Details of Drug Off-Target (DOT)

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

• DOT Name: GTP-binding protein Rheb (RHEB)
• Synonyms: Ras homolog enriched in brain; EC 3.6.5.-
• Gene Name: RHEB
• Related Disease:
  Hepatitis B virus infection
  Adrenoleukodystrophy
  Advanced cancer
  Allergic asthma
  Bladder transitional cell carcinoma
  Breast cancer
  Breast carcinoma
  Clear cell renal carcinoma
  Colorectal carcinoma
  FADD-related immunodeficiency
  Hepatitis C virus infection
  Kidney cancer
  Melanoma
  Neoplasm
  Non-small-cell lung cancer
  Parkinson disease
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Renal carcinoma
  Renal cell carcinoma
  Urinary bladder neoplasm
  Von hippel-lindau disease
  Autoimmune disease
  Hepatocellular carcinoma
  Neurofibromatosis type 1
  Osteoarthritis
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Ankylosing spondylitis
  Complex neurodevelopmental disorder
  Hyperglycemia
  Leber congenital amaurosis 1
  Lymphoma
  Megalencephaly
  Tuberous sclerosis
  Tuberous sclerosis 2
  Type-1/2 diabetes
• UniProt ID: RHEB_HUMAN
• PDB ID: 1XTQ; 1XTR; 1XTS; 3SEA; 3T5G; 5YXH; 6BCU; 6BSX; 6BT0; 7BTA; 7BTC; 7BTD
• EC Number: 3.6.5.-
• Pfam ID: PF00071
• Sequence:
  MPQSKSRKIAILGYRSVGKSSLTIQFVEGQFVDSYDPTIENTFTKLITVNGQEYHLQLVD
  TAGQDEYSIFPQTYSIDINGYILVYSVTSIKSFEVIKVIHGKLLDMVGKVQIPIMLVGNK
  KDLHMERVISYEEGKALAESWNAAFLESSAKENQTAVDVFRRIILEAEKMDGAASQGKSS
  CSVM
• Function: Small GTPase that acts as an allosteric activator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular biomass generation and growth. In response to nutrients, growth factors or amino acids, specifically activates the protein kinase activity of MTOR, the catalytic component of the mTORC1 complex: acts by causing a conformational change that allows the alignment of residues in the active site of MTOR, thereby enhancing the phosphorylation of ribosomal protein S6 kinase (RPS6KB1 and RPS6KB2) and EIF4EBP1 (4E-BP1). RHEB is also required for localization of the TSC-TBC complex to lysosomal membranes. In response to starvation, RHEB is inactivated by the TSC-TBC complex, preventing activation of mTORC1. Has low intrinsic GTPase activity.
• Tissue Specificity: Ubiquitous . Highest levels observed in skeletal and cardiac muscle .
• KEGG Pathway:
  Phospholipase D sig.ling pathway (hsa04072)
  Autophagy - animal (hsa04140)
  mTOR sig.ling pathway (hsa04150)
  PI3K-Akt sig.ling pathway (hsa04151)
  AMPK sig.ling pathway (hsa04152)
  Longevity regulating pathway (hsa04211)
  Cellular senescence (hsa04218)
  Thermogenesis (hsa04714)
  Insulin sig.ling pathway (hsa04910)
  Thyroid hormone sig.ling pathway (hsa04919)
  Human cytomegalovirus infection (hsa05163)
  Human papillomavirus infection (hsa05165)
  Herpes simplex virus 1 infection (hsa05168)
  Choline metabolism in cancer (hsa05231)
• 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

38 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatitis B virus infection	DISLQ2XY	Definitive	Biomarker	[1]
Adrenoleukodystrophy	DISTUD1F	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Allergic asthma	DISHF0H3	Strong	Biomarker	[4]
Bladder transitional cell carcinoma	DISNL46A	Strong	Genetic Variation	[5]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[6]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[6]
Clear cell renal carcinoma	DISBXRFJ	Strong	Genetic Variation	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[8]
FADD-related immunodeficiency	DISLH7O6	Strong	Altered Expression	[6]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[9]
Kidney cancer	DISBIPKM	Strong	Genetic Variation	[7]
Melanoma	DIS1RRCY	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Altered Expression	[11]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[12]
Parkinson disease	DISQVHKL	Strong	Genetic Variation	[13]
Prostate cancer	DISF190Y	Strong	Altered Expression	[14]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[14]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[15]
Renal carcinoma	DISER9XT	Strong	Genetic Variation	[7]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[16]
Von hippel-lindau disease	DIS6ZFQQ	Strong	Altered Expression	[11]
Autoimmune disease	DISORMTM	moderate	Biomarker	[17]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[1]
Neurofibromatosis type 1	DIS53JH9	moderate	Biomarker	[18]
Osteoarthritis	DIS05URM	moderate	Altered Expression	[19]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Disputed	Altered Expression	[20]
Liver cancer	DISDE4BI	Disputed	Altered Expression	[20]
Ankylosing spondylitis	DISRC6IR	Limited	Biomarker	[21]
Complex neurodevelopmental disorder	DISB9AFI	Limited	Autosomal dominant	[22]
Hyperglycemia	DIS0BZB5	Limited	Biomarker	[23]
Leber congenital amaurosis 1	DISY2B33	Limited	Biomarker	[24]
Lymphoma	DISN6V4S	Limited	Altered Expression	[25]
Megalencephaly	DISYW5SV	Limited	Genetic Variation	[26]
Tuberous sclerosis	DISEMUGZ	Limited	Biomarker	[27]
Tuberous sclerosis 2	DISR6GKZ	Limited	Posttranslational Modification	[28]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	GTP-binding protein Rheb (RHEB) decreases the response to substance of Cisplatin.	[12]

