Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYA3GB4)

• DOT Name: Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PPP2R1A)
• Synonyms: Medium tumor antigen-associated 61 kDa protein; PP2A subunit A isoform PR65-alpha; PP2A subunit A isoform R1-alpha
• Gene Name: PPP2R1A
• Related Disease:
  Complex neurodevelopmental disorder
  Houge-Janssens syndrome 2
  Intellectual disability, autosomal dominant 40
  Ovarian cancer
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Cardiac failure
  Colorectal neoplasm
  Congestive heart failure
  Cystic fibrosis
  Endometrial carcinoma
  Endometriosis
  Epithelial ovarian cancer
  Gastric adenocarcinoma
  Gastric cancer
  Gastric neoplasm
  Head-neck squamous cell carcinoma
  Hepatocellular carcinoma
  Hereditary diffuse gastric adenocarcinoma
  Intellectual disability
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Melanoma
  Mucinous adenocarcinoma
  Ovarian neoplasm
  Ovarian serous cystadenocarcinoma
  Prostate adenocarcinoma
  Uterine serous carcinoma
  Gastrointestinal stromal tumour
  Malignant uterine tumour
  Metastatic malignant neoplasm
  Serous cystadenocarcinoma
  Undifferentiated carcinoma
  Childhood kidney Wilms tumor
  Endometrial cancer
  Hereditary Wilms tumor
  Osteoarthritis
  Wilms tumor
• UniProt ID: 2AAA_HUMAN
• PDB ID: 1B3U; 2IE3; 2IE4; 2NPP; 2NYL; 2NYM; 2PKG; 3C5W; 3DW8; 3K7V; 3K7W; 4I5L; 4I5N; 4LAC; 5W0W; 6IUR; 6NTS; 7CUN; 7K36; 7PKS; 7SOY; 7YCX; 8SO0; 8TTB; 8TWE; 8TWI
• Pfam ID: PF02985 ; PF13646
• Sequence:
  MAAADGDDSLYPIAVLIDELRNEDVQLRLNSIKKLSTIALALGVERTRSELLPFLTDTIY
  DEDEVLLALAEQLGTFTTLVGGPEYVHCLLPPLESLATVEETVVRDKAVESLRAISHEHS
  PSDLEAHFVPLVKRLAGGDWFTSRTSACGLFSVCYPRVSSAVKAELRQYFRNLCSDDTPM
  VRRAAASKLGEFAKVLELDNVKSEIIPMFSNLASDEQDSVRLLAVEACVNIAQLLPQEDL
  EALVMPTLRQAAEDKSWRVRYMVADKFTELQKAVGPEITKTDLVPAFQNLMKDCEAEVRA
  AASHKVKEFCENLSADCRENVIMSQILPCIKELVSDANQHVKSALASVIMGLSPILGKDN
  TIEHLLPLFLAQLKDECPEVRLNIISNLDCVNEVIGIRQLSQSLLPAIVELAEDAKWRVR
  LAIIEYMPLLAGQLGVEFFDEKLNSLCMAWLVDHVYAIREAATSNLKKLVEKFGKEWAHA
  TIIPKVLAMSGDPNYLHRMTTLFCINVLSEVCGQDITTKHMLPTVLRMAGDPVANVRFNV
  AKSLQKIGPILDNSTLQSEVKPILEKLTQDQDVDVKYFAQEALTVLSLA
• 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. Upon interaction with GNA12 promotes dephosphorylation of microtubule associated protein TAU/MAPT. Required for proper chromosome segregation and for centromeric localization of SGO1 in mitosis. Together with RACK1 adapter, mediates dephosphorylation of AKT1 at 'Ser-473', preventing AKT1 activation and AKT-mTOR signaling pathway. Dephosphorylation of AKT1 is essential for regulatory T-cells (Treg) homeostasis and stability.
• 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:
  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)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)
  Initiation of Nuclear Envelope (NE) Reformation (R-HSA-2995383)
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  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)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  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)
  AURKA Activation by TPX2 (R-HSA-8854518)
  Regulation of glycolysis by fructose 2,6-bisphosphate metabolism (R-HSA-9634600)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) (R-HSA-975957)
  PKR-mediated signaling (R-HSA-9833482)
  Inhibition of replication initiation of damaged DNA by RB1/E2F1 (R-HSA-113501)
• BioCyc Pathway: MetaCyc:ENSG00000105568-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

