Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJ7J1WA)

• DOT Name: Rho-related GTP-binding protein RhoG (RHOG)
• Gene Name: RHOG
• Related Disease:
  Advanced cancer
  Alcohol dependence
  Endometriosis
  Polycystic ovarian syndrome
• UniProt ID: RHOG_HUMAN
• PDB ID: 6UKA; 7Y4A
• Pfam ID: PF00071
• Sequence:
  MQSIKCVVVGDGAVGKTCLLICYTTNAFPKEYIPTVFDNYSAQSAVDGRTVNLNLWDTAG
  QEEYDRLRTLSYPQTNVFVICFSIASPPSYENVRHKWHPEVCHHCPDVPILLVGTKKDLR
  AQPDTLRRLKEQGQAPITPQQGQALAKQIHAVRYLECSALQQDGVKEVFAEAVRAVLNPT
  PIKRGRSCILL
• Function: Plays a role in immunological synaptic F-actin density and architecture organization. Regulates actin reorganization in lymphocytes, possibly through the modulation of Rac1 activity. Required for the formation of membrane ruffles during macropinocytosis. Plays a role in cell migration and is required for the formation of cup-like structures during trans-endothelial migration of leukocytes. Binds phospholipids in an activation-dependent manner; thereby acting as an anchor for other proteins to the plasma membrane (PM). Plays a role in exocytosis of cytotoxic granules (CG) by lymphocytes/Component of the exocytosis machinery in natural killer (NK) and CD8+ T cells. Promotes the docking of cytotoxic granules (CG) to the plasma membrane through the interaction with UNC13D. Involved in the cytotoxic activity of lymphocytes/primary CD8+ T cells ; (Microbial infection) In case of Salmonella enterica infection, activated by SopB and ARHGEF26/SGEF, which induces cytoskeleton rearrangements and promotes bacterial entry.
• KEGG Pathway:
  Bacterial invasion of epithelial cells (hsa05100)
  Salmonella infection (hsa05132)
  Yersinia infection (hsa05135)
• Reactome Pathway:
  PIP3 activates AKT signaling (R-HSA-1257604)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  RHO GTPases activate KTN1 (R-HSA-5625970)
  Neutrophil degranulation (R-HSA-6798695)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  RHOG GTPase cycle (R-HSA-9013408)
  GPVI-mediated activation cascade (R-HSA-114604)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alcohol dependence	DIS4ZSCO	Strong	Genetic Variation	[2]
Endometriosis	DISX1AG8	Strong	Biomarker	[3]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Rho-related GTP-binding protein RhoG (RHOG).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Rho-related GTP-binding protein RhoG (RHOG).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rho-related GTP-binding protein RhoG (RHOG).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Rho-related GTP-binding protein RhoG (RHOG).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Rho-related GTP-binding protein RhoG (RHOG).	[10]
Selenium	DM25CGV	Approved	Selenium increases the expression of Rho-related GTP-binding protein RhoG (RHOG).	[11]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Rho-related GTP-binding protein RhoG (RHOG).	[12]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Rho-related GTP-binding protein RhoG (RHOG).	[13]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Rho-related GTP-binding protein RhoG (RHOG).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Rho-related GTP-binding protein RhoG (RHOG).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Rho-related GTP-binding protein RhoG (RHOG).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Rho-related GTP-binding protein RhoG (RHOG).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Rho-related GTP-binding protein RhoG (RHOG).	[14]

References

• [1] RHOG Activates RAC1 through CDC42 Leading to Tube Formation in Vascular Endothelial Cells.Cells. 2019 Feb 18;8(2):171. doi: 10.3390/cells8020171.
• [2] A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53.Mol Psychiatry. 2013 Nov;18(11):1218-24. doi: 10.1038/mp.2012.143. Epub 2012 Oct 23.
• [3] A high level of TGF-B1 promotes endometriosis development via cell migration, adhesiveness, colonization, and invasiveness?,Soni UK. Kumar V
• [4] RHOG-DOCK1-RAC1 Signaling Axis Is Perturbed in DHEA-Induced Polycystic Ovary in Rat Model.Reprod Sci. 2017 May;24(5):738-752. doi: 10.1177/1933719116669057. Epub 2016 Sep 22.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [11] 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.
• [12] 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.
• [13] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [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] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [16] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.