Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL06RG2)

• DOT Name: Ras GTPase-activating protein 2 (RASA2)
• Synonyms: GTPase-activating protein 1m; GAP1m
• Gene Name: RASA2
• Related Disease:
  Familial prostate carcinoma
  T-cell acute lymphoblastic leukaemia
  Breast cancer
  Breast carcinoma
  Colon carcinoma
  Creutzfeldt Jacob disease
  Fatal familial insomnia
  Head and neck cancer
  Head and neck carcinoma
  Liposarcoma
  Lung cancer
  Lung carcinoma
  Medullary thyroid gland carcinoma
  Melanoma
  Obesity
  Trophoblastic neoplasm
  Advanced cancer
  Neurofibromatosis type 1
  Noonan syndrome
  Acute myelogenous leukaemia
  Capillary malformation-arteriovenous malformation syndrome
  Carcinoma of liver and intrahepatic biliary tract
  Liver cancer
  Prostate cancer
  Prostate carcinoma
• UniProt ID: RASA2_HUMAN
• Pfam ID: PF00779 ; PF00168 ; PF00169 ; PF00616
• Sequence:
  MAAAAPAAAAASSEAPAASATAEPEAGDQDSREVRVLQSLRGKICEAKNLLPYLGPHKMR
  DCFCTINLDQEEVYRTQVVEKSLSPFFSEEFYFEIPRTFQYLSFYVYDKNVLQRDLRIGK
  VAIKKEDLCNHSGKETWFSLQPVDSNSEVQGKVHLELKLNELITENGTVCQQLVVHIKAC
  HGLPLINGQSCDPYATVSLVGPSRNDQKKTKVKKKTSNPQFNEIFYFEVTRSSSYTRKSQ
  FQVEEEDIEKLEIRIDLWNNGNLVQDVFLGEIKVPVNVLRTDSSHQAWYLLQPRDNGNKS
  SKTDDLGSLRLNICYTEDYVLPSEYYGPLKTLLLKSPDVQPISASAAYILSEICRDKNDA
  VLPLVRLLLHHDKLVPFATAVAELDLKDTQDANTIFRGNSLATRCLDEMMKIVGGHYLKV
  TLKPILDEICDSSKSCEIDPIKLKEGDNVENNKENLRYYVDKLFNTIVKSSMSCPTVMCD
  IFYSLRQMATQRFPNDPHVQYSAVSSFVFLRFFAVAVVSPHTFHLRPHHPDAQTIRTLTL
  ISKTIQTLGSWGSLSKSKSSFKETFMCEFFKMFQEEGYIIAVKKFLDEISSTETKESSGT
  SEPVHLKEGEMYKRAQGRTRIGKKNFKKRWFCLTSRELTYHKQPGSKDAIYTIPVKNILA
  VEKLEESSFNKKNMFQVIHTEKPLYVQANNCVEANEWIDVLCRVSRCNQNRLSFYHPSVY
  LNGNWLCCQETGENTLGCKPCTAGVPADIQIDIDEDRETERIYSLFTLSLLKLQKMEEAC
  GTIAVYQGPQKEPDDYSNFVIEDSVTTFKTIQQIKSIIEKLDEPHEKYRKKRSSSAKYGS
  KENPIVGKAS
• Function: Inhibitory regulator of the Ras-cyclic AMP pathway. Binds inositol tetrakisphosphate (IP4).
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Viral carcinogenesis (hsa05203)
• Reactome Pathway: Regulation of RAS by GAPs (R-HSA-5658442)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial prostate carcinoma	DISL9KNO	Definitive	Genetic Variation	[1]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Definitive	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Creutzfeldt Jacob disease	DISCB6RX	Strong	Biomarker	[6]
Fatal familial insomnia	DIS1FL1J	Strong	Genetic Variation	[7]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[8]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[8]
Liposarcoma	DIS8IZVM	Strong	Biomarker	[8]
Lung cancer	DISCM4YA	Strong	Biomarker	[8]
Lung carcinoma	DISTR26C	Strong	Biomarker	[8]
Medullary thyroid gland carcinoma	DISHBL3K	Strong	Biomarker	[9]
Melanoma	DIS1RRCY	Strong	Altered Expression	[10]
Obesity	DIS47Y1K	Strong	Genetic Variation	[4]
Trophoblastic neoplasm	DISY8WKT	Strong	Altered Expression	[11]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[12]
Neurofibromatosis type 1	DIS53JH9	moderate	Altered Expression	[13]
Noonan syndrome	DIS7Q7DN	Supportive	Autosomal dominant	[14]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[15]
Capillary malformation-arteriovenous malformation syndrome	DISMN03Q	Limited	Genetic Variation	[16]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[17]
Liver cancer	DISDE4BI	Limited	Biomarker	[17]
Prostate cancer	DISF190Y	Limited	Biomarker	[8]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Ras GTPase-activating protein 2 (RASA2).	[18]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ras GTPase-activating protein 2 (RASA2).	[19]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ras GTPase-activating protein 2 (RASA2).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ras GTPase-activating protein 2 (RASA2).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ras GTPase-activating protein 2 (RASA2).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ras GTPase-activating protein 2 (RASA2).	[23]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Ras GTPase-activating protein 2 (RASA2).	[25]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Ras GTPase-activating protein 2 (RASA2).	[25]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Ras GTPase-activating protein 2 (RASA2).	[25]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Ras GTPase-activating protein 2 (RASA2).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ras GTPase-activating protein 2 (RASA2).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Ras GTPase-activating protein 2 (RASA2).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Ras GTPase-activating protein 2 (RASA2).	[30]

