Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5N57RK)

• DOT Name: Ras-related protein Rab-6B (RAB6B)
• Synonyms: EC 3.6.5.2
• Gene Name: RAB6B
• Related Disease:
  Neuroblastoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Capillary malformation-arteriovenous malformation syndrome
  Myotonic dystrophy
  Neoplasm
  Testicular germ cell tumor
  Gastric cancer
  Parkinson disease
  Stomach cancer
• UniProt ID: RAB6B_HUMAN
• PDB ID: 2E9S; 2FE4; 2FFQ
• EC Number: 3.6.5.2
• Pfam ID: PF00071
• Sequence:
  MSAGGDFGNPLRKFKLVFLGEQSVGKTSLITRFMYDSFDNTYQATIGIDFLSKTMYLEDR
  TVRLQLWDTAGQERFRSLIPSYIRDSTVAVVVYDITNLNSFQQTSKWIDDVRTERGSDVI
  IMLVGNKTDLADKRQITIEEGEQRAKELSVMFIETSAKTGYNVKQLFRRVASALPGMENV
  QEKSKEGMIDIKLDKPQEPPASEGGCSC
• Function: The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between active GTP-bound and inactive GDP-bound states. In their active state, drive transport of vesicular carriers from donor organelles to acceptor organelles to regulate the membrane traffic that maintains organelle identity and morphology (Probable). Recruits VPS13B to the Golgi membrane. Regulates the compacted morphology of the Golgi. Seems to have a role in retrograde membrane traffic at the level of the Golgi complex. May function in retrograde transport in neuronal cells. Plays a role in neuron projection development.
• Tissue Specificity: Predominantly expressed in brain.
• Reactome Pathway:
  Retrograde transport at the Trans-Golgi-Network (R-HSA-6811440)
  TBC/RABGAPs (R-HSA-8854214)
  RAB geranylgeranylation (R-HSA-8873719)
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)
  COPI-independent Golgi-to-ER retrograde traffic (R-HSA-6811436)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neuroblastoma	DISVZBI4	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Capillary malformation-arteriovenous malformation syndrome	DISMN03Q	Strong	Genetic Variation	[4]
Myotonic dystrophy	DISNBEMX	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Testicular germ cell tumor	DIS5RN24	Strong	Biomarker	[7]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[8]
Parkinson disease	DISQVHKL	Limited	Biomarker	[9]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Ras-related protein Rab-6B (RAB6B).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ras-related protein Rab-6B (RAB6B).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ras-related protein Rab-6B (RAB6B).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ras-related protein Rab-6B (RAB6B).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ras-related protein Rab-6B (RAB6B).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ras-related protein Rab-6B (RAB6B).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ras-related protein Rab-6B (RAB6B).	[16]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ras-related protein Rab-6B (RAB6B).	[17]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 increases the expression of Ras-related protein Rab-6B (RAB6B).	[18]
Mivebresib	DMCPF90	Phase 1	Mivebresib increases the expression of Ras-related protein Rab-6B (RAB6B).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ras-related protein Rab-6B (RAB6B).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ras-related protein Rab-6B (RAB6B).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Ras-related protein Rab-6B (RAB6B).	[22]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Ras-related protein Rab-6B (RAB6B).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Ras-related protein Rab-6B (RAB6B).	[19]

References

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• [5] The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase.EMBO J. 1996 Apr 15;15(8):1885-93.
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• [7] Overexpression of RhoA mRNA is associated with advanced stage in testicular germ cell tumour.BJU Int. 2001 Feb;87(3):227-31. doi: 10.1046/j.1464-410x.2001.02030.x.
• [8] MicroRNA-4268 inhibits cell proliferation via AKT/JNK signalling pathways by targeting Rab6B in human gastric cancer.Cancer Gene Ther. 2020 Jun;27(6):461-472. doi: 10.1038/s41417-019-0118-6. Epub 2019 Jul 15.
• [9] GTP binding is essential to the protein kinase activity of LRRK2, a causative gene product for familial Parkinson's disease.Biochemistry. 2007 Feb 6;46(5):1380-8. doi: 10.1021/bi061960m.
• [10] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [11] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [12] 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.
• [13] 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.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] 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.
• [17] 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.
• [18] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [19] 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.
• [20] 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.
• [21] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [22] 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.
• [23] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.