Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNA9G8V)

• DOT Name: MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2)
• Synonyms: EC 2.7.11.1; MAP kinase signal-integrating kinase 2; MAPK signal-integrating kinase 2; Mnk2
• Gene Name: MKNK2
• UniProt ID: MKNK2_HUMAN
• PDB ID: 2AC3; 2AC5; 2HW7; 6CJ5; 6CJE; 6CJH; 6CJW; 6CJY; 6CK3; 6CK6; 6CKI; 6JLR
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MVQKKPAELQGFHRSFKGQNPFELAFSLDQPDHGDSDFGLQCSARPDMPASQPIDIPDAK
  KRGKKKKRGRATDSFSGRFEDVYQLQEDVLGEGAHARVQTCINLITSQEYAVKIIEKQPG
  HIRSRVFREVEMLYQCQGHRNVLELIEFFEEEDRFYLVFEKMRGGSILSHIHKRRHFNEL
  EASVVVQDVASALDFLHNKGIAHRDLKPENILCEHPNQVSPVKICDFDLGSGIKLNGDCS
  PISTPELLTPCGSAEYMAPEVVEAFSEEASIYDKRCDLWSLGVILYILLSGYPPFVGRCG
  SDCGWDRGEACPACQNMLFESIQEGKYEFPDKDWAHISCAAKDLISKLLVRDAKQRLSAA
  QVLQHPWVQGCAPENTLPTPMVLQRNSCAKDLTSFAAEAIAMNRQLAQHDEDLAEEEAAG
  QGQPVLVRATSRCLQLSPPSQSKLAQRRQRASLSSAPVVLVGDHA
• Function: Serine/threonine-protein kinase that phosphorylates SFPQ/PSF, HNRNPA1 and EIF4E. May play a role in the response to environmental stress and cytokines. Appears to regulate translation by phosphorylating EIF4E, thus increasing the affinity of this protein for the 7-methylguanosine-containing mRNA cap. Required for mediating PP2A-inhibition-induced EIF4E phosphorylation. Triggers EIF4E shuttling from cytoplasm to nucleus. Isoform 1 displays a high basal kinase activity, but isoform 2 exhibits a very low kinase activity. Acts as a mediator of the suppressive effects of IFNgamma on hematopoiesis. Negative regulator for signals that control generation of arsenic trioxide As(2)O(3)-dependent apoptosis and anti-leukemic responses. Involved in anti-apoptotic signaling in response to serum withdrawal.
• Tissue Specificity: Ubiquitously expressed in all tissues examined. Isoform 2 is expressed at higher levels in the ovary than is isoform 1.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  HIF-1 sig.ling pathway (hsa04066)
  Insulin sig.ling pathway (hsa04910)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2) decreases the response to substance of Arsenic trioxide.	[22]
Topotecan	DMP6G8T	Approved	MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2) affects the response to substance of Topotecan.	[23]

1 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 MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[8]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[5]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[10]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[11]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[12]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[13]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[14]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[20]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of MAP kinase-interacting serine/threonine-protein kinase 2 (MKNK2).	[21]

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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [6] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [9] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [10] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [11] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] 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.
• [16] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [17] 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.
• [18] 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.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [21] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [22] Regulation of arsenic trioxide-induced cellular responses by Mnk1 and Mnk2. J Biol Chem. 2008 May 2;283(18):12034-42. doi: 10.1074/jbc.M708816200. Epub 2008 Feb 25.
• [23] 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.