Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWXG0DO)

• DOT Name: Liprin-alpha-4 (PPFIA4)
• Synonyms: Protein tyrosine phosphatase receptor type f polypeptide-interacting protein alpha-4; PTPRF-interacting protein alpha-4
• Gene Name: PPFIA4
• Related Disease:
  Atrial fibrillation
  Pancreatic cancer
  Renal cell carcinoma
  Familial atrial fibrillation
  Small-cell lung cancer
• UniProt ID: LIPA4_HUMAN
• Pfam ID: PF00536 ; PF07647
• Sequence:
  MCEVMPTINEGDRLGPPHGADADANFEQLMVNMLDEREKLLESLRESQETLAATQSRLQD
  AIHERDQLQRHLNSALPQEFATLTRELSMCREQLLEREEEISELKAERNNTRLLLEHLEC
  LVSRHERSLRMTVVKRQAQSPSGVSSEVEVLKALKSLFEHHKALDEKVRERLRAALERVT
  TLEEQLAGAHQQVSALQQGAGVRDGAAEEEGTVELGPKRLWKEDTGRVEELQELLEKQNF
  ELSQARERLVTLTTTVTELEEDLGTARRDLIKSEELSSKHQRDLREALAQKEDMEERITT
  LEKRYLAAQREATSIHDLNDKLENELANKESLHRQCEEKARHLQELLEVAEQKLQQTMRK
  AETLPEVEAELAQRIAALTKAEERHGNIEEHLRQLEGQLEEKNQELARTAVQVRQREKMN
  EDHNKRLSDTVDRLLSESNERLQLHLKERMAALEEKNTLIQELESSQRQIEEQHHHKGRL
  SEEIEKLRQEVDQLKGRGGPFVDGVHSRSHMGSAADVRFSLGTTTHAPPGVHRRYSALRE
  ESAKLALPLTVTLRSPTWMRMSQGVCCNLEYHSSGTLCGSSGPLPVPEMIQEEKESTELR
  AEEIETRVTSGSMEALNLKQLRKRGSIPTSLTALSLASASPPLSGRSTPKLTSRSAAQDL
  DRMGVMTLPSDLRKHRRKLLSPVSREENREDKATIKCETSPPSSPRTLRLEKLGHPALSQ
  EEGKSALEDQGSNPSSSNSSQDSLHKGAKRKGIKSSIGRLFGKKEKGRLIQLSRDGATGH
  VLLTDSEFSMQEPMVPAKLGTQAEKDRRLKKKHQLLEDARRKGMPFAQWDGPTVVSWLEL
  WVGMPAWYVAACRANVKSGAIMSALSDTEIQREIGISNALHRLKLRLAIQEMVSLTSPSA
  PPTSRTSSGNVWVTHEEMETLETSTKTDSEEGSWAQTLAYGDMNHEWIGNEWLPSLGLPQ
  YRSYFMECLVDARMLDHLTKKDLRVHLKMVDSFHRTSLQYGIMCLKRLNYDRKELEKRRE
  ESQHEIKDVLVWTNDQVVHWVQSIGLRDYAGNLHESGVHGALLALDENFDHNTLALILQI
  PTQNTQARQVMEREFNNLLALGTDRKLDDGDDKVFRRAPSWRKRFRPREHHGRGGMLSAS
  AETLPAGFRVSTLGTLQPPPAPPKKIMPEAHSHYLYGHMLSAFRD
• Function: May regulate the disassembly of focal adhesions. May localize receptor-like tyrosine phosphatases type 2A at specific sites on the plasma membrane, possibly regulating their interaction with the extracellular environment and their association with substrates.
• Tissue Specificity: Expressed only in the heart, brain, and skeletal muscle.
• Reactome Pathway:
  Norepinephrine Neurotransmitter Release Cycle (R-HSA-181430)
  Glutamate Neurotransmitter Release Cycle (R-HSA-210500)
  Dopamine Neurotransmitter Release Cycle (R-HSA-212676)
  Acetylcholine Neurotransmitter Release Cycle (R-HSA-264642)
  Receptor-type tyrosine-protein phosphatases (R-HSA-388844)
  Serotonin Neurotransmitter Release Cycle (R-HSA-181429)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[1]
Pancreatic cancer	DISJC981	Strong	Biomarker	[2]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[3]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[1]
Small-cell lung cancer	DISK3LZD	Limited	Biomarker	[4]

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 Liprin-alpha-4 (PPFIA4).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Liprin-alpha-4 (PPFIA4).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Liprin-alpha-4 (PPFIA4).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Liprin-alpha-4 (PPFIA4).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Liprin-alpha-4 (PPFIA4).	[8]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Liprin-alpha-4 (PPFIA4).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Liprin-alpha-4 (PPFIA4).	[10]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Liprin-alpha-4 (PPFIA4).	[11]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Liprin-alpha-4 (PPFIA4).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Liprin-alpha-4 (PPFIA4).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Liprin-alpha-4 (PPFIA4).	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Liprin-alpha-4 (PPFIA4).	[16]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Liprin-alpha-4 (PPFIA4).	[17]

References

• [1] Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
• [2] Liprin-4 as a Possible New Therapeutic Target for Pancreatic Cancer.Anticancer Res. 2017 Dec;37(12):6649-6654. doi: 10.21873/anticanres.12122.
• [3] Liprin-4 is a new hypoxia-inducible target gene required for maintenance of cell-cell contacts.Exp Cell Res. 2010 Oct 15;316(17):2883-92. doi: 10.1016/j.yexcr.2010.06.022. Epub 2010 Jul 1.
• [4] Liprin-4 as a New Therapeutic Target for SCLC as an Upstream Mediator of HIF1.Anticancer Res. 2019 Mar;39(3):1179-1184. doi: 10.21873/anticanres.13227.
• [5] 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.
• [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] 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.
• [8] 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.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] 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.
• [11] Effects of acute ethanol treatment on NCCIT cells and NCCIT cell-derived embryoid bodies (EBs). Toxicol In Vitro. 2010 Sep;24(6):1696-704. doi: 10.1016/j.tiv.2010.05.017. Epub 2010 May 26.
• [12] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [13] 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.
• [14] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [15] 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.
• [16] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [17] Effects of nickel treatment on H3K4 trimethylation and gene expression. PLoS One. 2011 Mar 24;6(3):e17728. doi: 10.1371/journal.pone.0017728.