Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTE70JLY)

• DOT Name: GATOR1 complex protein DEPDC5 (DEPDC5)
• Synonyms: DEP domain-containing protein 5
• Gene Name: DEPDC5
• Related Disease:
  Epilepsy, familial focal, with variable foci 1
  Focal epilepsy
  Liver cirrhosis
  Autism spectrum disorder
  Band heterotopia of brain
  Childhood epilepsy with centrotemporal spikes
  Fleck corneal dystrophy
  Hepatitis B virus infection
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Isolated cleft lip
  Leiomyoma
  Macular corneal dystrophy
  Metastatic malignant neoplasm
  Multiple endocrine neoplasia type 1
  Neoplasm
  Non-insulin dependent diabetes
  Uterine fibroids
  West syndrome
  Frontal lobe epilepsy
  Gastrointestinal stromal tumour
  Tuberous sclerosis
  Autosomal dominant epilepsy with auditory features
  Autosomal dominant nocturnal frontal lobe epilepsy
  Familial focal epilepsy with variable foci
  Brugada syndrome
  Neuroblastoma
  Temporal lobe epilepsy
• UniProt ID: DEPD5_HUMAN
• PDB ID: 6CES; 6CET; 7T3A; 7T3B; 7T3C; 8FW5
• Pfam ID: PF00610 ; PF19418 ; PF12257
• Sequence:
  MRTTKVYKLVIHKKGFGGSDDELVVNPKVFPHIKLGDIVEIAHPNDEYSPLLLQVKSLKE
  DLQKETISVDQTVTQVFRLRPYQDVYVNVVDPKDVTLDLVELTFKDQYIGRGDMWRLKKS
  LVSTCAYITQKVEFAGIRAQAGELWVKNEKVMCGYISEDTRVVFRSTSAMVYIFIQMSCE
  MWDFDIYGDLYFEKAVNGFLADLFTKWKEKNCSHEVTVVLFSRTFYDAKSVDEFPEINRA
  SIRQDHKGRFYEDFYKVVVQNERREEWTSLLVTIKKLFIQYPVLVRLEQAEGFPQGDNST
  SAQGNYLEAINLSFNVFDKHYINRNFDRTGQMSVVITPGVGVFEVDRLLMILTKQRMIDN
  GIGVDLVCMGEQPLHAVPLFKLHNRSAPRDSRLGDDYNIPHWINHSFYTSKSQLFCNSFT
  PRIKLAGKKPASEKAKNGRDTSLGSPKESENALPIQVDYDAYDAQVFRLPGPSRAQCLTT
  CRSVRERESHSRKSASSCDVSSSPSLPSRTLPTEEVRSQASDDSSLGKSANILMIPHPHL
  HQYEVSSSLGYTSTRDVLENMMEPPQRDSSAPGRFHVGSAESMLHVRPGGYTPQRALINP
  FAPSRMPMKLTSNRRRWMHTFPVGPSGEAIQIHHQTRQNMAELQGSGQRDPTHSSAELLE
  LAYHEAAGRHSNSRQPGDGMSFLNFSGTEELSVGLLSNSGAGMNPRTQNKDSLEDSVSTS
  PDPILTLSAPPVVPGFCCTVGVDWKSLTTPACLPLTTDYFPDRQGLQNDYTEGCYDLLPE
  ADIDRRDEDGVQMTAQQVFEEFICQRLMQGYQIIVQPKTQKPNPAVPPPLSSSPLYSRGL
  VSRNRPEEEDQYWLSMGRTFHKVTLKDKMITVTRYLPKYPYESAQIHYTYSLCPSHSDSE
  FVSCWVEFSHERLEEYKWNYLDQYICSAGSEDFSLIESLKFWRTRFLLLPACVTATKRIT
  EGEAHCDIYGDRPRADEDEWQLLDGFVRFVEGLNRIRRRHRSDRMMRKGTAMKGLQMTGP
  ISTHSLESTAPPVGKKGTSALSALLEMEASQKCLGEQQAAVHGGKSSAQSAESSSVAMTP
  TYMDSPRKDGAFFMEFVRSPRTASSAFYPQVSVDQTATPMLDGTSLGICTGQSMDRGNSQ
  TFGNSQNIGEQGYSSTNSSDSSSQQLVASSLTSSSTLTEILEAMKHPSTGVQLLSEQKGL
  SPYCFISAEVVHWLVNHVEGIQTQAMAIDIMQKMLEEQLITHASGEAWRTFIYGFYFYKI
  VTDKEPDRVAMQQPATTWHTAGVDDFASFQRKWFEVAFVAEELVHSEIPAFLLPWLPSRP
  ASYASRHSSFSRSFGGRSQAAALLAATVPEQRTVTLDVDVNNRTDRLEWCSCYYHGNFSL
  NAAFEIKLHWMAVTAAVLFEMVQGWHRKATSCGFLLVPVLEGPFALPSYLYGDPLRAQLF
  IPLNISCLLKEGSEHLFDSFEPETYWDRMHLFQEAIAHRFGFVQDKYSASAFNFPAENKP
  QYIHVTGTVFLQLPYSKRKFSGQQRRRRNSTSSTNQNMFCEERVGYNWAYNTMLTKTWRS
  SATGDEKFADRLLKDFTDFCINRDNRLVTFWTSCLEKMHASAP
