Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZJ3LP4)

• DOT Name: Ras GTPase-activating protein 1 (RASA1)
• Synonyms: GAP; GTPase-activating protein; RasGAP; Ras p21 protein activator; p120GAP
• Gene Name: RASA1
• Related Disease:
  Capillary malformation-arteriovenous malformation 1
  Capillary malformation-arteriovenous malformation syndrome
  Obsolete Parkes Weber syndrome
  Noonan syndrome
  Telangiectasia, hereditary hemorrhagic, type 1
• UniProt ID: RASA1_HUMAN
• PDB ID: 1WER; 1WQ1; 2GQI; 2GSB; 2J05; 2J06; 2M51; 4FSS; 6PXB; 6PXC; 6WAX; 6WAY; 8BOS; 8DGQ
• Pfam ID: PF00168 ; PF00169 ; PF00616 ; PF00017 ; PF00018
• Sequence:
  MMAAEAGSEEGGPVTAGAGGGGAAAGSSAYPAVCRVKIPAALPVAAAPYPGLVETGVAGT
  LGGGAALGSEFLGAGSVAGALGGAGLTGGGTAAGVAGAAAGVAGAAVAGPSGDMALTKLP
  TSLLAETLGPGGGFPPLPPPPYLPPLGAGLGTVDEGDSLDGPEYEEEEVAIPLTAPPTNQ
  WYHGKLDRTIAEERLRQAGKSGSYLIRESDRRPGSFVLSFLSQMNVVNHFRIIAMCGDYY
  IGGRRFSSLSDLIGYYSHVSCLLKGEKLLYPVAPPEPVEDRRRVRAILPYTKVPDTDEIS
  FLKGDMFIVHNELEDGWMWVTNLRTDEQGLIVEDLVEEVGREEDPHEGKIWFHGKISKQE
  AYNLLMTVGQVCSFLVRPSDNTPGDYSLYFRTNENIQRFKICPTPNNQFMMGGRYYNSIG
  DIIDHYRKEQIVEGYYLKEPVPMQDQEQVLNDTVDGKEIYNTIRRKTKDAFYKNIVKKGY
  LLKKGKGKRWKNLYFILEGSDAQLIYFESEKRATKPKGLIDLSVCSVYVVHDSLFGRPNC
  FQIVVQHFSEEHYIFYFAGETPEQAEDWMKGLQAFCNLRKSSPGTSNKRLRQVSSLVLHI
  EEAHKLPVKHFTNPYCNIYLNSVQVAKTHAREGQNPVWSEEFVFDDLPPDINRFEITLSN
  KTKKSKDPDILFMRCQLSRLQKGHATDEWFLLSSHIPLKGIEPGSLRVRARYSMEKIMPE
  EEYSEFKELILQKELHVVYALSHVCGQDRTLLASILLRIFLHEKLESLLLCTLNDREISM
  EDEATTLFRATTLASTLMEQYMKATATQFVHHALKDSILKIMESKQSCELSPSKLEKNED
  VNTNLTHLLNILSELVEKIFMASEILPPTLRYIYGCLQKSVQHKWPTNTTMRTRVVSGFV
  FLRLICPAILNPRMFNIISDSPSPIAARTLILVAKSVQNLANLVEFGAKEPYMEGVNPFI
  KSNKHRMIMFLDELGNVPELPDTTEHSRTDLSRDLAALHEICVAHSDELRTLSNERGAQQ
  HVLKKLLAITELLQQKQNQYTKTNDVR
• Function: Inhibitory regulator of the Ras-cyclic AMP pathway. Stimulates the GTPase of normal but not oncogenic Ras p21; this stimulation may be further increased in the presence of NCK1.
• Tissue Specificity: In placental villi, detected only in the trophoblast layer (cytotrophoblast and syncytiotrophoblast). Not detected in stromal, endothelial or Hofbauer cells (at protein level).
