Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEMEV3P)

• DOT Name: Ras guanyl-releasing protein 3 (RASGRP3)
• Synonyms: Calcium and DAG-regulated guanine nucleotide exchange factor III; Guanine nucleotide exchange factor for Rap1
• Gene Name: RASGRP3
• Related Disease:
  Prostate cancer
  Prostate carcinoma
  Advanced cancer
  Esophageal squamous cell carcinoma
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Immunodeficiency
  Medulloblastoma
  Neoplasm
  Nephritis
  Prostate neoplasm
  Systemic lupus erythematosus
  Vasculitis
  Acute myelogenous leukaemia
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Melanoma
  Metastatic malignant neoplasm
  Severe combined immunodeficiency
  Thyroid gland papillary carcinoma
  Uveal Melanoma
• UniProt ID: GRP3_HUMAN
• Pfam ID: PF00130 ; PF13499 ; PF00617
• Sequence:
  MGSSGLGKAATLDELLCTCIEMFDDNGELDNSYLPRIVLLMHRWYLSSTELAEKLLCMYR
  NATGESCNEFRLKICYFMRYWILKFPAEFNLDLGLIRMTEEFREVASQLGYEKHVSLIDI
  SSIPSYDWMRRVTQRKKVSKKGKACLLFDHLEPIELAEHLTFLEHKSFRRISFTDYQSYV
  IHGCLENNPTLERSIALFNGISKWVQLMVLSKPTPQQRAEVITKFINVAKKLLQLKNFNT
  LMAVVGGLSHSSISRLKETHSHLSSEVTKNWNEMTELVSSNGNYCNYRKAFADCDGFKIP
  ILGVHLKDLIAVHVIFPDWTEENKVNIVKMHQLSVTLSELVSLQNASHHLEPNMDLINLL
  TLSLDLYHTEDDIYKLSLVLEPRNSKSQPTSPTTPNKPVVPLEWALGVMPKPDPTVINKH
  IRKLVESVFRNYDHDHDGYISQEDFESIAANFPFLDSFCVLDKDQDGLISKDEMMAYFLR
  AKSQLHCKMGPGFIHNFQEMTYLKPTFCEHCAGFLWGIIKQGYKCKDCGANCHKQCKDLL
  VLACRRFARAPSLSSGHGSLPGSPSLPPAQDEVFEFPGVTAGHRDLDSRAITLVTGSSRK
  ISVRLQRATTSQATQTEPVWSEAGWGDSGSHTFPKMKSKFHDKAAKDKGFAKWENEKPRV
  HAGVDVVDRGTEFELDQDEGEETRQDGEDG
• Function: Guanine nucleotide exchange factor (GEF) for Ras and Rap1.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  B cell receptor sig.ling pathway (hsa04662)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  RAF/MAP kinase cascade (R-HSA-5673001)
  Activation of RAS in B cells (R-HSA-1169092)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	Definitive	Altered Expression	[1]
Prostate carcinoma	DISMJPLE	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[3]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[4]
Glioma	DIS5RPEH	Strong	Altered Expression	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Immunodeficiency	DIS093I0	Strong	Biomarker	[6]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Nephritis	DISQZQ70	Strong	Genetic Variation	[9]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[10]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[11]
Vasculitis	DISQRKDX	Strong	Genetic Variation	[9]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[12]
Breast cancer	DIS7DPX1	Limited	Biomarker	[13]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[13]
Breast neoplasm	DISNGJLM	Limited	Altered Expression	[13]
Carcinoma	DISH9F1N	Limited	Biomarker	[1]
Melanoma	DIS1RRCY	Limited	Biomarker	[14]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[15]
Severe combined immunodeficiency	DIS6MF4Q	Limited	Biomarker	[13]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Biomarker	[8]
Uveal Melanoma	DISA7ZGL	Limited	Biomarker	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Ras guanyl-releasing protein 3 (RASGRP3).	[16]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Ras guanyl-releasing protein 3 (RASGRP3).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ras guanyl-releasing protein 3 (RASGRP3).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ras guanyl-releasing protein 3 (RASGRP3).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Ras guanyl-releasing protein 3 (RASGRP3).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ras guanyl-releasing protein 3 (RASGRP3).	[19]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Ras guanyl-releasing protein 3 (RASGRP3).	[20]
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the expression of Ras guanyl-releasing protein 3 (RASGRP3).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ras guanyl-releasing protein 3 (RASGRP3).	[24]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Ras guanyl-releasing protein 3 (RASGRP3).	[25]

