Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8GPFT5)

• DOT Name: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform (PPP2R5E)
• Synonyms: PP2A B subunit isoform B'-epsilon; PP2A B subunit isoform B56-epsilon; PP2A B subunit isoform PR61-epsilon; PP2A B subunit isoform R5-epsilon
• Gene Name: PPP2R5E
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Alzheimer disease
  B-cell lymphoma
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Fragile X syndrome
  Glioblastoma multiforme
  Lung cancer
  Lung carcinoma
  Neoplasm
  Sarcoma
  Soft tissue sarcoma
  Gastric cancer
  Stomach cancer
  Dengue
• UniProt ID: 2A5E_HUMAN
• Pfam ID: PF01603
• Sequence:
  MSSAPTTPPSVDKVDGFSRKSVRKARQKRSQSSSQFRSQGKPIELTPLPLLKDVPSSEQP
  ELFLKKLQQCCVIFDFMDTLSDLKMKEYKRSTLNELVDYITISRGCLTEQTYPEVVRMVS
  CNIFRTLPPSDSNEFDPEEDEPTLEASWPHLQLVYEFFIRFLESQEFQPSIAKKYIDQKF
  VLQLLELFDSEDPRERDYLKTVLHRIYGKFLGLRAFIRKQINNIFLRFVYETEHFNGVAE
  LLEILGSIINGFALPLKAEHKQFLVKVLIPLHTVRSLSLFHAQLAYCIVQFLEKDPSLTE
  PVIRGLMKFWPKTCSQKEVMFLGELEEILDVIEPSQFVKIQEPLFKQIAKCVSSPHFQVA
  ERALYYWNNEYIMSLIEENSNVILPIMFSSLYRISKEHWNPAIVALVYNVLKAFMEMNST
  MFDELTATYKSDRQREKKKEKEREELWKKLEDLELKRGLRRDGIIPT
• Function: The B regulatory subunit might modulate substrate selectivity and catalytic activity, and also might direct the localization of the catalytic enzyme to a particular subcellular compartment.
• KEGG Pathway:
  mR. surveillance pathway (hsa03015)
  Sphingolipid sig.ling pathway (hsa04071)
  Cell cycle (hsa04110)
  Oocyte meiosis (hsa04114)
  PI3K-Akt sig.ling pathway (hsa04151)
  AMPK sig.ling pathway (hsa04152)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  T cell receptor sig.ling pathway (hsa04660)
  Dopaminergic sy.pse (hsa04728)
  Human papillomavirus infection (hsa05165)
• Reactome Pathway:
  Degradation of beta-catenin by the destruction complex (R-HSA-195253)
  Beta-catenin phosphorylation cascade (R-HSA-196299)
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  CTLA4 inhibitory signaling (R-HSA-389513)
  Platelet sensitization by LDL (R-HSA-432142)
  Disassembly of the destruction complex and recruitment of AXIN to the membrane (R-HSA-4641262)
  Signaling by GSK3beta mutants (R-HSA-5339716)
  CTNNB1 S33 mutants aren't phosphorylated (R-HSA-5358747)
  CTNNB1 S37 mutants aren't phosphorylated (R-HSA-5358749)
  CTNNB1 S45 mutants aren't phosphorylated (R-HSA-5358751)
  CTNNB1 T41 mutants aren't phosphorylated (R-HSA-5358752)
  APC truncation mutants have impaired AXIN binding (R-HSA-5467337)
  AXIN missense mutants destabilize the destruction complex (R-HSA-5467340)
  Truncations of AMER1 destabilize the destruction complex (R-HSA-5467348)
  RHO GTPases Activate Formins (R-HSA-5663220)
  RAF activation (R-HSA-5673000)
  Negative regulation of MAPK pathway (R-HSA-5675221)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  Mitotic Prometaphase (R-HSA-68877)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[1]
B-cell lymphoma	DISIH1YQ	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Fragile X syndrome	DISE8W3A	Strong	Biomarker	[6]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[1]
Lung cancer	DISCM4YA	Strong	Biomarker	[7]
Lung carcinoma	DISTR26C	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Sarcoma	DISZDG3U	Strong	Genetic Variation	[8]
Soft tissue sarcoma	DISSN8XB	Strong	Genetic Variation	[8]
Gastric cancer	DISXGOUK	moderate	Biomarker	[2]
Stomach cancer	DISKIJSX	moderate	Biomarker	[2]
Dengue	DISKH221	Limited	Genetic Variation	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitomycin	DMH0ZJE	Approved	Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform (PPP2R5E) decreases the response to substance of Mitomycin.	[22]
Camptothecin	DM6CHNJ	Phase 3	Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform (PPP2R5E) decreases the response to substance of Camptothecin.	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform (PPP2R5E).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform (PPP2R5E).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform (PPP2R5E).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform (PPP2R5E).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform (PPP2R5E).	[14]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform (PPP2R5E).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform (PPP2R5E).	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform (PPP2R5E).	[20]
Taurine	DMVW7N3	Investigative	Taurine decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform (PPP2R5E).	[21]

