Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP0EX18)

• DOT Name: Importin subunit alpha-3 (KPNA4)
• Synonyms: Importin alpha Q1; Qip1; Karyopherin subunit alpha-4
• Gene Name: KPNA4
• Related Disease:
  Arteriosclerosis
  Ataxia-telangiectasia
  Atherosclerosis
  Cardiovascular disease
  Ellis-van Creveld syndrome
  Influenza
  Lung cancer
  Lung carcinoma
  Neoplasm
  Polydactyly
  Prostate cancer
  Prostate carcinoma
  Viral encephalitis
  Rabies
  Cutaneous squamous cell carcinoma
  Dental caries
• UniProt ID: IMA3_HUMAN
• PDB ID: 4UAE; 5TBK; 5XZX; 6BVV; 6BVZ; 6BW9; 6BWA; 6BWB; 6WX8; 7JJL; 7LF4; 7LFC; 7RFY; 7RG5; 8FUB; 8FZM; 8HKW
• Pfam ID: PF00514 ; PF16186 ; PF01749
• Sequence:
  MADNEKLDNQRLKNFKNKGRDLETMRRQRNEVVVELRKNKRDEHLLKRRNVPHEDICEDS
  DIDGDYRVQNTSLEAIVQNASSDNQGIQLSAVQAARKLLSSDRNPPIDDLIKSGILPILV
  HCLERDDNPSLQFEAAWALTNIASGTSEQTQAVVQSNAVPLFLRLLHSPHQNVCEQAVWA
  LGNIIGDGPQCRDYVISLGVVKPLLSFISPSIPITFLRNVTWVMVNLCRHKDPPPPMETI
  QEILPALCVLIHHTDVNILVDTVWALSYLTDAGNEQIQMVIDSGIVPHLVPLLSHQEVKV
  QTAALRAVGNIVTGTDEQTQVVLNCDALSHFPALLTHPKEKINKEAVWFLSNITAGNQQQ
  VQAVIDANLVPMIIHLLDKGDFGTQKEAAWAISNLTISGRKDQVAYLIQQNVIPPFCNLL
  TVKDAQVVQVVLDGLSNILKMAEDEAETIGNLIEECGGLEKIEQLQNHENEDIYKLAYEI
  IDQFFSSDDIDEDPSLVPEAIQGGTFGFNSSANVPTEGFQF
• Function: Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1. Binds specifically and directly to substrates containing either a simple or bipartite NLS motif. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS. In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS.
• Tissue Specificity: Highly expressed in testis, ovary, small intestine, heart, skeletal muscle, lung and pancreas, but barely detectable in kidney, thymus, colon and peripheral blood leukocytes.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  Salmonella infection (hsa05132)
  Chemical carcinogenesis - receptor activation (hsa05207)
• Reactome Pathway:
  NS1 Mediated Effects on Host Pathways (R-HSA-168276)
  ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[1]
Ataxia-telangiectasia	DISP3EVR	Strong	Genetic Variation	[2]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[1]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[3]
Ellis-van Creveld syndrome	DISWSKIF	Strong	Genetic Variation	[2]
Influenza	DIS3PNU3	Strong	Genetic Variation	[4]
Lung cancer	DISCM4YA	Strong	Altered Expression	[5]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Polydactyly	DIS25BMZ	Strong	Genetic Variation	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[6]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[6]
Viral encephalitis	DIS9G09S	Strong	Biomarker	[7]
Rabies	DISSC4V5	Disputed	Biomarker	[8]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Biomarker	[9]
Dental caries	DISRBCMD	Limited	Genetic Variation	[10]

1 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 Importin subunit alpha-3 (KPNA4).	[11]

