Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0JVGOZ)

• DOT Name: Phostensin (PPP1R18)
• Synonyms: Protein phosphatase 1 F-actin cytoskeleton-targeting subunit; Protein phosphatase 1 regulatory subunit 18
• Gene Name: PPP1R18
• Related Disease:
  Cardiac failure
  Congestive heart failure
  Esophageal squamous cell carcinoma
  Lung adenocarcinoma
  Type-1 diabetes
  Lung cancer
  Lung carcinoma
  Systemic lupus erythematosus
• UniProt ID: PPR18_HUMAN
• Pfam ID: PF13914 ; PF13916
• Sequence:
  MATIPDWKLQLLARRRQEEASVRGREKAERERLSQMPAWKRGLLERRRAKLGLSPGEPSP
  VLGTVEAGPPDPDESAVLLEAIGPVHQNRFIRQERQQQQQQQQRSEELLAERKPGPLEAR
  ERRPSPGEMRDQSPKGRESREERLSPRETRERRLGIGGAQELSLRPLEARDWRQSPGEVG
  DRSSRLSEAWKWRLSPGETPERSLRLAESREQSPRRKEVESRLSPGESAYQKLGLTEAHK
  WRPDSRESQEQSLVQLEATEWRLRSGEERQDYSEECGRKEEWPVPGVAPKETAELSETLT
  REAQGNSSAGVEAAEQRPVEDGERGMKPTEGWKWTLNSGKAREWTPRDIEAQTQKPEPPE
  SAEKLLESPGVEAGEGEAEKEEAGAQGRPLRALQNCCSVPSPLPPEDAGTGGLRQQEEEA
  VELQPPPPAPLSPPPPAPTAPQPPGDPLMSRLFYGVKAGPGVGAPRRSGHTFTVNPRRSV
  PPATPATPTSPATVDAAVPGAGKKRYPTAEEILVLGGYLRLSRSCLAKGSPERHHKQLKI
  SFSETALETTYQYPSESSVLEELGPEPEVPSAPNPPAAQPDDEEDEEELLLLQPELQGGL
  RTKALIVDESCRR
• Function: [Isoform 1]: May target protein phosphatase 1 to F-actin cytoskeleton; [Isoform 4]: May target protein phosphatase 1 to F-actin cytoskeleton.
• Tissue Specificity: Isoform 4 is predominantly expressed in leukocytes and spleen.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac failure	DISDC067	Strong	Biomarker	[1]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[1]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[2]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[3]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[4]
Lung cancer	DISCM4YA	Limited	Genetic Variation	[5]
Lung carcinoma	DISTR26C	Limited	Genetic Variation	[6]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phostensin (PPP1R18).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Phostensin (PPP1R18).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phostensin (PPP1R18).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Phostensin (PPP1R18).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Phostensin (PPP1R18).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Phostensin (PPP1R18).	[13]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Phostensin (PPP1R18).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Phostensin (PPP1R18).	[12]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Phostensin (PPP1R18).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Phostensin (PPP1R18).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Phostensin (PPP1R18).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Phostensin (PPP1R18).	[22]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Phostensin (PPP1R18).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	Triclosan increases the methylation of Phostensin (PPP1R18).	[15]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Phostensin (PPP1R18).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Phostensin (PPP1R18).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Phostensin (PPP1R18).	[20]

References

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• [2] Cell Signaling Pathway in 12-O-Tetradecanoylphorbol-13-acetate-Induced LCN2 Gene Transcription in Esophageal Squamous Cell Carcinoma.Biomed Res Int. 2017;2017:9592501. doi: 10.1155/2017/9592501. Epub 2017 Oct 2.
• [3] A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma.Am J Hum Genet. 2009 Nov;85(5):679-91. doi: 10.1016/j.ajhg.2009.09.012. Epub 2009 Oct 15.
• [4] A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene.Nature. 2007 Aug 2;448(7153):591-4. doi: 10.1038/nature06010. Epub 2007 Jul 15.
• [5] Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls.Hum Mol Genet. 2012 Nov 15;21(22):4980-95. doi: 10.1093/hmg/dds334. Epub 2012 Aug 16.
• [6] Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.Nat Genet. 2017 Jul;49(7):1126-1132. doi: 10.1038/ng.3892. Epub 2017 Jun 12.
• [7] GWAS identifies novel SLE susceptibility genes and explains the association of the HLA region.Genes Immun. 2014 Sep;15(6):347-54. doi: 10.1038/gene.2014.23. Epub 2014 May 29.
• [8] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [9] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [10] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [15] Pregnancy exposure to synthetic phenols and placental DNA methylation - An epigenome-wide association study in male infants from the EDEN cohort. Environ Pollut. 2021 Dec 1;290:118024. doi: 10.1016/j.envpol.2021.118024. Epub 2021 Aug 21.
• [16] 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.
• [17] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [18] 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.
• [19] 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.
• [20] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [21] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.