Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9C54MN)

• DOT Name: Ras GTPase-activating protein 3 (RASA3)
• Synonyms: GAP1(IP4BP); Ins P4-binding protein
• Gene Name: RASA3
• Related Disease:
  Anemia
  Pancytopenia
  Acute erythroid leukemia
  Aplastic anemia
  Colorectal neoplasm
  Thrombocytopenia
  Hepatocellular carcinoma
  Nervous system inflammation
• UniProt ID: RASA3_HUMAN
• Pfam ID: PF00779 ; PF00168 ; PF00169 ; PF00616
• Sequence:
  MAVEDEGLRVFQSVKIKIGEAKNLPSYPGPSKMRDCYCTVNLDQEEVFRTKIVEKSLCPF
  YGEDFYCEIPRSFRHLSFYIFDRDVFRRDSIIGKVAIQKEDLQKYHNRDTWFQLQHVDAD
  SEVQGKVHLELRLSEVITDTGVVCHKLATRIVECQGLPIVNGQCDPYATVTLAGPFRSEA
  KKTKVKRKTNNPQFDEVFYFEVTRPCSYSKKSHFDFEEEDVDKLEIRVDLWNASNLKFGD
  EFLGELRIPLKVLRQSSSYEAWYFLQPRDNGSKSLKPDDLGSLRLNVVYTEDHVFSSDYY
  SPLRDLLLKSADVEPVSASAAHILGEVCREKQEAAVPLVRLFLHYGRVVPFISAIASAEV
  KRTQDPNTIFRGNSLASKCIDETMKLAGMHYLHVTLKPAIEEICQSHKPCEIDPVKLKDG
  ENLENNMENLRQYVDRVFHAITESGVSCPTVMCDIFFSLREAAAKRFQDDPDVRYTAVSS
  FIFLRFFAPAILSPNLFQLTPHHTDPQTSRTLTLISKTVQTLGSLSKSKSASFKESYMAT
  FYEFFNEQKYADAVKNFLDLISSSGRRDPKSVEQPIVLKEGFMIKRAQGRKRFGMKNFKK
  RWFRLTNHEFTYHKSKGDQPLYSIPIENILAVEKLEEESFKMKNMFQVIQPERALYIQAN
  NCVEAKDWIDILTKVSQCNQKRLTVYHPSAYLSGHWLCCRAPSDSAPGCSPCTGGLPANI
  QLDIDGDRETERIYSLFNLYMSKLEKMQEACGSKSVYDGPEQEEYSTFVIDDPQETYKTL
  KQVIAGVGALEQEHAQYKRDKFKKTKYGSQEHPIGDKSFQNYIRQQSETSTHSI
• Function: Inhibitory regulator of the Ras-cyclic AMP pathway. Binds inositol tetrakisphosphate (IP4) with high affinity. Might be a specific IP4 receptor.
• KEGG Pathway: Ras sig.ling pathway (hsa04014)
• Reactome Pathway: Regulation of RAS by GAPs (R-HSA-5658442)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anemia	DISTVL0C	Definitive	Genetic Variation	[1]
Pancytopenia	DISVKEHV	Definitive	Biomarker	[1]
Acute erythroid leukemia	DISZFC1O	Strong	Biomarker	[2]
Aplastic anemia	DISJRSC0	Strong	Biomarker	[1]
Colorectal neoplasm	DISR1UCN	Strong	Biomarker	[3]
Thrombocytopenia	DISU61YW	Strong	Genetic Variation	[4]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[5]
Nervous system inflammation	DISB3X5A	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Ras GTPase-activating protein 3 (RASA3).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the methylation of Ras GTPase-activating protein 3 (RASA3).	[8]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Ras GTPase-activating protein 3 (RASA3).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Ras GTPase-activating protein 3 (RASA3).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ras GTPase-activating protein 3 (RASA3).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Ras GTPase-activating protein 3 (RASA3).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras GTPase-activating protein 3 (RASA3).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Ras GTPase-activating protein 3 (RASA3).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ras GTPase-activating protein 3 (RASA3).	[14]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Ras GTPase-activating protein 3 (RASA3).	[15]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Ras GTPase-activating protein 3 (RASA3).	[16]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Ras GTPase-activating protein 3 (RASA3).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Ras GTPase-activating protein 3 (RASA3).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ras GTPase-activating protein 3 (RASA3).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Ras GTPase-activating protein 3 (RASA3).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Ras GTPase-activating protein 3 (RASA3).	[21]
Glyphosate	DM0AFY7	Investigative	Glyphosate increases the expression of Ras GTPase-activating protein 3 (RASA3).	[22]

References

• [1] Increased Reactive Oxygen Species and Cell Cycle Defects Contribute to Anemia in the RASA3 Mutant Mouse Model scat.Front Physiol. 2018 Jun 5;9:689. doi: 10.3389/fphys.2018.00689. eCollection 2018.
• [2] Antisense knock out of the inositol 1,3,4,5-tetrakisphosphate receptor GAP1(IP4BP) in the human erythroleukemia cell line leads to the appearance of intermediate conductance K(Ca) channels that hyperpolarize the membrane and enhance calcium influx.J Gen Physiol. 1999 Jan;113(1):81-96. doi: 10.1085/jgp.113.1.81.
• [3] Cancer driver-passenger distinction via sporadic human and dog cancer comparison: a proof-of-principle study with colorectal cancer.Oncogene. 2014 Feb 13;33(7):814-22. doi: 10.1038/onc.2013.17. Epub 2013 Feb 18.
• [4] The Phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) Binder Rasa3 Regulates Phosphoinositide 3-kinase (PI3K)-dependent Integrin IIb3 Outside-in Signaling.J Biol Chem. 2017 Feb 3;292(5):1691-1704. doi: 10.1074/jbc.M116.746867. Epub 2016 Nov 30.
• [5] Methylation patterns of RASA3 associated with clinicopathological factors in hepatocellular carcinoma.J Cancer. 2018 May 25;9(12):2116-2122. doi: 10.7150/jca.24567. eCollection 2018.
• [6] RAS P21 Protein Activator 3 (RASA3) Specifically Promotes Pathogenic T Helper 17 Cell Generation by Repressing T-Helper-2-Cell-Biased Programs.Immunity. 2018 Nov 20;49(5):886-898.e5. doi: 10.1016/j.immuni.2018.09.004. Epub 2018 Nov 13.
• [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] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [9] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [10] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [11] 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.
• [12] 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.
• [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] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [15] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [16] 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.
• [17] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [18] 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.
• [19] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [20] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.