Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1Q40TZ)

• DOT Name: Dual specificity mitogen-activated protein kinase kinase 7 (MAP2K7)
• Synonyms: MAP kinase kinase 7; MAPKK 7; EC 2.7.12.2; JNK-activating kinase 2; MAPK/ERK kinase 7; MEK 7; Stress-activated protein kinase kinase 4; SAPK kinase 4; SAPKK-4; SAPKK4; c-Jun N-terminal kinase kinase 2; JNK kinase 2; JNKK 2
• Gene Name: MAP2K7
• Related Disease: Schizophrenia
• UniProt ID: MP2K7_HUMAN
• PDB ID: 2DYL ; 3WZU ; 4UX9 ; 5B2K ; 5B2L ; 5B2M ; 5Y8U ; 5Y90 ; 5Z1D ; 5Z1E ; 6IB0 ; 6IB2 ; 6QFL ; 6QFR ; 6QFT ; 6QG4 ; 6QG7 ; 6QHO ; 6QHR ; 6YFZ ; 6YG0 ; 6YG1 ; 6YG2 ; 6YG3 ; 6YG4 ; 6YG5 ; 6YG6 ; 6YG7 ; 6YZ4 ; 7CBX ; 7OVI ; 7OVJ ; 7OVK ; 7OVL ; 7OVM ; 7OVN
• EC Number: 2.7.12.2
• Pfam ID: PF00069
• Sequence:
  MAASSLEQKLSRLEAKLKQENREARRRIDLNLDISPQRPRPTLQLPLANDGGSRSPSSES
  SPQHPTPPARPRHMLGLPSTLFTPRSMESIEIDQKLQEIMKQTGYLTIGGQRYQAEINDL
  ENLGEMGSGTCGQVWKMRFRKTGHVIAVKQMRRSGNKEENKRILMDLDVVLKSHDCPYIV
  QCFGTFITNTDVFIAMELMGTCAEKLKKRMQGPIPERILGKMTVAIVKALYYLKEKHGVI
  HRDVKPSNILLDERGQIKLCDFGISGRLVDSKAKTRSAGCAAYMAPERIDPPDPTKPDYD
  IRADVWSLGISLVELATGQFPYKNCKTDFEVLTKVLQEEPPLLPGHMGFSGDFQSFVKDC
  LTKDHRKRPKYNKLLEHSFIKRYETLEVDVASWFKDVMAKTESPRTSGVLSQPHLPFFR
• Function: Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K4/MKK4, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4/MKK4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The monophosphorylation of JNKs on the Thr residue is sufficient to increase JNK activity indicating that MAP2K7/MKK7 is important to trigger JNK activity, while the additional phosphorylation of the Tyr residue by MAP2K4/MKK4 ensures optimal JNK activation. Has a specific role in JNK signal transduction pathway activated by pro-inflammatory cytokines. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Part of a non-canonical MAPK signaling pathway, composed of the upstream MAP3K12 kinase and downstream MAP kinases MAPK1/ERK2 and MAPK3/ERK1, that enhances the AP-1-mediated transcription of APP in response to APOE.
• Tissue Specificity: Ubiquitous; with highest level of expression in skeletal muscle. Isoform 3 is found at low levels in placenta, fetal liver, and skeletal muscle.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  ErbB sig.ling pathway (hsa04012)
  Protein processing in endoplasmic reticulum (hsa04141)
  Osteoclast differentiation (hsa04380)
  Tight junction (hsa04530)
  Toll-like receptor sig.ling pathway (hsa04620)
  T cell receptor sig.ling pathway (hsa04660)
  Fc epsilon RI sig.ling pathway (hsa04664)
  TNF sig.ling pathway (hsa04668)
  Neurotrophin sig.ling pathway (hsa04722)
  GnRH sig.ling pathway (hsa04912)
  Relaxin sig.ling pathway (hsa04926)
  Alcoholic liver disease (hsa04936)
  Alzheimer disease (hsa05010)
  Huntington disease (hsa05016)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Salmonella infection (hsa05132)
  Yersinia infection (hsa05135)
  Hepatitis B (hsa05161)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Lipid and atherosclerosis (hsa05417)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  FCERI mediated MAPK activation (R-HSA-2871796)
  JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 (R-HSA-450321)
  Uptake and function of anthrax toxins (R-HSA-5210891)
  Oxidative Stress Induced Senescence (R-HSA-2559580)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Schizophrenia	DISSRV2N	No Known	Unknown	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	Dual specificity mitogen-activated protein kinase kinase 7 (MAP2K7) decreases the response to substance of Afimoxifene.	[15]

4 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 mitogen-activated protein kinase kinase 7 (MAP2K7).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Dual specificity mitogen-activated protein kinase kinase 7 (MAP2K7).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Dual specificity mitogen-activated protein kinase kinase 7 (MAP2K7).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Dual specificity mitogen-activated protein kinase kinase 7 (MAP2K7).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dual specificity mitogen-activated protein kinase kinase 7 (MAP2K7).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dual specificity mitogen-activated protein kinase kinase 7 (MAP2K7).	[4]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Dual specificity mitogen-activated protein kinase kinase 7 (MAP2K7).	[5]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Dual specificity mitogen-activated protein kinase kinase 7 (MAP2K7).	[6]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Dual specificity mitogen-activated protein kinase kinase 7 (MAP2K7).	[7]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Dual specificity mitogen-activated protein kinase kinase 7 (MAP2K7).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Dual specificity mitogen-activated protein kinase kinase 7 (MAP2K7).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Dual specificity mitogen-activated protein kinase kinase 7 (MAP2K7).	[13]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Dual specificity mitogen-activated protein kinase kinase 7 (MAP2K7).	[14]

References

• [1] Map2k7 Haploinsufficiency Induces Brain Imaging Endophenotypes and Behavioral Phenotypes Relevant to Schizophrenia. Schizophr Bull. 2020 Jan 4;46(1):211-223. doi: 10.1093/schbul/sbz044.
• [2] 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.
• [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] 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.
• [5] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [6] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [7] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [10] 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.
• [11] 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.
• [12] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Deguelin inhibits the migration and invasion of U-2 OS human osteosarcoma cells via the inhibition of matrix metalloproteinase-2/-9 in vitro. Molecules. 2014 Oct 15;19(10):16588-608.
• [15] 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.