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Axon guidance (hsa04360)
• Reactome Pathway:
  EPHB-mediated forward signaling (R-HSA-3928662)
  VEGFR2 mediated cell proliferation (R-HSA-5218921)
  Regulation of RAS by GAPs (R-HSA-5658442)
  PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases (R-HSA-8849471)
  Downstream signal transduction (R-HSA-186763)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Capillary malformation-arteriovenous malformation 1	DISBGIEI	Definitive	Autosomal dominant	[1]
Capillary malformation-arteriovenous malformation syndrome	DISMN03Q	Supportive	Autosomal dominant	[2]
Obsolete Parkes Weber syndrome	DISKR0FC	Supportive	Autosomal dominant	[3]
Noonan syndrome	DIS7Q7DN	Disputed	Autosomal dominant	[4]
Telangiectasia, hereditary hemorrhagic, type 1	DIS6IJC1	No Known	Autosomal dominant	[5]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitoxantrone	DMM39BF	Approved	Ras GTPase-activating protein 1 (RASA1) affects the response to substance of Mitoxantrone.	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Ras GTPase-activating protein 1 (RASA1).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ras GTPase-activating protein 1 (RASA1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ras GTPase-activating protein 1 (RASA1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Ras GTPase-activating protein 1 (RASA1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras GTPase-activating protein 1 (RASA1).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Ras GTPase-activating protein 1 (RASA1).	[12]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ras GTPase-activating protein 1 (RASA1).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Ras GTPase-activating protein 1 (RASA1).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ras GTPase-activating protein 1 (RASA1).	[15]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Ras GTPase-activating protein 1 (RASA1).	[16]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Ras GTPase-activating protein 1 (RASA1).	[17]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Ras GTPase-activating protein 1 (RASA1).	[15]
Rofecoxib	DM3P5DA	Approved	Rofecoxib affects the expression of Ras GTPase-activating protein 1 (RASA1).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ras GTPase-activating protein 1 (RASA1).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ras GTPase-activating protein 1 (RASA1).	[20]
Taxifolin	DMQJSF9	Preclinical	Taxifolin decreases the expression of Ras GTPase-activating protein 1 (RASA1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Ras GTPase-activating protein 1 (RASA1).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ras GTPase-activating protein 1 (RASA1).	[24]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Ras GTPase-activating protein 1 (RASA1).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Ras GTPase-activating protein 1 (RASA1).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Ras GTPase-activating protein 1 (RASA1).	[21]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Capillary malformation-arteriovenous malformation, a new clinical and genetic disorder caused by RASA1 mutations. Am J Hum Genet. 2003 Dec;73(6):1240-9. doi: 10.1086/379793. Epub 2003 Nov 24.
• [3] Parkes Weber syndrome, vein of Galen aneurysmal malformation, and other fast-flow vascular anomalies are caused by RASA1 mutations. Hum Mutat. 2008 Jul;29(7):959-65. doi: 10.1002/humu.20746.
• [4] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [5] VarRanker: rapid prioritization of sequence variations associated with human disease. BMC Bioinformatics. 2013;14 Suppl 13(Suppl 13):S1. doi: 10.1186/1471-2105-14-S13-S1. Epub 2013 Oct 1.
• [6] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [7] 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.
• [8] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [9] Estradiol downregulates miR-21 expression and increases miR-21 target gene expression in MCF-7 breast cancer cells. Nucleic Acids Res. 2009 May;37(8):2584-95. doi: 10.1093/nar/gkp117. Epub 2009 Mar 5.
• [10] 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.
• [11] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [12] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [13] 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.
• [14] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [15] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [16] Effects of folate deficiency on gene expression in the apoptosis and cancer pathways in colon cancer cells. Carcinogenesis. 2006 May;27(5):916-24. doi: 10.1093/carcin/bgi312. Epub 2005 Dec 16.
• [17] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [18] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] The chemopreventive effect of taxifolin is exerted through ARE-dependent gene regulation. Biol Pharm Bull. 2007 Jun;30(6):1074-9.
• [23] 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.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [25] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [26] Prediction of doxorubicin sensitivity in breast tumors based on gene expression profiles of drug-resistant cell lines correlates with patient survival. Oncogene. 2005 Nov 17;24(51):7542-51. doi: 10.1038/sj.onc.1208908.