Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT83PT85)

• DOT Name: Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform (PPP2CA)
• Synonyms: PP2A-alpha; EC 3.1.3.16; Replication protein C; RP-C
• Gene Name: PPP2CA
• Related Disease: Houge-Janssens syndrome 3
• UniProt ID: PP2AA_HUMAN
• PDB ID: 2IAE; 2IE3; 2IE4; 2NPP; 2NYL; 2NYM; 3C5W; 3DW8; 3FGA; 3K7V; 3K7W; 3P71; 4I5L; 4I5N; 4IYP; 4LAC; 4NY3; 5W0W; 6NTS; 7CUN; 7K36; 7PKS; 7SOY; 7YCX; 8SO0; 8TTB; 8TWE; 8TWI
• EC Number: 3.1.3.16
• Pfam ID: PF00149
• Sequence:
  MDEKVFTKELDQWIEQLNECKQLSESQVKSLCEKAKEILTKESNVQEVRCPVTVCGDVHG
  QFHDLMELFRIGGKSPDTNYLFMGDYVDRGYYSVETVTLLVALKVRYRERITILRGNHES
  RQITQVYGFYDECLRKYGNANVWKYFTDLFDYLPLTALVDGQIFCLHGGLSPSIDTLDHI
  RALDRLQEVPHEGPMCDLLWSDPDDRGGWGISPRGAGYTFGQDISETFNHANGLTLVSRA
  HQLVMEGYNWCHDRNVVTIFSAPNYCYRCGNQAAIMELDDTLKYSFLQFDPAPRRGEPHV
  TRRTPDYFL
• Function: PP2A is the major phosphatase for microtubule-associated proteins (MAPs). PP2A can modulate the activity of phosphorylase B kinase casein kinase 2, mitogen-stimulated S6 kinase, and MAP-2 kinase. Cooperates with SGO2 to protect centromeric cohesin from separase-mediated cleavage in oocytes specifically during meiosis I. Can dephosphorylate SV40 large T antigen and p53/TP53. Activates RAF1 by dephosphorylating it at 'Ser-259'. Mediates dephosphorylation of WEE1, preventing its ubiquitin-mediated proteolysis, increasing WEE1 protein levels, and promoting the G2/M checkpoint. Mediates dephosphorylation of MYC; promoting its ubiquitin-mediated proteolysis: interaction with AMBRA1 enhances interaction between PPP2CA and MYC. Mediates dephosphorylation of FOXO3; promoting its stabilization: interaction with AMBRA1 enhances interaction between PPP2CA and FOXO3. Catalyzes dephosphorylation of the pyrin domain of NLRP3, promoting assembly of the NLRP3 inflammasome.
• 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)
  Initiation of Nuclear Envelope (NE) Reformation (R-HSA-2995383)
  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)
  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:HS03696-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Houge-Janssens syndrome 3	DIS53611	Strong	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform (PPP2CA).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform (PPP2CA).	[3]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform (PPP2CA).	[4]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform (PPP2CA).	[5]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform (PPP2CA).	[6]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform (PPP2CA).	[7]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform (PPP2CA).	[8]
Daunorubicin	DMQUSBT	Approved	Daunorubicin increases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform (PPP2CA).	[9]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform (PPP2CA).	[10]
Imatinib	DM7RJXL	Approved	Imatinib increases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform (PPP2CA).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform (PPP2CA).	[14]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform (PPP2CA).	[15]
Okadaic acid	DM47CO1	Investigative	Okadaic acid decreases the activity of Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform (PPP2CA).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform (PPP2CA).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 affects the binding of Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform (PPP2CA).	[13]
Microcystin-LR	DMTMLRN	Investigative	Microcystin-LR affects the binding of Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform (PPP2CA).	[17]

References

• [1] A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Genet Med. 2017 Sep;19(9):1055-1063. doi: 10.1038/gim.2017.1. Epub 2017 Mar 23.
• [2] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Arsenic trioxide inhibits CXCR4-mediated metastasis by interfering miR-520h/PP2A/NF-B signaling in cervical cancer. Ann Surg Oncol. 2014 Dec;21 Suppl 4:S687-95. doi: 10.1245/s10434-014-3812-5. Epub 2014 Jul 22.
• [5] Neuroprotective effects of glucomoringin-isothiocyanate against H(2)O(2)-Induced cytotoxicity in neuroblastoma (SH-SY5Y) cells. Neurotoxicology. 2019 Dec;75:89-104. doi: 10.1016/j.neuro.2019.09.008. Epub 2019 Sep 12.
• [6] p38 MAPK/PP2Ac/TTP pathway on the connection of TNF- and caspases activation on hydroquinone-induced apoptosis. Carcinogenesis. 2013 Apr;34(4):818-27. doi: 10.1093/carcin/bgs409. Epub 2013 Jan 3.
• [7] Methylation status of CpG islands flanking a cAMP response element motif on the protein phosphatase 2Ac alpha promoter determines CREB binding and activity. J Immunol. 2009 Feb 1;182(3):1500-8. doi: 10.4049/jimmunol.182.3.1500.
• [8] Transcriptional profiling in the human prefrontal cortex: evidence for two activational states associated with cocaine abuse. Pharmacogenomics J. 2003;3(1):27-40.
• [9] CREB/Sp1-mediated MCL1 expression and NFB-mediated ABCB1 expression modulate the cytotoxicity of daunorubicin in chronic myeloid leukemia cells. Toxicol Appl Pharmacol. 2022 Jan 15;435:115847. doi: 10.1016/j.taap.2021.115847. Epub 2021 Dec 25.
• [10] Effects of metformin and pioglitazone combination on apoptosis and AMPK/mTOR signaling pathway in human anaplastic thyroid cancer cells. J Biochem Mol Toxicol. 2020 Oct;34(10):e22547. doi: 10.1002/jbt.22547. Epub 2020 Jun 26.
• [11] A systems biology understanding of the synergistic effects of arsenic sulfide and Imatinib in BCR/ABL-associated leukemia. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3378-83.
• [12] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [13] "Minimalist" cyclopropene-containing photo-cross-linkers suitable for live-cell imaging and affinity-based protein labeling. J Am Chem Soc. 2014 Jul 16;136(28):9990-8. doi: 10.1021/ja502780z. Epub 2014 Jul 3.
• [14] 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.
• [15] Global expression profiling of theophylline response genes in macrophages: evidence of airway anti-inflammatory regulation. Respir Res. 2005 Aug 8;6(1):89. doi: 10.1186/1465-9921-6-89.
• [16] Protein phosphatase 2A regulates estrogen receptor alpha (ER) expression through modulation of ER mRNA stability. J Biol Chem. 2005 Aug 19;280(33):29519-24. doi: 10.1074/jbc.M505317200. Epub 2005 Jun 17.
• [17] 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.