Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV3XCV8)

• DOT Name: Ras-related GTP-binding protein C (RRAGC)
• Synonyms: Rag C; RagC; EC 3.6.5.-; GTPase-interacting protein 2; TIB929
• Gene Name: RRAGC
• Related Disease:
  Follicular lymphoma
  Advanced cancer
  Neoplasm
• UniProt ID: RRAGC_HUMAN
• PDB ID: 3LLU; 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:
  MSLQYGAEETPLAGSYGAADSFPKDFGYGVEEEEEEAAAAGGGVGAGAGGGCGPGGADSS
  KPRILLMGLRRSGKSSIQKVVFHKMSPNETLFLESTNKIYKDDISNSSFVNFQIWDFPGQ
  MDFFDPTFDYEMIFRGTGALIYVIDAQDDYMEALTRLHITVSKAYKVNPDMNFEVFIHKV
  DGLSDDHKIETQRDIHQRANDDLADAGLEKLHLSFYLTSIYDHSIFEAFSKVVQKLIPQL
  PTLENLLNIFISNSGIEKAFLFDVVSKIYIATDSSPVDMQSYELCCDMIDVVIDVSCIYG
  LKEDGSGSAYDKESMAIIKLNNTTVLYLKEVTKFLALVCILREESFERKGLIDYNFHCFR
  KAIHEVFEVGVTSHRSCGHQTSASSLKALTHNGTPRNAI
• 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 RagA/RRAGA or RagB/RRAGB and cycles between an inactive GTP-bound and an active GDP-bound form: RagC/RRAGC is in its active form when GDP-bound RagC/RRAGC forms a complex with GTP-bound RagA/RRAGA (or RagB/RRAGB) and in an inactive form when GTP-bound RagC/RRAGC heterodimerizes with GDP-bound RagA/RRAGA (or RagB/RRAGB). In its GDP-bound active form, promotes the recruitment of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB. This is a crucial step in the activation of the MTOR signaling cascade by amino acids. Also plays a central role in the non-canonical mTORC1 complex, which acts independently of RHEB and specifically mediates phosphorylation of MiT/TFE factors TFEB and TFE3: GDP-bound RagC/RRAGC mediates recruitment of MiT/TFE factors TFEB and TFE3.
• 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)
  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

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Follicular lymphoma	DISVEUR6	moderate	Biomarker	[1]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[2]
Neoplasm	DISZKGEW	Limited	Biomarker	[2]

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 GTP-binding protein C (RRAGC).	[3]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Ras-related GTP-binding protein C (RRAGC).	[17]

18 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 GTP-binding protein C (RRAGC).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ras-related GTP-binding protein C (RRAGC).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ras-related GTP-binding protein C (RRAGC).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ras-related GTP-binding protein C (RRAGC).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ras-related GTP-binding protein C (RRAGC).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Ras-related GTP-binding protein C (RRAGC).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ras-related GTP-binding protein C (RRAGC).	[10]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Ras-related GTP-binding protein C (RRAGC).	[11]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Ras-related GTP-binding protein C (RRAGC).	[12]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Ras-related GTP-binding protein C (RRAGC).	[13]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the expression of Ras-related GTP-binding protein C (RRAGC).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ras-related GTP-binding protein C (RRAGC).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ras-related GTP-binding protein C (RRAGC).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ras-related GTP-binding protein C (RRAGC).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Ras-related GTP-binding protein C (RRAGC).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ras-related GTP-binding protein C (RRAGC).	[12]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Ras-related GTP-binding protein C (RRAGC).	[20]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Ras-related GTP-binding protein C (RRAGC).	[21]

References

• [1] Recurrent mTORC1-activating RRAGC mutations in follicular lymphoma.Nat Genet. 2016 Feb;48(2):183-8. doi: 10.1038/ng.3473. Epub 2015 Dec 21.
• [2] Recurrent Mutations in the MTOR Regulator RRAGC in Follicular Lymphoma.Clin Cancer Res. 2016 Nov 1;22(21):5383-5393. doi: 10.1158/1078-0432.CCR-16-0609. Epub 2016 Jun 7.
• [3] 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.
• [4] 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.
• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [10] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [11] 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.
• [12] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [13] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [14] Capsaicin inhibits the migration, invasion and EMT of renal cancer cells by inducing AMPK/mTOR-mediated autophagy. Chem Biol Interact. 2022 Oct 1;366:110043. doi: 10.1016/j.cbi.2022.110043. Epub 2022 Aug 28.
• [15] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [16] 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.
• [17] 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.
• [18] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [19] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [21] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.