Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF7H7L7)

• DOT Name: Mitogen-activated protein kinase 7 (MAPK7)
• Synonyms: MAP kinase 7; MAPK 7; EC 2.7.11.24; Big MAP kinase 1; BMK-1; Extracellular signal-regulated kinase 5; ERK-5
• Gene Name: MAPK7
• UniProt ID: MK07_HUMAN
• PDB ID: 2Q8Y; 4B99; 4IC7; 4IC8; 4ZSG; 4ZSJ; 4ZSL; 5BYY; 5BYZ; 5O7I; 6HKM; 6HKN; 7PUS
• EC Number: 2.7.11.24
• Pfam ID: PF00069
• Sequence:
  MAEPLKEEDGEDGSAEPPGPVKAEPAHTAASVAAKNLALLKARSFDVTFDVGDEYEIIET
  IGNGAYGVVSSARRRLTGQQVAIKKIPNAFDVVTNAKRTLRELKILKHFKHDNIIAIKDI
  LRPTVPYGEFKSVYVVLDLMESDLHQIIHSSQPLTLEHVRYFLYQLLRGLKYMHSAQVIH
  RDLKPSNLLVNENCELKIGDFGMARGLCTSPAEHQYFMTEYVATRWYRAPELMLSLHEYT
  QAIDLWSVGCIFGEMLARRQLFPGKNYVHQLQLIMMVLGTPSPAVIQAVGAERVRAYIQS
  LPPRQPVPWETVYPGADRQALSLLGRMLRFEPSARISAAAALRHPFLAKYHDPDDEPDCA
  PPFDFAFDREALTRERIKEAIVAEIEDFHARREGIRQQIRFQPSLQPVASEPGCPDVEMP
  SPWAPSGDCAMESPPPAPPPCPGPAPDTIDLTLQPPPPVSEPAPPKKDGAISDNTKAALK
  AALLKSLRSRLRDGPSAPLEAPEPRKPVTAQERQREREEKRRRRQERAKEREKRRQERER
  KERGAGASGGPSTDPLAGLVLSDNDRSLLERWTRMARPAAPALTSVPAPAPAPTPTPTPV
  QPTSPPPGPVAQPTGPQPQSAGSTSGPVPQPACPPPGPAPHPTGPPGPIPVPAPPQIATS
  TSLLAAQSLVPPPGLPGSSTPGVLPYFPPGLPPPDAGGAPQSSMSESPDVNLVTQQLSKS
  QVEDPLPPVFSGTPKGSGAGYGVGFDLEEFLNQSFDMGVADGPQDGQADSASLSASLLAD
  WLEGHGMNPADIESLQREIQMDSPMLLADLPDLQDP
• Function: Plays a role in various cellular processes such as proliferation, differentiation and cell survival. The upstream activator of MAPK7 is the MAPK kinase MAP2K5. Upon activation, it translocates to the nucleus and phosphorylates various downstream targets including MEF2C. EGF activates MAPK7 through a Ras-independent and MAP2K5-dependent pathway. As part of the MAPK/ERK signaling pathway, acts as a negative regulator of apoptosis in cardiomyocytes via interaction with STUB1/CHIP and promotion of STUB1-mediated ubiquitination and degradation of ICER-type isoforms of CREM. May have a role in muscle cell differentiation. May be important for endothelial function and maintenance of blood vessel integrity. MAP2K5 and MAPK7 interact specifically with one another and not with MEK1/ERK1 or MEK2/ERK2 pathways. Phosphorylates SGK1 at Ser-78 and this is required for growth factor-induced cell cycle progression. Involved in the regulation of p53/TP53 by disrupting the PML-MDM2 interaction.
• Tissue Specificity: Expressed in many adult tissues. Abundant in heart, placenta, lung, kidney and skeletal muscle. Not detectable in liver.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Gap junction (hsa04540)
  IL-17 sig.ling pathway (hsa04657)
  Neurotrophin sig.ling pathway (hsa04722)
  GnRH sig.ling pathway (hsa04912)
  Oxytocin sig.ling pathway (hsa04921)
  MicroR.s in cancer (hsa05206)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  Signalling to ERK5 (R-HSA-198765)
  ERKs are inactivated (R-HSA-202670)
  Senescence-Associated Secretory Phenotype (SASP) (R-HSA-2559582)
  Gastrin-CREB signalling pathway via PKC and MAPK (R-HSA-881907)
  RET signaling (R-HSA-8853659)
  ERK/MAPK targets (R-HSA-198753)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Mitogen-activated protein kinase 7 (MAPK7) decreases the response to substance of Cisplatin.	[15]
Fluorouracil	DMUM7HZ	Approved	Mitogen-activated protein kinase 7 (MAPK7) decreases the response to substance of Fluorouracil.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Mitogen-activated protein kinase 7 (MAPK7).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Mitogen-activated protein kinase 7 (MAPK7).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitogen-activated protein kinase 7 (MAPK7).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Mitogen-activated protein kinase 7 (MAPK7).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Mitogen-activated protein kinase 7 (MAPK7).	[6]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Mitogen-activated protein kinase 7 (MAPK7).	[7]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Mitogen-activated protein kinase 7 (MAPK7).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Mitogen-activated protein kinase 7 (MAPK7).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mitogen-activated protein kinase 7 (MAPK7).	[11]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Mitogen-activated protein kinase 7 (MAPK7).	[13]
Cycloheximide	DMGDA3C	Investigative	Cycloheximide increases the expression of Mitogen-activated protein kinase 7 (MAPK7).	[14]

4 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 7 (MAPK7).	[5]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the phosphorylation of Mitogen-activated protein kinase 7 (MAPK7).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Mitogen-activated protein kinase 7 (MAPK7).	[12]
(E)-4-(3,5-dimethoxystyryl)phenol	DMYXI2V	Investigative	(E)-4-(3,5-dimethoxystyryl)phenol increases the phosphorylation of Mitogen-activated protein kinase 7 (MAPK7).	[9]

References

• [1] 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.
• [2] 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.
• [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] Estrogen Regulates MAPK-Related Genes through Genomic and Nongenomic Interactions between IGF-I Receptor Tyrosine Kinase and Estrogen Receptor-Alpha Signaling Pathways in Human Uterine Leiomyoma Cells. J Signal Transduct. 2012;2012:204236. doi: 10.1155/2012/204236. Epub 2012 Oct 9.
• [5] 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.
• [6] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [7] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] ERK5/HDAC5-mediated, resveratrol-, and pterostilbene-induced expression of MnSOD in human endothelial cells. Mol Nutr Food Res. 2016 Feb;60(2):266-77. doi: 10.1002/mnfr.201500466. Epub 2015 Oct 23.
• [10] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [11] 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.
• [12] 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.
• [13] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [14] Comparative analysis of AhR-mediated TCDD-elicited gene expression in human liver adult stem cells. Toxicol Sci. 2009 Nov;112(1):229-44.
• [15] A new high resolution screening method for study of phenotype stress responses of Saccharomyces cerevisae mutants. J Microbiol Methods. 2011 Dec;87(3):363-7. doi: 10.1016/j.mimet.2011.10.003. Epub 2011 Oct 8.