Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9297OG)

• DOT Name: Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A)
• Synonyms: PP2A subunit B isoform B55-alpha; PP2A subunit B isoform PR55-alpha; PP2A subunit B isoform R2-alpha; PP2A subunit B isoform alpha
• Gene Name: PPP2R2A
• Related Disease:
  Bone osteosarcoma
  Familial prostate carcinoma
  Osteosarcoma
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Carcinoma
  Colorectal carcinoma
  Epithelial ovarian cancer
  Germ cell tumor
  Matthew-Wood syndrome
  Neoplasm
  Non-small-cell lung cancer
  Obesity
  Ovarian cancer
  Ovarian neoplasm
  Prostate carcinoma
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Prostate cancer
  Prostate neoplasm
• UniProt ID: 2ABA_HUMAN
• PDB ID: 3DW8; 8SO0; 8TTB; 8TWE
• Sequence:
  MAGAGGGNDIQWCFSQVKGAVDDDVAEADIISTVEFNHSGELLATGDKGGRVVIFQQEQE
  NKIQSHSRGEYNVYSTFQSHEPEFDYLKSLEIEEKINKIRWLPQKNAAQFLLSTNDKTIK
  LWKISERDKRPEGYNLKEEDGRYRDPTTVTTLRVPVFRPMDLMVEASPRRIFANAHTYHI
  NSISINSDYETYLSADDLRINLWHLEITDRSFNIVDIKPANMEELTEVITAAEFHPNSCN
  TFVYSSSKGTIRLCDMRASALCDRHSKLFEEPEDPSNRSFFSEIISSISDVKFSHSGRYM
  MTRDYLSVKIWDLNMENRPVETYQVHEYLRSKLCSLYENDCIFDKFECCWNGSDSVVMTG
  SYNNFFRMFDRNTKRDITLEASRENNKPRTVLKPRKVCASGKRKKDEISVDSLDFNKKIL
  HTAWHPKENIIAVATTNNLYIFQDKVN
• 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. Essential for serine/threonine-protein phosphatase 2A-mediated dephosphorylation of WEE1, preventing its ubiquitin-mediated proteolysis, increasing WEE1 protein levels, and promoting the G2/M checkpoint.
• Tissue Specificity: Expressed in all tissues examined.
• KEGG Pathway:
  mR. surveillance pathway (hsa03015)
  Sphingolipid sig.ling pathway (hsa04071)
  PI3K-Akt sig.ling pathway (hsa04151)
  AMPK sig.ling pathway (hsa04152)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Hippo sig.ling pathway (hsa04390)
  Tight junction (hsa04530)
  T cell receptor sig.ling pathway (hsa04660)
  Dopaminergic sy.pse (hsa04728)
  Chagas disease (hsa05142)
  Hepatitis C (hsa05160)
  Human papillomavirus infection (hsa05165)
• Reactome Pathway:
  Cyclin D associated events in G1 (R-HSA-69231)
  Cyclin A/B1/B2 associated events during G2/M transition (R-HSA-69273)
  Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) (R-HSA-975957)
  Initiation of Nuclear Envelope (NE) Reformation (R-HSA-2995383)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Definitive	Biomarker	[1]
Familial prostate carcinoma	DISL9KNO	Definitive	Genetic Variation	[2]
Osteosarcoma	DISLQ7E2	Definitive	Biomarker	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[5]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[6]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[7]
Germ cell tumor	DIS62070	Strong	Biomarker	[8]
Matthew-Wood syndrome	DISA7HR7	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[11]
Obesity	DIS47Y1K	Strong	Biomarker	[12]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[7]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[7]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[13]
Bladder cancer	DISUHNM0	moderate	Biomarker	[10]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[4]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[4]
Urinary bladder cancer	DISDV4T7	moderate	Biomarker	[10]
Urinary bladder neoplasm	DIS7HACE	moderate	Biomarker	[10]
Prostate cancer	DISF190Y	Limited	Biomarker	[13]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[13]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitomycin	DMH0ZJE	Approved	Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A) decreases the response to substance of Mitomycin.	[32]
Josamycin	DMKJ8LB	Approved	Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A) affects the response to substance of Josamycin.	[33]
Camptothecin	DM6CHNJ	Phase 3	Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A) decreases the response to substance of Camptothecin.	[32]