4 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 affects the methylation of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform (PPP2R5E).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform (PPP2R5E).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform (PPP2R5E).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit epsilon isoform (PPP2R5E).	[17]

References

• [1] Downregulation of protein phosphatase 2A by apolipoprotein E: Implications for Alzheimer's disease.Mol Cell Neurosci. 2017 Sep;83:83-91. doi: 10.1016/j.mcn.2017.07.002. Epub 2017 Jul 15.
• [2] Downregulation of PPP2R5E expression by miR-23a suppresses apoptosis to facilitate the growth of gastric cancer cells.FEBS Lett. 2014 Aug 25;588(17):3160-9. doi: 10.1016/j.febslet.2014.05.068. Epub 2014 Jul 2.
• [3] MiR-17-92 represses PTPROt and PP2A phosphatases and amplifies tonic BCR signaling in DLBCL cells.Exp Hematol. 2017 Feb;46:56-61.e1. doi: 10.1016/j.exphem.2016.09.011. Epub 2016 Oct 6.
• [4] Protein phosphatase 2A subunit gene haplotypes and proliferative breast disease modify breast cancer risk.Cancer. 2010 Jan 1;116(1):8-19. doi: 10.1002/cncr.24702.
• [5] PP2A inhibition is a common event in colorectal cancer and its restoration using FTY720 shows promising therapeutic potential.Mol Cancer Ther. 2014 Apr;13(4):938-47. doi: 10.1158/1535-7163.MCT-13-0150. Epub 2014 Jan 21.
• [6] High expression of miR-510 was associated with CGG expansion located at upstream of FMR1 into full mutation.J Cell Biochem. 2019 Feb;120(2):1916-1923. doi: 10.1002/jcb.27505. Epub 2018 Aug 30.
• [7] Functional genetic polymorphisms in PP2A subunit genes confer increased risks of lung cancer in southern and eastern Chinese.PLoS One. 2013 Oct 29;8(10):e77285. doi: 10.1371/journal.pone.0077285. eCollection 2013.
• [8] PP2A:B56{epsilon}, a substrate of caspase-3, regulates p53-dependent and p53-independent apoptosis during development.J Biol Chem. 2010 Nov 5;285(45):34493-502. doi: 10.1074/jbc.M110.169581. Epub 2010 Aug 31.
• [9] Joint ancestry and association test indicate two distinct pathogenic pathways involved in classical dengue fever and dengue shock syndrome.PLoS Negl Trop Dis. 2018 Feb 15;12(2):e0006202. doi: 10.1371/journal.pntd.0006202. eCollection 2018 Feb.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [15] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [16] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [17] 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.
• [18] 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.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [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] Taurine-responsive genes related to signal transduction as identified by cDNA microarray analyses of HepG2 cells. J Med Food. 2006 Spring;9(1):33-41. doi: 10.1089/jmf.2006.9.33.
• [22] PP2A-B56? complex is involved in dephosphorylation of -H2AX in the repair process of CPT-induced DNA double-strand breaks. Toxicology. 2015 May 4;331:57-65. doi: 10.1016/j.tox.2015.03.007. Epub 2015 Mar 12.