Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKISLG4)

• DOT Name: Ras-related GTP-binding protein A (RRAGA)
• Synonyms: Rag A; RagA; EC 3.6.5.-; Adenovirus E3 14.7 kDa-interacting protein 1; FIP-1
• Gene Name: RRAGA
• Related Disease:
  Delirium
  Advanced cancer
  Neoplasm
  Hypereosinophilic syndrome
  Chronic eosinophilic leukemia
  Idiopathic hypereosinophilic syndrome
• UniProt ID: RRAGA_HUMAN
• PDB ID: 5X6V; 6CES; 6EHR; 6NZD; 6S6A; 6S6D; 6SB0; 6SB2; 6U62; 6ULG; 6WJ2; 6WJ3; 7T3A; 7T3B; 7T3C; 7UX2; 7UXC; 7UXH; 8DHB
• EC Number: 3.6.5.-
• Pfam ID: PF04670
• Sequence:
  MPNTAMKKKVLLMGKSGSGKTSMRSIIFANYIARDTRRLGATIDVEHSHVRFLGNLVLNL
  WDCGGQDTFMENYFTSQRDNIFRNVEVLIYVFDVESRELEKDMHYYQSCLEAILQNSPDA
  KIFCLVHKMDLVQEDQRDLIFKEREEDLRRLSRPLECACFRTSIWDETLYKAWSSIVYQL
  IPNVQQLEMNLRNFAQIIEADEVLLFERATFLVISHYQCKEQRDVHRFEKISNIIKQFKL
  SCSKLAASFQSMEVRNSNFAAFIDIFTSNTYVMVVMSDPSIPSAATLINIRNARKHFEKL
  ERVDGPKHSLLMR
• Function: Guanine nucleotide-binding protein that plays a crucial role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade. Forms heterodimeric Rag complexes with RagC/RRAGC or RagD/RRAGD and cycles between an inactive GDP-bound and an active GTP-bound form: RagA/RRAGA is in its active form when GTP-bound RagA/RRAGA forms a complex with GDP-bound RagC/RRAGC (or RagD/RRAGD) and in an inactive form when GDP-bound RagA/RRAGA heterodimerizes with GTP-bound RagC/RRAGC (or RagD/RRAGD). In its GTP-bound active form, promotes the recruitment of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB. Involved in the RCC1/Ran-GTPase pathway. May play a direct role in a TNF-alpha signaling pathway leading to induction of cell death ; (Microbial infection) May alternatively act as a cellular target for adenovirus E3-14.7K, an inhibitor of TNF-alpha functions, thereby affecting cell death.
• Tissue Specificity: Ubiquitously expressed with highest levels of expression in skeletal muscle, heart, and brain.
• KEGG Pathway:
  Autophagy - animal (hsa04140)
  mTOR sig.ling pathway (hsa04150)
  Shigellosis (hsa05131)
• Reactome Pathway:
  MTOR signalling (R-HSA-165159)
  mTORC1-mediated signalling (R-HSA-166208)
  Energy dependent regulation of mTOR by LKB1-AMPK (R-HSA-380972)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
  E3 ubiquitin ligases ubiquitinate target proteins (R-HSA-8866654)
  Regulation of PTEN gene transcription (R-HSA-8943724)
  Amino acids regulate mTORC1 (R-HSA-9639288)
  Macroautophagy (R-HSA-1632852)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Delirium	DIS2OKP1	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Hypereosinophilic syndrome	DISVK62S	moderate	Genetic Variation	[4]
Chronic eosinophilic leukemia	DISAJOUO	Limited	Biomarker	[5]
Idiopathic hypereosinophilic syndrome	DISXAPO9	Limited	Genetic Variation	[4]

11 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 GTP-binding protein A (RRAGA).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ras-related GTP-binding protein A (RRAGA).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Ras-related GTP-binding protein A (RRAGA).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ras-related GTP-binding protein A (RRAGA).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Ras-related GTP-binding protein A (RRAGA).	[10]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of Ras-related GTP-binding protein A (RRAGA).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Ras-related GTP-binding protein A (RRAGA).	[12]
Phenol	DM1QSM3	Phase 2/3	Phenol decreases the expression of Ras-related GTP-binding protein A (RRAGA).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Ras-related GTP-binding protein A (RRAGA).	[14]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Ras-related GTP-binding protein A (RRAGA).	[16]
Resorcinol	DMM37C0	Investigative	Resorcinol increases the expression of Ras-related GTP-binding protein A (RRAGA).	[17]

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 increases the methylation of Ras-related GTP-binding protein A (RRAGA).	[15]

References

• [1] Comparison of regional with general anaesthesia on postoperative delirium (RAGA-delirium) in the older patients undergoing hip fracture surgery: study protocol for a multicentre randomised controlled trial.BMJ Open. 2017 Oct 22;7(10):e016937. doi: 10.1136/bmjopen-2017-016937.
• [2] R-loop-mediated genome instability in mRNA cleavage and polyadenylation mutants.Genes Dev. 2012 Jan 15;26(2):163-75. doi: 10.1101/gad.179721.111.
• [3] Hes1 upregulation contributes to the development of FIP1L1-PDGRA-positive leukemia in blast crisis.Exp Hematol. 2014 May;42(5):369-379.e3. doi: 10.1016/j.exphem.2014.01.009. Epub 2014 Jan 31.
• [4] PDGFRalpha/FIP1L1-positive chronic eosinophilic leukemia presenting with retro-orbital localization: efficacy of imatinib treatment.Cancer Chemother Pharmacol. 2008 Apr;61(4):713-6. doi: 10.1007/s00280-007-0507-7. Epub 2007 Jun 5.
• [5] Lyn mediates FIP1L1-PDGFRA signal pathway facilitating IL-5RA intracellular signal through FIP1L1-PDGFRA/JAK2/Lyn/Akt network complex in CEL.Oncotarget. 2016 Aug 19;8(39):64984-64998. doi: 10.18632/oncotarget.11401. eCollection 2017 Sep 12.
• [6] 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.
• [7] Effect of all-trans retinoic acid on sodium/iodide symporter expression, radioiodine uptake and gene expression profiles in a human anaplastic thyroid carcinoma cell line. Nucl Med Biol. 2006 Oct;33(7):875-82. doi: 10.1016/j.nucmedbio.2006.07.004.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] 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.
• [11] Comparative gene expression analysis of a chronic myelogenous leukemia cell line resistant to cyclophosphamide using oligonucleotide arrays and response to tyrosine kinase inhibitors. Leuk Res. 2007 Nov;31(11):1511-20.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [14] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [15] 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.
• [16] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [17] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.