152. doi: 10.1007/s13105-019-00681-9. Epub 2019 Apr 23.
• [5] Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response. Clin Pharmacol Ther. 2015 May;97(5):518-25.
• [6] A regulatory BMI1/let-7i/ERK3 pathway controls the motility of head and neck cancer cells.Mol Oncol. 2017 Feb;11(2):194-207. doi: 10.1002/1878-0261.12021. Epub 2017 Jan 12.
• [7] Metformin potentiates the effect of arsenic trioxide suppressing intrahepatic cholangiocarcinoma: roles of p38 MAPK, ERK3, and mTORC1.J Hematol Oncol. 2017 Feb 28;10(1):59. doi: 10.1186/s13045-017-0424-0.
• [8] Effects of miR-26a-5p on neuropathic pain development by targeting MAPK6 in in CCI rat models.Biomed Pharmacother. 2018 Nov;107:644-649. doi: 10.1016/j.biopha.2018.08.005. Epub 2018 Aug 15.
• [9] Induction of p97MAPK expression regulates collagen mediated inhibition of proliferation and migration in human squamous cell carcinoma lines.Int J Oncol. 2004 May;24(5):1159-63.
• [10] L290P/V mutations increase ERK3's cytoplasmic localization and migration/invasion-promoting capability in cancer cells.Sci Rep. 2017 Nov 3;7(1):14979. doi: 10.1038/s41598-017-15135-9.
• [11] Early induction of cytokines/cytokine receptors and Cox2, and activation of NF-B in 4-nitroquinoline 1-oxide-induced murine oral cancer model.Toxicol Appl Pharmacol. 2012 Jul 15;262(2):107-16. doi: 10.1016/j.taap.2012.04.023. Epub 2012 Apr 25.
• [12] LncMAPK6 drives MAPK6 expression and liver TIC self-renewal.J Exp Clin Cancer Res. 2018 May 15;37(1):105. doi: 10.1186/s13046-018-0770-y.
• [13] Reevaluation of the Role of Extracellular Signal-Regulated Kinase 3 in Perinatal Survival and Postnatal Growth Using New Genetically Engineered Mouse Models.Mol Cell Biol. 2019 Mar 1;39(6):e00527-18. doi: 10.1128/MCB.00527-18. Print 2019 Mar 15.
• [14] The atypical MAPK ERK3 potently suppresses melanoma cell growth and invasiveness.J Cell Physiol. 2019 Aug;234(8):13220-13232. doi: 10.1002/jcp.27994. Epub 2018 Dec 19.
• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [16] 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.
• [17] 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.
• [18] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [19] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [20] 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.
• [21] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [22] Differentially expressed genes in the prostate cancer cell line LNCaP after exposure to androgen and anti-androgen. Cancer Genet Cytogenet. 2006 Apr 15;166(2):130-8. doi: 10.1016/j.cancergencyto.2005.09.012.
• [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] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [26] 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.
• [27] Chromatin modifiers: A new class of pollutants with potential epigenetic effects revealed by in vitro assays and transcriptomic analyses. Toxicology. 2023 Jan 15;484:153413. doi: 10.1016/j.tox.2022.153413. Epub 2022 Dec 26.