Details of Drug Off-Target (DOT)

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

• DOT Name: RAS guanyl-releasing protein 2 (RASGRP2)
• Synonyms: Calcium and DAG-regulated guanine nucleotide exchange factor I; CalDAG-GEFI; Cdc25-like protein; hCDC25L; F25B3.3 kinase-like protein
• Gene Name: RASGRP2
• Related Disease:
  Platelet-type bleeding disorder 18
  Breast cancer
  Breast carcinoma
  Leukocyte adhesion deficiency 3
  Osteopetrosis
  Thrombocytopenia
  Arthritis
  Inherited bleeding disorder, platelet-type
  Osteoarthritis
  Rheumatoid arthritis
  Coagulation defect
  Small lymphocytic lymphoma
• UniProt ID: GRP2_HUMAN
• PDB ID: 2MA2; 6AXF
• Pfam ID: PF00130 ; PF13499 ; PF00617 ; PF00618
• Sequence:
  MAGTLDLDKGCTVEELLRGCIEAFDDSGKVRDPQLVRMFLMMHPWYIPSSQLAAKLLHIY
  QQSRKDNSNSLQVKTCHLVRYWISAFPAEFDLNPELAEQIKELKALLDQEGNRRHSSLID
  IDSVPTYKWKRQVTQRNPVGQKKRKMSLLFDHLEPMELAEHLTYLEYRSFCKILFQDYHS
  FVTHGCTVDNPVLERFISLFNSVSQWVQLMILSKPTAPQRALVITHFVHVAEKLLQLQNF
  NTLMAVVGGLSHSSISRLKETHSHVSPETIKLWEGLTELVTATGNYGNYRRRLAACVGFR
  FPILGVHLKDLVALQLALPDWLDPARTRLNGAKMKQLFSILEELAMVTSLRPPVQANPDL
  LSLLTVSLDQYQTEDELYQLSLQREPRSKSSPTSPTSCTPPPRPPVLEEWTSAAKPKLDQ
  ALVVEHIEKMVESVFRNFDVDGDGHISQEEFQIIRGNFPYLSAFGDLDQNQDGCISREEM
  VSYFLRSSSVLGGRMGFVHNFQESNSLRPVACRHCKALILGIYKQGLKCRACGVNCHKQC
  KDRLSVECRRRAQSVSLEGSAPSPSPMHSHHHRAFSFSLPRPGRRGSRPPEIREEEVQTV
  EDGVFDIHL
• Function: Functions as a calcium- and DAG-regulated nucleotide exchange factor specifically activating Rap through the exchange of bound GDP for GTP. May also activate other GTPases such as RRAS, RRAS2, NRAS, KRAS but not HRAS. Functions in aggregation of platelets and adhesion of T-lymphocytes and neutrophils probably through inside-out integrin activation. May function in the muscarinic acetylcholine receptor M1/CHRM1 signaling pathway.
• Tissue Specificity: Detected in platelets, neutrophils and T lymphocytes (at protein level). Expressed in brain where it is enriched in the striatum. Also expressed in the hematopoietic system. Detected in heart, brain, lung, placenta, liver, skeletal muscle and kidney.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  Chemokine sig.ling pathway (hsa04062)
  Platelet activation (hsa04611)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  FCERI mediated NF-kB activation (R-HSA-2871837)
  Integrin signaling (R-HSA-354192)
  Rap1 signalling (R-HSA-392517)
  Effects of PIP2 hydrolysis (R-HSA-114508)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Platelet-type bleeding disorder 18	DISQ9PV4	Definitive	Autosomal recessive	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Leukocyte adhesion deficiency 3	DISTEN13	Strong	Genetic Variation	[3]
Osteopetrosis	DIS7GHNM	Strong	Autosomal recessive	[4]
Thrombocytopenia	DISU61YW	Strong	Biomarker	[5]
Arthritis	DIST1YEL	moderate	Biomarker	[6]
Inherited bleeding disorder, platelet-type	DISIUNXT	moderate	Biomarker	[7]
Osteoarthritis	DIS05URM	moderate	Altered Expression	[6]
Rheumatoid arthritis	DISTSB4J	moderate	Altered Expression	[6]
Coagulation defect	DIS9X3H6	Limited	Genetic Variation	[3]
Small lymphocytic lymphoma	DIS30POX	Limited	Biomarker	[8]

2 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 guanyl-releasing protein 2 (RASGRP2).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of RAS guanyl-releasing protein 2 (RASGRP2).	[19]

11 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 2 (RASGRP2).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of RAS guanyl-releasing protein 2 (RASGRP2).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of RAS guanyl-releasing protein 2 (RASGRP2).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of RAS guanyl-releasing protein 2 (RASGRP2).	[13]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of RAS guanyl-releasing protein 2 (RASGRP2).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of RAS guanyl-releasing protein 2 (RASGRP2).	[15]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of RAS guanyl-releasing protein 2 (RASGRP2).	[12]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of RAS guanyl-releasing protein 2 (RASGRP2).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of RAS guanyl-releasing protein 2 (RASGRP2).	[17]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of RAS guanyl-releasing protein 2 (RASGRP2).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of RAS guanyl-releasing protein 2 (RASGRP2).	[20]

References

• [1] 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.
• [2] Effects of the ninein-like protein centrosomal protein on breast cancer cell invasion and migration.Mol Med Rep. 2015 Aug;12(2):1659-64. doi: 10.3892/mmr.2015.3650. Epub 2015 Apr 20.
• [3] Novel variants in FERMT3 and RASGRP2-Genetic linkage in Glanzmann-like bleeding disorders.Pediatr Blood Cancer. 2020 Feb;67(2):e28078. doi: 10.1002/pbc.28078. Epub 2019 Nov 14.
• [4] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [5] CalDAG-GEFI deficiency protects mice in a novel model of Fc RIIA-mediated thrombosis and thrombocytopenia.Blood. 2011 Jul 28;118(4):1113-20. doi: 10.1182/blood-2011-03-342352. Epub 2011 Jun 7.
• [6] Ectopic RASGRP2 (CalDAG-GEFI) expression in rheumatoid synovium contributes to the development of destructive arthritis.Ann Rheum Dis. 2018 Dec;77(12):1765-1772. doi: 10.1136/annrheumdis-2018-213588. Epub 2018 Aug 3.
• [7] Update on the inherited platelet disorders.Curr Opin Hematol. 2015 Sep;22(5):460-6. doi: 10.1097/MOH.0000000000000171.
• [8] Calcium-RasGRP2-Rap1 signaling mediates CD38-induced migration of chronic lymphocytic leukemia cells.Blood Adv. 2018 Jul 10;2(13):1551-1561. doi: 10.1182/bloodadvances.2017014506.
• [9] 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.
• [10] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [11] 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.
• [12] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [13] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [14] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [15] 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.
• [16] Endometrial receptivity is affected in women with high circulating progesterone levels at the end of the follicular phase: a functional genomics analysis. Hum Reprod. 2011 Jul;26(7):1813-25.
• [17] 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.
• [18] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [19] 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.
• [20] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.