Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAK40ED)

• DOT Name: Importin-5 (IPO5)
• Synonyms: Imp5; Importin subunit beta-3; Karyopherin beta-3; Ran-binding protein 5; RanBP5
• Gene Name: IPO5
• Related Disease:
  Colorectal carcinoma
  Lung adenocarcinoma
  Peripheral arterial disease
  Influenza
  Keratoconus
  Schizophrenia
• UniProt ID: IPO5_HUMAN
• PDB ID: 6XTE; 6XU2
• Pfam ID: PF02985 ; PF13513 ; PF18808 ; PF18816 ; PF18829
• Sequence:
  MAAAAAEQQQFYLLLGNLLSPDNVVRKQAEETYENIPGQSKITFLLQAIRNTTAAEEARQ
  MAAVLLRRLLSSAFDEVYPALPSDVQTAIKSELLMIIQMETQSSMRKKVCDIAAELARNL
  IDEDGNNQWPEGLKFLFDSVSSQNVGLREAALHIFWNFPGIFGNQQQHYLDVIKRMLVQC
  MQDQEHPSIRTLSARATAAFILANEHNVALFKHFADLLPGFLQAVNDSCYQNDDSVLKSL
  VEIADTVPKYLRPHLEATLQLSLKLCGDTSLNNMQRQLALEVIVTLSETAAAMLRKHTNI
  VAQTIPQMLAMMVDLEEDEDWANADELEDDDFDSNAVAGESALDRMACGLGGKLVLPMIK
  EHIMQMLQNPDWKYRHAGLMALSAIGEGCHQQMEGILNEIVNFVLLFLQDPHPRVRYAAC
  NAVGQMATDFAPGFQKKFHEKVIAALLQTMEDQGNQRVQAHAAAALINFTEDCPKSLLIP
  YLDNLVKHLHSIMVLKLQELIQKGTKLVLEQVVTSIASVADTAEEKFVPYYDLFMPSLKH
  IVENAVQKELRLLRGKTIECISLIGLAVGKEKFMQDASDVMQLLLKTQTDFNDMEDDDPQ
  ISYMISAWARMCKILGKEFQQYLPVVMGPLMKTASIKPEVALLDTQDMENMSDDDGWEFV
  NLGDQQSFGIKTAGLEEKSTACQMLVCYAKELKEGFVEYTEQVVKLMVPLLKFYFHDGVR
  VAAAESMPLLLECARVRGPEYLTQMWHFMCDALIKAIGTEPDSDVLSEIMHSFAKCIEVM
  GDGCLNNEHFEELGGILKAKLEEHFKNQELRQVKRQDEDYDEQVEESLQDEDDNDVYILT
  KVSDILHSIFSSYKEKVLPWFEQLLPLIVNLICPHRPWPDRQWGLCIFDDVIEHCSPASF
  KYAEYFLRPMLQYVCDNSPEVRQAAAYGLGVMAQYGGDNYRPFCTEALPLLVRVIQSADS
  KTKENVNATENCISAVGKIMKFKPDCVNVEEVLPHWLSWLPLHEDKEEAVQTFNYLCDLI
  ESNHPIVLGPNNTNLPKIFSIIAEGEMHEAIKHEDPCAKRLANVVRQVQTSGGLWTECIA
  QLSPEQQAAIQELLNSA
• Function: Functions in nuclear protein import as nuclear transport receptor. Serves as receptor for nuclear localization signals (NLS) in cargo substrates. Is thought to mediate docking of the importin/substrate complex to the nuclear pore complex (NPC) through binding to nucleoporin 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 the importin, the importin/substrate complex dissociates and importin is re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran. 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. Mediates the nuclear import of ribosomal proteins RPL23A, RPS7 and RPL5. In vitro, mediates nuclear import of H2A, H2B, H3 and H4 histones. Binds to CPEB3 and mediates its nuclear import following neuronal stimulation. In case of HIV-1 infection, binds and mediates the nuclear import of HIV-1 Rev.
• KEGG Pathway: Nucleocytoplasmic transport (hsa03013)
• Reactome Pathway: vRNP Assembly (R-HSA-192905)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[1]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[2]
Peripheral arterial disease	DIS78WFB	Strong	Genetic Variation	[3]
Influenza	DIS3PNU3	moderate	Biomarker	[4]
Keratoconus	DISOONXH	moderate	Biomarker	[5]
Schizophrenia	DISSRV2N	moderate	Biomarker	[6]

4 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-5 (IPO5).	[7]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Importin-5 (IPO5).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Importin-5 (IPO5).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Importin-5 (IPO5).	[22]

15 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-5 (IPO5).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Importin-5 (IPO5).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Importin-5 (IPO5).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Importin-5 (IPO5).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Importin-5 (IPO5).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Importin-5 (IPO5).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Importin-5 (IPO5).	[14]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Importin-5 (IPO5).	[16]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Importin-5 (IPO5).	[17]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Importin-5 (IPO5).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Importin-5 (IPO5).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Importin-5 (IPO5).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Importin-5 (IPO5).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Importin-5 (IPO5).	[16]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Importin-5 (IPO5).	[23]

References

• [1] IPO5 promotes the proliferation and tumourigenicity of colorectal cancer cells by mediating RASAL2 nuclear transportation.J Exp Clin Cancer Res. 2019 Jul 9;38(1):296. doi: 10.1186/s13046-019-1290-0.
• [2] c-Myc targeted regulators of cell metabolism in a transgenic mouse model of papillary lung adenocarcinoma.Oncotarget. 2016 Oct 4;7(40):65514-65539. doi: 10.18632/oncotarget.11804.
• [3] Genome-Wide Association Study of Peripheral Arterial Disease in a Japanese Population.PLoS One. 2015 Oct 21;10(10):e0139262. doi: 10.1371/journal.pone.0139262. eCollection 2015.
• [4] Novel influenza inhibitors designed to target PB1 interactions with host importin RanBP5.Antiviral Res. 2019 Apr;164:81-90. doi: 10.1016/j.antiviral.2019.02.003. Epub 2019 Feb 8.
• [5] Molecular Screening of Keratoconus Susceptibility Sequence Variants in VSX1, TGFBI, DOCK9, STK24, and IPO5 Genes in Polish Patients and Novel TGFBI Variant Identification.Ophthalmic Genet. 2016;37(1):37-43. doi: 10.3109/13816810.2014.926375. Epub 2014 Jun 18.
• [6] Genetic and functional study of the IPO5 gene in schizophrenia.Psychiatry Res. 2011 May 30;187(3):460-1. doi: 10.1016/j.psychres.2010.05.010. Epub 2010 Jun 12.
• [7] 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.
• [8] 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.
• [9] 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.
• [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] 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.
• [12] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [13] 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.
• [14] 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.
• [15] 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.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [18] 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.
• [19] 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.
• [20] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [21] 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.
• [22] 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.
• [23] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.