Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2AMYLY)

• DOT Name: Phospholipid scramblase 4 (PLSCR4)
• Synonyms: PL scramblase 4; Ca(2+)-dependent phospholipid scramblase 4; Cell growth-inhibiting gene 43 protein; TRA1
• Gene Name: PLSCR4
• Related Disease:
  Cardiac failure
  Choroid plexus carcinoma
  Congestive heart failure
  Non-small-cell lung cancer
  Plasma cell myeloma
  Teratoma
  Adult lymphoma
  Lymphoma
  Pediatric lymphoma
  Small-cell lung cancer
  Follicular lymphoma
• UniProt ID: PLS4_HUMAN
• PDB ID: 3Q5U
• Pfam ID: PF03803
• Sequence:
  MSGVVPTAPEQPAGEMENQTKPPDPRPDAPPEYNSHFLPGPPGTAVPPPTGYPGGLPMGY
  YSPQQPSTFPLYQPVGGIHPVRYQPGKYPMPNQSVPITWMPGPTPMANCPPGLEYLVQLD
  NIHVLQHFEPLEMMTCFETNNRYDIKNNSDQMVYIVTEDTDDFTRNAYRTLRPFVLRVTD
  CMGREIMTMQRPFRCTCCCFCCPSARQELEVQCPPGVTIGFVAEHWNLCRAVYSIQNEKK
  ENVMRVRGPCSTYGCGSDSVFEVKSLDGISNIGSIIRKWNGLLSAMADADHFDIHFPLDL
  DVKMKAMIFGACFLIDFMYFERSPPQRSR
• Function: May mediate accelerated ATP-independent bidirectional transbilayer migration of phospholipids upon binding calcium ions that results in a loss of phospholipid asymmetry in the plasma membrane. May play a central role in the initiation of fibrin clot formation, in the activation of mast cells and in the recognition of apoptotic and injured cells by the reticuloendothelial system.
• Tissue Specificity: Expressed in heart, brain, placenta, lung, liver, kidney, pancreas, spleen, thymus, prostate, testis, uterus, small intestine and colon. Not detected in peripheral blood lymphocytes.

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardiac failure	DISDC067	Strong	Biomarker	[1]
Choroid plexus carcinoma	DISQ04MQ	Strong	Biomarker	[2]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[1]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[3]
Plasma cell myeloma	DIS0DFZ0	Strong	Altered Expression	[4]
Teratoma	DIS6ICY4	Strong	Altered Expression	[5]
Adult lymphoma	DISK8IZR	moderate	Genetic Variation	[6]
Lymphoma	DISN6V4S	moderate	Genetic Variation	[6]
Pediatric lymphoma	DIS51BK2	moderate	Genetic Variation	[6]
Small-cell lung cancer	DISK3LZD	moderate	Biomarker	[7]
Follicular lymphoma	DISVEUR6	Disputed	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Phospholipid scramblase 4 (PLSCR4).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Phospholipid scramblase 4 (PLSCR4).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Phospholipid scramblase 4 (PLSCR4).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Phospholipid scramblase 4 (PLSCR4).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Phospholipid scramblase 4 (PLSCR4).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Phospholipid scramblase 4 (PLSCR4).	[14]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Phospholipid scramblase 4 (PLSCR4).	[15]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Phospholipid scramblase 4 (PLSCR4).	[16]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of Phospholipid scramblase 4 (PLSCR4).	[17]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Phospholipid scramblase 4 (PLSCR4).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Phospholipid scramblase 4 (PLSCR4).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phospholipid scramblase 4 (PLSCR4).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Phospholipid scramblase 4 (PLSCR4).	[23]

2 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 affects the methylation of Phospholipid scramblase 4 (PLSCR4).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Phospholipid scramblase 4 (PLSCR4).	[22]

References

• [1] The lncRNA Plscr4 Controls Cardiac Hypertrophy by Regulating miR-214.Mol Ther Nucleic Acids. 2018 Mar 2;10:387-397. doi: 10.1016/j.omtn.2017.12.018. Epub 2017 Dec 30.
• [2] DNA methylation signature is prognostic of choroid plexus tumor aggressiveness.Clin Epigenetics. 2019 Aug 13;11(1):117. doi: 10.1186/s13148-019-0708-z.
• [3] Long non-coding RNA LINC00641 suppresses non-small-cell lung cancer by sponging miR-424-5p to upregulate PLSCR4.Cancer Biomark. 2019;26(1):79-91. doi: 10.3233/CBM-190142.
• [4] A molecular compendium of genes expressed in multiple myeloma.Blood. 2002 Sep 15;100(6):2175-86. doi: 10.1182/blood-2002-01-0008.
• [5] Differentiation of spontaneously contracting cardiomyocytes from non-virally reprogrammed human amniotic fluid stem cells.PLoS One. 2017 May 17;12(5):e0177824. doi: 10.1371/journal.pone.0177824. eCollection 2017.
• [6] The common viral insertion site Evi12 is located in the 5'-noncoding region of Gnn, a novel gene with enhanced expression in two subclasses of human acute myeloid leukemia.J Virol. 2005 May;79(9):5249-58. doi: 10.1128/JVI.79.9.5249-5258.2005.
• [7] Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer.Nat Genet. 2012 Oct;44(10):1111-6. doi: 10.1038/ng.2405. Epub 2012 Sep 2.
• [8] Identification of TRA-1-60-positive cells as a potent refractory population in follicular lymphomas.Cancer Sci. 2019 Jan;110(1):443-457. doi: 10.1111/cas.13870. Epub 2018 Dec 8.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] 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.
• [14] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [15] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [16] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [17] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [18] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [19] 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.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] 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.
• [22] 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.
• [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.