Details of Drug Off-Target (DOT)

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

• DOT Name: Protein phosphatase 1 regulatory subunit 14A (PPP1R14A)
• Synonyms: 17 kDa PKC-potentiated inhibitory protein of PP1; Protein kinase C-potentiated inhibitor protein of 17 kDa; CPI-17
• Gene Name: PPP1R14A
• Related Disease:
  Advanced cancer
  Bartonellosis
  Benign prostatic hyperplasia
  Colorectal carcinoma
  Lyme disease
  Neoplasm
  Orthostatic hypotension
  Pancreatic cancer
  Prostate cancer
  Prostate carcinoma
  High blood pressure
  Mesothelioma
  Obesity
  Colorectal neoplasm
  Lymphoma
  Melanoma
• UniProt ID: PP14A_HUMAN
• Pfam ID: PF05361
• Sequence:
  MAAQRLGKRVLSKLQSPSRARGPGGSPGGLQKRHARVTVKYDRRELQRRLDVEKWIDGRL
  EELYRGMEADMPDEINIDELLELESEEERSRKIQGLLKSCGKPVEDFIQELLAKLQGLHR
  QPGLRQPSPSHDGSLSPLQDRARTAHP
• Function: Inhibitor of PPP1CA. Has over 1000-fold higher inhibitory activity when phosphorylated, creating a molecular switch for regulating the phosphorylation status of PPP1CA substrates and smooth muscle contraction.
• Tissue Specificity: Isoform 1 is detected in aorta and testis. Isoform 2 is detected in aorta.
• KEGG Pathway: Vascular smooth muscle contraction (hsa04270)
• Reactome Pathway: RHO GTPases activate PKNs (R-HSA-5625740)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Posttranslational Modification	[1]
Bartonellosis	DISMKP1N	Strong	Biomarker	[2]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Lyme disease	DISO70G5	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Orthostatic hypotension	DISBKQGT	Strong	Posttranslational Modification	[7]
Pancreatic cancer	DISJC981	Strong	Biomarker	[1]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[8]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[8]
High blood pressure	DISY2OHH	moderate	Altered Expression	[9]
Mesothelioma	DISKWK9M	moderate	Biomarker	[10]
Obesity	DIS47Y1K	moderate	Altered Expression	[9]
Colorectal neoplasm	DISR1UCN	Disputed	Biomarker	[11]
Lymphoma	DISN6V4S	Limited	Biomarker	[12]
Melanoma	DIS1RRCY	Limited	Biomarker	[13]

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 Protein phosphatase 1 regulatory subunit 14A (PPP1R14A).	[14]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein phosphatase 1 regulatory subunit 14A (PPP1R14A).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein phosphatase 1 regulatory subunit 14A (PPP1R14A).	[21]

8 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 Protein phosphatase 1 regulatory subunit 14A (PPP1R14A).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Protein phosphatase 1 regulatory subunit 14A (PPP1R14A).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Protein phosphatase 1 regulatory subunit 14A (PPP1R14A).	[18]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein phosphatase 1 regulatory subunit 14A (PPP1R14A).	[19]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Protein phosphatase 1 regulatory subunit 14A (PPP1R14A).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein phosphatase 1 regulatory subunit 14A (PPP1R14A).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein phosphatase 1 regulatory subunit 14A (PPP1R14A).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein phosphatase 1 regulatory subunit 14A (PPP1R14A).	[23]

References

• [1] Nuclear localization of CPI-17, a protein phosphatase-1 inhibitor protein, affects histone H3 phosphorylation and corresponds to proliferation of cancer and smooth muscle cells.Biochem Biophys Res Commun. 2013 Apr 26;434(1):137-42. doi: 10.1016/j.bbrc.2013.03.055. Epub 2013 Mar 26.
• [2] Characterization of a 17-kilodalton antigen of Bartonella henselae reactive with sera from patients with cat scratch disease.J Clin Microbiol. 1995 Sep;33(9):2358-65. doi: 10.1128/jcm.33.9.2358-2365.1995.
• [3] GATA-6 and NF-B activate CPI-17 gene transcription and regulate Ca2+ sensitization of smooth muscle contraction.Mol Cell Biol. 2013 Mar;33(5):1085-102. doi: 10.1128/MCB.00626-12. Epub 2012 Dec 28.
• [4] Identification of novel methylated targets in colorectal cancer by microarray analysis and construction of co-expression network.Oncol Lett. 2017 Sep;14(3):2643-2648. doi: 10.3892/ol.2017.6506. Epub 2017 Jun 30.
• [5] Osp17, a novel immunodominant outer surface protein of Borrelia afzelii: recombinant expression in Escherichia coli and its use as a diagnostic antigen for serodiagnosis of Lyme borreliosis.Med Microbiol Immunol. 1999 May;187(4):213-9. doi: 10.1007/s004300050095.
• [6] CPI-17 Overexpression and Its Correlation With the NF2 Mutation Spectrum in Sporadic Vestibular Schwannomas.Otol Neurotol. 2020 Jan;41(1):e94-e102. doi: 10.1097/MAO.0000000000002430.
• [7] Prolonged bed rest impairs rapid CPI-17 phosphorylation and contraction in rat mesenteric resistance arteries to cause orthostatic hypotension.Pflugers Arch. 2017 Dec;469(12):1651-1662. doi: 10.1007/s00424-017-2031-x. Epub 2017 Jul 17.
• [8] Association of imputed prostate cancer transcriptome with disease risk reveals novel mechanisms.Nat Commun. 2019 Jul 15;10(1):3107. doi: 10.1038/s41467-019-10808-7.
• [9] CPI-17-mediated contraction of vascular smooth muscle is essential for the development of hypertension in obese mice.J Genet Genomics. 2019 Mar 20;46(3):109-118. doi: 10.1016/j.jgg.2019.02.005. Epub 2019 Mar 15.
• [10] Functional inactivation of NF2/merlin in human mesothelioma.Lung Cancer. 2009 May;64(2):140-7. doi: 10.1016/j.lungcan.2008.08.014. Epub 2008 Oct 4.
• [11] Comparing the DNA hypermethylome with gene mutations in human colorectal cancer.PLoS Genet. 2007 Sep;3(9):1709-23. doi: 10.1371/journal.pgen.0030157. Epub 2007 Jul 31.
• [12] Identification of highly methylated genes across various types of B-cell non-hodgkin lymphoma.PLoS One. 2013 Nov 19;8(11):e79602. doi: 10.1371/journal.pone.0079602. eCollection 2013.
• [13] CPI-17 drives oncogenic Ras signaling in human melanomas via Ezrin-Radixin-Moesin family proteins.Oncotarget. 2016 Nov 29;7(48):78242-78254. doi: 10.18632/oncotarget.12919.
• [14] 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.
• [15] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [16] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [17] 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.
• [18] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [19] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [20] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [21] 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.
• [22] 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.
• [23] 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.