Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4B0TNV)

• DOT Name: Serine/threonine-protein phosphatase 4 catalytic subunit (PPP4C)
• Synonyms: PP4C; Pp4; EC 3.1.3.16; Protein phosphatase X; PP-X
• Gene Name: PPP4C
• Related Disease:
  Coronary heart disease
  Parkinson disease
  Hemorrhoids
  Leiomyoma
  Matthew-Wood syndrome
  Pancreatic ductal carcinoma
  Uterine fibroids
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Metastatic malignant neoplasm
  Neuroendocrine neoplasm
• UniProt ID: PP4C_HUMAN
• EC Number: 3.1.3.16
• Pfam ID: PF00149
• Sequence:
  MAEISDLDRQIEQLRRCELIKESEVKALCAKAREILVEESNVQRVDSPVTVCGDIHGQFY
  DLKELFRVGGDVPETNYLFMGDFVDRGFYSVETFLLLLALKVRYPDRITLIRGNHESRQI
  TQVYGFYDECLRKYGSVTVWRYCTEIFDYLSLSAIIDGKIFCVHGGLSPSIQTLDQIRTI
  DRKQEVPHDGPMCDLLWSDPEDTTGWGVSPRGAGYLFGSDVVAQFNAANDIDMICRAHQL
  VMEGYKWHFNETVLTVWSAPNYCYRCGNVAAILELDEHLQKDFIIFEAAPQETRGIPSKK
  PVADYFL
• Function: Protein phosphatase that is involved in many processes such as microtubule organization at centrosomes, maturation of spliceosomal snRNPs, apoptosis, DNA repair, tumor necrosis factor (TNF)-alpha signaling, activation of c-Jun N-terminal kinase MAPK8, regulation of histone acetylation, DNA damage checkpoint signaling, NF-kappa-B activation and cell migration. The PPP4C-PPP4R1 PP4 complex may play a role in dephosphorylation and regulation of HDAC3. The PPP4C-PPP4R2-PPP4R3A PP4 complex specifically dephosphorylates H2AX phosphorylated on Ser-140 (gamma-H2AX) generated during DNA replication and required for DNA double strand break repair. Dephosphorylates NDEL1 at CDK1 phosphorylation sites and negatively regulates CDK1 activity in interphase. In response to DNA damage, catalyzes RPA2 dephosphorylation, an essential step for DNA repair since it allows the efficient RPA2-mediated recruitment of RAD51 to chromatin.
• KEGG Pathway: Glucagon sig.ling pathway (hsa04922)
• Reactome Pathway: Processing of DNA double-strand break ends (R-HSA-5693607)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coronary heart disease	DIS5OIP1	Definitive	Biomarker	[1]
Parkinson disease	DISQVHKL	Definitive	Biomarker	[2]
Hemorrhoids	DISQ5G6G	Strong	Genetic Variation	[3]
Leiomyoma	DISLDDFN	Strong	Altered Expression	[4]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[5]
Pancreatic ductal carcinoma	DIS26F9Q	Strong	Biomarker	[6]
Uterine fibroids	DISBZRMJ	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	moderate	Biomarker	[6]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[6]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[7]
Neuroendocrine neoplasm	DISNPLOO	moderate	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Serine/threonine-protein phosphatase 4 catalytic subunit (PPP4C).	[8]
Selenium	DM25CGV	Approved	Selenium increases the expression of Serine/threonine-protein phosphatase 4 catalytic subunit (PPP4C).	[9]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Serine/threonine-protein phosphatase 4 catalytic subunit (PPP4C).	[10]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Serine/threonine-protein phosphatase 4 catalytic subunit (PPP4C).	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Serine/threonine-protein phosphatase 4 catalytic subunit (PPP4C).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serine/threonine-protein phosphatase 4 catalytic subunit (PPP4C).	[13]

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 increases the methylation of Serine/threonine-protein phosphatase 4 catalytic subunit (PPP4C).	[12]

References

• [1] Integrative analysis of promising molecular biomarkers and pathways for coronary artery disease using WGCNA and MetaDE methods.Mol Med Rep. 2018 Sep;18(3):2789-2797. doi: 10.3892/mmr.2018.9277. Epub 2018 Jul 16.
• [2] Neuroprotective effects of pramipexole transdermal patch in the MPTP-induced mouse model of Parkinson's disease.J Pharmacol Sci. 2018 Sep;138(1):31-37. doi: 10.1016/j.jphs.2018.08.008. Epub 2018 Aug 26.
• [3] Implementation of a New High-Volume Circular Stapler in Stapled Anopexy for Hemorrhoidal Disease: Is Patient's Short-Term Outcome Affected by a Higher Volume of Resected Tissue?.Dig Surg. 2018;35(5):406-410. doi: 10.1159/000480355. Epub 2017 Nov 2.
• [4] G protein-coupled estrogen receptor 1 (GPER 1) mediates estrogen-induced, proliferation of leiomyoma cells.Gynecol Endocrinol. 2015;31(11):894-8. doi: 10.3109/09513590.2015.1092022. Epub 2015 Sep 29.
• [5] Overexpression of protein phosphatase 4 correlates with poor prognosis in patients with stage II pancreatic ductal adenocarcinoma.Cancer Epidemiol Biomarkers Prev. 2012 Aug;21(8):1336-43. doi: 10.1158/1055-9965.EPI-12-0223. Epub 2012 Jun 4.
• [6] High expression of protein phosphatase 4 is associated with the aggressive malignant behavior of colorectal carcinoma.Mol Cancer. 2015 Apr 28;14:95. doi: 10.1186/s12943-015-0356-7.
• [7] Can PPH3 be helpful to assess the discordant grade in primary and metastatic enteropancreatic neuroendocrine tumors?.Endocrine. 2016 Aug;53(2):395-401. doi: 10.1007/s12020-016-0944-3. Epub 2016 Apr 5.
• [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] 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.
• [10] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [11] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [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] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.