References

• [1] Upregulation of RASGRP3 expression in prostate cancer correlates with aggressive capabilities and predicts biochemical recurrence after radical prostatectomy.Prostate Cancer Prostatic Dis. 2014 Jun;17(2):119-25. doi: 10.1038/pcan.2013.51. Epub 2014 Jan 14.
• [2] RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma.Cancer Cell. 2017 May 8;31(5):685-696.e6. doi: 10.1016/j.ccell.2017.04.002.
• [3] RasGRP3, a Ras guanyl releasing protein 3 that contributes to malignant proliferation and aggressiveness in human esophageal squamous cell carcinoma.Clin Exp Pharmacol Physiol. 2018 Jul;45(7):720-728. doi: 10.1111/1440-1681.12926. Epub 2018 Apr 10.
• [4] RasGRP3 regulates the migration of glioma cells via interaction with Arp3.Oncotarget. 2015 Jan 30;6(3):1850-64. doi: 10.18632/oncotarget.2575.
• [5] Hepatoma cells from mice deficient in glycine N-methyltransferase have increased RAS signaling and activation of liver kinase B1.Gastroenterology. 2012 Sep;143(3):787-798.e13. doi: 10.1053/j.gastro.2012.05.050. Epub 2012 Jun 8.
• [6] RasGRP3, a Ras activator, contributes to signaling and the tumorigenic phenotype in human melanoma.Oncogene. 2011 Nov 10;30(45):4590-4600. doi: 10.1038/onc.2011.166. Epub 2011 May 23.
• [7] Combined functional genomic and chemical screens identify SETD8 as a therapeutic target in MYC-driven medulloblastoma.JCI Insight. 2019 Jan 10;4(1):e122933. doi: 10.1172/jci.insight.122933.
• [8] RasGRP3 controls cell proliferation and migration in papillary thyroid cancer by regulating the Akt-MDM2 pathway.Gene. 2017 Oct 30;633:35-41. doi: 10.1016/j.gene.2017.08.024. Epub 2017 Aug 31.
• [9] TNIP1, SLC15A4, ETS1, RasGRP3 and IKZF1 are associated with clinical features of systemic lupus erythematosus in a Chinese Han population.Lupus. 2010 Sep;19(10):1181-6. doi: 10.1177/0961203310367918. Epub 2010 Jun 1.
• [10] RasGRP3 contributes to formation and maintenance of the prostate cancer phenotype.Cancer Res. 2010 Oct 15;70(20):7905-17. doi: 10.1158/0008-5472.CAN-09-4729. Epub 2010 Sep 28.
• [11] Transancestral mapping and genetic load in systemic lupus erythematosus.Nat Commun. 2017 Jul 17;8:16021. doi: 10.1038/ncomms16021.
• [12] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [13] Function of RasGRP3 in the formation and progression of human breast cancer.Mol Cancer. 2014 Apr 29;13:96. doi: 10.1186/1476-4598-13-96.
• [14] GNA11 Q209L Mouse Model Reveals RasGRP3 as an Essential Signaling Node in Uveal Melanoma.Cell Rep. 2018 Feb 27;22(9):2455-2468. doi: 10.1016/j.celrep.2018.01.081.
• [15] A somatic mutation of RasGRP3 decreases Na(+)/I(-) symporter expression in metastases of radioactive iodine-refractory thyroid cancer by stimulating the Akt signaling pathway.Am J Cancer Res. 2018 Sep 1;8(9):1847-1855. eCollection 2018.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [20] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [21] 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.
• [22] Methamphetamine alters the normal progression by inducing cell cycle arrest in astrocytes. PLoS One. 2014 Oct 7;9(10):e109603.
• [23] 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.
• [24] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [25] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.