• Function: As a component of the GATOR1 complex functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway. In response to amino acid depletion, the GATOR1 complex has GTPase activating protein (GAP) activity and strongly increases GTP hydrolysis by RagA/RRAGA (or RagB/RRAGB) within heterodimeric Rag complexes, thereby turning them into their inactive GDP-bound form, releasing mTORC1 from lysosomal surface and inhibiting mTORC1 signaling. In the presence of abundant amino acids, the GATOR1 complex is negatively regulated by GATOR2, the other GATOR subcomplex, in this amino acid-sensing branch of the TORC1 pathway. Within the GATOR1 complex, DEPDC5 mediates direct interaction with the nucleotide-binding pocket of small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD) and coordinates their nucleotide loading states by promoting RagA/RRAGA or RagB/RRAGB into their GDP-binding state and RagC/RRAGC or RagD/RRAGD into their GTP-binding state. However, it does not execute the GAP activity, which is mediated by NPRL2.
• Tissue Specificity: Expressed in developing and adult brain.
• KEGG Pathway: mTOR sig.ling pathway (hsa04150)
• Reactome Pathway: Amino acids regulate mTORC1 (R-HSA-9639288)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epilepsy, familial focal, with variable foci 1	DIS50UO4	Definitive	Autosomal dominant	[1]
Focal epilepsy	DIS4LY5L	Definitive	Autosomal dominant	[2]
Liver cirrhosis	DIS4G1GX	Definitive	Genetic Variation	[3]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[4]
Band heterotopia of brain	DISQF9HP	Strong	Biomarker	[5]
Childhood epilepsy with centrotemporal spikes	DISKT2L5	Strong	CausalMutation	[6]
Fleck corneal dystrophy	DISERQJ1	Strong	Biomarker	[7]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[8]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[10]
Isolated cleft lip	DIS2O2JV	Strong	Genetic Variation	[11]
Leiomyoma	DISLDDFN	Strong	Genetic Variation	[12]
Macular corneal dystrophy	DISOLD0H	Strong	Biomarker	[13]
Metastatic malignant neoplasm	DIS86UK6	Strong	Genetic Variation	[14]
Multiple endocrine neoplasia type 1	DIS0RJRK	Strong	Genetic Variation	[14]
Neoplasm	DISZKGEW	Strong	Biomarker	[15]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[16]
Uterine fibroids	DISBZRMJ	Strong	Genetic Variation	[12]
West syndrome	DISLIAU9	Strong	Biomarker	[17]
Frontal lobe epilepsy	DISHN8AO	moderate	Genetic Variation	[18]
Gastrointestinal stromal tumour	DIS6TJYS	moderate	Biomarker	[19]
Tuberous sclerosis	DISEMUGZ	moderate	Biomarker	[20]
Autosomal dominant epilepsy with auditory features	DISFZN2O	Supportive	Autosomal dominant	[21]
Autosomal dominant nocturnal frontal lobe epilepsy	DISE3C4O	Supportive	Autosomal dominant	[21]
Familial focal epilepsy with variable foci	DIS50BKW	Supportive	Autosomal dominant	[21]
Brugada syndrome	DISSGN0E	Limited	Autosomal dominant	[22]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[13]
Temporal lobe epilepsy	DISNOPXX	Limited	Genetic Variation	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of GATOR1 complex protein DEPDC5 (DEPDC5).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of GATOR1 complex protein DEPDC5 (DEPDC5).	[27]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of GATOR1 complex protein DEPDC5 (DEPDC5).	[28]

2 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 decreases the methylation of GATOR1 complex protein DEPDC5 (DEPDC5).	[25]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of GATOR1 complex protein DEPDC5 (DEPDC5).	[26]

References

• [1] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] DEPDC5 variants increase fibrosis progression in Europeans with chronic hepatitis C virus infection.Hepatology. 2016 Feb;63(2):418-27. doi: 10.1002/hep.28322. Epub 2015 Dec 18.
