Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT24GMCM)

• DOT Name: Serine/threonine-protein phosphatase 2A catalytic subunit beta isoform (PPP2CB)
• Synonyms: PP2A-beta; EC 3.1.3.16
• Gene Name: PPP2CB
• Related Disease:
  Bladder cancer
  Prostate neoplasm
  Urinary bladder cancer
  Urinary bladder neoplasm
  Werner syndrome
  Adenocarcinoma
  Neoplasm
• UniProt ID: PP2AB_HUMAN
• EC Number: 3.1.3.16
• Pfam ID: PF00149
• Sequence:
  MDDKAFTKELDQWVEQLNECKQLNENQVRTLCEKAKEILTKESNVQEVRCPVTVCGDVHG
  QFHDLMELFRIGGKSPDTNYLFMGDYVDRGYYSVETVTLLVALKVRYPERITILRGNHES
  RQITQVYGFYDECLRKYGNANVWKYFTDLFDYLPLTALVDGQIFCLHGGLSPSIDTLDHI
  RALDRLQEVPHEGPMCDLLWSDPDDRGGWGISPRGAGYTFGQDISETFNHANGLTLVSRA
  HQLVMEGYNWCHDRNVVTIFSAPNYCYRCGNQAAIMELDDTLKYSFLQFDPAPRRGEPHV
  TRRTPDYFL
• Function: Catalytic subunit of protein phosphatase 2A (PP2A), a serine/threonine phosphatase involved in the regulation of a wide variety of enzymes, signal transduction pathways, and cellular events (Probable). PP2A can modulate the activity of phosphorylase B kinase, casein kinase 2, mitogen-stimulated S6 kinase, and MAP-2 kinase.
• KEGG Pathway:
  mR. surveillance pathway (hsa03015)
  Sphingolipid sig.ling pathway (hsa04071)
  Cell cycle (hsa04110)
  Oocyte meiosis (hsa04114)
  Autophagy - other (hsa04136)
  Autophagy - animal (hsa04140)
  PI3K-Akt sig.ling pathway (hsa04151)
  AMPK sig.ling pathway (hsa04152)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  TGF-beta sig.ling pathway (hsa04350)
  Hippo sig.ling pathway (hsa04390)
  Tight junction (hsa04530)
  T cell receptor sig.ling pathway (hsa04660)
  Dopaminergic sy.pse (hsa04728)
  Long-term depression (hsa04730)
  Chagas disease (hsa05142)
  Hepatitis C (hsa05160)
  Human papillomavirus infection (hsa05165)
• Reactome Pathway:
  Spry regulation of FGF signaling (R-HSA-1295596)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)
  Integration of energy metabolism (R-HSA-163685)
  PP2A-mediated dephosphorylation of key metabolic factors (R-HSA-163767)
  DARPP-32 events (R-HSA-180024)
  Degradation of beta-catenin by the destruction complex (R-HSA-195253)
  Beta-catenin phosphorylation cascade (R-HSA-196299)
  ERK/MAPK targets (R-HSA-198753)
  ERKs are inactivated (R-HSA-202670)
  MASTL Facilitates Mitotic Progression (R-HSA-2465910)
  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)
  Regulation of TP53 Degradation (R-HSA-6804757)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  Mitotic Prometaphase (R-HSA-68877)
  Cyclin D associated events in G1 (R-HSA-69231)
  Cyclin A/B1/B2 associated events during G2/M transition (R-HSA-69273)
  Regulation of glycolysis by fructose 2,6-bisphosphate metabolism (R-HSA-9634600)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  PKR-mediated signaling (R-HSA-9833482)
  Inhibition of replication initiation of damaged DNA by RB1/E2F1 (R-HSA-113501)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder cancer	DISUHNM0	Strong	Biomarker	[1]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[2]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[1]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[1]
Werner syndrome	DISZY45W	moderate	Biomarker	[3]
Adenocarcinoma	DIS3IHTY	Disputed	Genetic Variation	[4]
Neoplasm	DISZKGEW	Disputed	Biomarker	[5]

15 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 Serine/threonine-protein phosphatase 2A catalytic subunit beta isoform (PPP2CB).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit beta isoform (PPP2CB).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit beta isoform (PPP2CB).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit beta isoform (PPP2CB).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit beta isoform (PPP2CB).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit beta isoform (PPP2CB).	[12]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Serine/threonine-protein phosphatase 2A catalytic subunit beta isoform (PPP2CB).	[13]
Menadione	DMSJDTY	Approved	Menadione increases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit beta isoform (PPP2CB).	[11]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit beta isoform (PPP2CB).	[14]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit beta isoform (PPP2CB).	[15]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit beta isoform (PPP2CB).	[16]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit beta isoform (PPP2CB).	[17]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit beta isoform (PPP2CB).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit beta isoform (PPP2CB).	[19]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit beta isoform (PPP2CB).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Serine/threonine-protein phosphatase 2A catalytic subunit beta isoform (PPP2CB).	[9]

References

• [1] Mutation analysis of 8p genes POLB and PPP2CB in bladder cancer.Cancer Genet Cytogenet. 1997 Feb;93(2):167-71. doi: 10.1016/s0165-4608(96)00200-2.
• [2] Protein phosphatase and TRAIL receptor genes as new candidate tumor genes on chromosome 8p in prostate cancer.Cancer Genomics Proteomics. 2008 Mar-Apr;5(2):123-36.
• [3] A 2.8 megabase YAC contig spanning D8S339, which is tightly linked to the Werner syndrome locus.Genome. 1997 Feb;40(1):77-83. doi: 10.1139/g97-010.
• [4] Integrated analysis of genome-wide copy number alterations and gene expression in microsatellite stable, CpG island methylator phenotype-negative colon cancer.Genes Chromosomes Cancer. 2013 May;52(5):450-66. doi: 10.1002/gcc.22043. Epub 2013 Jan 23.
• [5] miRNA-1246 induces pro-inflammatory responses in mesenchymal stem/stromal cells by regulating PKA and PP2A.Oncotarget. 2017 Jul 4;8(27):43897-43914. doi: 10.18632/oncotarget.14915.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [11] Gene expression after treatment with hydrogen peroxide, menadione, or t-butyl hydroperoxide in breast cancer cells. Cancer Res. 2002 Nov 1;62(21):6246-54.
• [12] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [13] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [14] Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery. Mol Cancer. 2006 May 18;5:20. doi: 10.1186/1476-4598-5-20.
• [15] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [16] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [17] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [18] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [19] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [20] Integrated analysis of paraquat-induced microRNAs-mRNAs changes in human neural progenitor cells. Toxicol In Vitro. 2017 Oct;44:196-205. doi: 10.1016/j.tiv.2017.06.010. Epub 2017 Jun 12.