Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGGNG6M)

• DOT Name: Protein phosphatase 1L (PPM1L)
• Synonyms: EC 3.1.3.16; Protein phosphatase 1-like; Protein phosphatase 2C isoform epsilon; PP2C-epsilon
• Gene Name: PPM1L
• Related Disease:
  Acute myocardial infarction
  Familial adenomatous polyposis
  Myocardial infarction
  Neoplasm
  Obesity
  Polyp
• UniProt ID: PPM1L_HUMAN
• EC Number: 3.1.3.16
• Pfam ID: PF00481
• Sequence:
  MIEDTMTLLSLLGRIMRYFLLRPETLFLLCISLALWSYFFHTDEVKTIVKSSRDAVKMVK
  GKVAEIMQNDRLGGLDVLEAEFSKTWEFKNHNVAVYSIQGRRDHMEDRFEVLTDLANKTH
  PSIFGIFDGHGGETAAEYVKSRLPEALKQHLQDYEKDKENSVLSYQTILEQQILSIDREM
  LEKLTVSYDEAGTTCLIALLSDKDLTVANVGDSRGVLCDKDGNAIPLSHDHKPYQLKERK
  RIKRAGGFISFNGSWRVQGILAMSRSLGDYPLKNLNVVIPDPDILTFDLDKLQPEFMILA
  SDGLWDAFSNEEAVRFIKERLDEPHFGAKSIVLQSFYRGCPDNITVMVVKFRNSSKTEEQ
• Function: Acts as a suppressor of the SAPK signaling pathways by associating with and dephosphorylating MAP3K7/TAK1 and MAP3K5, and by attenuating the association between MAP3K7/TAK1 and MAP2K4 or MAP2K6.
• Tissue Specificity: Ubiquitous. Highly expressed in heart, placenta, lung, liver, kidney and pancreas.
• Reactome Pathway: Sphingolipid de novo biosynthesis (R-HSA-1660661)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myocardial infarction	DISE3HTG	Strong	Biomarker	[1]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[2]
Myocardial infarction	DIS655KI	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Obesity	DIS47Y1K	Strong	Biomarker	[3]
Polyp	DISRSLYF	Strong	Altered Expression	[2]

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 1L (PPM1L).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein phosphatase 1L (PPM1L).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Protein phosphatase 1L (PPM1L).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein phosphatase 1L (PPM1L).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein phosphatase 1L (PPM1L).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein phosphatase 1L (PPM1L).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein phosphatase 1L (PPM1L).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein phosphatase 1L (PPM1L).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein phosphatase 1L (PPM1L).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Protein phosphatase 1L (PPM1L).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein phosphatase 1L (PPM1L).	[13]

References

• [1] Phosphatase PPM1L Prevents Excessive Inflammatory Responses and Cardiac Dysfunction after Myocardial Infarction by Inhibiting IKK Activation.J Immunol. 2019 Sep 1;203(5):1338-1347. doi: 10.4049/jimmunol.1900148. Epub 2019 Jul 22.
• [2] Genome-wide scan identifies a copy number variable region at 3q26 that regulates PPM1L in APC mutation-negative familial colorectal cancer patients.Genes Chromosomes Cancer. 2010 Feb;49(2):99-106. doi: 10.1002/gcc.20724.
• [3] Variations in DNA elucidate molecular networks that cause disease.Nature. 2008 Mar 27;452(7186):429-35. doi: 10.1038/nature06757. Epub 2008 Mar 16.
• [4] 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.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [9] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [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] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [13] 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.
• [14] 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.