Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6T408U)

• DOT Name: Dual specificity mitogen-activated protein kinase kinase 5 (MAP2K5)
• Synonyms: MAP kinase kinase 5; MAPKK 5; EC 2.7.12.2; MAPK/ERK kinase 5; MEK 5
• Gene Name: MAP2K5
• UniProt ID: MP2K5_HUMAN
• PDB ID: 2NPT; 2O2V; 4IC7
• EC Number: 2.7.12.2
• Pfam ID: PF00564 ; PF00069
• Sequence:
  MLWLALGPFPAMENQVLVIRIKIPNSGAVDWTVHSGPQLLFRDVLDVIGQVLPEATTTAF
  EYEDEDGDRITVRSDEEMKAMLSYYYSTVMEQQVNGQLIEPLQIFPRACKPPGERNIHGL
  KVNTRAGPSQHSSPAVSDSLPSNSLKKSSAELKKILANGQMNEQDIRYRDTLGHGNGGTV
  YKAYHVPSGKILAVKVILLDITLELQKQIMSELEILYKCDSSYIIGFYGAFFVENRISIC
  TEFMDGGSLDVYRKMPEHVLGRIAVAVVKGLTYLWSLKILHRDVKPSNMLVNTRGQVKLC
  DFGVSTQLVNSIAKTYVGTNAYMAPERISGEQYGIHSDVWSLGISFMELALGRFPYPQIQ
  KNQGSLMPLQLLQCIVDEDSPVLPVGEFSEPFVHFITQCMRKQPKERPAPEELMGHPFIV
  QFNDGNAAVVSMWVCRALEERRSQQGPP
• Function: Acts as a scaffold for the formation of a ternary MAP3K2/MAP3K3-MAP3K5-MAPK7 signaling complex. Activation of this pathway appears to play a critical role in protecting cells from stress-induced apoptosis, neuronal survival and cardiac development and angiogenesis. As part of the MAPK/ERK signaling pathway, acts as a negative regulator of apoptosis in cardiomyocytes via promotion of STUB1/CHIP-mediated ubiquitination and degradation of ICER-type isoforms of CREM.
• Tissue Specificity: Expressed in many adult tissues. Abundant in heart and skeletal muscle.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Gap junction (hsa04540)
  Neurotrophin sig.ling pathway (hsa04722)
  Oxytocin sig.ling pathway (hsa04921)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway: Signalling to ERK5 (R-HSA-198765)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methamphetamine	DMPM4SK	Approved	Dual specificity mitogen-activated protein kinase kinase 5 (MAP2K5) affects the response to substance of Methamphetamine.	[15]
Afimoxifene	DMFORDT	Phase 2	Dual specificity mitogen-activated protein kinase kinase 5 (MAP2K5) decreases the response to substance of Afimoxifene.	[16]
Formaldehyde	DM7Q6M0	Investigative	Dual specificity mitogen-activated protein kinase kinase 5 (MAP2K5) affects the response to substance of Formaldehyde.	[17]

13 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 Dual specificity mitogen-activated protein kinase kinase 5 (MAP2K5).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Dual specificity mitogen-activated protein kinase kinase 5 (MAP2K5).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dual specificity mitogen-activated protein kinase kinase 5 (MAP2K5).	[3]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Dual specificity mitogen-activated protein kinase kinase 5 (MAP2K5).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Dual specificity mitogen-activated protein kinase kinase 5 (MAP2K5).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Dual specificity mitogen-activated protein kinase kinase 5 (MAP2K5).	[7]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Dual specificity mitogen-activated protein kinase kinase 5 (MAP2K5).	[8]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Dual specificity mitogen-activated protein kinase kinase 5 (MAP2K5).	[7]
Azacitidine	DMTA5OE	Approved	Azacitidine decreases the expression of Dual specificity mitogen-activated protein kinase kinase 5 (MAP2K5).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Dual specificity mitogen-activated protein kinase kinase 5 (MAP2K5).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Dual specificity mitogen-activated protein kinase kinase 5 (MAP2K5).	[12]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Dual specificity mitogen-activated protein kinase kinase 5 (MAP2K5).	[13]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Dual specificity mitogen-activated protein kinase kinase 5 (MAP2K5).	[6]

3 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 mitogen-activated protein kinase kinase 5 (MAP2K5).	[5]
Hesperidin	DMI5DW1	Approved	Hesperidin decreases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 5 (MAP2K5).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Dual specificity mitogen-activated protein kinase kinase 5 (MAP2K5).	[14]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [4] 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.
• [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] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [7] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [8] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [9] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [10] Hesperidin delays cell cycle progression into the G0/G1 phase via suspension of MAPK signaling pathway in intrahepatic cholangiocarcinoma. J Biochem Mol Toxicol. 2022 Apr;36(4):e22981. doi: 10.1002/jbt.22981. Epub 2022 Jan 4.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [13] The genome-wide expression profile of Scrophularia ningpoensis-treated thapsigargin-stimulated U-87MG cells. Neurotoxicology. 2009 May;30(3):368-76.
• [14] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [15] Genome-wide association for methamphetamine dependence: convergent results from 2 samples. Arch Gen Psychiatry. 2008 Mar;65(3):345-55. doi: 10.1001/archpsyc.65.3.345.
• [16] 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.
• [17] Identification of Genes That Modulate Susceptibility to Formaldehyde and Imatinib by Functional Genomic Screening in Human Haploid KBM7 Cells. Toxicol Sci. 2016 May;151(1):10-22. doi: 10.1093/toxsci/kfw032. Epub 2016 Mar 22.