• [4] Autistic Siblings with Novel Mutations in Two Different Genes: Insight for Genetic Workups of Autistic Siblings and Connection to Mitochondrial Dysfunction.Front Pediatr. 2017 Oct 12;5:219. doi: 10.3389/fped.2017.00219. eCollection 2017.
• [5] Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations.Ann Neurol. 2014 May;75(5):782-7. doi: 10.1002/ana.24126. Epub 2014 Apr 14.
• [6] Exome-wide analysis of mutational burden in patients with typical and atypical Rolandic epilepsy.Eur J Hum Genet. 2018 Feb;26(2):258-264. doi: 10.1038/s41431-017-0034-x. Epub 2018 Jan 22.
• [7] Functional screening of GATOR1 complex variants reveals a role for mTORC1 deregulation in FCD and focal epilepsy.Neurobiol Dis. 2020 Feb;134:104640. doi: 10.1016/j.nbd.2019.104640. Epub 2019 Oct 19.
• [8] Genetic insights on host and hepatitis B virus in liver diseases.Mutat Res Rev Mutat Res. 2014 Oct-Dec;762:65-75. doi: 10.1016/j.mrrev.2014.06.001. Epub 2014 Jul 2.
• [9] Correlation between the DEPDC5 rs1012068 polymorphism and the risk of HBV-related hepatocellular carcinoma.Clin Res Hepatol Gastroenterol. 2019 Aug;43(4):446-450. doi: 10.1016/j.clinre.2018.12.005. Epub 2019 Jan 23.
• [10] A variant in the MICA gene is associated with liver fibrosis progression in chronic hepatitis C through TGF-1 dependent mechanisms.Sci Rep. 2019 Feb 5;9(1):1439. doi: 10.1038/s41598-018-35736-2.
• [11] Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity.Nat Commun. 2017 Feb 24;8:14364. doi: 10.1038/ncomms14364.
• [12] Clonally related uterine leiomyomas are common and display branched tumor evolution.Hum Mol Genet. 2015 Aug 1;24(15):4407-16. doi: 10.1093/hmg/ddv177. Epub 2015 May 10.
• [13] DEPDC5 and NPRL3 modulate cell size, filopodial outgrowth, and localization of mTOR in neural progenitor cells and neurons.Neurobiol Dis. 2018 Jun;114:184-193. doi: 10.1016/j.nbd.2018.02.013. Epub 2018 Feb 24.
• [14] Loss of Chromatin-Remodeling Proteins and/or CDKN2A Associates With Metastasis of Pancreatic Neuroendocrine Tumors and Reduced Patient Survival Times.Gastroenterology. 2018 Jun;154(8):2060-2063.e8. doi: 10.1053/j.gastro.2018.02.026. Epub 2018 Mar 2.
• [15] Phosphorylation of DEPDC5, a component of the GATOR1 complex, releases inhibition of mTORC1 and promotes tumor growth.Proc Natl Acad Sci U S A. 2019 Oct 8;116(41):20505-20510. doi: 10.1073/pnas.1904774116. Epub 2019 Sep 23.
• [16] Pilot genome-wide association study identifying novel risk loci for type 2 diabetes in a Maya population.Gene. 2018 Nov 30;677:324-331. doi: 10.1016/j.gene.2018.08.041. Epub 2018 Aug 18.
• [17] Genotype-phenotype correlation on 45 individuals with West syndrome.Eur J Paediatr Neurol. 2020 Mar;25:134-138. doi: 10.1016/j.ejpn.2019.11.010. Epub 2019 Nov 26.
• [18] Nocturnal frontal lobe epilepsy caused by a mutation in the GATOR1 complex gene NPRL3.Epilepsia. 2016 Mar;57(3):e60-3. doi: 10.1111/epi.13307. Epub 2016 Jan 20.
• [19] Mutational inactivation of mTORC1 repressor gene DEPDC5 in human gastrointestinal stromal tumors.Proc Natl Acad Sci U S A. 2019 Nov 5;116(45):22746-22753. doi: 10.1073/pnas.1914542116. Epub 2019 Oct 21.
• [20] mTOR signaling in epilepsy: insights from malformations of cortical development.Cold Spring Harb Perspect Med. 2015 Apr 1;5(4):a022442. doi: 10.1101/cshperspect.a022442.
• [21] Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet. 2013 May;45(5):546-51. doi: 10.1038/ng.2599. Epub 2013 Mar 31.
• [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] DEPDC5 mutations are not a frequent cause of familial temporal lobe epilepsy.Epilepsia. 2015 Oct;56(10):e168-71. doi: 10.1111/epi.13094. Epub 2015 Jul 27.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [28] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.