42 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[1]
Houge-Janssens syndrome 2	DISLJZW8	Definitive	Autosomal dominant	[2]
Intellectual disability, autosomal dominant 40	DISAI0IH	Definitive	Autosomal dominant	[2]
Ovarian cancer	DISZJHAP	Definitive	Genetic Variation	[3]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[5]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[6]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[7]
Cardiac failure	DISDC067	Strong	Altered Expression	[8]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[6]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[8]
Cystic fibrosis	DIS2OK1Q	Strong	Genetic Variation	[9]
Endometrial carcinoma	DISXR5CY	Strong	Genetic Variation	[10]
Endometriosis	DISX1AG8	Strong	Genetic Variation	[11]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[3]
Gastric adenocarcinoma	DISWWLTC	Strong	Genetic Variation	[6]
Gastric cancer	DISXGOUK	Strong	Biomarker	[12]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[12]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Genetic Variation	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[13]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[12]
Intellectual disability	DISMBNXP	Strong	Biomarker	[2]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[6]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[14]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[14]
Melanoma	DIS1RRCY	Strong	Genetic Variation	[15]
Mucinous adenocarcinoma	DISKNFE8	Strong	Genetic Variation	[16]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[3]
Ovarian serous cystadenocarcinoma	DISMYAWR	Strong	Genetic Variation	[6]
Prostate adenocarcinoma	DISBZYU8	Strong	Genetic Variation	[6]
Uterine serous carcinoma	DISAW5MD	Strong	Genetic Variation	[17]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Genetic Variation	[18]
Malignant uterine tumour	DIS3QDT8	moderate	Genetic Variation	[19]
Metastatic malignant neoplasm	DIS86UK6	moderate	Genetic Variation	[20]
Serous cystadenocarcinoma	DISVK716	moderate	Genetic Variation	[21]
Undifferentiated carcinoma	DISIAZST	moderate	Genetic Variation	[22]
Childhood kidney Wilms tumor	DIS0NMK3	Limited	Genetic Variation	[23]
Endometrial cancer	DISW0LMR	Limited	Genetic Variation	[10]
Hereditary Wilms tumor	DISYBXFF	Limited	Biomarker	[23]
Osteoarthritis	DIS05URM	Limited	Biomarker	[24]
Wilms tumor	DISB6T16	Limited	Genetic Variation	[23]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Camptothecin	DM6CHNJ	Phase 3	Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PPP2R1A) decreases the response to substance of Camptothecin.	[39]

1 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 Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PPP2R1A).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PPP2R1A).	[26]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PPP2R1A).	[27]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PPP2R1A).	[28]
Selenium	DM25CGV	Approved	Selenium increases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PPP2R1A).	[29]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PPP2R1A).	[30]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PPP2R1A).	[31]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PPP2R1A).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PPP2R1A).	[32]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PPP2R1A).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PPP2R1A).	[34]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PPP2R1A).	[35]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PPP2R1A).	[36]
Okadaic acid	DM47CO1	Investigative	Okadaic acid increases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PPP2R1A).	[37]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR decreases the expression of Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PPP2R1A).	[38]

