Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL3PLD2)

• DOT Name: Golgi reassembly-stacking protein 2 (GORASP2)
• Synonyms: GRS2; Golgi phosphoprotein 6; GOLPH6; Golgi reassembly-stacking protein of 55 kDa; GRASP55; p59
• Gene Name: GORASP2
• Related Disease:
  Type-1 diabetes
  Type-1/2 diabetes
  Cryptococcosis
  Endometrial cancer
  Endometrial carcinoma
  Lung adenocarcinoma
  Non-insulin dependent diabetes
  Obesity
  Parkinson disease
• UniProt ID: GORS2_HUMAN
• PDB ID: 3RLE; 4EDJ
• Pfam ID: PF04495
• Sequence:
  MGSSQSVEIPGGGTEGYHVLRVQENSPGHRAGLEPFFDFIVSINGSRLNKDNDTLKDLLK
  ANVEKPVKMLIYSSKTLELRETSVTPSNLWGGQGLLGVSIRFCSFDGANENVWHVLEVES
  NSPAALAGLRPHSDYIIGADTVMNESEDLFSLIETHEAKPLKLYVYNTDTDNCREVIITP
  NSAWGGEGSLGCGIGYGYLHRIPTRPFEEGKKISLPGQMAGTPITPLKDGFTEVQLSSVN
  PPSLSPPGTTGIEQSLTGLSISSTPPAVSSVLSTGVPTVPLLPPQVNQSLTSVPPMNPAT
  TLPGLMPLPAGLPNLPNLNLNLPAPHIMPGVGLPELVNPGLPPLPSMPPRNLPGIAPLPL
  PSEFLPSFPLVPESSSAASSGELLSSLPPTSNAPSDPATTTAKADAASSLTVDVTPPTAK
  APTTVEDRVGDSTPVSEKPVSAAVDANASESP
• Function: Key structural protein of the Golgi apparatus. The membrane cisternae of the Golgi apparatus adhere to each other to form stacks, which are aligned side by side to form the Golgi ribbon. Acting in concert with GORASP1/GRASP65, is required for the formation and maintenance of the Golgi ribbon, and may be dispensable for the formation of stacks. However, other studies suggest that GORASP2 plays a role in the assembly and membrane stacking of the Golgi cisternae, and in the process by which Golgi stacks reform after breakdown during mitosis and meiosis. May regulate the intracellular transport and presentation of a defined set of transmembrane proteins, such as transmembrane TGFA. Required for normal acrosome formation during spermiogenesis and normal male fertility, probably by promoting colocalization of JAM2 and JAM3 at contact sites between germ cells and Sertoli cells. Mediates ER stress-induced unconventional (ER/Golgi-independent) trafficking of core-glycosylated CFTR to cell membrane.
• KEGG Pathway: Autophagy - animal (hsa04140)
• Reactome Pathway: Golgi Cisternae Pericentriolar Stack Reorganization (R-HSA-162658)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Type-1 diabetes	DIS7HLUB	Definitive	Biomarker	[1]
Type-1/2 diabetes	DISIUHAP	Definitive	Biomarker	[1]
Cryptococcosis	DISDYDTK	Strong	Genetic Variation	[2]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[3]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[3]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[4]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[5]
Obesity	DIS47Y1K	Strong	Biomarker	[6]
Parkinson disease	DISQVHKL	Strong	Biomarker	[7]

8 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 Golgi reassembly-stacking protein 2 (GORASP2).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Golgi reassembly-stacking protein 2 (GORASP2).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Golgi reassembly-stacking protein 2 (GORASP2).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Golgi reassembly-stacking protein 2 (GORASP2).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Golgi reassembly-stacking protein 2 (GORASP2).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Golgi reassembly-stacking protein 2 (GORASP2).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Golgi reassembly-stacking protein 2 (GORASP2).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Golgi reassembly-stacking protein 2 (GORASP2).	[18]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
G1	DMTV42K	Phase 1/2	G1 decreases the phosphorylation of Golgi reassembly-stacking protein 2 (GORASP2).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Golgi reassembly-stacking protein 2 (GORASP2).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Golgi reassembly-stacking protein 2 (GORASP2).	[17]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Golgi reassembly-stacking protein 2 (GORASP2).	[17]

References

• [1] Development and Standardization of an Improved Type 1 Diabetes Genetic Risk Score for Use in Newborn Screening and Incident Diagnosis.Diabetes Care. 2019 Feb;42(2):200-207. doi: 10.2337/dc18-1785.
• [2] The GRASP domain in golgi reassembly and stacking proteins: differences and similarities between lower and higher Eukaryotes.FEBS J. 2019 Sep;286(17):3340-3358. doi: 10.1111/febs.14869. Epub 2019 May 22.
• [3] Joint Effect of Genotypic and Phenotypic Features of Reproductive Factors on Endometrial Cancer Risk.Sci Rep. 2015 Oct 26;5:15582. doi: 10.1038/srep15582.
• [4] DNA hypomethylation-related overexpression of SFN, GORASP2 and ZYG11A is a novel prognostic biomarker for early stage lung adenocarcinoma.Oncotarget. 2019 Feb 26;10(17):1625-1636. doi: 10.18632/oncotarget.26676. eCollection 2019 Feb 26.
• [5] Type 2 diabetes-related genetic risk scores associated with variations in fasting plasma glucose and development of impaired glucose homeostasis in the prospective DESIR study.Diabetologia. 2014 Aug;57(8):1601-10. doi: 10.1007/s00125-014-3277-x. Epub 2014 Jun 4.
• [6] Genetic susceptibility, birth weight and obesity risk in young Chinese.Int J Obes (Lond). 2013 May;37(5):673-7. doi: 10.1038/ijo.2012.87. Epub 2012 Jun 19.
• [7] Effect of polygenic load on striatal dopaminergic deterioration in Parkinson disease.Neurology. 2019 Aug 13;93(7):e665-e674. doi: 10.1212/WNL.0000000000007939. Epub 2019 Jul 9.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [10] 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.
• [11] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] The G Protein-Coupled Estrogen Receptor Agonist G-1 Inhibits Nuclear Estrogen Receptor Activity and Stimulates Novel Phosphoproteomic Signatures. Toxicol Sci. 2016 Jun;151(2):434-46. doi: 10.1093/toxsci/kfw057. Epub 2016 Mar 29.
• [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] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.