Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1ALJ63)

• DOT Name: TBC1 domain family member 7 (TBC1D7)
• Synonyms: Cell migration-inducing protein 23
• Gene Name: TBC1D7
• Related Disease:
  Lung cancer
  Lung carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Coeliac disease
  Macrocephaly/megalencephaly syndrome, autosomal recessive
  Megalencephaly
  Tuberous sclerosis
• UniProt ID: TBCD7_HUMAN
• PDB ID: 3QWL; 4Z6Y; 5EJC; 5ULO; 7DL2
• Pfam ID: PF00566
• Sequence:
  MTEDSQRNFRSVYYEKVGFRGVEEKKSLEILLKDDRLDTEKLCTFSQRFPLPSMYRALVW
  KVLLGILPPHHESHAKVMMYRKEQYLDVLHALKVVRFVSDATPQAEVYLRMYQLESGKLP
  RSPSFPLEPDDEVFLAIAKAMEEMVEDSVDCYWITRRFVNQLNTKYRDSLPQLPKAFEQY
  LNLEDGRLLTHLRMCSAAPKLPYDLWFKRCFAGCLPESSLQRVWDKVVSGSCKILVFVAV
  EILLTFKIKVMALNSAEKITKFLENIPQDSSDAIVSKAIDLWHKHCGTPVHSS
• Function: Non-catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator 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. The TSC-TBC complex acts as a GTPase-activating protein (GAP) for the small GTPase RHEB, a direct activator of the protein kinase activity of mTORC1. In absence of nutrients, the TSC-TBC complex inhibits mTORC1, thereby preventing phosphorylation of ribosomal protein S6 kinase (RPS6KB1 and RPS6KB2) and EIF4EBP1 (4E-BP1) by the mTORC1 signaling. The TSC-TBC complex is inactivated in response to nutrients, relieving inhibition of mTORC1.
• Tissue Specificity: Highly expressed in heart, and slightly in kidney, liver and placenta.
• KEGG Pathway: mTOR sig.ling pathway (hsa04150)
• Reactome Pathway: TBC/RABGAPs (R-HSA-8854214)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung cancer	DISCM4YA	Definitive	Biomarker	[1]
Lung carcinoma	DISTR26C	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Non-small-cell lung cancer	DIS5Y6R9	Definitive	Altered Expression	[1]
Coeliac disease	DISIY60C	Strong	Genetic Variation	[2]
Macrocephaly/megalencephaly syndrome, autosomal recessive	DISAMPTJ	Strong	Autosomal recessive	[3]
Megalencephaly	DISYW5SV	moderate	Genetic Variation	[2]
Tuberous sclerosis	DISEMUGZ	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of TBC1 domain family member 7 (TBC1D7).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of TBC1 domain family member 7 (TBC1D7).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of TBC1 domain family member 7 (TBC1D7).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of TBC1 domain family member 7 (TBC1D7).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of TBC1 domain family member 7 (TBC1D7).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of TBC1 domain family member 7 (TBC1D7).	[10]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of TBC1 domain family member 7 (TBC1D7).	[11]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of TBC1 domain family member 7 (TBC1D7).	[12]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of TBC1 domain family member 7 (TBC1D7).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of TBC1 domain family member 7 (TBC1D7).	[12]

References

• [1] Activation of an oncogenic TBC1D7 (TBC1 domain family, member 7) protein in pulmonary carcinogenesis.Genes Chromosomes Cancer. 2010 Apr;49(4):353-67. doi: 10.1002/gcc.20747.
• [2] TBC1D7 mutations are associated with intellectual disability, macrocrania, patellar dislocation, and celiac disease.Hum Mutat. 2014 Apr;35(4):447-51. doi: 10.1002/humu.22529.
• [3] Disruption of TBC1D7, a subunit of the TSC1-TSC2 protein complex, in intellectual disability and megalencephaly. J Med Genet. 2013 Nov;50(11):740-4. doi: 10.1136/jmedgenet-2013-101680. Epub 2013 May 17.
• [4] dTBC1D7 regulates systemic growth independently of TSC through insulin signaling.J Cell Biol. 2018 Feb 5;217(2):517-526. doi: 10.1083/jcb.201706027. Epub 2017 Nov 29.
• [5] 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.
• [6] 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.
• [7] 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.
• [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] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] 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.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.