Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYYFA9C)

• DOT Name: Liprin-alpha-1 (PPFIA1)
• Synonyms: LAR-interacting protein 1; LIP-1; Protein tyrosine phosphatase receptor type f polypeptide-interacting protein alpha-1; PTPRF-interacting protein alpha-1
• Gene Name: PPFIA1
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Head-neck squamous cell carcinoma
  Neoplasm
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Peutz-Jeghers syndrome
  Squamous cell carcinoma
• UniProt ID: LIPA1_HUMAN
• PDB ID: 1N7F
• Pfam ID: PF00536 ; PF07647
• Sequence:
  MMCEVMPTISEAEGPPGGGGGHGSGSPSQPDADSHFEQLMVSMLEERDRLLDTLRETQET
  LALTQGKLHEVGHERDSLQRQLNTALPQEFAALTKELNVCREQLLEREEEIAELKAERNN
  TRLLLEHLECLVSRHERSLRMTVVKRQAQSPAGVSSEVEVLKALKSLFEHHKALDEKVRE
  RLRVALERCSLLEEELGATHKELMILKEQNNQKKTLTDGVLDINHEQENTPSTSGKRSSD
  GSLSHEEDLAKVIELQEIISKQSREQSQMKERLASLSSHVTELEEDLDTARKDLIKSEEM
  NTKLQRDVREAMAQKEDMEERITTLEKRYLAAQREATSVHDLNDKLENEIANKDSMHRQT
  EDKNRQLQERLELAEQKLQQTLRKAETLPEVEAELAQRVAALSKAEERHGNIEERLRQME
  AQLEEKNQELQRARQREKMNEEHNKRLSDTVDKLLSESNERLQLHLKERMAALEDKNSLL
  REVESAKKQLEETQHDKDQLVLNIEALRAELDHMRLRGASLHHGRPHLGSVPDFRFPMAD
  GHTDSYSTSAVLRRPQKGRLAALRDEPSKVQTLNEQDWERAQQASVLANVAQAFESDADV
  SDGEDDRDTLLSSVDLLSPSGQADAHTLAMMLQEQLDAINKEIRLIQEEKENTEQRAEEI
  ESRVGSGSLDNLGRFRSMSSIPPYPASSLASSSPPGSGRSTPRRIPHSPAREVDRLGVMT
  LLPPSREEVRDDKTTIKCETSPPSSPRALRLDRLHKGALHTVSHEDIRDIRNSTGSQDGP
  VSNPSSSNSSQDSLHKAPKKKGIKSSIGRLFGKKEKGRPGQTGKEALGQAGVSETDNSSQ
  DALGLSKLGGQAEKNRKLQKKHELLEEARRQGLPFAQWDGPTVVVWLELWVGMPAWYVAA
  CRANVKSGAIMSALSDTEIQREIGISNPLHRLKLRLAIQEIMSLTSPSAPPTSRTTLAYG
  DMNHEWIGNEWLPSLGLPQYRSYFMECLVDARMLDHLTKKDLRGQLKMVDSFHRNSFQCG
  IMCLRRLNYDRKELERKREESQSEIKDVLVWSNDRVIRWILSIGLKEYANNLIESGVHGA
  LLALDETFDFSALALLLQIPTQNTQARAVLEREFNNLLVMGTDRRFDEDDDKSFRRAPSW
  RKKFRPKDIRGLAAGSAETLPANFRVTSSMSSPSMQPKKMQMDGNVSGTQRLDSATVRTY
  SC
• 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: Ubiquitous.
• 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

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Carcinoma	DISH9F1N	Strong	Biomarker	[4]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	moderate	Genetic Variation	[7]
Liver cancer	DISDE4BI	moderate	Genetic Variation	[7]
Peutz-Jeghers syndrome	DISF27ZJ	Limited	Biomarker	[8]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[9]

12 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 Liprin-alpha-1 (PPFIA1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Liprin-alpha-1 (PPFIA1).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Liprin-alpha-1 (PPFIA1).	[12]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Liprin-alpha-1 (PPFIA1).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Liprin-alpha-1 (PPFIA1).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Liprin-alpha-1 (PPFIA1).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Liprin-alpha-1 (PPFIA1).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Liprin-alpha-1 (PPFIA1).	[18]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Liprin-alpha-1 (PPFIA1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Liprin-alpha-1 (PPFIA1).	[20]
NS398	DMINUWH	Terminated	NS398 increases the expression of Liprin-alpha-1 (PPFIA1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Liprin-alpha-1 (PPFIA1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Liprin-alpha-1 (PPFIA1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Liprin-alpha-1 (PPFIA1).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Liprin-alpha-1 (PPFIA1).	[21]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Liprin-alpha-1 (PPFIA1).	[21]

References

• [1] Liprin-1 modulates cancer cell signaling by transmembrane protein CD82 in adhesive membrane domains linked to cytoskeleton.Cell Commun Signal. 2018 Jul 13;16(1):41. doi: 10.1186/s12964-018-0253-y.
• [2] Explorative results from multistep screening for potential genetic risk loci of Alzheimer's disease in the longitudinal VITA study cohort.J Neural Transm (Vienna). 2018 Jan;125(1):77-87. doi: 10.1007/s00702-017-1796-6. Epub 2017 Oct 12.
• [3] PPFIA1 is upregulated in liver metastasis of breast cancer and is a potential poor prognostic indicator of metastatic relapse.Tumour Biol. 2017 Jul;39(7):1010428317713492. doi: 10.1177/1010428317713492.
• [4] Amplification of the PPFIA1 gene region on 11q13 in oral squamous cell carcinomas (OSCC).J Craniomaxillofac Surg. 2013 Dec;41(8):845-9. doi: 10.1016/j.jcms.2013.01.040. Epub 2013 Feb 26.
• [5] Combined expression and prognostic significance of PPFIA1 and ALG3 in head and neck squamous cell carcinoma.Mol Biol Rep. 2019 Jun;46(3):2693-2701. doi: 10.1007/s11033-019-04712-y. Epub 2019 Feb 25.
• [6] EWSR1 genetic rearrangements in salivary gland tumors: a specific and very common feature of hyalinizing clear cell carcinoma.Am J Surg Pathol. 2013 Apr;37(4):571-8. doi: 10.1097/PAS.0b013e3182772a15.
• [7] Comparative genomics on mammalian Fgf3-Fgf4 locus.Int J Oncol. 2005 Jul;27(1):281-5.
• [8] Search for the second Peutz-Jeghers syndrome locus: exclusion of the STK13, PRKCG, KLK10, and PSCD2 genes on chromosome 19 and the STK11IP gene on chromosome 2.Cytogenet Genome Res. 2002;97(3-4):171-8. doi: 10.1159/000066620.
• [9] Amplification and overexpression of PPFIA1, a putative 11q13 invasion suppressor gene, in head and neck squamous cell carcinoma.Genes Chromosomes Cancer. 2008 Apr;47(4):353-62. doi: 10.1002/gcc.20539.
• [10] 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.
• [11] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [12] 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.
• [13] 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.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [16] 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.
• [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] 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] 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.
• [21] 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.
• [22] Detection of differentially expressed genes in human colon carcinoma cells treated with a selective COX-2 inhibitor. Oncogene. 2001 Jul 27;20(33):4450-6. doi: 10.1038/sj.onc.1204588.
• [23] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.