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 Ras GTPase-activating protein 2 (RASA2).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Ras GTPase-activating protein 2 (RASA2).	[28]

References

• [1] A novel human RasGAP-like gene that maps within the prostate cancer susceptibility locus at chromosome 1q25.FEBS Lett. 1998 Dec 11;441(1):127-31. doi: 10.1016/s0014-5793(98)01530-0.
• [2] RasGRP1 overexpression in T-ALL increases basal nucleotide exchange on Ras rendering the Ras/PI3K/Akt pathway responsive to protumorigenic cytokines.Oncogene. 2016 Jul 14;35(28):3658-68. doi: 10.1038/onc.2015.431. Epub 2015 Nov 9.
• [3] Loss of RasGAP Tumor Suppressors Underlies the Aggressive Nature of Luminal B Breast Cancers.Cancer Discov. 2017 Feb;7(2):202-217. doi: 10.1158/2159-8290.CD-16-0520. Epub 2016 Dec 14.
• [4] Interactions between RASA2, CADM1, HIF1AN gene polymorphisms and body fatness with breast cancer: a population-based case-control study in China.Oncotarget. 2017 Oct 5;8(58):98258-98269. doi: 10.18632/oncotarget.21530. eCollection 2017 Nov 17.
• [5] RasGAP-derived peptide 38GAP potentiates the cytotoxicity of cisplatin through inhibitions of Akt, ERK and NF-B in colon carcinoma HCT116 cells.Cancer Lett. 2011 Sep 1;308(1):62-70. doi: 10.1016/j.canlet.2011.04.014. Epub 2011 May 13.
• [6] Genetics of prion diseases.Curr Opin Genet Dev. 2013 Jun;23(3):345-51. doi: 10.1016/j.gde.2013.02.012. Epub 2013 Mar 19.
• [7] The associations of two SNPs in miRNA-146a and one SNP in ZBTB38-RASA2 with the disease susceptibility and the clinical features of the Chinese patients of sCJD and FFI.Prion. 2018 Jan 2;12(1):34-41. doi: 10.1080/19336896.2017.1405885. Epub 2018 Jan 2.
• [8] Clinical application of genomic profiling to find druggable targets for adolescent and young adult (AYA) cancer patients with metastasis.BMC Cancer. 2016 Feb 29;16:170. doi: 10.1186/s12885-016-2209-1.
• [9] Two GEO MicroRNA Expression Profile Based High-Throughput Screen to Identify MicroRNA-31-3p Regulating Growth of Medullary Thyroid Carcinoma Cell by Targeting RASA2.Med Sci Monit. 2019 Jul 12;25:5170-5180. doi: 10.12659/MSM.916815.
• [10] Inactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation.Oncotarget. 2016 Apr 26;7(17):23885-96. doi: 10.18632/oncotarget.8127.
• [11] The role of ras GTPase activating protein in human tumorigenesis.Pathobiology. 1995;63(6):348-50. doi: 10.1159/000163971.
• [12] Recurrent inactivating RASA2 mutations in melanoma.Nat Genet. 2015 Dec;47(12):1408-10. doi: 10.1038/ng.3427. Epub 2015 Oct 26.
• [13] Restoring functional neurofibromin by protein transduction.Sci Rep. 2018 Apr 18;8(1):6171. doi: 10.1038/s41598-018-24310-5.
• [14] Next-generation sequencing identifies rare variants associated with Noonan syndrome. Proc Natl Acad Sci U S A. 2014 Aug 5;111(31):11473-8. doi: 10.1073/pnas.1324128111. Epub 2014 Jul 21.
• [15] Identification of a novel RAS GTPase-activating protein (RASGAP) gene at 9q34 as an MLL fusion partner in a patient with de novo acute myeloid leukemia.Genes Chromosomes Cancer. 2004 Apr;39(4):324-34. doi: 10.1002/gcc.20004.
• [16] A novel RASA1 mutation causing capillary malformation-arteriovenous malformation (CM-AVM): the first genetic clinical report in East Asia.Hereditas. 2018 Jul 16;155:24. doi: 10.1186/s41065-018-0062-8. eCollection 2018.
• [17] The caspase-3/p120 RasGAP stress-sensing module reduces liver cancer incidence but does not affect overall survival in gamma-irradiated and carcinogen-treated mice.Mol Carcinog. 2017 Jun;56(6):1680-1684. doi: 10.1002/mc.22624. Epub 2017 Feb 16.
• [18] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [21] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [22] 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.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] 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.
• [25] 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.
• [26] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.