10 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 GTP-binding protein Rheb (RHEB).	[29]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of GTP-binding protein Rheb (RHEB).	[30]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of GTP-binding protein Rheb (RHEB).	[31]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of GTP-binding protein Rheb (RHEB).	[32]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of GTP-binding protein Rheb (RHEB).	[33]
Pioglitazone	DMKJ485	Approved	Pioglitazone increases the expression of GTP-binding protein Rheb (RHEB).	[34]
Lonafarnib	DMGM2Z6	Approved	Lonafarnib decreases the activity of GTP-binding protein Rheb (RHEB).	[12]
Zarnestra	DMF30HL	Phase 3	Zarnestra decreases the activity of GTP-binding protein Rheb (RHEB).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of GTP-binding protein Rheb (RHEB).	[37]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of GTP-binding protein Rheb (RHEB).	[38]

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 GTP-binding protein Rheb (RHEB).	[36]

References

• [1] CircRNA-100338 Is Associated With mTOR Signaling Pathway and Poor Prognosis in Hepatocellular Carcinoma.Front Oncol. 2019 May 14;9:392. doi: 10.3389/fonc.2019.00392. eCollection 2019.
• [2] Dysregulated Autophagy and Lysosome Function Are Linked to Exosome Production by Micro-RNA 155 in Alcoholic Liver Disease.Hepatology. 2019 Dec;70(6):2123-2141. doi: 10.1002/hep.30766. Epub 2019 Jun 24.
• [3] An oncogenic mutant of RHEB, RHEB Y35N, exhibits an altered interaction with BRAF resulting in cancer transformation.BMC Cancer. 2018 Jan 10;18(1):69. doi: 10.1186/s12885-017-3938-5.
• [4] Rheb1 deletion in myeloid cells aggravates OVA-induced allergic inflammation in mice.Sci Rep. 2017 Feb 22;7:42655. doi: 10.1038/srep42655.
• [5] Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.Nat Biotechnol. 2016 Feb;34(2):155-63. doi: 10.1038/nbt.3391. Epub 2015 Nov 30.
• [6] Fas-associated protein with death domain (FADD) regulates autophagy through promoting the expression of Ras homolog enriched in brain (Rheb) in human breast adenocarcinoma cells.Oncotarget. 2016 Apr 26;7(17):24572-84. doi: 10.18632/oncotarget.8249.
• [7] Point mutations of the mTOR-RHEB pathway in renal cell carcinoma.Oncotarget. 2015 Jul 20;6(20):17895-910. doi: 10.18632/oncotarget.4963.
• [8] Silencing of RHEB inhibits cell proliferation and promotes apoptosis in colorectal cancer cells via inhibition of the mTOR signaling pathway.J Cell Physiol. 2020 Jan;235(1):442-453. doi: 10.1002/jcp.28984. Epub 2019 Jul 22.
• [9] Impaired interferon signaling in chronic hepatitis C patients with advanced fibrosis via the transforming growth factor beta signaling pathway.Hepatology. 2014 Nov;60(5):1519-30. doi: 10.1002/hep.27277. Epub 2014 Oct 2.
• [10] mTOR is activated in the majority of malignant melanomas.J Invest Dermatol. 2008 Apr;128(4):980-7. doi: 10.1038/sj.jid.5701074. Epub 2007 Oct 4.
• [11] Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin.J Clin Invest. 2016 Sep 1;126(9):3526-40. doi: 10.1172/JCI86120. Epub 2016 Aug 2.
• [12] Ras homologue enriched in brain is a critical target of farnesyltransferase inhibitors in non-small cell lung cancer cells. Cancer Lett. 2010 Nov 1;297(1):117-25. doi: 10.1016/j.canlet.2010.05.004.
• [13] Protection of nigral dopaminergic neurons by AAV1 transduction with Rheb(S16H) against neurotoxic inflammation in vivo.Exp Mol Med. 2018 Feb 9;50(2):e440. doi: 10.1038/emm.2017.261.
• [14] Regulation of androgen receptor transactivity and mTOR-S6 kinase pathway by Rheb in prostate cancer cell proliferation.Prostate. 2010 Jun 1;70(8):866-74. doi: 10.1002/pros.21120.
