Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKPHRD0)

• DOT Name: Ras-related protein Rab-1A (RAB1A)
• Synonyms: EC 3.6.5.2; YPT1-related protein
• Gene Name: RAB1A
• Related Disease:
  Advanced cancer
  Asthma
  Ataxia-telangiectasia
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Colorectal carcinoma
  Congenital disorder of glycosylation
  Congestive heart failure
  Gastric adenocarcinoma
  Glioma
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Intrahepatic cholangiocarcinoma
  Neoplasm
  Rectal carcinoma
  Spinal muscular atrophy
  Triple negative breast cancer
  Carcinoma
  Parkinson disease
  Amyotrophic lateral sclerosis
  Bladder cancer
  Cardiomyopathy
  Castration-resistant prostate carcinoma
  Lung cancer
  Lung carcinoma
  Neuroblastoma
  Spinocerebellar ataxia type 3
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: RAB1A_HUMAN
• PDB ID: 2FOL; 2WWX; 3L0I; 3SFV; 3TKL; 4FMB; 4FMC; 4FMD; 4FME; 4IRU; 4JVS; 7EQ2
• EC Number: 3.6.5.2
• Pfam ID: PF00071
• Sequence:
  MSSMNPEYDYLFKLLLIGDSGVGKSCLLLRFADDTYTESYISTIGVDFKIRTIELDGKTI
  KLQIWDTAGQERFRTITSSYYRGAHGIIVVYDVTDQESFNNVKQWLQEIDRYASENVNKL
  LVGNKCDLTTKKVVDYTTAKEFADSLGIPFLETSAKNATNVEQSFMTMAAEIKKRMGPGA
  TAGGAEKSNVKIQSTPVKQSGGGCC
• 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. RAB1A regulates vesicular protein transport from the endoplasmic reticulum (ER) to the Golgi compartment and on to the cell surface, and plays a role in IL-8 and growth hormone secretion. Required to modulate the compacted morphology of the Golgi. Regulates the level of CASR present at the cell membrane. Plays a role in cell adhesion and cell migration, via its role in protein trafficking. Plays a role in autophagosome assembly and cellular defense reactions against pathogenic bacteria. Plays a role in microtubule-dependent protein transport by early endosomes and in anterograde melanosome transport.
• KEGG Pathway:
  Autophagy - animal (hsa04140)
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Pathogenic Escherichia coli infection (hsa05130)
  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

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Asthma	DISW9QNS	Strong	Biomarker	[2]
Ataxia-telangiectasia	DISP3EVR	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Cardiac failure	DISDC067	Strong	Altered Expression	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[5]
Congenital disorder of glycosylation	DIS400QP	Strong	Altered Expression	[6]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[4]
Gastric adenocarcinoma	DISWWLTC	Strong	Biomarker	[7]
Glioma	DIS5RPEH	Strong	Biomarker	[8]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[10]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Rectal carcinoma	DIS8FRR7	Strong	Genetic Variation	[12]
Spinal muscular atrophy	DISTLKOB	Strong	Biomarker	[13]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[14]
Carcinoma	DISH9F1N	moderate	Biomarker	[15]
Parkinson disease	DISQVHKL	moderate	Altered Expression	[16]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[17]
Bladder cancer	DISUHNM0	Limited	Biomarker	[18]
Cardiomyopathy	DISUPZRG	Limited	Altered Expression	[16]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Biomarker	[19]
Lung cancer	DISCM4YA	Limited	Biomarker	[20]
Lung carcinoma	DISTR26C	Limited	Biomarker	[20]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[21]
Spinocerebellar ataxia type 3	DISQBQID	Limited	Biomarker	[22]
Urinary bladder cancer	DISDV4T7	Limited	Biomarker	[18]
Urinary bladder neoplasm	DIS7HACE	Limited	Biomarker	[18]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Ras-related protein Rab-1A (RAB1A) affects the response to substance of Methotrexate.	[37]

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-1A (RAB1A).	[23]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ras-related protein Rab-1A (RAB1A).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ras-related protein Rab-1A (RAB1A).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ras-related protein Rab-1A (RAB1A).	[26]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ras-related protein Rab-1A (RAB1A).	[27]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras-related protein Rab-1A (RAB1A).	[28]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Ras-related protein Rab-1A (RAB1A).	[29]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Ras-related protein Rab-1A (RAB1A).	[30]
Testosterone Undecanoate	DMZO10Y	Approved	Testosterone Undecanoate increases the expression of Ras-related protein Rab-1A (RAB1A).	[31]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Ras-related protein Rab-1A (RAB1A).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Ras-related protein Rab-1A (RAB1A).	[32]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ras-related protein Rab-1A (RAB1A).	[34]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ras-related protein Rab-1A (RAB1A).	[35]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ras-related protein Rab-1A (RAB1A).	[36]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Ras-related protein Rab-1A (RAB1A).	[33]

