Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTLI3TM2)

• DOT Name: Importin subunit alpha-4 (KPNA3)
• Synonyms: Importin alpha Q2; Qip2; Karyopherin subunit alpha-3; SRP1-gamma
• Gene Name: KPNA3
• Related Disease:
  Neu-Laxova syndrome
  Spinocerebellar ataxia type 3
  Alcohol dependence
  Arteriosclerosis
  Atherosclerosis
  Ciliopathy
  Colorectal carcinoma
  Hepatocellular carcinoma
  Influenza
  Major depressive disorder
  Mental disorder
  Neoplasm
  Opioid dependence
  Schizophrenia
  Spastic paraplegia 88, autosomal dominant
  Viral encephalitis
• UniProt ID: IMA4_HUMAN
• Pfam ID: PF00514 ; PF16186 ; PF01749
• Sequence:
  MAENPSLENHRIKSFKNKGRDVETMRRHRNEVTVELRKNKRDEHLLKKRNVPQEESLEDS
  DVDADFKAQNVTLEAILQNATSDNPVVQLSAVQAARKLLSSDRNPPIDDLIKSGILPILV
  KCLERDDNPSLQFEAAWALTNIASGTSAQTQAVVQSNAVPLFLRLLRSPHQNVCEQAVWA
  LGNIIGDGPQCRDYVISLGVVKPLLSFISPSIPITFLRNVTWVIVNLCRNKDPPPPMETV
  QEILPALCVLIYHTDINILVDTVWALSYLTDGGNEQIQMVIDSGVVPFLVPLLSHQEVKV
  QTAALRAVGNIVTGTDEQTQVVLNCDVLSHFPNLLSHPKEKINKEAVWFLSNITAGNQQQ
  VQAVIDAGLIPMIIHQLAKGDFGTQKEAAWAISNLTISGRKDQVEYLVQQNVIPPFCNLL
  SVKDSQVVQVVLDGLKNILIMAGDEASTIAEIIEECGGLEKIEVLQQHENEDIYKLAFEI
  IDQYFSGDDIDEDPCLIPEATQGGTYNFDPTANLQTKEFNF
• 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. Recognizes NLSs of influenza A virus nucleoprotein probably through ARM repeats 7-9.
• Tissue Specificity: Ubiquitous. Highest levels in heart and skeletal muscle.
• 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
Neu-Laxova syndrome	DISKU3GJ	Definitive	Biomarker	[1]
Spinocerebellar ataxia type 3	DISQBQID	Definitive	Biomarker	[1]
Alcohol dependence	DIS4ZSCO	Strong	Genetic Variation	[2]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[3]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[3]
Ciliopathy	DIS10G4I	Strong	Genetic Variation	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Influenza	DIS3PNU3	Strong	Biomarker	[7]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[2]
Mental disorder	DIS3J5R8	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Opioid dependence	DIS6WEHK	Strong	Genetic Variation	[2]
Schizophrenia	DISSRV2N	Strong	Biomarker	[2]
Spastic paraplegia 88, autosomal dominant	DIS9XHJR	Strong	Autosomal dominant	[2]
Viral encephalitis	DIS9G09S	Strong	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Importin subunit alpha-4 (KPNA3).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Importin subunit alpha-4 (KPNA3).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Importin subunit alpha-4 (KPNA3).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Importin subunit alpha-4 (KPNA3).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Importin subunit alpha-4 (KPNA3).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Importin subunit alpha-4 (KPNA3).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Importin subunit alpha-4 (KPNA3).	[15]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Importin subunit alpha-4 (KPNA3).	[16]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Importin subunit alpha-4 (KPNA3).	[17]
Aspirin	DM672AH	Approved	Aspirin increases the expression of Importin subunit alpha-4 (KPNA3).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Importin subunit alpha-4 (KPNA3).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Importin subunit alpha-4 (KPNA3).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Importin subunit alpha-4 (KPNA3).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Importin subunit alpha-4 (KPNA3).	[20]

References

• [1] Karyopherin -3 is a key protein in the pathogenesis of spinocerebellar ataxia type 3 controlling the nuclear localization of ataxin-3.Proc Natl Acad Sci U S A. 2018 Mar 13;115(11):E2624-E2633. doi: 10.1073/pnas.1716071115. Epub 2018 Feb 23.
• [2] KPNA3 variation is associated with schizophrenia, major depression, opiate dependence and alcohol dependence. Dis Markers. 2012;33(4):163-70. doi: 10.3233/DMA-2012-0921.
• [3] 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.
• [4] Beemer-Langer syndrome is a ciliopathy due to biallelic mutations in IFT122.Am J Med Genet A. 2017 May;173(5):1186-1189. doi: 10.1002/ajmg.a.38157. Epub 2017 Mar 28.
• [5] LncRNA DLEU1 contributes to colorectal cancer progression via activation of KPNA3.Mol Cancer. 2018 Aug 11;17(1):118. doi: 10.1186/s12943-018-0873-2.
• [6] KPNA3 Confers Sorafenib Resistance to Advanced Hepatocellular Carcinoma via TWIST Regulated Epithelial-Mesenchymal Transition.J Cancer. 2019 Jun 24;10(17):3914-3925. doi: 10.7150/jca.31448. eCollection 2019.
• [7] Schizophrenia susceptibility genes directly implicated in the life cycles of pathogens: cytomegalovirus, influenza, herpes simplex, rubella, and Toxoplasma gondii.Schizophr Bull. 2009 Nov;35(6):1163-82. doi: 10.1093/schbul/sbn054. Epub 2008 Jun 13.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [12] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Distinct genetic profile in peripheral blood mononuclear cells of psoriatic arthritis patients treated with methotrexate and TNF-inhibitors. Clin Rheumatol. 2014 Dec;33(12):1815-21. doi: 10.1007/s10067-014-2807-8. Epub 2014 Oct 24.
• [17] Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery. Mol Cancer. 2006 May 18;5:20. doi: 10.1186/1476-4598-5-20.
• [18] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [19] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [20] 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.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.