Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI8ESC3)

• DOT Name: Ran-binding protein 3 (RANBP3)
• Synonyms: RanBP3
• Gene Name: RANBP3
• Related Disease:
  Colon cancer
  Colon carcinoma
  Hepatocellular carcinoma
  Male infertility
  T-cell leukaemia
  Advanced cancer
  Melanoma
• UniProt ID: RANB3_HUMAN
• PDB ID: 2CRF; 2Y8F; 2Y8G; 5XZX
• Pfam ID: PF00638
• Sequence:
  MADLANEEKPAIAPPVFVFQKDKGQKSPAEQKNLSDSGEEPRGEAEAPHHGTGHPESAGE
  HALEPPAPAGASASTPPPPAPEAQLPPFPRELAGRSAGGSSPEGGEDSDREDGNYCPPVK
  RERTSSLTQFPPSQSEERSSGFRLKPPTLIHGQAPSAGLPSQKPKEQQRSVLRPAVLQAP
  QPKALSQTVPSSGTNGVSLPADCTGAVPAASPDTAAWRSPSEAADEVCALEEKEPQKNES
  SNASEEEACEKKDPATQQAFVFGQNLRDRVKLINESVDEADMENAGHPSADTPTATNYFL
  QYISSSLENSTNSADASSNKFVFGQNMSERVLSPPKLNEVSSDANRENAAAESGSESSSQ
  EATPEKESLAESAAAYTKATARKCLLEKVEVITGEEAESNVLQMQCKLFVFDKTSQSWVE
  RGRGLLRLNDMASTDDGTLQSRLVMRTQGSLRLILNTKLWAQMQIDKASEKSIRITAMDT
  EDQGVKVFLISASSKDTGQLYAALHHRILALRSRVEQEQEAKMPAPEPGAAPSNEEDDSD
  DDDVLAPSGATAAGAGDEGDGQTTGST
• Function: Acts as a cofactor for XPO1/CRM1-mediated nuclear export, perhaps as export complex scaffolding protein. Bound to XPO1/CRM1, stabilizes the XPO1/CRM1-cargo interaction. In the absence of Ran-bound GTP prevents binding of XPO1/CRM1 to the nuclear pore complex. Binds to CHC1/RCC1 and increases the guanine nucleotide exchange activity of CHC1/RCC1. Recruits XPO1/CRM1 to CHC1/RCC1 in a Ran-dependent manner. Negative regulator of TGF-beta signaling through interaction with the R-SMAD proteins, SMAD2 and SMAD3, and mediating their nuclear export.
• Tissue Specificity: Widely expressed with high levels in testis and heart.
• KEGG Pathway: Human T-cell leukemia virus 1 infection (hsa05166)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colon cancer	DISVC52G	Strong	Altered Expression	[1]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[2]
Male infertility	DISY3YZZ	Strong	Altered Expression	[3]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[4]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[5]
Melanoma	DIS1RRCY	Limited	Altered Expression	[5]

5 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 Ran-binding protein 3 (RANBP3).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Ran-binding protein 3 (RANBP3).	[13]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Ran-binding protein 3 (RANBP3).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Ran-binding protein 3 (RANBP3).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Ran-binding protein 3 (RANBP3).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ran-binding protein 3 (RANBP3).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Ran-binding protein 3 (RANBP3).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ran-binding protein 3 (RANBP3).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of Ran-binding protein 3 (RANBP3).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ran-binding protein 3 (RANBP3).	[11]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Ran-binding protein 3 (RANBP3).	[12]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Ran-binding protein 3 (RANBP3).	[10]

References

• [1] Microarray-based identification and RT-PCR test screening for epithelial-specific mRNAs in peripheral blood of patients with colon cancer.BMC Cancer. 2006 Oct 20;6:250. doi: 10.1186/1471-2407-6-250.
• [2] Pegylated interferon alpha targets Wnt signaling by inducing nuclear export of -catenin.J Hepatol. 2011 Mar;54(3):506-12. doi: 10.1016/j.jhep.2010.07.020. Epub 2010 Oct 29.
• [3] Ran-binding protein 3 is associated with human spermatogenesis and male infertility.Andrologia. 2020 Mar;52(2):e13446. doi: 10.1111/and.13446. Epub 2019 Dec 13.
• [4] A multifunctional domain in human CRM1 (exportin 1) mediates RanBP3 binding and multimerization of human T-cell leukemia virus type 1 Rex protein.Mol Cell Biol. 2003 Dec;23(23):8751-61. doi: 10.1128/MCB.23.23.8751-8761.2003.
• [5] RanBP3 Regulates Melanoma Cell Proliferation via Selective Control of Nuclear Export.J Invest Dermatol. 2016 Jan;136(1):264-74. doi: 10.1038/JID.2015.401.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Analysis of estrogen agonism and antagonism of tamoxifen, raloxifene, and ICI182780 in endometrial cancer cells: a putative role for the epidermal growth factor receptor ligand amphiregulin. J Soc Gynecol Investig. 2005 Oct;12(7):e55-67.
• [9] 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.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [13] 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.
• [14] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [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.