Details of Drug Off-Target (DOT)

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

• DOT Name: Transportin-2 (TNPO2)
• Synonyms: Karyopherin beta-2b
• Gene Name: TNPO2
• Related Disease:
  B-cell lymphoma
  Multiple sclerosis
  Neoplasm
  Intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies
  Polycystic ovarian syndrome
• UniProt ID: TNPO2_HUMAN
• Pfam ID: PF02985 ; PF13513 ; PF03810
• Sequence:
  MDWQPDEQGLQQVLQLLKDSQSPNTATQRIVQDKLKQLNQFPDFNNYLIFVLTRLKSEDE
  PTRSLSGLILKNNVKAHYQSFPPPVADFIKQECLNNIGDASSLIRATIGILITTIASKGE
  LQMWPELLPQLCNLLNSEDYNTCEGAFGALQKICEDSSELLDSDALNRPLNIMIPKFLQF
  FKHCSPKIRSHAIACVNQFIMDRAQALMDNIDTFIEHLFALAVDDDPEVRKNVCRALVML
  LEVRIDRLIPHMHSIIQYMLQRTQDHDENVALEACEFWLTLAEQPICKEVLASHLVQLIP
  ILVNGMKYSEIDIILLKGDVEEDEAVPDSEQDIKPRFHKSRTVTLPHEAERPDGSEDAED
  DDDDDALSDWNLRKCSAAALDVLANVFREELLPHLLPLLKGLLFHPEWVVKESGILVLGA
  IAEGCMQGMVPYLPELIPHLIQCLSDKKALVRSIACWTLSRYAHWVVSQPPDMHLKPLMT
  ELLKRILDGNKRVQEAACSAFATLEEEACTELVPYLSYILDTLVFAFGKYQHKNLLILYD
  AIGTLADSVGHHLNQPEYIQKLMPPLIQKWNELKDEDKDLFPLLECLSSVATALQSGFLP
  YCEPVYQRCVTLVQKTLAQAMMYTQHPEQYEAPDKDFMIVALDLLSGLAEGLGGHVEQLV
  ARSNIMTLLFQCMQDSMPEVRQSSFALLGDLTKACFIHVKPCIAEFMPILGTNLNPEFIS
  VCNNATWAIGEICMQMGAEMQPYVQMVLNNLVEIINRPNTPKTLLENTGRLTSPSAIPAI
  TIGRLGYVCPQEVAPMLQQFIRPWCTSLRNIRDNEEKDSAFRGICMMIGVNPGGVVQDFI
  FFCDAVASWVSPKDDLRDMFYKILHGFKDQVGEDNWQQFSEQFPPLLKERLAAFYGV
• Function: Probably 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.
• KEGG Pathway: Nucleocytoplasmic transport (hsa03013)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell lymphoma	DISIH1YQ	Definitive	Genetic Variation	[1]
Multiple sclerosis	DISB2WZI	Definitive	Genetic Variation	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[2]
Intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies	DISTTDR1	Strong	Autosomal dominant	[3]
Polycystic ovarian syndrome	DISZ2BNG	Strong	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 Transportin-2 (TNPO2).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Transportin-2 (TNPO2).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Transportin-2 (TNPO2).	[15]

9 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 Transportin-2 (TNPO2).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Transportin-2 (TNPO2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Transportin-2 (TNPO2).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Transportin-2 (TNPO2).	[9]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Transportin-2 (TNPO2).	[10]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Transportin-2 (TNPO2).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Transportin-2 (TNPO2).	[12]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Transportin-2 (TNPO2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Transportin-2 (TNPO2).	[14]

References

• [1] Genetic overlap between autoimmune diseases and non-Hodgkin lymphoma subtypes.Genet Epidemiol. 2019 Oct;43(7):844-863. doi: 10.1002/gepi.22242. Epub 2019 Aug 13.
• [2] TNPO2 operates downstream of DYNC1I1 and promotes gastric cancer cell proliferation and inhibits apoptosis.Cancer Med. 2019 Dec;8(17):7299-7312. doi: 10.1002/cam4.2582. Epub 2019 Oct 11.
• [3] Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med. 2012 Nov 15;367(20):1921-9. doi: 10.1056/NEJMoa1206524. Epub 2012 Oct 3.
• [4] Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
• [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] Differentiation-associated alteration in gene expression of importins and exportins in human leukemia HL-60 cells. Biomed Res. 2008 Jun;29(3):141-5. doi: 10.2220/biomedres.29.141.
• [7] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [14] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [15] 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.