Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTCKE27)

• DOT Name: Mitogen-activated protein kinase 12 (MAPK12)
• Synonyms: MAP kinase 12; MAPK 12; EC 2.7.11.24; Extracellular signal-regulated kinase 6; ERK-6; Mitogen-activated protein kinase p38 gamma; MAP kinase p38 gamma; Stress-activated protein kinase 3
• Gene Name: MAPK12
• UniProt ID: MK12_HUMAN
• PDB ID: 1CM8; 4QUM; 6UNA; 7CGA
• EC Number: 2.7.11.24
• Pfam ID: PF00069
• Sequence:
  MSSPPPARSGFYRQEVTKTAWEVRAVYRDLQPVGSGAYGAVCSAVDGRTGAKVAIKKLYR
  PFQSELFAKRAYRELRLLKHMRHENVIGLLDVFTPDETLDDFTDFYLVMPFMGTDLGKLM
  KHEKLGEDRIQFLVYQMLKGLRYIHAAGIIHRDLKPGNLAVNEDCELKILDFGLARQADS
  EMTGYVVTRWYRAPEVILNWMRYTQTVDIWSVGCIMAEMITGKTLFKGSDHLDQLKEIMK
  VTGTPPAEFVQRLQSDEAKNYMKGLPELEKKDFASILTNASPLAVNLLEKMLVLDAEQRV
  TAGEALAHPYFESLHDTEDEPQVQKYDDSFDDVDRTLDEWKRVTYKEVLSFKPPRQLGAR
  VSKETPL
• Function: Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK12 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as pro-inflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in myoblast differentiation and also in the down-regulation of cyclin D1 in response to hypoxia in adrenal cells suggesting MAPK12 may inhibit cell proliferation while promoting differentiation. Phosphorylates DLG1. Following osmotic shock, MAPK12 in the cell nucleus increases its association with nuclear DLG1, thereby causing dissociation of DLG1-SFPQ complexes. This function is independent of its catalytic activity and could affect mRNA processing and/or gene transcription to aid cell adaptation to osmolarity changes in the environment. Regulates UV-induced checkpoint signaling and repair of UV-induced DNA damage and G2 arrest after gamma-radiation exposure. MAPK12 is involved in the regulation of SLC2A1 expression and basal glucose uptake in L6 myotubes; and negatively regulates SLC2A4 expression and contraction-mediated glucose uptake in adult skeletal muscle. C-Jun (JUN) phosphorylation is stimulated by MAPK14 and inhibited by MAPK12, leading to a distinct AP-1 regulation. MAPK12 is required for the normal kinetochore localization of PLK1, prevents chromosomal instability and supports mitotic cell viability. MAPK12-signaling is also positively regulating the expansion of transient amplifying myogenic precursor cells during muscle growth and regeneration.
• Tissue Specificity: Highly expressed in skeletal muscle and heart.
• KEGG Pathway:
  Endocrine resistance (hsa01522)
  MAPK sig.ling pathway (hsa04010)
  Rap1 sig.ling pathway (hsa04015)
  FoxO sig.ling pathway (hsa04068)
  Sphingolipid sig.ling pathway (hsa04071)
  Oocyte meiosis (hsa04114)
  Efferocytosis (hsa04148)
  Cellular senescence (hsa04218)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  VEGF sig.ling pathway (hsa04370)
  Osteoclast differentiation (hsa04380)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  Platelet activation (hsa04611)
  Neutrophil extracellular trap formation (hsa04613)
  Toll-like receptor sig.ling pathway (hsa04620)
  NOD-like receptor sig.ling pathway (hsa04621)
  RIG-I-like receptor sig.ling pathway (hsa04622)
  C-type lectin receptor sig.ling pathway (hsa04625)
  IL-17 sig.ling pathway (hsa04657)
  Th1 and Th2 cell differentiation (hsa04658)
  Th17 cell differentiation (hsa04659)
  T cell receptor sig.ling pathway (hsa04660)
  Fc epsilon RI sig.ling pathway (hsa04664)
  TNF sig.ling pathway (hsa04668)
  Leukocyte transendothelial migration (hsa04670)
  Thermogenesis (hsa04714)
  Neurotrophin sig.ling pathway (hsa04722)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Dopaminergic sy.pse (hsa04728)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  GnRH sig.ling pathway (hsa04912)
  Progesterone-mediated oocyte maturation (hsa04914)
  Prolactin sig.ling pathway (hsa04917)
  Relaxin sig.ling pathway (hsa04926)
  Non-alcoholic fatty liver disease (hsa04932)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Growth hormone synthesis, secretion and action (hsa04935)
  Alcoholic liver disease (hsa04936)
  Amyotrophic lateral sclerosis (hsa05014)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Epithelial cell sig.ling in Helicobacter pylori infection (hsa05120)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Pertussis (hsa05133)
  Yersinia infection (hsa05135)
  Leishmaniasis (hsa05140)
  Chagas disease (hsa05142)
  Toxoplasmosis (hsa05145)
  Tuberculosis (hsa05152)
  Hepatitis B (hsa05161)
  Human cytomegalovirus infection (hsa05163)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Coro.virus disease - COVID-19 (hsa05171)
  Proteoglycans in cancer (hsa05205)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
  Diabetic cardiomyopathy (hsa05415)
  Lipid and atherosclerosis (hsa05417)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  p38MAPK events (R-HSA-171007)
  Activation of PPARGC1A (PGC-1alpha) by phosphorylation (R-HSA-2151209)
  DSCAM interactions (R-HSA-376172)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  Myogenesis (R-HSA-525793)
  Negative regulation of MAPK pathway (R-HSA-5675221)
  NOD1/2 Signaling Pathway (R-HSA-168638)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	Mitogen-activated protein kinase 12 (MAPK12) decreases the response to substance of Afimoxifene.	[17]

