Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT67DAGF)

• DOT Name: Ras-specific guanine nucleotide-releasing factor 2 (RASGRF2)
• Synonyms: Ras-GRF2; Ras guanine nucleotide exchange factor 2
• Gene Name: RASGRF2
• Related Disease:
  Coronary atherosclerosis
  Coronary heart disease
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Myocardial infarction
  Non-small-cell lung cancer
  Small-cell lung cancer
  Stroke
  Vascular dementia
  Adrenoleukodystrophy
  Advanced cancer
  Alcohol dependence
  Alcoholic cirrhosis of liver
  Bipolar disorder
  Breast neoplasm
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Drug dependence
  Eating disorder
  Hepatitis C virus infection
  Liver cirrhosis
  Major depressive disorder
  Metastatic malignant neoplasm
  T-cell lymphoma
  Carcinoma
  Undifferentiated carcinoma
  Neoplasm
• UniProt ID: RGRF2_HUMAN
• Pfam ID: PF00169 ; PF00617 ; PF00618 ; PF00621
• Sequence:
  MQKSVRYNEGHALYLAFLARKEGTKRGFLSKKTAEASRWHEKWFALYQNVLFYFEGEQSC
  RPAGMYLLEGCSCERTPAPPRAGAGQGGVRDALDKQYYFTVLFGHEGQKPLELRCEEEQD
  GKEWMEAIHQASYADILIEREVLMQKYIHLVQIVETEKIAANQLRHQLEDQDTEIERLKS
  EIIALNKTKERMRPYQSNQEDEDPDIKKIKKVQSFMRGWLCRRKWKTIVQDYICSPHAES
  MRKRNQIVFTMVEAESEYVHQLYILVNGFLRPLRMAASSKKPPISHDDVSSIFLNSETIM
  FLHEIFHQGLKARIANWPTLILADLFDILLPMLNIYQEFVRNHQYSLQVLANCKQNRDFD
  KLLKQYEANPACEGRMLETFLTYPMFQIPRYIITLHELLAHTPHEHVERKSLEFAKSKLE
  ELSRVMHDEVSDTENIRKNLAIERMIVEGCDILLDTSQTFIRQGSLIQVPSVERGKLSKV
  RLGSLSLKKEGERQCFLFTKHFLICTRSSGGKLHLLKTGGVLSLIDCTLIEEPDASDDDS
  KGSGQVFGHLDFKIVVEPPDAAAFTVVLLAPSRQEKAAWMSDISQCVDNIRCNGLMTIVF
  EENSKVTVPHMIKSDARLHKDDTDICFSKTLNSCKVPQIRYASVERLLERLTDLRFLSID
  FLNTFLHTYRIFTTAAVVLGKLSDIYKRPFTSIPVRSLELFFATSQNNRGEHLVDGKSPR
  LCRKFSSPPPLAVSRTSSPVRARKLSLTSPLNSKIGALDLTTSSSPTTTTQSPAASPPPH
  TGQIPLDLSRGLSSPEQSPGTVEENVDNPRVDLCNKLKRSIQKAVLESAPADRAGVESSP
  AADTTELSPCRSPSTPRHLRYRQPGGQTADNAHCSVSPASAFAIATAAAGHGSPPGFNNT
  ERTCDKEFIIRRTATNRVLNVLRHWVSKHAQDFELNNELKMNVLNLLEEVLRDPDLLPQE
  RKAAANILRALSQDDQDDIHLKLEDIIQMTDCMKAECFESLSAMELAEQITLLDHVIFRS
  IPYEEFLGQGWMKLDKNERTPYIMKTSQHFNDMSNLVASQIMNYADVSSRANAIEKWVAV
  ADICRCLHNYNGVLEITSALNRSAIYRLKKTWAKVSKQTKALMDKLQKTVSSEGRFKNLR
  ETLKNCNPPAVPYLGMYLTDLAFIEEGTPNFTEEGLVNFSKMRMISHIIREIRQFQQTSY
  RIDHQPKVAQYLLDKDLIIDEDTLYELSLKIEPRLPA
• Function: Functions as a calcium-regulated nucleotide exchange factor activating both Ras and RAC1 through the exchange of bound GDP for GTP. Preferentially activates HRAS in vivo compared to RRAS based on their different types of prenylation. Functions in synaptic plasticity by contributing to the induction of long term potentiation.
• Tissue Specificity: Widely expressed with higher expression in brain, followed by heart, lung, pancreas and kidney. Detected in placenta. Expressed in brain and lung (at protein level).
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
• Reactome Pathway:
  G alpha (12/13) signalling events (R-HSA-416482)
  Ras activation upon Ca2+ influx through NMDA receptor (R-HSA-442982)
  RAF/MAP kinase cascade (R-HSA-5673001)
  RHOA GTPase cycle (R-HSA-8980692)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coronary atherosclerosis	DISKNDYU	Definitive	Biomarker	[1]
Coronary heart disease	DIS5OIP1	Definitive	Biomarker	[1]
Lung cancer	DISCM4YA	Definitive	Altered Expression	[2]
Lung carcinoma	DISTR26C	Definitive	Altered Expression	[2]
Lung neoplasm	DISVARNB	Definitive	Posttranslational Modification	[2]
Myocardial infarction	DIS655KI	Definitive	Genetic Variation	[1]
Non-small-cell lung cancer	DIS5Y6R9	Definitive	Posttranslational Modification	[2]
Small-cell lung cancer	DISK3LZD	Definitive	Posttranslational Modification	[2]
Stroke	DISX6UHX	Definitive	Genetic Variation	[1]
Vascular dementia	DISVO82H	Definitive	Genetic Variation	[3]
Adrenoleukodystrophy	DISTUD1F	Strong	Genetic Variation	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[6]
Alcoholic cirrhosis of liver	DISQ1WRT	Strong	Genetic Variation	[4]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[7]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[8]
Colon cancer	DISVC52G	Strong	Altered Expression	[5]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Drug dependence	DIS9IXRC	Strong	Biomarker	[9]
Eating disorder	DISVGXN0	Strong	Genetic Variation	[10]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[11]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[4]
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[7]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[5]
T-cell lymphoma	DISSXRTQ	Strong	Altered Expression	[12]
Carcinoma	DISH9F1N	Disputed	Biomarker	[13]
Undifferentiated carcinoma	DISIAZST	Disputed	Biomarker	[13]
Neoplasm	DISZKGEW	Limited	Altered Expression	[5]

