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
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
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]
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⏷ Show the Full List of 42 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
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]
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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]
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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]
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⏷ Show the Full List of 14 Drug(s)

References

1 Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
2 Large-scale discovery of novel genetic causes of developmental disorders. Nature. 2015 Mar 12;519(7542):223-8. doi: 10.1038/nature14135. Epub 2014 Dec 24.
3 Infrequent mutations of the PPP2R1A and PPP2R1B genes in patients with ovarian cancer.Mol Med Rep. 2013 Jun;7(6):1826-30. doi: 10.3892/mmr.2013.1416. Epub 2013 Apr 9.
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.
6 Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.Nat Biotechnol. 2016 Feb;34(2):155-63. doi: 10.1038/nbt.3391. Epub 2015 Nov 30.
7 Patient derived mutation W257G of PPP2R1A enhances cancer cell migration through SRC-JNK-c-Jun pathway.Sci Rep. 2016 Jun 7;6:27391. doi: 10.1038/srep27391.
8 PR65A phosphorylation regulates PP2A complex signaling.PLoS One. 2014 Jan 21;9(1):e85000. doi: 10.1371/journal.pone.0085000. eCollection 2014.
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.
10 Precision Therapy for Aggressive Endometrial Cancer by Reactivation of Protein Phosphatase 2A.Cancer Res. 2019 Aug 15;79(16):4009-4010. doi: 10.1158/0008-5472.CAN-19-1938.
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.