3 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 Mitogen-activated protein kinase 12 (MAPK12).	[1]
Sorbitol	DMAN0DE	Approved	Sorbitol increases the phosphorylation of Mitogen-activated protein kinase 12 (MAPK12).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Mitogen-activated protein kinase 12 (MAPK12).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Mitogen-activated protein kinase 12 (MAPK12).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Mitogen-activated protein kinase 12 (MAPK12).	[3]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Mitogen-activated protein kinase 12 (MAPK12).	[4]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Mitogen-activated protein kinase 12 (MAPK12).	[5]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Mitogen-activated protein kinase 12 (MAPK12).	[6]
Etoposide	DMNH3PG	Approved	Etoposide increases the activity of Mitogen-activated protein kinase 12 (MAPK12).	[7]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Mitogen-activated protein kinase 12 (MAPK12).	[8]
Amsacrine	DMZKYIV	Approved	Amsacrine increases the activity of Mitogen-activated protein kinase 12 (MAPK12).	[7]
Curcumin	DMQPH29	Phase 3	Curcumin increases the activity of Mitogen-activated protein kinase 12 (MAPK12).	[10]
SB 203580	DMAET6F	Terminated	SB 203580 decreases the expression of Mitogen-activated protein kinase 12 (MAPK12).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Mitogen-activated protein kinase 12 (MAPK12).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Mitogen-activated protein kinase 12 (MAPK12).	[14]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Mitogen-activated protein kinase 12 (MAPK12).	[15]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Mitogen-activated protein kinase 12 (MAPK12).	[16]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl decreases the expression of Mitogen-activated protein kinase 12 (MAPK12).	[16]
Methyl Mercury Ion	DM6YEW4	Investigative	Methyl Mercury Ion decreases the expression of Mitogen-activated protein kinase 12 (MAPK12).	[16]

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] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Real-time monitoring of cisplatin-induced cell death. PLoS One. 2011;6(5):e19714. doi: 10.1371/journal.pone.0019714. Epub 2011 May 16.
• [4] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [5] Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis. J Cell Biochem. 2017 Apr;118(4):819-828. doi: 10.1002/jcb.25757. Epub 2016 Nov 28.
• [6] Aspirin and alterations in DNA repair proteins in the SW480 colorectal cancer cell line. Oncol Rep. 2010 Jul;24(1):37-46. doi: 10.3892/or_00000826.
• [7] Phosphorylation and stabilization of topoisomerase II protein by p38 mitogen-activated protein kinase sensitize breast cancer cells to its poisons. J Biol Chem. 2011 Oct 14;286(41):35883-35890. doi: 10.1074/jbc.M111.229260. Epub 2011 Aug 30.
• [8] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [9] A novel UBA and UBX domain protein that binds polyubiquitin and VCP and is a substrate for SAPKs. Biochem J. 2004 Dec 1;384(Pt 2):391-400. doi: 10.1042/BJ20041498.
• [10] Curcumin suppresses growth of mesothelioma cells in vitro and in vivo, in part, by stimulating apoptosis. Mol Cell Biochem. 2011 Nov;357(1-2):83-94. doi: 10.1007/s11010-011-0878-2. Epub 2011 May 19.
• [11] 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.
• [12] Cadmium effects on p38/MAPK isoforms in MDA-MB231 breast cancer cells. Biometals. 2010 Feb;23(1):83-92. doi: 10.1007/s10534-009-9268-6. Epub 2009 Sep 15.
• [13] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [14] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [15] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [16] Inhibition of CXCL12-mediated chemotaxis of Jurkat cells by direct immunotoxicants. Arch Toxicol. 2016 Jul;90(7):1685-94. doi: 10.1007/s00204-015-1585-7. Epub 2015 Aug 28.
• [17] 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.