• [15] Aberrant Rheb-mediated mTORC1 activation and Pten haploinsufficiency are cooperative oncogenic events.Genes Dev. 2008 Aug 15;22(16):2172-7. doi: 10.1101/gad.1699608.
• [16] Spectrum of phosphatidylinositol 3-kinase pathway gene alterations in bladder cancer.Clin Cancer Res. 2009 Oct 1;15(19):6008-17. doi: 10.1158/1078-0432.CCR-09-0898. Epub 2009 Sep 29.
• [17] Amino Acids License Kinase mTORC1 Activity and Treg Cell Function via Small G Proteins Rag and Rheb.Immunity. 2019 Dec 17;51(6):1012-1027.e7. doi: 10.1016/j.immuni.2019.10.001. Epub 2019 Oct 24.
• [18] Type I neurofibromatosis: a geno-oculo-dermatologic update.Curr Opin Ophthalmol. 2012 Sep;23(5):364-72. doi: 10.1097/ICU.0b013e3283570127.
• [19] RHEB gene therapy maintains the chondrogenic characteristics and protects cartilage tissue from degenerative damage during experimental murine osteoarthritis.Osteoarthritis Cartilage. 2019 Oct;27(10):1508-1517. doi: 10.1016/j.joca.2019.05.024. Epub 2019 Jun 20.
• [20] Overexpression of RHEB is associated with metastasis and poor prognosis in hepatocellular carcinoma.Oncol Lett. 2018 Mar;15(3):3838-3845. doi: 10.3892/ol.2018.7759. Epub 2018 Jan 10.
• [21] MicroRNA-199a-5p Induced Autophagy and Inhibits the Pathogenesis of Ankylosing Spondylitis by Modulating the mTOR Signaling via Directly Targeting Ras Homolog Enriched in Brain (Rheb).Cell Physiol Biochem. 2017;42(6):2481-2491. doi: 10.1159/000480211. Epub 2017 Aug 22.
• [22] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [23] Upregulation of the mammalian target of rapamycin complex 1 pathway by Ras homolog enriched in brain in pancreatic beta-cells leads to increased beta-cell mass and prevention of hyperglycemia.Diabetes. 2009 Jun;58(6):1321-32. doi: 10.2337/db08-0519. Epub 2009 Mar 3.
• [24] Licochalcone A restrains microphthalmia-associated transcription factor expression and growth by activating autophagy in melanoma cells via miR-142-3p/Rheb/mTOR pathway.Phytother Res. 2020 Feb;34(2):349-358. doi: 10.1002/ptr.6525. Epub 2019 Dec 2.
• [25] Tumorigenic activity and therapeutic inhibition of Rheb GTPase.Genes Dev. 2008 Aug 15;22(16):2178-88. doi: 10.1101/gad.1690808.
• [26] Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability.Nat Commun. 2017 Oct 20;8(1):1052. doi: 10.1038/s41467-017-00933-6.
• [27] MCRS1 binds and couples Rheb to amino acid-dependent mTORC1 activation.Dev Cell. 2015 Apr 6;33(1):67-81. doi: 10.1016/j.devcel.2015.02.010. Epub 2015 Mar 26.
• [28] TSC2/Rheb signaling mediates ERK-dependent regulation of mTORC1 activity in C2C12 myoblasts.FEBS Open Bio. 2017 Jan 30;7(3):424-433. doi: 10.1002/2211-5463.12195. eCollection 2017 Mar.
• [29] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [30] 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.
• [31] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [32] 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.
• [33] 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.
• [34] Effects of metformin and pioglitazone combination on apoptosis and AMPK/mTOR signaling pathway in human anaplastic thyroid cancer cells. J Biochem Mol Toxicol. 2020 Oct;34(10):e22547. doi: 10.1002/jbt.22547. Epub 2020 Jun 26.
• [35] Ras homologue enriched in brain is a critical target of farnesyltransferase inhibitors in non-small cell lung cancer cells. Cancer Lett. 2010 Nov 1;297(1):117-25. doi: 10.1016/j.canlet.2010.05.004.
• [36] 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.
• [37] 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.
• [38] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [39] Ras homologue enriched in brain is a critical target of farnesyltransferase inhibitors in non-small cell lung cancer cells. Cancer Lett. 2010 Nov 1;297(1):117-25. doi: 10.1016/j.canlet.2010.05.004.