Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFNVEJ4)

• DOT Name: GRB10-interacting GYF protein 2 (GIGYF2)
• Synonyms: PERQ amino acid-rich with GYF domain-containing protein 2; Trinucleotide repeat-containing gene 15 protein
• Gene Name: GIGYF2
• Related Disease:
  Neurodevelopmental disorder
  Anxiety disorder
  Breast cancer
  Breast carcinoma
  Coronary heart disease
  Late-onset Parkinson disease
  Schizophrenia
  Parkinson disease 11, autosomal dominant, susceptibility to
• UniProt ID: GGYF2_HUMAN
• PDB ID: 5NVL; 5NVM; 7RUP
• Pfam ID: PF02213
• Sequence:
  MAAETQTLNFGPEWLRALSSGGSITSPPLSPALPKYKLADYRYGREEMLALFLKDNKIPS
  DLLDKEFLPILQEEPLPPLALVPFTEEEQRNFSMSVNSAAVLRLTGRGGGGTVVGAPRGR
  SSSRGRGRGRGECGFYQRSFDEVEGVFGRGGGREMHRSQSWEERGDRRFEKPGRKDVGRP
  NFEEGGPTSVGRKHEFIRSESENWRIFREEQNGEDEDGGWRLAGSRRDGERWRPHSPDGP
  RSAGWREHMERRRRFEFDFRDRDDERGYRRVRSGSGSIDDDRDSLPEWCLEDAEEEMGTF
  DSSGAFLSLKKVQKEPIPEEQEMDFRPVDEGEECSDSEGSHNEEAKEPDKTNKKEGEKTD
  RVGVEASEETPQTSSSSARPGTPSDHQSQEASQFERKDEPKTEQTEKAEEETRMENSLPA
  KVPSRGDEMVADVQQPLSQIPSDTASPLLILPPPVPNPSPTLRPVETPVVGAPGMGSVST
  EPDDEEGLKHLEQQAEKMVAYLQDSALDDERLASKLQEHRAKGVSIPLMHEAMQKWYYKD
  PQGEIQGPFNNQEMAEWFQAGYFTMSLLVKRACDESFQPLGDIMKMWGRVPFSPGPAPPP
  HMGELDQERLTRQQELTALYQMQHLQYQQFLIQQQYAQVLAQQQKAALSSQQQQQLALLL
  QQFQTLKMRISDQNIIPSVTRSVSVPDTGSIWELQPTASQPTVWEGGSVWDLPLDTTTPG
  PALEQLQQLEKAKAAKLEQERREAEMRAKREEEERKRQEELRRQQEEILRRQQEEERKRR
  EEEELARRKQEEALRRQREQEIALRRQREEEERQQQEEALRRLEERRREEEERRKQEELL
  RKQEEEAAKWAREEEEAQRRLEENRLRMEEEAARLRHEEEERKRKELEVQRQKELMRQRQ
  QQQEALRRLQQQQQQQQLAQMKLPSSSTWGQQSNTTACQSQATLSLAEIQKLEEERERQL
  REEQRRQQRELMKALQQQQQQQQQKLSGWGNVSKPSGTTKSLLEIQQEEARQMQKQQQQQ
  QQHQQPNRARNNTHSNLHTSIGNSVWGSINTGPPNQWASDLVSSIWSNADTKNSNMGFWD
  DAVKEVGPRNSTNKNKNNASLSKSVGVSNRQNKKVEEEEKLLKLFQGVNKAQDGFTQWCE
  QMLHALNTANNLDVPTFVSFLKEVESPYEVHDYIRAYLGDTSEAKEFAKQFLERRAKQKA
  NQQRQQQQLPQQQQQQPPQQPPQQPQQQDSVWGMNHSTLHSVFQTNQSNNQQSNFEAVQS
  GKKKKKQKMVRADPSLLGFSVNASSERLNMGEIETLDDY
• Function: Key component of the 4EHP-GYF2 complex, a multiprotein complex that acts as a repressor of translation initiation. In the 4EHP-GYF2 complex, acts as a factor that bridges EIF4E2 to ZFP36/TTP, linking translation repression with mRNA decay. Also recruits and bridges the association of the 4EHP complex with the decapping effector protein DDX6, which is required for the ZFP36/TTP-mediated down-regulation of AU-rich mRNA. May act cooperatively with GRB10 to regulate tyrosine kinase receptor signaling, including IGF1 and insulin receptors. In association with EIF4E2, assists ribosome-associated quality control (RQC) by sequestering the mRNA cap, blocking ribosome initiation and decreasing the translational load on problematic messages. Part of a pathway that works in parallel to RQC-mediated degradation of the stalled nascent polypeptide. GIGYF2 and EIF4E2 work downstream and independently of ZNF598, which seems to work as a scaffold that can recruit them to faulty mRNA even if alternative recruitment mechanisms may exist ; (Microbial infection) Upon SARS coronavirus-2/SARS-CoV-2 infection, the interaction with non-structural protein 2 (nsp2) enhances GIGYF2 binding to EIF4E2 and increases repression of translation initiation of genes involved in antiviral innate immune response such as IFNB1.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder	DIS372XH	Definitive	Biomarker	[1]
Anxiety disorder	DISBI2BT	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Posttranslational Modification	[3]
Breast carcinoma	DIS2UE88	Strong	Posttranslational Modification	[3]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[4]
Late-onset Parkinson disease	DIS9IOUI	Strong	Genetic Variation	[5]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[6]
Parkinson disease 11, autosomal dominant, susceptibility to	DIS1S1E4	Moderate	Autosomal dominant	[7]

3 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 GRB10-interacting GYF protein 2 (GIGYF2).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of GRB10-interacting GYF protein 2 (GIGYF2).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of GRB10-interacting GYF protein 2 (GIGYF2).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of GRB10-interacting GYF protein 2 (GIGYF2).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of GRB10-interacting GYF protein 2 (GIGYF2).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of GRB10-interacting GYF protein 2 (GIGYF2).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of GRB10-interacting GYF protein 2 (GIGYF2).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of GRB10-interacting GYF protein 2 (GIGYF2).	[13]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of GRB10-interacting GYF protein 2 (GIGYF2).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of GRB10-interacting GYF protein 2 (GIGYF2).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of GRB10-interacting GYF protein 2 (GIGYF2).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of GRB10-interacting GYF protein 2 (GIGYF2).	[14]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of GRB10-interacting GYF protein 2 (GIGYF2).	[19]

References

• [1] Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet. 2017 Apr;49(4):515-526. doi: 10.1038/ng.3792. Epub 2017 Feb 13.
• [2] Genetic Variants Associated With Anxiety and Stress-Related Disorders: A Genome-Wide Association Study and Mouse-Model Study.JAMA Psychiatry. 2019 Sep 1;76(9):924-932. doi: 10.1001/jamapsychiatry.2019.1119.
• [3] Involvement of RQCD1 overexpression, a novel cancer-testis antigen, in the Akt pathway in breast cancer cells.Int J Oncol. 2009 Oct;35(4):673-81.
• [4] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [5] GIGYF2 mutation in late-onset Parkinson's disease with cognitive impairment.J Hum Genet. 2015 Oct;60(10):637-40. doi: 10.1038/jhg.2015.69. Epub 2015 Jul 2.
• [6] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [7] 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.
• [8] 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.
• [9] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [13] 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.
• [14] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [15] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [16] 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.
• [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] 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.