Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAQUX6E)

• DOT Name: Gamma-aminobutyric acid receptor-associated protein (GABARAP)
• Synonyms: GABA(A) receptor-associated protein; MM46
• Gene Name: GABARAP
• Related Disease:
  Acute myelogenous leukaemia
  Parkinson disease
  Advanced cancer
  Breast lobular carcinoma
  Breast neoplasm
  Epilepsy
  Friedreich ataxia 1
  Hepatitis C virus infection
  Hereditary sensory and autonomic neuropathy
  Hereditary sensory and autonomic neuropathy type 1
  Neoplasm
  Nicotine dependence
  Polycystic ovarian syndrome
  Schizophrenia
  Breast cancer
  Breast carcinoma
  Megalencephaly
  Mesothelioma
  Osteoarthritis
  Spinocerebellar ataxia type 3
• UniProt ID: GBRAP_HUMAN
• PDB ID: 1GNU; 1KLV; 1KM7; 1KOT; 3D32; 3DOW; 3WIM; 4XC2; 5DPS; 6HB9; 6HOG; 6HOH; 6HOJ; 6HOK; 6HYL; 6HYM; 6HYN; 6HYO; 6YOP; 7AA8; 7BRQ; 7BRT; 7BRU; 7BV4; 7EA7; 7LSW; 7LT6; 7VEC; 7VED; 7YO9; 7ZKR; 7ZL7; 8AFI
• Pfam ID: PF02991
• Sequence:
  MKFVYKEEHPFEKRRSEGEKIRKKYPDRVPVIVEKAPKARIGDLDKKKYLVPSDLTVGQF
  YFLIRKRIHLRAEDALFFFVNNVIPPTSATMGQLYQEHHEEDFFLYIAYSDESVYGL
• Function: Ubiquitin-like modifier that plays a role in intracellular transport of GABA(A) receptors and its interaction with the cytoskeleton. Involved in autophagy: while LC3s are involved in elongation of the phagophore membrane, the GABARAP/GATE-16 subfamily is essential for a later stage in autophagosome maturation. Through its interaction with the reticulophagy receptor TEX264, participates in the remodeling of subdomains of the endoplasmic reticulum into autophagosomes upon nutrient stress, which then fuse with lysosomes for endoplasmic reticulum turnover. Also required for the local activation of the CUL3(KBTBD6/7) E3 ubiquitin ligase complex, regulating ubiquitination and degradation of TIAM1, a guanyl-nucleotide exchange factor (GEF) that activates RAC1 and downstream signal transduction. Thereby, regulates different biological processes including the organization of the cytoskeleton, cell migration and proliferation. Involved in apoptosis.
• Tissue Specificity: Heart, brain, placenta, liver, skeletal muscle, kidney and pancreas.
• KEGG Pathway:
  FoxO sig.ling pathway (hsa04068)
  Autophagy - other (hsa04136)
  Mitophagy - animal (hsa04137)
  Autophagy - animal (hsa04140)
  NOD-like receptor sig.ling pathway (hsa04621)
  GABAergic sy.pse (hsa04727)
• Reactome Pathway:
  TBC/RABGAPs (R-HSA-8854214)
  Macroautophagy (R-HSA-1632852)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
Parkinson disease	DISQVHKL	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Breast lobular carcinoma	DISBY98Q	Strong	Altered Expression	[4]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Epilepsy	DISBB28L	Strong	Biomarker	[5]
Friedreich ataxia 1	DIS285GE	Strong	Biomarker	[6]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[7]
Hereditary sensory and autonomic neuropathy	DIS2VOAM	Strong	Genetic Variation	[8]
Hereditary sensory and autonomic neuropathy type 1	DISLSPO4	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Nicotine dependence	DISZD9W7	Strong	Biomarker	[10]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[11]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[12]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[13]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[13]
Megalencephaly	DISYW5SV	Limited	Biomarker	[14]
Mesothelioma	DISKWK9M	Limited	Genetic Variation	[15]
Osteoarthritis	DIS05URM	Limited	Biomarker	[16]
Spinocerebellar ataxia type 3	DISQBQID	Limited	Biomarker	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Gamma-aminobutyric acid receptor-associated protein (GABARAP).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Gamma-aminobutyric acid receptor-associated protein (GABARAP).	[19]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Gamma-aminobutyric acid receptor-associated protein (GABARAP).	[20]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Gamma-aminobutyric acid receptor-associated protein (GABARAP).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Gamma-aminobutyric acid receptor-associated protein (GABARAP).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Gamma-aminobutyric acid receptor-associated protein (GABARAP).	[24]

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 Gamma-aminobutyric acid receptor-associated protein (GABARAP).	[22]

