Details of Drug Off-Target (DOT)

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

• DOT Name: Mitogen-activated protein kinase 4 (MAPK4)
• Synonyms: MAP kinase 4; MAPK 4; EC 2.7.11.24; Extracellular signal-regulated kinase 4; ERK-4; MAP kinase isoform p63; p63-MAPK
• Gene Name: MAPK4
• Related Disease:
  Advanced cancer
  Lung adenocarcinoma
  Neoplasm
  Thyroid gland carcinoma
  Leishmaniasis
  Psychotic disorder
  Schizophrenia
• UniProt ID: MK04_HUMAN
• EC Number: 2.7.11.24
• Pfam ID: PF00069
• Sequence:
  MAEKGDCIASVYGYDLGGRFVDFQPLGFGVNGLVLSAVDSRACRKVAVKKIALSDARSMK
  HALREIKIIRRLDHDNIVKVYEVLGPKGTDLQGELFKFSVAYIVQEYMETDLARLLEQGT
  LAEEHAKLFMYQLLRGLKYIHSANVLHRDLKPANIFISTEDLVLKIGDFGLARIVDQHYS
  HKGYLSEGLVTKWYRSPRLLLSPNNYTKAIDMWAAGCILAEMLTGRMLFAGAHELEQMQL
  ILETIPVIREEDKDELLRVMPSFVSSTWEVKRPLRKLLPEVNSEAIDFLEKILTFNPMDR
  LTAEMGLQHPYMSPYSCPEDEPTSQHPFRIEDEIDDIVLMAANQSQLSNWDTCSSRYPVS
  LSSDLEWRPDRCQDASEVQRDPRAGSAPLAEDVQVDPRKDSHSSSERFLEQSHSSMERAF
  EADYGRSCDYKVGSPSYLDKLLWRDNKPHHYSEPKLILDLSHWKQAAGAPPTATGLADTG
  AREDEPASLFLEIAQWVKSTQGGPEHASPPADDPERRLSASPPGRPAPVDGGASPQFDLD
  VFISRALKLCTKPEDLPDNKLGDLNGACIPEHPGDLVQTEAFSKERW
• Function: Atypical MAPK protein. Phosphorylates microtubule-associated protein 2 (MAP2) and MAPKAPK5. The precise role of the complex formed with MAPKAPK5 is still unclear, but the complex follows a complex set of phosphorylation events: upon interaction with atypical MAPKAPK5, ERK4/MAPK4 is phosphorylated at Ser-186 and then mediates phosphorylation and activation of MAPKAPK5, which in turn phosphorylates ERK4/MAPK4. May promote entry in the cell cycle.
• Tissue Specificity: High expression in heart and brain.
• KEGG Pathway: IL-17 sig.ling pathway (hsa04657)
• Reactome Pathway: MAPK6/MAPK4 signaling (R-HSA-5687128)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Thyroid gland carcinoma	DISMNGZ0	Strong	Altered Expression	[1]
Leishmaniasis	DISABTW7	Disputed	Biomarker	[2]
Psychotic disorder	DIS4UQOT	Limited	Genetic Variation	[3]
Schizophrenia	DISSRV2N	Limited	Biomarker	[3]

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 Mitogen-activated protein kinase 4 (MAPK4).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Mitogen-activated protein kinase 4 (MAPK4).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Mitogen-activated protein kinase 4 (MAPK4).	[11]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the acetylation of Mitogen-activated protein kinase 4 (MAPK4).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitogen-activated protein kinase 4 (MAPK4).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Mitogen-activated protein kinase 4 (MAPK4).	[6]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Mitogen-activated protein kinase 4 (MAPK4).	[7]
IRX4204	DM9SCME	Phase 1	IRX4204 decreases the expression of Mitogen-activated protein kinase 4 (MAPK4).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Mitogen-activated protein kinase 4 (MAPK4).	[10]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Mitogen-activated protein kinase 4 (MAPK4).	[12]

References

• [1] MAPK4 overexpression promotes tumor progression via noncanonical activation of AKT/mTOR signaling.J Clin Invest. 2019 Mar 1;129(3):1015-1029. doi: 10.1172/JCI97712. Epub 2019 Jan 28.
• [2] Linear B-cell epitope mapping of MAPK3 and MAPK4 from Leishmania braziliensis: implications for the serodiagnosis of human and canine leishmaniasis.Appl Microbiol Biotechnol. 2015 Feb;99(3):1323-36. doi: 10.1007/s00253-014-6168-7. Epub 2014 Oct 31.
• [3] Pilot study for family-based association analysis of schizophrenia in a Korean population: Analysis for candidate genes positionally on chromosome 18q21.Asia Pac Psychiatry. 2015 Sep;7(3):268-75. doi: 10.1111/appy.12167. Epub 2014 Dec 12.
• [4] 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.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [7] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [8] 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.
• [9] A retinoid X receptor (RXR)-selective retinoid reveals that RXR-alpha is potentially a therapeutic target in breast cancer cell lines, and that it potentiates antiproliferative and apoptotic responses to peroxisome proliferator-activated receptor ligands. Breast Cancer Res. 2004;6(5):R546-55. doi: 10.1186/bcr913. Epub 2004 Jul 23.
• [10] 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.
• [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] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [13] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.