17 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 55 kDa regulatory subunit B alpha isoform (PPP2R2A).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A).	[17]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A).	[19]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A).	[20]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A).	[21]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A).	[23]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A).	[24]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A).	[25]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A).	[29]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone decreases the expression of Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A).	[30]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR decreases the expression of Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A).	[22]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform (PPP2R2A).	[27]

References

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• [2] Evaluation of PPP2R2A as a prostate cancer susceptibility gene: a comprehensive germline and somatic study.Cancer Genet. 2011 Jul;204(7):375-81. doi: 10.1016/j.cancergen.2011.05.002.
• [3] The protein phosphatase 2A regulatory subunit B55 is a modulator of signaling and microRNA expression in acute myeloid leukemia cells.Biochim Biophys Acta. 2014 Sep;1843(9):1969-77. doi: 10.1016/j.bbamcr.2014.05.006. Epub 2014 May 21.
• [4] Altered PPP2R2A and Cyclin D1 expression defines a subgroup of aggressive luminal-like breast cancer.BMC Cancer. 2015 Apr 15;15:285. doi: 10.1186/s12885-015-1266-1.
• [5] MicroRNA-136 Promotes Vascular Muscle Cell Proliferation Through the ERK1/2 Pathway by Targeting PPP2R2A in Atherosclerosis.Curr Vasc Pharmacol. 2015;13(3):405-12. doi: 10.2174/1570161112666141118094612.
• [6] miR-892a regulated PPP2R2A expression and promoted cell proliferation of human colorectal cancer cells.Biomed Pharmacother. 2015 May;72:119-24. doi: 10.1016/j.biopha.2015.04.015. Epub 2015 Apr 27.
• [7] Upregulation of miR-614 promotes proliferation and inhibits apoptosis in ovarian cancer by suppressing PPP2R2A expression.Mol Med Rep. 2018 May;17(5):6285-6292. doi: 10.3892/mmr.2018.8714. Epub 2018 Mar 9.
• [8] Fusion of the tumor-suppressor gene CHEK2 and the gene for the regulatory subunit B of protein phosphatase 2 PPP2R2A in childhood teratoma.Neoplasia. 2006 May;8(5):413-8. doi: 10.1593/neo.06139.
• [9] The biological features of PanIN initiated from oncogenic Kras mutation in genetically engineered mouse models.Cancer Lett. 2013 Oct 1;339(1):135-43. doi: 10.1016/j.canlet.2013.07.010. Epub 2013 Jul 22.
• [10] MKAD-21 Suppresses the Oncogenic Activity of the miR-21/PPP2R2A/ERK Molecular Network in Bladder Cancer.Mol Cancer Ther. 2018 Jul;17(7):1430-1440. doi: 10.1158/1535-7163.MCT-17-1049. Epub 2018 Apr 27.
• [11] Upregulation of miR-136 in human non-small cell lung cancer cells promotes Erk1/2 activation by targeting PPP2R2A.Tumour Biol. 2014 Jan;35(1):631-40. doi: 10.1007/s13277-013-1087-2.
• [12] Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.Nat Genet. 2013 May;45(5):501-12. doi: 10.1038/ng.2606. Epub 2013 Apr 7.
• [13] PPP2R2A prostate cancer haploinsufficiency is associated with worse prognosis and a high vulnerability to B55/PP2A reconstitution that triggers centrosome destabilization.Oncogenesis. 2019 Dec 10;8(12):72. doi: 10.1038/s41389-019-0180-9.
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• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [19] 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.
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• [21] 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.
• [22] 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.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
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• [28] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [29] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [30] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.
• [31] 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.
• [32] 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.
• [33] A genome-wide analysis of targets of macrolide antibiotics in mammalian cells. J Biol Chem. 2020 Feb 14;295(7):2057-2067. doi: 10.1074/jbc.RA119.010770. Epub 2020 Jan 8.