References

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• [4] Association of PPP2R1A with Alzheimer's disease and specific cognitive domains.Neurobiol Aging. 2019 Sep;81:234-243. doi: 10.1016/j.neurobiolaging.2019.06.008. Epub 2019 Jul 2.
• [5] 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.
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• [9] Identification of SNPs in the cystic fibrosis interactome influencing pulmonary progression in cystic fibrosis.Eur J Hum Genet. 2013 Apr;21(4):397-403. doi: 10.1038/ejhg.2012.181. Epub 2012 Aug 15.
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• [11] Frequent POLE1 p.S297F mutation in Chinese patients with ovarian endometrioid carcinoma.Mutat Res. 2014 Mar;761:49-52. doi: 10.1016/j.mrfmmm.2014.01.003. Epub 2014 Jan 25.
• [12] A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.PLoS One. 2011 Feb 18;6(2):e16694. doi: 10.1371/journal.pone.0016694.
• [13] Role of a novel functional variant in the PPP2R1A promoter on the regulation of PP2A-Aalpha and the risk of hepatocellular carcinoma.PLoS One. 2013;8(3):e59574. doi: 10.1371/journal.pone.0059574. Epub 2013 Mar 29.
• [14] Genetic variations in cancer-related significantly mutated genes and lung cancer susceptibility.Ann Oncol. 2017 Jul 1;28(7):1625-1630. doi: 10.1093/annonc/mdx161.
• [15] Low frequency of alterations of the alpha (PPP2R1A) and beta (PPP2R1B) isoforms of the subunit A of the serine-threonine phosphatase 2A in human neoplasms.Oncogene. 2000 Feb 24;19(9):1191-5. doi: 10.1038/sj.onc.1203389.
• [16] Somatic mutations of PPP2R1A in ovarian and uterine carcinomas.Am J Pathol. 2011 Apr;178(4):1442-7. doi: 10.1016/j.ajpath.2011.01.009. Epub 2011 Feb 26.
• [17] Mutation of PPP2R1A: a new clue in unveiling the pathogenesis of uterine serous carcinoma.J Pathol. 2011 May;224(1):1-4. doi: 10.1002/path.2884. Epub 2011 Mar 22.
• [18] Clinicopathological effects of protein phosphatase 2, regulatory subunit A, alpha mutations in gastrointestinal stromal tumors.Mod Pathol. 2016 Nov;29(11):1424-1432. doi: 10.1038/modpathol.2016.138. Epub 2016 Jul 29.
• [19] Recurrent PPP2R1A Mutations in Uterine Cancer Act through a Dominant-Negative Mechanism to Promote Malignant Cell Growth.Cancer Res. 2016 Oct 1;76(19):5719-5731. doi: 10.1158/0008-5472.CAN-15-3342. Epub 2016 Aug 2.
• [20] Colorectal Cancer Genetic Heterogeneity Delineated by Multi-Region Sequencing.PLoS One. 2016 Mar 29;11(3):e0152673. doi: 10.1371/journal.pone.0152673. eCollection 2016.
• [21] Targeted mutation analysis of endometrial clear cell carcinoma.Histopathology. 2015 Apr;66(5):664-74. doi: 10.1111/his.12581. Epub 2015 Jan 13.
• [22] Molecular characterization of undifferentiated carcinoma associated with endometrioid carcinoma.Am J Surg Pathol. 2014 May;38(5):660-5. doi: 10.1097/PAS.0000000000000166.
• [23] Absence of PPP2R1A mutations in Wilms tumor.Oncogene. 2001 Apr 12;20(16):2050-4. doi: 10.1038/sj.onc.1204301.
• [24] Mitochondrial dysregulation of osteoarthritic human articular chondrocytes analyzed by proteomics: a decrease in mitochondrial superoxide dismutase points to a redox imbalance.Mol Cell Proteomics. 2009 Jan;8(1):172-89. doi: 10.1074/mcp.M800292-MCP200. Epub 2008 Sep 9.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [29] 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.
• [30] Growth inhibition of ovarian tumor-initiating cells by niclosamide. Mol Cancer Ther. 2012 Aug;11(8):1703-12.
• [31] Rosiglitazone sensitizes MDA-MB-231 breast cancer cells to anti-tumour effects of tumour necrosis factor-alpha, CH11 and CYC202. Endocr Relat Cancer. 2007 Jun;14(2):305-15. doi: 10.1677/ERC-06-0003.
• [32] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [33] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [34] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [35] Identification of formaldehyde-responsive genes by suppression subtractive hybridization. Toxicology. 2008 Jan 14;243(1-2):224-35.
• [36] 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.
• [37] Morphological and biochemical changes associated with apoptosis induced by okadaic acid in human amniotic FL cells. Environ Toxicol. 2009 Oct;24(5):437-45. doi: 10.1002/tox.20446.
• [38] Protein phosphatase 2A inhibition and subsequent cytoskeleton reorganization contributes to cell migration caused by microcystin-LR in human laryngeal epithelial cells (Hep-2). Environ Toxicol. 2017 Mar;32(3):890-903. doi: 10.1002/tox.22289. Epub 2016 Jul 9.
• [39] ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res. 2014 Dec 1;74(23):6968-79.