Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAWW3KI)

• DOT Name: Ras GTPase-activating protein-binding protein 2 (G3BP2)
• Synonyms: G3BP-2; GAP SH3 domain-binding protein 2
• Gene Name: G3BP2
• Related Disease:
  Breast cancer
  Breast carcinoma
  Chikungunya virus infection
  Metastatic malignant neoplasm
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Breast neoplasm
  Gastritis
  Precancerous condition
• UniProt ID: G3BP2_HUMAN
• PDB ID: 5DRV
• Pfam ID: PF02136 ; PF00076
• Sequence:
  MVMEKPSPLLVGREFVRQYYTLLNKAPEYLHRFYGRNSSYVHGGVDASGKPQEAVYGQND
  IHHKVLSLNFSECHTKIRHVDAHATLSDGVVVQVMGLLSNSGQPERKFMQTFVLAPEGSV
  PNKFYVHNDMFRYEDEVFGDSEPELDEESEDEVEEEQEERQPSPEPVQENANSGYYEAHP
  VTNGIEEPLEESSHEPEPEPESETKTEELKPQVEEKNLEELEEKSTTPPPAEPVSLPQEP
  PKAFSWASVTSKNLPPSGTVSSSGIPPHVKAPVSQPRVEAKPEVQSQPPRVREQRPRERP
  GFPPRGPRPGRGDMEQNDSDNRRIIRYPDSHQLFVGNLPHDIDENELKEFFMSFGNVVEL
  RINTKGVGGKLPNFGFVVFDDSEPVQRILIAKPIMFRGEVRLNVEEKKTRAARERETRGG
  GDDRRDIRRNDRGPGGPRGIVGGGMMRDRDGRGPPPRGGMAQKLGSGRGTGQMEGRFTGQ
  RR
• Function: Scaffold protein that plays an essential role in cytoplasmic stress granule formation which acts as a platform for antiviral signaling. Plays an essential role in stress granule formation. Stress granules are membraneless compartments that store mRNAs and proteins, such as stalled translation pre-initiation complexes, in response to stress. Promotes formation of stress granules phase-separated membraneless compartment by undergoing liquid-liquid phase separation (LLPS) upon unfolded RNA-binding: functions as a molecular switch that triggers RNA-dependent LLPS in response to a rise in intracellular free RNA concentrations.
• Reactome Pathway: SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Chikungunya virus infection	DISDXEHY	Strong	Biomarker	[2]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[3]
Neoplasm	DISZKGEW	moderate	Biomarker	[3]
Prostate cancer	DISF190Y	moderate	Altered Expression	[4]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[5]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[1]
Gastritis	DIS8G07K	Limited	Altered Expression	[6]
Precancerous condition	DISV06FL	Limited	Altered Expression	[6]

5 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 Ras GTPase-activating protein-binding protein 2 (G3BP2).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ras GTPase-activating protein-binding protein 2 (G3BP2).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Ras GTPase-activating protein-binding protein 2 (G3BP2).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Ras GTPase-activating protein-binding protein 2 (G3BP2).	[15]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the methylation of Ras GTPase-activating protein-binding protein 2 (G3BP2).	[18]

9 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 Ras GTPase-activating protein-binding protein 2 (G3BP2).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras GTPase-activating protein-binding protein 2 (G3BP2).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ras GTPase-activating protein-binding protein 2 (G3BP2).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Ras GTPase-activating protein-binding protein 2 (G3BP2).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ras GTPase-activating protein-binding protein 2 (G3BP2).	[12]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Ras GTPase-activating protein-binding protein 2 (G3BP2).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ras GTPase-activating protein-binding protein 2 (G3BP2).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Ras GTPase-activating protein-binding protein 2 (G3BP2).	[17]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Ras GTPase-activating protein-binding protein 2 (G3BP2).	[19]

References

• [1] Stress granule-associated protein G3BP2 regulates breast tumor initiation.Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):1033-1038. doi: 10.1073/pnas.1525387114. Epub 2017 Jan 17.
• [2] Stress granule components G3BP1 and G3BP2 play a proviral role early in Chikungunya virus replication.J Virol. 2015 Apr;89(8):4457-69. doi: 10.1128/JVI.03612-14. Epub 2015 Feb 4.
• [3] Matrix stiffness drives epithelial-mesenchymal transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway.Nat Cell Biol. 2015 May;17(5):678-88. doi: 10.1038/ncb3157. Epub 2015 Apr 20.
• [4] TRIM25 enhances cell growth and cell survival by modulating p53 signals via interaction with G3BP2 in prostate cancer.Oncogene. 2018 Apr;37(16):2165-2180. doi: 10.1038/s41388-017-0095-x. Epub 2018 Jan 30.
• [5] Association of USP10 with G3BP2 Inhibits p53 Signaling and Contributes to Poor Outcome in Prostate Cancer.Mol Cancer Res. 2018 May;16(5):846-856. doi: 10.1158/1541-7786.MCR-17-0471. Epub 2018 Jan 29.
• [6] Carcinogenic Helicobacter pylori Strains Selectively Dysregulate the In Vivo Gastric Proteome, Which May Be Associated with Stomach Cancer Progression.Mol Cell Proteomics. 2019 Feb;18(2):352-371. doi: 10.1074/mcp.RA118.001181. Epub 2018 Nov 19.
• [7] 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.
• [8] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [9] 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.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [12] 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.
• [13] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [14] 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.
• [15] 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.
• [16] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [17] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [18] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [19] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.