References

• [1] Rab1A promotes proliferation and migration abilities via regulation of the HER2/AKT-independent mTOR/S6K1 pathway in colorectal cancer.Oncol Rep. 2019 May;41(5):2717-2728. doi: 10.3892/or.2019.7071. Epub 2019 Mar 15.
• [2] Association analysis of member RAS oncogene family gene polymorphisms with aspirin intolerance in asthmatic patients.DNA Cell Biol. 2014 Mar;33(3):155-61. doi: 10.1089/dna.2013.2213. Epub 2014 Feb 20.
• [3] miR?39?p suppresses the invasion and migration properties of breast cancer cells by targeting RAB1A.Oncol Rep. 2019 Nov;42(5):1699-1708. doi: 10.3892/or.2019.7297. Epub 2019 Aug 29.
• [4] Increased myocardial Rab GTPase expression: a consequence and cause of cardiomyopathy.Circ Res. 2001 Dec 7;89(12):1130-7. doi: 10.1161/hh2401.100427.
• [5] Circ_0000218 plays a carcinogenic role in colorectal cancer progression by regulating miR-139-3p/RAB1A axis.J Biochem. 2020 Jan 1;167(1):55-65. doi: 10.1093/jb/mvz078.
• [6] COG7 deficiency in Drosophila generates multifaceted developmental, behavioral and protein glycosylation phenotypes.J Cell Sci. 2017 Nov 1;130(21):3637-3649. doi: 10.1242/jcs.209049. Epub 2017 Sep 7.
• [7] Significance and prognostic role of human epidermal growth factor receptor 2 and RAB1A expression in gastric cancer.Oncol Lett. 2018 Apr;15(4):5185-5192. doi: 10.3892/ol.2018.7992. Epub 2018 Feb 7.
• [8] LncRNA DANCR functions as a competing endogenous RNA to regulate RAB1A expression by sponging miR-634 in glioma.Biosci Rep. 2018 Feb 2;38(1):BSR20171664. doi: 10.1042/BSR20171664. Print 2018 Feb 28.
• [9] Role for TBC1D20 and Rab1 in hepatitis C virus replication via interaction with lipid droplet-bound nonstructural protein 5A.J Virol. 2012 Jun;86(12):6491-502. doi: 10.1128/JVI.00496-12. Epub 2012 Apr 4.
• [10] Expression analysis and implication of Rab1A in gastrointestinal relevant tumor.Sci Rep. 2019 Sep 16;9(1):13384. doi: 10.1038/s41598-019-49786-7.
• [11] Hypoxia-mediated miR-212-3p downregulation enhances progression of intrahepatic cholangiocarcinoma through upregulation of Rab1a.Cancer Biol Ther. 2018;19(11):984-993. doi: 10.1080/15384047.2018.1456608. Epub 2018 May 14.
• [12] Pathologic Staging Inconsistency Between ypT4N0 (stage II) and ypT1-2N1 (stage III) After Preoperative Chemoradiotherapy and Total Mesorectal Excision in Rectal Cancer: A Multi-Institutional Study.Clin Colorectal Cancer. 2019 Mar;18(1):e130-e139. doi: 10.1016/j.clcc.2018.11.003. Epub 2018 Nov 23.
• [13] YAC contigs of the Rab1 and wobbler (wr) spinal muscular atrophy gene region on proximal mouse chromosome 11 and of the homologous region on human chromosome 2p.Genomics. 1996 Mar 15;32(3):447-54. doi: 10.1006/geno.1996.0140.
• [14] Inhibition of RAB1A suppresses epithelial-mesenchymal transition and proliferation of triple-negative breast cancer cells.Oncol Rep. 2017 Mar;37(3):1619-1626. doi: 10.3892/or.2017.5404. Epub 2017 Jan 25.
• [15] Can clinicopathological parameters predict for lymph node metastases in ypT0-2 rectal carcinoma? Results of the CAO/ARO/AIO-94 and CAO/ARO/AIO-04 phase 3 trials.Radiother Oncol. 2018 Sep;128(3):557-563. doi: 10.1016/j.radonc.2018.06.008. Epub 2018 Jun 18.
• [16] Rab1 in cell signaling, cancer and other diseases.Oncogene. 2016 Nov 3;35(44):5699-5704. doi: 10.1038/onc.2016.81. Epub 2016 Apr 4.
• [17] Rab1-dependent ER-Golgi transport dysfunction is a common pathogenic mechanism in SOD1, TDP-43 and FUS-associated ALS.Acta Neuropathol. 2015 Nov;130(5):679-97. doi: 10.1007/s00401-015-1468-2. Epub 2015 Aug 23.
• [18] Long Noncoding RNA MNX1 antisense RNA 1 Exerts Oncogenic Functions in Bladder Cancer by Regulating miR-218-5p/RAB1A Axis.J Pharmacol Exp Ther. 2020 Mar;372(3):237-247. doi: 10.1124/jpet.119.262949. Epub 2019 Dec 16.
• [19] MiR-221 promotes the development of androgen independence in prostate cancer cells via downregulation of HECTD2 and RAB1A.Oncogene. 2014 May 22;33(21):2790-800. doi: 10.1038/onc.2013.230. Epub 2013 Jun 17.
• [20] Expression of Rab1A is upregulated in human lung cancer and associated with tumor size and T stage.Aging (Albany NY). 2016 Nov 29;8(11):2790-2798. doi: 10.18632/aging.101087.
• [21] Interaction between optineurin and Rab1a regulates autophagosome formation in neuroblastoma cells.J Neurosci Res. 2018 Mar;96(3):407-415. doi: 10.1002/jnr.24143. Epub 2017 Aug 26.
• [22] Deregulation of autophagy in postmortem brains of Machado-Joseph disease patients.Neuropathology. 2018 Apr;38(2):113-124. doi: 10.1111/neup.12433. Epub 2017 Dec 8.
• [23] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [24] 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.
• [25] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [26] 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.
• [27] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [28] 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.
• [29] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [30] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [31] Levonorgestrel enhances spermatogenesis suppression by testosterone with greater alteration in testicular gene expression in men. Biol Reprod. 2009 Mar;80(3):484-92.
• [32] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [33] 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.
• [34] 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.
• [35] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [36] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [37] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.