19 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 Importin subunit alpha-3 (KPNA4).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Importin subunit alpha-3 (KPNA4).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Importin subunit alpha-3 (KPNA4).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Importin subunit alpha-3 (KPNA4).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Importin subunit alpha-3 (KPNA4).	[16]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Importin subunit alpha-3 (KPNA4).	[17]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Importin subunit alpha-3 (KPNA4).	[18]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Importin subunit alpha-3 (KPNA4).	[19]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Importin subunit alpha-3 (KPNA4).	[20]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Importin subunit alpha-3 (KPNA4).	[20]
Benzatropine	DMF7EXL	Approved	Benzatropine increases the expression of Importin subunit alpha-3 (KPNA4).	[20]
Haloperidol	DM96SE0	Approved	Haloperidol increases the expression of Importin subunit alpha-3 (KPNA4).	[20]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Importin subunit alpha-3 (KPNA4).	[21]
Phenol	DM1QSM3	Phase 2/3	Phenol increases the expression of Importin subunit alpha-3 (KPNA4).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Importin subunit alpha-3 (KPNA4).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Importin subunit alpha-3 (KPNA4).	[24]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Importin subunit alpha-3 (KPNA4).	[25]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Importin subunit alpha-3 (KPNA4).	[26]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Importin subunit alpha-3 (KPNA4).	[22]

References

• [1] MicroRNA-24 inhibits the proliferation and migration of endothelial cells in patients with atherosclerosis by targeting importin-3 and regulating inflammatory responses.Exp Ther Med. 2018 Jan;15(1):338-344. doi: 10.3892/etm.2017.5355. Epub 2017 Oct 23.
• [2] Exclusion of the Ellis-van Creveld region on chromosome 4p16 in some families with asphyxiating thoracic dystrophy and short-rib polydactyly syndromes.Eur J Hum Genet. 2000 Aug;8(8):645-8. doi: 10.1038/sj.ejhg.5200507.
• [3] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [4] Importin 3/Qip1 is involved in multiplication of mutant influenza virus with alanine mutation at amino acid 9 independently of nuclear transport function.PLoS One. 2013;8(1):e55765. doi: 10.1371/journal.pone.0055765. Epub 2013 Jan 30.
• [5] YY1-mediated overexpression of long noncoding RNA MCM3AP-AS1 accelerates angiogenesis and progression in lung cancer by targeting miR-340-5p/KPNA4 axis.J Cell Biochem. 2020 Mar;121(3):2258-2267. doi: 10.1002/jcb.29448. Epub 2019 Nov 6.
• [6] Inhibition of KPNA4 attenuates prostate cancer metastasis.Oncogene. 2017 May 18;36(20):2868-2878. doi: 10.1038/onc.2016.440. Epub 2016 Dec 12.
• [7] Japanese Encephalitis Virus NS5 Inhibits Type I Interferon (IFN) Production by Blocking the Nuclear Translocation of IFN Regulatory Factor 3 and NF-B.J Virol. 2017 Mar 29;91(8):e00039-17. doi: 10.1128/JVI.00039-17. Print 2017 Apr 15.
• [8] Postgenomics biomarkers for rabiesthe next decade of proteomics.OMICS. 2015 Feb;19(2):67-79. doi: 10.1089/omi.2014.0127. Epub 2015 Jan 22.
• [9] MiR-3619-5p hampers proliferation and cisplatin resistance in cutaneous squamous-cell carcinoma via KPNA4.Biochem Biophys Res Commun. 2019 May 28;513(2):419-425. doi: 10.1016/j.bbrc.2019.03.203. Epub 2019 Apr 6.
• [10] Genome-wide association study of primary dentition pit-and-fissure and smooth surface caries.Caries Res. 2014;48(4):330-8. doi: 10.1159/000356299.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] 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.
• [18] DNA microarray analysis of changes in gene expression induced by 1,25-dihydroxyvitamin D3 in human promyelocytic leukemia HL-60 cells. Biomed Res. 2006 Jun;27(3):99-109. doi: 10.2220/biomedres.27.99.
• [19] 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.
• [20] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [23] 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.
• [24] 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.
• [25] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [26] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.