Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8ZN26V)

• DOT Name: Ras-related protein Rab-10 (RAB10)
• Synonyms: EC 3.6.5.2
• Gene Name: RAB10
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Bone osteosarcoma
  Esophageal squamous cell carcinoma
  Glioma
  Hepatocellular carcinoma
  Neoplasm
  Osteosarcoma
  Parkinson disease
  Acute myelogenous leukaemia
  Hyperglycemia
  Neuroblastoma
• UniProt ID: RAB10_HUMAN
• PDB ID: 5LPN; 5SZJ
• EC Number: 3.6.5.2
• Pfam ID: PF00071
• Sequence:
  MAKKTYDLLFKLLLIGDSGVGKTCVLFRFSDDAFNTTFISTIGIDFKIKTVELQGKKIKL
  QIWDTAGQERFHTITTSYYRGAMGIMLVYDITNGKSFENISKWLRNIDEHANEDVERMLL
  GNKCDMDDKRVVPKGKGEQIAREHGIRFFETSAKANINIEKAFLTLAEDILRKTPVKEPN
  SENVDISSGGGVTGWKSKCC
• 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. That Rab is mainly involved in the biosynthetic transport of proteins from the Golgi to the plasma membrane. Regulates, for instance, SLC2A4/GLUT4 glucose transporter-enriched vesicles delivery to the plasma membrane. In parallel, it regulates the transport of TLR4, a toll-like receptor to the plasma membrane and therefore may be important for innate immune response. Also plays a specific role in asymmetric protein transport to the plasma membrane. In neurons, it is involved in axonogenesis through regulation of vesicular membrane trafficking toward the axonal plasma membrane. In epithelial cells, it regulates transport from the Golgi to the basolateral membrane. May play a role in the basolateral recycling pathway and in phagosome maturation. May play a role in endoplasmic reticulum dynamics and morphology controlling tubulation along microtubules and tubules fusion. Together with LRRK2, RAB8A, and RILPL1, it regulates ciliogenesis. When phosphorylated by LRRK2 on Thr-73, binds RILPL1 and inhibits ciliogenesis. Participates in the export of a subset of neosynthesized proteins through a Rab8-Rab10-Rab11-dependent endososomal export route ; (Microbial infection) Upon Legionella pneumophila infection promotes endoplasmic reticulum recruitment and bacterial replication. Plays a role in remodeling the Legionella-containing vacuole (LCV) into an endoplasmic reticulum-like vacuole.
• Tissue Specificity: Expressed in the hippocampus . Expressed in neutrophils (at protein level) . Expressed in the testis (at protein level) .
• KEGG Pathway:
  Endocytosis (hsa04144)
  AMPK sig.ling pathway (hsa04152)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  RAB geranylgeranylation (R-HSA-8873719)
  RAB GEFs exchange GTP for GDP on RABs (R-HSA-8876198)
  Translocation of SLC2A4 (GLUT4) to the plasma membrane (R-HSA-1445148)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[3]
Parkinson disease	DISQVHKL	Strong	Biomarker	[8]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[9]
Hyperglycemia	DIS0BZB5	Limited	Biomarker	[10]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Ras-related protein Rab-10 (RAB10).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ras-related protein Rab-10 (RAB10).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ras-related protein Rab-10 (RAB10).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ras-related protein Rab-10 (RAB10).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ras-related protein Rab-10 (RAB10).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras-related protein Rab-10 (RAB10).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ras-related protein Rab-10 (RAB10).	[18]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Ras-related protein Rab-10 (RAB10).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ras-related protein Rab-10 (RAB10).	[21]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Ras-related protein Rab-10 (RAB10).	[22]

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-10 (RAB10).	[20]

References

• [1] Silencing of Rab3D suppresses the proliferation and invasion of esophageal squamous cell carcinoma cells.Biomed Pharmacother. 2017 Jul;91:402-407. doi: 10.1016/j.biopha.2017.04.010. Epub 2017 May 2.
• [2] RAB10: an Alzheimer's disease resilience locus and potential drug target.Clin Interv Aging. 2018 Dec 28;14:73-79. doi: 10.2147/CIA.S159148. eCollection 2019.
• [3] MiR-329 suppresses osteosarcoma development by downregulating Rab10. FEBS Lett. 2016 Sep;590(17):2973-81.
• [4] Long Non-Coding RNA LINC00152 Regulates Cell Proliferation, Migration And Invasion In Esophageal Squamous Cell Carcinoma Via miR-107/Rab10 Axis.Onco Targets Ther. 2019 Oct 17;12:8553-8567. doi: 10.2147/OTT.S221515. eCollection 2019.
• [5] PSMB8-AS1 activated by ELK1 promotes cell proliferation in glioma via regulating miR-574-5p/RAB10.Biomed Pharmacother. 2020 Feb;122:109658. doi: 10.1016/j.biopha.2019.109658. Epub 2019 Dec 4.
• [6] RAB10 overexpression promotes tumor growth and indicates poor prognosis of hepatocellular carcinoma.Oncotarget. 2017 Apr 18;8(16):26434-26447. doi: 10.18632/oncotarget.15507.
• [7] miR?78a?p exerts tumor suppressive function on the tumorigenesis of esophageal squamous cell carcinoma by targeting Rab10.Int J Mol Med. 2018 Jul;42(1):381-391. doi: 10.3892/ijmm.2018.3639. Epub 2018 Apr 24.
• [8] Rab10 Phosphorylation is a Prominent Pathological Feature in Alzheimer's Disease.J Alzheimers Dis. 2018;63(1):157-165. doi: 10.3233/JAD-180023.
• [9] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [10] [6]-Gingerol, from Zingiber officinale, potentiates GLP-1 mediated glucose-stimulated insulin secretion pathway in pancreatic -cells and increases RAB8/RAB10-regulated membrane presentation of GLUT4 transporters in skeletal muscle to improve hyperglycemia in Lepr(db/db) type 2 diabetic mice.BMC Complement Altern Med. 2017 Aug 9;17(1):395. doi: 10.1186/s12906-017-1903-0.
• [11] Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer's disease resilience.Genome Med. 2017 Nov 29;9(1):100. doi: 10.1186/s13073-017-0486-1.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [15] 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.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] 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.
• [18] 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.
• [19] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [20] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [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] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.