Details of Drug Off-Target (DOT)

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

• DOT Name: Ras-related protein Rab-18 (RAB18)
• Gene Name: RAB18
• Related Disease:
  Warburg micro syndrome 3
  Acromegaly
  Dengue
  Gastric cancer
  Glioma
  Hepatitis B virus infection
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Obesity
  Pituitary tumor
  Polyomavirus infection
  Stomach cancer
  Acrocephalopolysyndactyly
  Apert syndrome
  Cataract
  Craniofacial microsomia
  Fraser syndrome
  Freeman-Sheldon syndrome
  Isolated Pierre-Robin syndrome
  Malignant tumor of nasopharynx
  Mobius syndrome
  Nasopharyngeal carcinoma
  Neoplasm
  Orofaciodigital syndrome
  Warburg micro syndrome
  Charcot marie tooth disease
  Charcot-Marie-Tooth disease type 2B
• UniProt ID: RAB18_HUMAN
• PDB ID: 1X3S
• Pfam ID: PF00071
• Sequence:
  MDEDVLTTLKILIIGESGVGKSSLLLRFTDDTFDPELAATIGVDFKVKTISVDGNKAKLA
  IWDTAGQERFRTLTPSYYRGAQGVILVYDVTRRDTFVKLDNWLNELETYCTRNDIVNMLV
  GNKIDKENREVDRNEGLKFARKHSMLFIEASAKTCDGVQCAFEELVEKIIQTPGLWESEN
  QNKGVKLSHREEGQGGGACGGYCSVL
• 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 sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. Required for the localization of ZFYVE1 to lipid droplets and for its function in mediating the formation of endoplasmic reticulum-lipid droplets (ER-LD) contacts. Also required for maintaining endoplasmic reticulum structure. Plays a role in apical endocytosis/recycling. Plays a key role in eye and brain development and neurodegeneration.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway:
  COPI-independent Golgi-to-ER retrograde traffic (R-HSA-6811436)
  RAB geranylgeranylation (R-HSA-8873719)
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)
  Neutrophil degranulation (R-HSA-6798695)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Warburg micro syndrome 3	DISRA0YD	Definitive	Autosomal recessive	[1]
Acromegaly	DISCC73U	Strong	Altered Expression	[2]
Dengue	DISKH221	Strong	Biomarker	[3]
Gastric cancer	DISXGOUK	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[5]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[6]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[8]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[10]
Obesity	DIS47Y1K	Strong	Biomarker	[11]
Pituitary tumor	DISN67JD	Strong	Altered Expression	[2]
Polyomavirus infection	DISB8YKA	Strong	Biomarker	[12]
Stomach cancer	DISKIJSX	Strong	Biomarker	[4]
Acrocephalopolysyndactyly	DISKE9JR	moderate	Biomarker	[13]
Apert syndrome	DISGIYXQ	moderate	Biomarker	[13]
Cataract	DISUD7SL	moderate	Genetic Variation	[14]
Craniofacial microsomia	DISYHJ2P	moderate	Biomarker	[13]
Fraser syndrome	DISCLC2B	moderate	Biomarker	[13]
Freeman-Sheldon syndrome	DIS7V9PS	moderate	Biomarker	[13]
Isolated Pierre-Robin syndrome	DISVEHG7	moderate	Biomarker	[13]
Malignant tumor of nasopharynx	DISTGIGF	moderate	Biomarker	[15]
Mobius syndrome	DIS9YXP5	moderate	Biomarker	[13]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Biomarker	[15]
Neoplasm	DISZKGEW	moderate	Biomarker	[8]
Orofaciodigital syndrome	DISSB296	moderate	Biomarker	[13]
Warburg micro syndrome	DISSEZ2V	Moderate	Autosomal recessive	[16]
Charcot marie tooth disease	DIS3BT2L	Disputed	Biomarker	[17]
Charcot-Marie-Tooth disease type 2B	DIS00RWZ	Disputed	Genetic Variation	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Ras-related protein Rab-18 (RAB18).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ras-related protein Rab-18 (RAB18).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ras-related protein Rab-18 (RAB18).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ras-related protein Rab-18 (RAB18).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ras-related protein Rab-18 (RAB18).	[21]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ras-related protein Rab-18 (RAB18).	[22]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras-related protein Rab-18 (RAB18).	[23]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Ras-related protein Rab-18 (RAB18).	[24]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Ras-related protein Rab-18 (RAB18).	[25]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Ras-related protein Rab-18 (RAB18).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ras-related protein Rab-18 (RAB18).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Ras-related protein Rab-18 (RAB18).	[29]

