Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7IWJNI)

• DOT Name: MAP kinase-activated protein kinase 3 (MAPKAPK3)
• Synonyms: MAPK-activated protein kinase 3; MAPKAP kinase 3; MAPKAP-K3; MAPKAPK-3; MK-3; EC 2.7.11.1; Chromosome 3p kinase; 3pK
• Gene Name: MAPKAPK3
• Related Disease: Patterned macular dystrophy 3
• UniProt ID: MAPK3_HUMAN
• PDB ID: 3FHR; 3FXW; 3R1N; 3SHE; 7NRB
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MDGETAEEQGGPVPPPVAPGGPGLGGAPGGRREPKKYAVTDDYQLSKQVLGLGVNGKVLE
  CFHRRTGQKCALKLLYDSPKARQEVDHHWQASGGPHIVCILDVYENMHHGKRCLLIIMEC
  MEGGELFSRIQERGDQAFTEREAAEIMRDIGTAIQFLHSHNIAHRDVKPENLLYTSKEKD
  AVLKLTDFGFAKETTQNALQTPCYTPYYVAPEVLGPEKYDKSCDMWSLGVIMYILLCGFP
  PFYSNTGQAISPGMKRRIRLGQYGFPNPEWSEVSEDAKQLIRLLLKTDPTERLTITQFMN
  HPWINQSMVVPQTPLHTARVLQEDKDHWDEVKEEMTSALATMRVDYDQVKIKDLKTSNNR
  LLNKRRKKQAGSSSASQGCNNQ
• Function: Stress-activated serine/threonine-protein kinase involved in cytokines production, endocytosis, cell migration, chromatin remodeling and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38-alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X(2)-S, where Hyd is a large hydrophobic residue. MAPKAPK2 and MAPKAPK3, share the same function and substrate specificity, but MAPKAPK3 kinase activity and level in protein expression are lower compared to MAPKAPK2. Phosphorylates HSP27/HSPB1, KRT18, KRT20, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to dissociate HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impair their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins, such as TTP/ZFP36, leading to regulate the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity leading to inhibition of dependent degradation of ARE-containing transcript. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3. Also acts as a modulator of Polycomb-mediated repression.
• Tissue Specificity: Widely expressed, with a higher expression level observed in heart and skeletal muscle. No expression in brain. Expressed in the retinal pigment epithelium .
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  VEGF sig.ling pathway (hsa04370)
• Reactome Pathway:
  Oxidative Stress Induced Senescence (R-HSA-2559580)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  activated TAK1 mediates p38 MAPK activation (R-HSA-450302)
  p38MAPK events (R-HSA-171007)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Patterned macular dystrophy 3	DISWISXK	Strong	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cycloheximide	DMGDA3C	Investigative	MAP kinase-activated protein kinase 3 (MAPKAPK3) affects the response to substance of Cycloheximide.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of MAP kinase-activated protein kinase 3 (MAPKAPK3).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of MAP kinase-activated protein kinase 3 (MAPKAPK3).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of MAP kinase-activated protein kinase 3 (MAPKAPK3).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of MAP kinase-activated protein kinase 3 (MAPKAPK3).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of MAP kinase-activated protein kinase 3 (MAPKAPK3).	[6]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of MAP kinase-activated protein kinase 3 (MAPKAPK3).	[7]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of MAP kinase-activated protein kinase 3 (MAPKAPK3).	[8]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of MAP kinase-activated protein kinase 3 (MAPKAPK3).	[9]
Nefazodone	DM4ZS8M	Approved	Nefazodone increases the expression of MAP kinase-activated protein kinase 3 (MAPKAPK3).	[10]
Atazanavir	DMSYRBX	Approved	Atazanavir increases the expression of MAP kinase-activated protein kinase 3 (MAPKAPK3).	[10]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of MAP kinase-activated protein kinase 3 (MAPKAPK3).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of MAP kinase-activated protein kinase 3 (MAPKAPK3).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of MAP kinase-activated protein kinase 3 (MAPKAPK3).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of MAP kinase-activated protein kinase 3 (MAPKAPK3).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of MAP kinase-activated protein kinase 3 (MAPKAPK3).	[14]

References

• [1] A dominant mutation in MAPKAPK3, an actor of p38 signaling pathway, causes a new retinal dystrophy involving Bruch's membrane and retinal pigment epithelium. Hum Mol Genet. 2016 Mar 1;25(5):916-26. doi: 10.1093/hmg/ddv624. Epub 2016 Jan 6.
• [2] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [3] 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.
• [4] 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.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] 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.
• [8] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [9] 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.
• [10] Robustness testing and optimization of an adverse outcome pathway on cholestatic liver injury. Arch Toxicol. 2020 Apr;94(4):1151-1172. doi: 10.1007/s00204-020-02691-9. Epub 2020 Mar 10.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [14] 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.
• [15] 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.
• [16] Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study. Environ Health Perspect. 2015 May;123(5):458-66. doi: 10.1289/ehp.1408775. Epub 2015 Jan 13.