7 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 Ras-specific guanine nucleotide-releasing factor 2 (RASGRF2).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ras-specific guanine nucleotide-releasing factor 2 (RASGRF2).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ras-specific guanine nucleotide-releasing factor 2 (RASGRF2).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ras-specific guanine nucleotide-releasing factor 2 (RASGRF2).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ras-specific guanine nucleotide-releasing factor 2 (RASGRF2).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Ras-specific guanine nucleotide-releasing factor 2 (RASGRF2).	[21]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Ras-specific guanine nucleotide-releasing factor 2 (RASGRF2).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Ras-specific guanine nucleotide-releasing factor 2 (RASGRF2).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ras-specific guanine nucleotide-releasing factor 2 (RASGRF2).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Ras-specific guanine nucleotide-releasing factor 2 (RASGRF2).	[22]

References

• [1] Admixture Mapping of Subclinical Atherosclerosis and Subsequent Clinical Events Among African Americans in 2 Large Cohort Studies.Circ Cardiovasc Genet. 2017 Apr;10(2):e001569. doi: 10.1161/CIRCGENETICS.116.001569.
• [2] Aberrant methylation of RASGRF2 and RASSF1A in human non-small cell lung cancer.Oncol Rep. 2006 May;15(5):1281-5.
• [3] Genome-wide association study of vascular dementia.Stroke. 2012 Feb;43(2):315-9. doi: 10.1161/STROKEAHA.111.628768. Epub 2011 Nov 23.
• [4] A Single Nucleotide Polymorphism in the RASGRF2 Gene Is Associated with Alcoholic Liver Cirrhosis in Men.PLoS One. 2016 Dec 19;11(12):e0168685. doi: 10.1371/journal.pone.0168685. eCollection 2016.
• [5] RasGRF2 promotes migration and invasion of colorectal cancer cells by modulating expression of MMP9 through Src/Akt/NF-B pathway.Cancer Biol Ther. 2019;20(4):435-443. doi: 10.1080/15384047.2018.1529117. Epub 2018 Oct 25.
• [6] Rasgrf2 controls noradrenergic involvement in the acute and subchronic effects of alcohol in the brain.Psychopharmacology (Berl). 2014 Oct;231(21):4199-209. doi: 10.1007/s00213-014-3562-x. Epub 2014 Apr 16.
• [7] Exploratory genome-wide association analysis of response to ketamine and a polygenic analysis of response to scopolamine in depression.Transl Psychiatry. 2018 Dec 14;8(1):280. doi: 10.1038/s41398-018-0311-7.
• [8] Implication of calcium activated RasGRF2 in Annexin A6-mediated breast tumor cell growth and motility.Oncotarget. 2019 Jan 4;10(2):133-151. doi: 10.18632/oncotarget.26512. eCollection 2019 Jan 4.
• [9] The Inhibition of RasGRF2, But Not RasGRF1, Alters Cocaine Reward in Mice.J Neurosci. 2019 Aug 7;39(32):6325-6338. doi: 10.1523/JNEUROSCI.1120-18.2019. Epub 2019 Jun 10.
• [10] Genetic variants associated with disordered eating.Int J Eat Disord. 2013 Sep;46(6):594-608. doi: 10.1002/eat.22133. Epub 2013 Apr 9.
• [11] Human Endogenous Retrovirus-K HML-2 integration within RASGRF2 is associated with intravenous drug abuse and modulates transcription in a cell-line model.Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):10434-10439. doi: 10.1073/pnas.1811940115. Epub 2018 Sep 24.
• [12] The use of knockout mice reveals a synergistic role of the Vav1 and Rasgrf2 gene deficiencies in lymphomagenesis and metastasis.PLoS One. 2009 Dec 14;4(12):e8229. doi: 10.1371/journal.pone.0008229.
• [13] Allelic imbalance and altered expression of genes in chromosome 2q11-2q16 from rat mammary gland carcinomas induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine.Oncogene. 2003 Feb 27;22(8):1253-60. doi: 10.1038/sj.onc.1206233.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] 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.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] 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.
• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] 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.
• [23] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.