Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRZO26U)

• DOT Name: Serine/threonine-protein phosphatase PP1-gamma catalytic subunit (PPP1CC)
• Synonyms: PP-1G; EC 3.1.3.16; Protein phosphatase 1C catalytic subunit
• Gene Name: PPP1CC
• Related Disease:
  Advanced cancer
  Cardiac failure
  Congestive heart failure
  Male infertility
  Ovarian cancer
  Ovarian neoplasm
• UniProt ID: PP1G_HUMAN
• PDB ID: 1IT6; 1JK7; 1U32; 2BCD; 2BDX; 4UT2; 4UT3; 5INB; 5J28; 7SD0; 8B5R
• EC Number: 3.1.3.16
• Pfam ID: PF00149 ; PF16891
• Sequence:
  MADLDKLNIDSIIQRLLEVRGSKPGKNVQLQENEIRGLCLKSREIFLSQPILLELEAPLK
  ICGDIHGQYYDLLRLFEYGGFPPESNYLFLGDYVDRGKQSLETICLLLAYKIKYPENFFL
  LRGNHECASINRIYGFYDECKRRYNIKLWKTFTDCFNCLPIAAIVDEKIFCCHGGLSPDL
  QSMEQIRRIMRPTDVPDQGLLCDLLWSDPDKDVLGWGENDRGVSFTFGAEVVAKFLHKHD
  LDLICRAHQVVEDGYEFFAKRQLVTLFSAPNYCGEFDNAGAMMSVDETLMCSFQILKPAE
  KKKPNATRPVTPPRGMITKQAKK
• Function: Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets. Protein phosphatase 1 (PP1) is essential for cell division, and participates in the regulation of glycogen metabolism, muscle contractility and protein synthesis. Dephosphorylates RPS6KB1. Involved in regulation of ionic conductances and long-term synaptic plasticity. May play an important role in dephosphorylating substrates such as the postsynaptic density-associated Ca(2+)/calmodulin dependent protein kinase II. Component of the PTW/PP1 phosphatase complex, which plays a role in the control of chromatin structure and cell cycle progression during the transition from mitosis into interphase. In balance with CSNK1D and CSNK1E, determines the circadian period length, through the regulation of the speed and rhythmicity of PER1 and PER2 phosphorylation. May dephosphorylate CSNK1D and CSNK1E. Dephosphorylates the 'Ser-418' residue of FOXP3 in regulatory T-cells (Treg) from patients with rheumatoid arthritis, thereby inactivating FOXP3 and rendering Treg cells functionally defective.
• KEGG Pathway:
  mR. surveillance pathway (hsa03015)
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  Oocyte meiosis (hsa04114)
  Cellular senescence (hsa04218)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Vascular smooth muscle contraction (hsa04270)
  Hippo sig.ling pathway (hsa04390)
  Focal adhesion (hsa04510)
  Platelet activation (hsa04611)
  Long-term potentiation (hsa04720)
  Dopaminergic sy.pse (hsa04728)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Regulation of actin cytoskeleton (hsa04810)
  Insulin sig.ling pathway (hsa04910)
  Oxytocin sig.ling pathway (hsa04921)
  Insulin resistance (hsa04931)
  Amphetamine addiction (hsa05031)
  Alcoholism (hsa05034)
  Herpes simplex virus 1 infection (hsa05168)
  Proteoglycans in cancer (hsa05205)
  Diabetic cardiomyopathy (hsa05415)
• Reactome Pathway:
  Triglyceride catabolism (R-HSA-163560)
  Downregulation of TGF-beta receptor signaling (R-HSA-2173788)
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  Circadian Clock (R-HSA-400253)
  RHO GTPases Activate Formins (R-HSA-5663220)
  RAF activation (R-HSA-5673000)
  Mitotic Prometaphase (R-HSA-68877)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  SHOC2 M1731 mutant abolishes MRAS complex function (R-HSA-9726840)
  Gain-of-function MRAS complexes activate RAF signaling (R-HSA-9726842)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Cardiac failure	DISDC067	Strong	Altered Expression	[2]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[2]
Male infertility	DISY3YZZ	Strong	Altered Expression	[3]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[4]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[4]

3 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 PP1-gamma catalytic subunit (PPP1CC).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Serine/threonine-protein phosphatase PP1-gamma catalytic subunit (PPP1CC).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Serine/threonine-protein phosphatase PP1-gamma catalytic subunit (PPP1CC).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Serine/threonine-protein phosphatase PP1-gamma catalytic subunit (PPP1CC).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Serine/threonine-protein phosphatase PP1-gamma catalytic subunit (PPP1CC).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/threonine-protein phosphatase PP1-gamma catalytic subunit (PPP1CC).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Serine/threonine-protein phosphatase PP1-gamma catalytic subunit (PPP1CC).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Serine/threonine-protein phosphatase PP1-gamma catalytic subunit (PPP1CC).	[10]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Serine/threonine-protein phosphatase PP1-gamma catalytic subunit (PPP1CC).	[13]

References

• [1] A phosphatase holoenzyme comprised of Shoc2/Sur8 and the catalytic subunit of PP1 functions as an M-Ras effector to modulate Raf activity.Mol Cell. 2006 Apr 21;22(2):217-30. doi: 10.1016/j.molcel.2006.03.027.
• [2] Rearrangement of the Protein Phosphatase 1 Interactome During Heart Failure Progression.Circulation. 2018 Oct 9;138(15):1569-1581. doi: 10.1161/CIRCULATIONAHA.118.034361.
• [3] Significant expression levels of transgenic PPP1CC2 in testis and sperm are required to overcome the male infertility phenotype of Ppp1cc null mice.PLoS One. 2012;7(10):e47623. doi: 10.1371/journal.pone.0047623. Epub 2012 Oct 17.
• [4] URI is an oncogene amplified in ovarian cancer cells and is required for their survival. Cancer Cell. 2011 Mar 8;19(3):317-32. doi: 10.1016/j.ccr.2011.01.019.
• [5] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [6] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] 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.
• [13] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.