Details of Drug Off-Target (DOT)

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

• DOT Name: Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform (PPP2R1B)
• Synonyms: PP2A subunit A isoform PR65-beta; PP2A subunit A isoform R1-beta
• Gene Name: PPP2R1B
• Related Disease:
  Advanced cancer
  Adenoma
  Benign neoplasm
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Cervical cancer
  Cervical carcinoma
  Colon cancer
  Colon carcinoma
  Colorectal neoplasm
  Hepatocellular carcinoma
  Lung cancer
  Lung neoplasm
  Neoplasm
  Paraganglioma
  Cervical Intraepithelial neoplasia
  Colorectal carcinoma
• UniProt ID: 2AAB_HUMAN
• Pfam ID: PF02985 ; PF13646
• Sequence:
  MAGASELGTGPGAAGGDGDDSLYPIAVLIDELRNEDVQLRLNSIKKLSTIALALGVERTR
  SELLPFLTDTIYDEDEVLLALAEQLGNFTGLVGGPDFAHCLLPPLENLATVEETVVRDKA
  VESLRQISQEHTPVALEAYFVPLVKRLASGDWFTSRTSACGLFSVCYPRASNAVKAEIRQ
  QFRSLCSDDTPMVRRAAASKLGEFAKVLELDSVKSEIVPLFTSLASDEQDSVRLLAVEAC
  VSIAQLLSQDDLETLVMPTLRQAAEDKSWRVRYMVADRFSELQKAMGPKITLNDLIPAFQ
  NLLKDCEAEVRAAAAHKVKELGENLPIEDRETIIMNQILPYIKELVSDTNQHVKSALASV
  IMGLSTILGKENTIEHLLPLFLAQLKDECPDVRLNIISNLDCVNEVIGIRQLSQSLLPAI
  VELAEDAKWRVRLAIIEYMPLLAGQLGVEFFDEKLNSLCMAWLVDHVYAIREAATNNLMK
  LVQKFGTEWAQNTIVPKVLVMANDPNYLHRMTTLFCINALSEACGQEITTKQMLPIVLKM
  AGDQVANVRFNVAKSLQKIGPILDTNALQGEVKPVLQKLGQDEDMDVKYFAQEAISVLAL
  A
• Function: The PR65 subunit of protein phosphatase 2A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit.
• 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)
  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:
  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

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Adenoma	DIS78ZEV	Strong	Biomarker	[2]
Benign neoplasm	DISDUXAD	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[4]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[5]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[6]
Cervical cancer	DISFSHPF	Strong	Biomarker	[7]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[8]
Colon cancer	DISVC52G	Strong	Genetic Variation	[9]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[10]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[12]
Lung cancer	DISCM4YA	Strong	Biomarker	[3]
Lung neoplasm	DISVARNB	Strong	Genetic Variation	[13]
Neoplasm	DISZKGEW	Strong	Altered Expression	[14]
Paraganglioma	DIS2XXH5	Strong	Biomarker	[15]
Cervical Intraepithelial neoplasia	DISXP757	moderate	Biomarker	[8]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform (PPP2R1B).	[17]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform (PPP2R1B).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform (PPP2R1B).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform (PPP2R1B).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform (PPP2R1B).	[21]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform (PPP2R1B).	[22]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform (PPP2R1B).	[23]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform (PPP2R1B).	[24]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform (PPP2R1B).	[24]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform (PPP2R1B).	[25]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid increases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform (PPP2R1B).	[26]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform (PPP2R1B).	[19]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform (PPP2R1B).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform (PPP2R1B).	[30]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform (PPP2R1B).	[31]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform (PPP2R1B).	[32]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform (PPP2R1B).	[33]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform (PPP2R1B).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A beta isoform (PPP2R1B).	[29]

References

• [1] The tumor suppressor PP2A Abeta regulates the RalA GTPase.Cell. 2007 Jun 1;129(5):969-82. doi: 10.1016/j.cell.2007.03.047.
• [2] Alterations in the suppressor gene PPP2R1B in parathyroid hyperplasias and adenomas.Cancer Genet Cytogenet. 2002 Apr 1;134(1):13-7. doi: 10.1016/s0165-4608(01)00597-0.
• [3] Absence of PPP2R1B gene alterations in primary ovarian cancers.Oncogene. 1999 Nov 4;18(46):6367-9. doi: 10.1038/sj.onc.1203070.
• [4] The glycine 90 to aspartate alteration in the Abeta subunit of PP2A (PPP2R1B) associates with breast cancer and causes a deficit in protein function.Genes Chromosomes Cancer. 2006 Feb;45(2):182-90. doi: 10.1002/gcc.20284.
• [5] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [6] Mutation analysis of five candidate genes in familial breast cancer.Breast Cancer Res Treat. 2007 Nov;105(3):377-89. doi: 10.1007/s10549-006-9461-z. Epub 2006 Dec 23.
• [7] Mutation analysis of the tumor suppressor gene PPP2R1B in human cervical cancer.Int J Gynecol Cancer. 2007 Jul-Aug;17(4):868-71. doi: 10.1111/j.1525-1438.2007.00880.x. Epub 2007 Mar 2.
• [8] Alterations of ATM and CADM1 in chromosomal 11q22.3-23.2 region are associated with the development of invasive cervical carcinoma.Hum Genet. 2011 Dec;130(6):735-48. doi: 10.1007/s00439-011-1015-8. Epub 2011 Jun 5.
• [9] PPP2R1B gene in chronic lymphocytic leukemias and mantle cell lymphomas.Leuk Lymphoma. 2001 Mar;41(1-2):177-83. doi: 10.3109/10428190109057968.
• [10] Alterations of the PPP2R1B gene located at 11q23 in human colorectal cancers.Gut. 2000 Aug;47(2):268-71. doi: 10.1136/gut.47.2.268.
• [11] PPP2R1B gene alterations inhibit interaction of PP2A-Abeta and PP2A-C proteins in colorectal cancers.Oncol Rep. 2004 Mar;11(3):655-9.
• [12] Alterations of tumour suppressor gene PPP2R1B in hepatocellular carcinoma.Cancer Lett. 2007 Aug 8;253(1):138-43. doi: 10.1016/j.canlet.2007.01.016. Epub 2007 Feb 26.
• [13] Alterations of the PPP2R1B gene in human lung and colon cancer.Science. 1998 Oct 9;282(5387):284-7. doi: 10.1126/science.282.5387.284.
• [14] Possible predisposition for colorectal carcinogenesis due to altered gene expressions in normal appearing mucosa from patients with colorectal neoplasia.BMC Cancer. 2019 Jun 28;19(1):643. doi: 10.1186/s12885-019-5833-8.
• [15] Genomic organization and precise physical location of protein phosphatase 2A regulatory subunit A beta isoform gene on chromosome band 11q23.Gene. 1998 Sep 14;217(1-2):107-16. doi: 10.1016/s0378-1119(98)00350-3.
• [16] MicroRNA-587 antagonizes 5-FU-induced apoptosis and confers drug resistance by regulating PPP2R1B expression in colorectal cancer.Cell Death Dis. 2015 Aug 6;6(8):e1845. doi: 10.1038/cddis.2015.200.
• [17] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [18] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [19] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] 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.
• [22] 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.
• [23] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [24] 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.
• [25] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [26] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [27] 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.
• [28] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [29] 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.
• [30] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [31] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [32] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.
• [33] 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.