Details of Drug Off-Target (DOT)

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

• DOT Name: MAP kinase-activated protein kinase 5 (MAPKAPK5)
• Synonyms: MAPK-activated protein kinase 5; MAPKAP kinase 5; MAPKAP-K5; MAPKAPK-5; MK-5; MK5; EC 2.7.11.1; p38-regulated/activated protein kinase; PRAK
• Gene Name: MAPKAPK5
• Related Disease: Neurocardiofaciodigital syndrome
• UniProt ID: MAPK5_HUMAN
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MSEESDMDKAIKETSILEEYSINWTQKLGAGISGPVRVCVKKSTQERFALKILLDRPKAR
  NEVRLHMMCATHPNIVQIIEVFANSVQFPHESSPRARLLIVMEMMEGGELFHRISQHRHF
  TEKQASQVTKQIALALRHCHLLNIAHRDLKPENLLFKDNSLDAPVKLCDFGFAKIDQGDL
  MTPQFTPYYVAPQVLEAQRRHQKEKSGIIPTSPTPYTYNKSCDLWSLGVIIYVMLCGYPP
  FYSKHHSRTIPKDMRRKIMTGSFEFPEEEWSQISEMAKDVVRKLLKVKPEERLTIEGVLD
  HPWLNSTEALDNVLPSAQLMMDKAVVAGIQQAHAEQLANMRIQDLKVSLKPLHSVNNPIL
  RKRKLLGTKPKDSVYIHDHENGAEDSNVALEKLRDVIAQCILPQAGKGENEDEKLNEVMQ
  EAWKYNRECKLLRDTLQSFSWNGRGFTDKVDRLKLAEIVKQVIEEQTTSHESQ
• Function: Tumor suppressor serine/threonine-protein kinase involved in mTORC1 signaling and post-transcriptional regulation. Phosphorylates FOXO3, ERK3/MAPK6, ERK4/MAPK4, HSP27/HSPB1, p53/TP53 and RHEB. Acts as a tumor suppressor by mediating Ras-induced senescence and phosphorylating p53/TP53. Involved in post-transcriptional regulation of MYC by mediating phosphorylation of FOXO3: phosphorylation of FOXO3 leads to promote nuclear localization of FOXO3, enabling expression of miR-34b and miR-34c, 2 post-transcriptional regulators of MYC that bind to the 3'UTR of MYC transcript and prevent MYC translation. Acts as a negative regulator of mTORC1 signaling by mediating phosphorylation and inhibition of RHEB. Part of the atypical MAPK signaling via its interaction with ERK3/MAPK6 or ERK4/MAPK4: the precise role of the complex formed with ERK3/MAPK6 or ERK4/MAPK4 is still unclear, but the complex follows a complex set of phosphorylation events: upon interaction with atypical MAPK (ERK3/MAPK6 or ERK4/MAPK4), ERK3/MAPK6 (or ERK4/MAPK4) is phosphorylated and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK3/MAPK6 (or ERK4/MAPK4). Mediates phosphorylation of HSP27/HSPB1 in response to PKA/PRKACA stimulation, inducing F-actin rearrangement.
• Tissue Specificity: Expressed ubiquitously.
• KEGG Pathway: MAPK sig.ling pathway (hsa04010)
• Reactome Pathway:
  MAPK6/MAPK4 signaling (R-HSA-5687128)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  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
Neurocardiofaciodigital syndrome	DISBITY7	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	MAP kinase-activated protein kinase 5 (MAPKAPK5) affects the response to substance of Paclitaxel.	[12]
Vinblastine	DM5TVS3	Approved	MAP kinase-activated protein kinase 5 (MAPKAPK5) affects the response to substance of Vinblastine.	[12]

12 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 MAP kinase-activated protein kinase 5 (MAPKAPK5).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of MAP kinase-activated protein kinase 5 (MAPKAPK5).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of MAP kinase-activated protein kinase 5 (MAPKAPK5).	[4]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the activity of MAP kinase-activated protein kinase 5 (MAPKAPK5).	[5]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of MAP kinase-activated protein kinase 5 (MAPKAPK5).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of MAP kinase-activated protein kinase 5 (MAPKAPK5).	[8]
PMID26560530-Compound-35	DMO36RL	Patented	PMID26560530-Compound-35 decreases the activity of MAP kinase-activated protein kinase 5 (MAPKAPK5).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of MAP kinase-activated protein kinase 5 (MAPKAPK5).	[10]
cinnamaldehyde	DMZDUXG	Investigative	cinnamaldehyde increases the expression of MAP kinase-activated protein kinase 5 (MAPKAPK5).	[11]
U0126	DM31OGF	Investigative	U0126 decreases the activity of MAP kinase-activated protein kinase 5 (MAPKAPK5).	[9]
KN-62	DMLZ89P	Investigative	KN-62 decreases the activity of MAP kinase-activated protein kinase 5 (MAPKAPK5).	[9]
KT 5823	DMOBYU3	Investigative	KT 5823 decreases the activity of MAP kinase-activated protein kinase 5 (MAPKAPK5).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of MAP kinase-activated protein kinase 5 (MAPKAPK5).	[7]

References

• [1] Biallelic truncating variants in MAPKAPK5 cause a new developmental disorder involving neurological, cardiac, and facial anomalies combined with synpolydactyly. Genet Med. 2021 Apr;23(4):679-688. doi: 10.1038/s41436-020-01052-2. Epub 2021 Jan 13.
• [2] 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.
• [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] 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] The specificities of protein kinase inhibitors: an update. Biochem J. 2003 Apr 1;371(Pt 1):199-204. doi: 10.1042/BJ20021535.
• [6] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [7] 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.
• [8] 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.
• [9] Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct 1;351(Pt 1):95-105.
• [10] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [11] Comparative DNA microarray analysis of human monocyte derived dendritic cells and MUTZ-3 cells exposed to the moderate skin sensitizer cinnamaldehyde. Toxicol Appl Pharmacol. 2009 Sep 15;239(3):273-83.
• [12] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.