Details of Drug Off-Target (DOT)

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

• DOT Name: Ras-related protein Rab-1B (RAB1B)
• Synonyms: EC 3.6.5.2
• Gene Name: RAB1B
• Related Disease:
  Capillary malformation-arteriovenous malformation syndrome
  Colorectal carcinoma
  Hepatitis C virus infection
  Myocardial ischemia
  Myotonic dystrophy
  Testicular germ cell tumor
  Breast cancer
  Breast carcinoma
  Neoplasm
  Neuroblastoma
  Toxic shock syndrome
  Triple negative breast cancer
  Advanced cancer
  Parkinson disease
• UniProt ID: RAB1B_HUMAN
• PDB ID: 3JZA; 3NKV; 4HLQ; 4I1O; 5O74; 5SZH; 5SZK; 6SKU; 8ALK
• EC Number: 3.6.5.2
• Pfam ID: PF00071
• Sequence:
  MNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTIKLQ
  IWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESYANVKQWLQEIDRYASENVNKLLVG
  NKSDLTTKKVVDNTTAKEFADSLGIPFLETSAKNATNVEQAFMTMAAEIKKRMGPGAASG
  GERPNLKIDSTPVKPAGGGCC
• 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 an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different set of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. Plays a role in the initial events of the autophagic vacuole development which take place at specialized regions of the endoplasmic reticulum. Regulates vesicular transport between the endoplasmic reticulum and successive Golgi compartments. Required to modulate the compacted morphology of the Golgi. Promotes the recruitment of lipid phosphatase MTMR6 to the endoplasmic reticulum-Golgi intermediate compartment.
• KEGG Pathway: Legionellosis (hsa05134)
• Reactome Pathway:
  COPII-mediated vesicle transport (R-HSA-204005)
  COPI-mediated anterograde transport (R-HSA-6807878)
  COPI-dependent Golgi-to-ER retrograde traffic (R-HSA-6811434)
  RAB geranylgeranylation (R-HSA-8873719)
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)
  Golgi Cisternae Pericentriolar Stack Reorganization (R-HSA-162658)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Capillary malformation-arteriovenous malformation syndrome	DISMN03Q	Strong	Genetic Variation	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[3]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[4]
Myotonic dystrophy	DISNBEMX	Strong	Biomarker	[5]
Testicular germ cell tumor	DIS5RN24	Strong	Biomarker	[6]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[7]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[7]
Neoplasm	DISZKGEW	moderate	Biomarker	[8]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[9]
Toxic shock syndrome	DISX5S53	Disputed	Biomarker	[10]
Triple negative breast cancer	DISAMG6N	Disputed	Biomarker	[7]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[2]
Parkinson disease	DISQVHKL	Limited	Biomarker	[11]

2 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 Ras-related protein Rab-1B (RAB1B).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Ras-related protein Rab-1B (RAB1B).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ras-related protein Rab-1B (RAB1B).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ras-related protein Rab-1B (RAB1B).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras-related protein Rab-1B (RAB1B).	[15]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Ras-related protein Rab-1B (RAB1B).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ras-related protein Rab-1B (RAB1B).	[17]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Ras-related protein Rab-1B (RAB1B).	[18]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of Ras-related protein Rab-1B (RAB1B).	[19]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Ras-related protein Rab-1B (RAB1B).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ras-related protein Rab-1B (RAB1B).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ras-related protein Rab-1B (RAB1B).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ras-related protein Rab-1B (RAB1B).	[23]

References

• [1] RASA1 regulates the function of lymphatic vessel valves in mice.J Clin Invest. 2017 Jun 30;127(7):2569-2585. doi: 10.1172/JCI89607. Epub 2017 May 22.
• [2] Overexpression of Rab1B and MMP9 predicts poor survival and good response to chemotherapy in patients with colorectal cancer.Aging (Albany NY). 2017 Mar 18;9(3):914-931. doi: 10.18632/aging.101200.
• [3] Differential Regulation of Lipoprotein and Hepatitis C Virus Secretion by Rab1b.Cell Rep. 2017 Oct 10;21(2):431-441. doi: 10.1016/j.celrep.2017.09.053.
• [4] Cardioplegia prevents ischemia-induced transcriptional alterations of cytoprotective genes in rat hearts: a DNA microarray study.J Thorac Cardiovasc Surg. 2005 Oct;130(4):1151. doi: 10.1016/j.jtcvs.2005.06.027.
• [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.
• [6] 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.
• [7] Loss of RAB1B promotes triple-negative breast cancer metastasis by activating TGF-/SMAD signaling.Oncotarget. 2015 Jun 30;6(18):16352-65. doi: 10.18632/oncotarget.3877.
• [8] Rab25 augments cancer cell invasiveness through a 1 integrin/EGFR/VEGF-A/Snail signaling axis and expression of fascin.Exp Mol Med. 2018 Jan 26;50(1):e435. doi: 10.1038/emm.2017.248.
• [9] HaRas activates the NADPH oxidase complex in human neuroblastoma cells via extracellular signal-regulated kinase 1/2 pathway.J Neurochem. 2004 Nov;91(3):613-22. doi: 10.1111/j.1471-4159.2004.02754.x.
• [10] Staphylococcus aureus Alpha-Toxin Induces the Formation of Dynamic Tubules Labeled with LC3 within Host Cells in a Rab7 and Rab1b-Dependent Manner.Front Cell Infect Microbiol. 2017 Oct 4;7:431. doi: 10.3389/fcimb.2017.00431. eCollection 2017.
• [11] 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.
• [12] 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.
• [13] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [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] 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.
• [16] 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.
• [17] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [18] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [19] Rosiglitazone sensitizes MDA-MB-231 breast cancer cells to anti-tumour effects of tumour necrosis factor-alpha, CH11 and CYC202. Endocr Relat Cancer. 2007 Jun;14(2):305-15. doi: 10.1677/ERC-06-0003.
• [20] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [21] 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.
• [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] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.