Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF7CGO2)

• DOT Name: Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform (PPP2R5C)
• Synonyms: PP2A B subunit isoform B'-gamma; PP2A B subunit isoform B56-gamma; PP2A B subunit isoform PR61-gamma; PP2A B subunit isoform R5-gamma; Renal carcinoma antigen NY-REN-29
• Gene Name: PPP2R5C
• Related Disease:
  Advanced cancer
  Breast carcinoma
  Carcinoma
  leukaemia
  Leukemia
  Lung cancer
  Lung carcinoma
  Obesity
  Small lymphocytic lymphoma
  Thyroid gland papillary carcinoma
  Neoplasm
• UniProt ID: 2A5G_HUMAN
• PDB ID: 2IAE; 2JAK; 2NPP; 2NYL; 2NYM; 3FGA; 5JJA; 5K6S; 5SW9; 5SWF; 6OYL; 6TOQ; 6VOY; 6VRO; 7OUF; 7OUG; 7OUH; 7PEL; 7SOY
• Pfam ID: PF01603
• Sequence:
  MLTCNKAGSRMVVDAANSNGPFQPVVLLHIRDVPPADQEKLFIQKLRQCCVLFDFVSDPL
  SDLKWKEVKRAALSEMVEYITHNRNVITEPIYPEVVHMFAVNMFRTLPPSSNPTGAEFDP
  EEDEPTLEAAWPHLQLVYEFFLRFLESPDFQPNIAKKYIDQKFVLQLLELFDSEDPRERD
  FLKTTLHRIYGKFLGLRAYIRKQINNIFYRFIYETEHHNGIAELLEILGSIINGFALPLK
  EEHKIFLLKVLLPLHKVKSLSVYHPQLAYCVVQFLEKDSTLTEPVVMALLKYWPKTHSPK
  EVMFLNELEEILDVIEPSEFVKIMEPLFRQLAKCVSSPHFQVAERALYYWNNEYIMSLIS
  DNAAKILPIMFPSLYRNSKTHWNKTIHGLIYNALKLFMEMNQKLFDDCTQQFKAEKLKEK
  LKMKEREEAWVKIENLAKANPQYTVYSQASTMSIPVAMETDGPLFEDVQMLRKTVKDEAH
  QAQKDPKKDRPLARRKSELPQDPHTKKALEAHCRADELASQDGR
• 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. The PP2A-PPP2R5C holoenzyme may specifically dephosphorylate and activate TP53 and play a role in DNA damage-induced inhibition of cell proliferation. PP2A-PPP2R5C may also regulate the ERK signaling pathway through ERK dephosphorylation.
• Tissue Specificity: Highest levels in heart, skeletal muscle and brain. Lower levels in pancreas, kidney, lung and placenta. Very low levels in liver.
• 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)
  T cell receptor sig.ling pathway (hsa04660)
  Dopaminergic sy.pse (hsa04728)
  Human papillomavirus infection (hsa05165)
• Reactome Pathway:
  Degradation of beta-catenin by the destruction complex (R-HSA-195253)
  Beta-catenin phosphorylation cascade (R-HSA-196299)
  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)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[3]
leukaemia	DISS7D1V	Strong	Biomarker	[1]
Leukemia	DISNAKFL	Strong	Biomarker	[1]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[4]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[4]
Obesity	DIS47Y1K	Strong	Altered Expression	[5]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[6]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform (PPP2R5C) affects the response to substance of Methotrexate.	[22]
Mitomycin	DMH0ZJE	Approved	Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform (PPP2R5C) increases the response to substance of Mitomycin.	[23]
Camptothecin	DM6CHNJ	Phase 3	Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform (PPP2R5C) increases the response to substance of Camptothecin.	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform (PPP2R5C).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform (PPP2R5C).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform (PPP2R5C).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform (PPP2R5C).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform (PPP2R5C).	[13]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform (PPP2R5C).	[13]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform (PPP2R5C).	[14]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform (PPP2R5C).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform (PPP2R5C).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform (PPP2R5C).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform (PPP2R5C).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform (PPP2R5C).	[20]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform (PPP2R5C).	[21]

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 56 kDa regulatory subunit gamma isoform (PPP2R5C).	[16]

References

• [1] Expression and distribution of PPP2R5C gene in leukemia.J Hematol Oncol. 2011 May 6;4:21. doi: 10.1186/1756-8722-4-21.
• [2] 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.
• [3] Activation of ERK/IER3/PP2A-B56-positive feedback loop in lung adenocarcinoma by allelic deletion of B56 gene.Oncol Rep. 2016 May;35(5):2635-42. doi: 10.3892/or.2016.4677. Epub 2016 Mar 16.
• [4] A B56gamma mutation in lung cancer disrupts the p53-dependent tumor-suppressor function of protein phosphatase 2A.Oncogene. 2010 Jul 8;29(27):3933-41. doi: 10.1038/onc.2010.161. Epub 2010 May 17.
• [5] PPP2R5C Couples Hepatic Glucose and Lipid Homeostasis.PLoS Genet. 2015 Oct 6;11(10):e1005561. doi: 10.1371/journal.pgen.1005561. eCollection 2015 Oct.
• [6] Identification of progression markers in B-CLL by gene expression profiling.Exp Hematol. 2005 Aug;33(8):883-93. doi: 10.1016/j.exphem.2005.05.007.
• [7] Down-regulation of 14q32-encoded miRNAs and tumor suppressor role for miR-654-3p in papillary thyroid cancer.Oncotarget. 2017 Feb 7;8(6):9597-9607. doi: 10.18632/oncotarget.14162.
• [8] Gene expression profiling identifies WNT7A as a possible candidate gene for decreased cancer risk in fragile X syndrome patients.Arch Med Res. 2010 Feb;41(2):110-118.e2. doi: 10.1016/j.arcmed.2010.03.001.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [13] 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.
• [14] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [15] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [16] 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.
• [17] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [18] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [19] 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.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [22] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [23] 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.