Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYKB9G3)

• DOT Name: Target of rapamycin complex 2 subunit MAPKAP1 (MAPKAP1)
• Synonyms: TORC2 subunit MAPKAP1; Mitogen-activated protein kinase 2-associated protein 1; Stress-activated map kinase-interacting protein 1; SAPK-interacting protein 1; mSIN1
• Gene Name: MAPKAP1
• UniProt ID: SIN1_HUMAN
• PDB ID: 3VOQ; 5ZCS; 6ZWM; 6ZWO; 7LC1; 7LC2; 7PE7; 7PE8; 7PE9; 7TZO; 7VV8; 7VV9; 7VVB; 7VVG
• Pfam ID: PF16978 ; PF05422 ; PF16979
• Sequence:
  MAFLDNPTIILAHIRQSHVTSDDTGMCEMVLIDHDVDLEKIHPPSMPGDSGSEIQGSNGE
  TQGYVYAQSVDITSSWDFGIRRRSNTAQRLERLRKERQNQIKCKNIQWKERNSKQSAQEL
  KSLFEKKSLKEKPPISGKQSILSVRLEQCPLQLNNPFNEYSKFDGKGHVGTTATKKIDVY
  LPLHSSQDRLLPMTVVTMASARVQDLIGLICWQYTSEGREPKLNDNVSAYCLHIAEDDGE
  VDTDFPPLDSNEPIHKFGFSTLALVEKYSSPGLTSKESLFVRINAAHGFSLIQVDNTKVT
  MKEILLKAVKRRKGSQKVSGPQYRLEKQSEPNVAVDLDSTLESQSAWEFCLVRENSSRAD
  GVFEEDSQIDIATVQDMLSSHHYKSFKVSMIHRLRFTTDVQLGISGDKVEIDPVTNQKAS
  TKFWIKQKPISIDSDLLCACDLAEEKSPSHAIFKLTYLSNHDYKHLYFESDAATVNEIVL
  KVNYILESRASTARADYFAQKQRKLNRRTSFSFQKEKKSGQQ
• Function: Subunit of mTORC2, which regulates cell growth and survival in response to hormonal signals. mTORC2 is activated by growth factors, but, in contrast to mTORC1, seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. Within mTORC2, MAPKAP1 is required for complex formation and mTORC2 kinase activity. MAPKAP1 inhibits MAP3K2 by preventing its dimerization and autophosphorylation. Inhibits HRAS and KRAS signaling. Enhances osmotic stress-induced phosphorylation of ATF2 and ATF2-mediated transcription. Involved in ciliogenesis, regulates cilia length through its interaction with CCDC28B independently of mTORC2 complex.
• Tissue Specificity: Ubiquitously expressed, with highest levels in heart and skeletal muscle.
• KEGG Pathway: mTOR sig.ling pathway (hsa04150)
• Reactome Pathway:
  CD28 dependent PI3K/Akt signaling (R-HSA-389357)
  VEGFR2 mediated vascular permeability (R-HSA-5218920)
  Constitutive Signaling by AKT1 E17K in Cancer (R-HSA-5674400)
  Regulation of TP53 Degradation (R-HSA-6804757)
  PIP3 activates AKT signaling (R-HSA-1257604)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Target of rapamycin complex 2 subunit MAPKAP1 (MAPKAP1).	[1]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Target of rapamycin complex 2 subunit MAPKAP1 (MAPKAP1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Target of rapamycin complex 2 subunit MAPKAP1 (MAPKAP1).	[2]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Target of rapamycin complex 2 subunit MAPKAP1 (MAPKAP1).	[3]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Target of rapamycin complex 2 subunit MAPKAP1 (MAPKAP1).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Target of rapamycin complex 2 subunit MAPKAP1 (MAPKAP1).	[5]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Target of rapamycin complex 2 subunit MAPKAP1 (MAPKAP1).	[6]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Target of rapamycin complex 2 subunit MAPKAP1 (MAPKAP1).	[7]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Target of rapamycin complex 2 subunit MAPKAP1 (MAPKAP1).	[8]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Target of rapamycin complex 2 subunit MAPKAP1 (MAPKAP1).	[9]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Target of rapamycin complex 2 subunit MAPKAP1 (MAPKAP1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Target of rapamycin complex 2 subunit MAPKAP1 (MAPKAP1).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Target of rapamycin complex 2 subunit MAPKAP1 (MAPKAP1).	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Target of rapamycin complex 2 subunit MAPKAP1 (MAPKAP1).	[14]

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] 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.
• [3] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [4] 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.
• [5] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [6] 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.
• [7] Transcriptional profiling of MCF7 breast cancer cells in response to 5-Fluorouracil: relationship with cell cycle changes and apoptosis, and identification of novel targets of p53. Int J Cancer. 2006 Sep 1;119(5):1164-75.
• [8] Gingival Stromal Cells as an In Vitro Model: Cannabidiol Modulates Genes Linked With Amyotrophic Lateral Sclerosis. J Cell Biochem. 2017 Apr;118(4):819-828. doi: 10.1002/jcb.25757. Epub 2016 Nov 28.
• [9] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [10] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [11] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.