Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT460SBO)

• DOT Name: MAP kinase-activated protein kinase 2 (MAPKAPK2)
• Synonyms: MAPK-activated protein kinase 2; MAPKAP kinase 2; MAPKAP-K2; MAPKAPK-2; MK-2; MK2; EC 2.7.11.1
• Gene Name: MAPKAPK2
• UniProt ID: MAPK2_HUMAN
• PDB ID: 1KWP; 1NXK; 1NY3; 2JBO; 2JBP; 2OKR; 2ONL; 2OZA; 2P3G; 2PZY; 3A2C; 3FPM; 3FYJ; 3FYK; 3GOK; 3KA0; 3KC3; 3KGA; 3M2W; 3M42; 3R2B; 3R2Y; 3R30; 3WI6; 4TYH; 6T8X; 6TCA; 7NRY
• EC Number: 2.7.11.1
• Pfam ID: PF00069
• Sequence:
  MLSNSQGQSPPVPFPAPAPPPQPPTPALPHPPAQPPPPPPQQFPQFHVKSGLQIKKNAII
  DDYKVTSQVLGLGINGKVLQIFNKRTQEKFALKMLQDCPKARREVELHWRASQCPHIVRI
  VDVYENLYAGRKCLLIVMECLDGGELFSRIQDRGDQAFTEREASEIMKSIGEAIQYLHSI
  NIAHRDVKPENLLYTSKRPNAILKLTDFGFAKETTSHNSLTTPCYTPYYVAPEVLGPEKY
  DKSCDMWSLGVIMYILLCGYPPFYSNHGLAISPGMKTRIRMGQYEFPNPEWSEVSEEVKM
  LIRNLLKTEPTQRMTITEFMNHPWIMQSTKVPQTPLHTSRVLKEDKERWEDVKEEMTSAL
  ATMRVDYEQIKIKKIEDASNPLLLKRRKKARALEAAALAH
• Function: Stress-activated serine/threonine-protein kinase involved in cytokine production, endocytosis, reorganization of the cytoskeleton, cell migration, cell cycle control, chromatin remodeling, DNA damage response 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. Phosphorylates ALOX5, CDC25B, CDC25C, CEP131, ELAVL1, HNRNPA0, HSP27/HSPB1, KRT18, KRT20, LIMK1, LSP1, PABPC1, PARN, PDE4A, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Phosphorylates HSF1; leading to the interaction with HSP90 proteins and inhibiting HSF1 homotrimerization, DNA-binding and transactivation activities. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to the dissociation of HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impairment of 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 ELAVL1, HNRNPA0, PABPC1 and TTP/ZFP36, leading to the regulation of 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 transcripts. Phosphorylates CEP131 in response to cellular stress induced by ultraviolet irradiation which promotes binding of CEP131 to 14-3-3 proteins and inhibits formation of novel centriolar satellites. Also involved in late G2/M checkpoint following DNA damage through a process of post-transcriptional mRNA stabilization: following DNA damage, relocalizes from nucleus to cytoplasm and phosphorylates HNRNPA0 and PARN, leading to stabilization of GADD45A mRNA. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3.
• Tissue Specificity: Expressed in all tissues examined.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Efferocytosis (hsa04148)
  Cellular senescence (hsa04218)
  VEGF sig.ling pathway (hsa04370)
  C-type lectin receptor sig.ling pathway (hsa04625)
  Neurotrophin sig.ling pathway (hsa04722)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway:
  CREB phosphorylation (R-HSA-199920)
  Synthesis of Leukotrienes (LT) and Eoxins (EX) (R-HSA-2142691)
  Oxidative Stress Induced Senescence (R-HSA-2559580)
  Regulation of HSF1-mediated heat shock response (R-HSA-3371453)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  activated TAK1 mediates p38 MAPK activation (R-HSA-450302)
  Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA (R-HSA-450385)
  Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA (R-HSA-450513)
  Regulation of TNFR1 signaling (R-HSA-5357905)
  p38MAPK events (R-HSA-171007)
• BioCyc Pathway: MetaCyc:HS08751-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the activity of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[8]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[9]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[11]
Sorbitol	DMAN0DE	Approved	Sorbitol increases the activity of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[6]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[13]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[14]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the activity of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[16]
PMID26560530-Compound-35	DMO36RL	Patented	PMID26560530-Compound-35 decreases the activity of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[17]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[21]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[22]
KN-62	DMLZ89P	Investigative	KN-62 decreases the activity of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[17]
Talmapimod	DMMTSL2	Investigative	Talmapimod decreases the activity of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Decitabine	DMQL8XJ	Approved	Decitabine affects the methylation of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[10]
Rifampicin	DM5DSFZ	Approved	Rifampicin increases the phosphorylation of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[15]
SB 203580	DMAET6F	Terminated	SB 203580 decreases the phosphorylation of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[20]
Sulfate	DMW0ZBF	Investigative	Sulfate affects the methylation of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[23]
EM-101	DMQ63J2	Investigative	EM-101 increases the phosphorylation of MAP kinase-activated protein kinase 2 (MAPKAPK2).	[25]

References

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• [6] The phosphorylation of eukaryotic initiation factor eIF4E in response to phorbol esters, cell stresses, and cytokines is mediated by distinct MAP kinase pathways. J Biol Chem. 1998 Apr 17;273(16):9373-7. doi: 10.1074/jbc.273.16.9373.
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• [19] Fluoride-induced cyclooxygenase-2 expression and prostaglandin E2 production in A549 human pulmonary epithelial cells. Toxicol Lett. 2009 Aug 10;188(3):180-5.
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• [22] 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.
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• [24] Inhibition of p38alpha MAPK enhances proteasome inhibitor-induced apoptosis of myeloma cells by modulating Hsp27, Bcl-X(L), Mcl-1 and p53 levels in vitro and inhibits tumor growth in vivo. Leukemia. 2006 Jun;20(6):1017-27. doi: 10.1038/sj.leu.2404200.
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