References

• [1] Inhibition of GATE-16 attenuates ATRA-induced neutrophil differentiation of APL cells and interferes with autophagosome formation.Biochem Biophys Res Commun. 2013 Aug 23;438(2):283-8. doi: 10.1016/j.bbrc.2013.07.056. Epub 2013 Jul 24.
• [2] The lysosomal membrane protein LAMP2A promotes autophagic flux and prevents SNCA-induced Parkinson disease-like symptoms in the Drosophila brain.Autophagy. 2018;14(11):1898-1910. doi: 10.1080/15548627.2018.1491489. Epub 2018 Aug 10.
• [3] Identification of Kinases and Phosphatases That Regulate ATG4B Activity by siRNA and Small Molecule Screening in Cells.Front Cell Dev Biol. 2018 Nov 1;6:148. doi: 10.3389/fcell.2018.00148. eCollection 2018.
• [4] Characterization of {gamma}-aminobutyric acid type A receptor-associated protein, a novel tumor suppressor, showing reduced expression in breast cancer.Cancer Res. 2005 Jan 15;65(2):394-400.
• [5] A functional analysis of GABARAP on 17p13.1 by knockdown zebrafish.J Hum Genet. 2010 Mar;55(3):155-62. doi: 10.1038/jhg.2010.1. Epub 2010 Jan 29.
• [6] Mitofusin-Dependent ER Stress Triggers Glial Dysfunction and Nervous System Degeneration in a Drosophila Model of Friedreich's Ataxia.Front Mol Neurosci. 2018 Mar 6;11:38. doi: 10.3389/fnmol.2018.00038. eCollection 2018.
• [7] Downregulation of autophagy-related gene ATG5 and GABARAP expression by IFN-1 contributes to its anti-HCV activity in human hepatoma cells.Antiviral Res. 2017 Apr;140:83-94. doi: 10.1016/j.antiviral.2017.01.016. Epub 2017 Jan 26.
• [8] ATL3, a cargo receptor for reticulophagy.Autophagy. 2019 Aug;15(8):1465-1466. doi: 10.1080/15548627.2019.1609862. Epub 2019 Apr 28.
• [9] ATL3 Is a Tubular ER-Phagy Receptor for GABARAP-Mediated Selective Autophagy.Curr Biol. 2019 Mar 4;29(5):846-855.e6. doi: 10.1016/j.cub.2019.01.041. Epub 2019 Feb 14.
• [10] Fine mapping of a linkage region on chromosome 17p13 reveals that GABARAP and DLG4 are associated with vulnerability to nicotine dependence in European-Americans.Hum Mol Genet. 2007 Jan 15;16(2):142-53. doi: 10.1093/hmg/ddl450. Epub 2006 Dec 12.
• [11] Downregulation of autophagy gene expression in endometria from women with polycystic ovary syndrome.Mol Cell Endocrinol. 2017 Jan 15;440:116-124. doi: 10.1016/j.mce.2016.11.009. Epub 2016 Nov 11.
• [12] Protein-interaction-network-based analysis for genome-wide association analysis of schizophrenia in Han Chinese population.J Psychiatr Res. 2014 Mar;50:73-8. doi: 10.1016/j.jpsychires.2013.11.014. Epub 2013 Dec 13.
• [13] The autophagy GABARAPL1 gene is epigenetically regulated in breast cancer models.BMC Cancer. 2015 Oct 17;15:729. doi: 10.1186/s12885-015-1761-4.
• [14] Neurodevelopmental delays and macrocephaly in 17p13.1 microduplication syndrome.Am J Med Genet A. 2014 Nov;164A(11):2887-91. doi: 10.1002/ajmg.a.36708. Epub 2014 Aug 13.
• [15] Establishment of a cell line from a Japanese patient useful for generating an in vivo model of malignant pleural mesothelioma.Cancer Sci. 2011 Mar;102(3):648-55. doi: 10.1111/j.1349-7006.2010.01827.x. Epub 2011 Jan 18.
• [16] GABARAP promotes bone marrow mesenchymal stem cells-based the osteoarthritis cartilage regeneration through the inhibition of PI3K/AKT/mTOR signaling pathway.J Cell Physiol. 2019 Nov;234(11):21014-21026. doi: 10.1002/jcp.28705. Epub 2019 Apr 24.
• [17] The Machado-Joseph disease deubiquitylase ataxin-3 interacts with LC3C/GABARAP and promotes autophagy.Aging Cell. 2020 Jan;19(1):e13051. doi: 10.1111/acel.13051. Epub 2019 Oct 17.
• [18] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [19] 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.
• [20] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [21] Up-regulation of endothelial nitric oxide synthase (eNOS), silent mating type information regulation 2 homologue 1 (SIRT1) and autophagy-related genes by repeated treatments with resveratrol in human umbilical vein endothelial cells. Br J Nutr. 2013 Dec;110(12):2150-5.
• [22] 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.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.