References

• [1] RAB18 Deficiency. 2018 Jan 4. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [2] Rab18 is reduced in pituitary tumors causing acromegaly and its overexpression reverts growth hormone hypersecretion.J Clin Endocrinol Metab. 2008 Jun;93(6):2269-76. doi: 10.1210/jc.2007-1893. Epub 2008 Mar 18.
• [3] Rab18 facilitates dengue virus infection by targeting fatty acid synthase to sites of viral replication.J Virol. 2014 Jun;88(12):6793-804. doi: 10.1128/JVI.00045-14. Epub 2014 Apr 2.
• [4] MiR-455-5p acts as a novel tumor suppressor in gastric cancer by down-regulating RAB18.Gene. 2016 Nov 5;592(2):308-15. doi: 10.1016/j.gene.2016.07.034. Epub 2016 Jul 19.
• [5] miR-200b as a prognostic factor targets multiple members of RAB family in glioma.Med Oncol. 2014 Mar;31(3):859. doi: 10.1007/s12032-014-0859-x. Epub 2014 Jan 30.
• [6] Hepatitis B virus X protein upregulates oncogene Rab18 to result in the dysregulation of lipogenesis and proliferation of hepatoma cells.Carcinogenesis. 2013 Jul;34(7):1644-52. doi: 10.1093/carcin/bgt089. Epub 2013 Mar 7.
• [7] Rab18 binds to hepatitis C virus NS5A and promotes interaction between sites of viral replication and lipid droplets.PLoS Pathog. 2013;9(8):e1003513. doi: 10.1371/journal.ppat.1003513. Epub 2013 Aug 1.
• [8] RAB18 promotes proliferation and metastasis in hepatocellular carcinoma.Am J Transl Res. 2019 Feb 15;11(2):1009-1019. eCollection 2019.
• [9] Cloning of Rab GTPases expressed in human skeletal muscle: studies in insulin-resistant subjects.Horm Metab Res. 1998 Nov;30(11):656-62. doi: 10.1055/s-2007-978953.
• [10] MicroRNA-30b/c inhibits non-small cell lung cancer cell proliferation by targeting Rab18.BMC Cancer. 2014 Sep 24;14:703. doi: 10.1186/1471-2407-14-703.
• [11] Rab18 dynamics in adipocytes in relation to lipogenesis, lipolysis and obesity.PLoS One. 2011;6(7):e22931. doi: 10.1371/journal.pone.0022931. Epub 2011 Jul 28.
• [12] Identification of Rab18 as an Essential Host Factor for BK Polyomavirus Infection Using a Whole-Genome RNA Interference Screen.mSphere. 2017 Jul 26;2(4):e00291-17. doi: 10.1128/mSphereDirect.00291-17. eCollection 2017 Jul-Aug.
• [13] ENU mutagenesis identifies mice modeling Warburg Micro Syndrome with sensory axon degeneration caused by a deletion in Rab18.Exp Neurol. 2015 May;267:143-51. doi: 10.1016/j.expneurol.2015.03.003. Epub 2015 Mar 13.
• [14] Loss-of-function mutations in TBC1D20 cause cataracts and male infertility in blind sterile mice and Warburg micro syndrome in humans. Am J Hum Genet. 2013 Dec 5;93(6):1001-14. doi: 10.1016/j.ajhg.2013.10.011. Epub 2013 Nov 14.
• [15] Novel tumor antigens identified by autologous antibody screening of childhood medulloblastoma cDNA libraries.Int J Cancer. 2003 Aug 20;106(2):244-51. doi: 10.1002/ijc.11208.
• [16] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [17] Rab18 Collaborates with Rab7 to Modulate Lysosomal and Autophagy Activities in the Nervous System: an Overlapping Mechanism for Warburg Micro Syndrome and Charcot-Marie-Tooth Neuropathy Type 2B.Mol Neurobiol. 2019 Sep;56(9):6095-6105. doi: 10.1007/s12035-019-1471-z. Epub 2019 Feb 5.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [23] 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.
• [24] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [25] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [26] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [27] 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.
• [28] 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.
• [29] 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.