Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT02N7LD)

• DOT Name: Type-1 angiotensin II receptor-associated protein (AGTRAP)
• Synonyms: AT1 receptor-associated protein
• Gene Name: AGTRAP
• Related Disease:
  High blood pressure
  Metabolic disorder
  Retinopathy
• UniProt ID: ATRAP_HUMAN
• Pfam ID: PF06396
• Sequence:
  MELPAVNLKVILLGHWLLTTWGCIVFSGSYAWANFTILALGVWAVAQRDSIDAISMFLGG
  LLATIFLDIVHISIFYPRVSLTDTGRFGVGMAILSLLLKPLSCCFVYHMYRERGGELLVH
  TGFLGSSQDRSAYQTIDSAEAPADPFAVPEGRSQDARGY
• Function: Appears to be a negative regulator of type-1 angiotensin II receptor-mediated signaling by regulating receptor internalization as well as mechanism of receptor desensitization such as phosphorylation. Induces also a decrease in cell proliferation and angiotensin II-stimulated transcriptional activity.
• Tissue Specificity: Ubiquitous but more abundant in kidney, heart, pancreas and thyroid.
• Reactome Pathway: Signaling by BRAF and RAF1 fusions (R-HSA-6802952)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
High blood pressure	DISY2OHH	Strong	Biomarker	[1]
Metabolic disorder	DIS71G5H	Strong	Altered Expression	[2]
Retinopathy	DISB4B0F	Limited	Biomarker	[3]

16 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 Type-1 angiotensin II receptor-associated protein (AGTRAP).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Type-1 angiotensin II receptor-associated protein (AGTRAP).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Type-1 angiotensin II receptor-associated protein (AGTRAP).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Type-1 angiotensin II receptor-associated protein (AGTRAP).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Type-1 angiotensin II receptor-associated protein (AGTRAP).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Type-1 angiotensin II receptor-associated protein (AGTRAP).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Type-1 angiotensin II receptor-associated protein (AGTRAP).	[10]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Type-1 angiotensin II receptor-associated protein (AGTRAP).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Type-1 angiotensin II receptor-associated protein (AGTRAP).	[12]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the activity of Type-1 angiotensin II receptor-associated protein (AGTRAP).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Type-1 angiotensin II receptor-associated protein (AGTRAP).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Type-1 angiotensin II receptor-associated protein (AGTRAP).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Type-1 angiotensin II receptor-associated protein (AGTRAP).	[16]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Type-1 angiotensin II receptor-associated protein (AGTRAP).	[17]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Type-1 angiotensin II receptor-associated protein (AGTRAP).	[18]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine decreases the expression of Type-1 angiotensin II receptor-associated protein (AGTRAP).	[19]

References

• [1] Effects of ATRAP in Renal Proximal Tubules on Angiotensin-Dependent Hypertension.J Am Heart Assoc. 2019 Apr 16;8(8):e012395. doi: 10.1161/JAHA.119.012395.
• [2] Effect of prehypertensive losartan therapy on AT1R and ATRAP methylation of adipose tissue in the later life of highfatfed spontaneously hypertensive rats.Mol Med Rep. 2018 Jan;17(1):1753-1761. doi: 10.3892/mmr.2017.8081. Epub 2017 Nov 15.
• [3] Ablation of Immunoproteasome 5i Subunit Suppresses Hypertensive Retinopathy by Blocking ATRAP Degradation in Mice.Mol Ther. 2020 Jan 8;28(1):279-292. doi: 10.1016/j.ymthe.2019.09.025. Epub 2019 Oct 5.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] 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.
• [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] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [8] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Melinjo (Gnetum gnemon L.) Seed Extract Decreases Serum Uric Acid Levels in Nonobese Japanese Males: A Randomized Controlled Study. Evid Based Complement Alternat Med. 2013;2013:589169. doi: 10.1155/2013/589169. Epub 2013 Dec 17.
• [14] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [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] 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.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [19] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.