Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT15PWN4)

• DOT Name: RAS guanyl-releasing protein 4 (RASGRP4)
• Gene Name: RASGRP4
• Related Disease:
  B-cell lymphoma
  Mast cell leukaemia
  Mastocytosis
  T-cell leukaemia
  Asthma
  Advanced cancer
  T-cell acute lymphoblastic leukaemia
  Acute myelogenous leukaemia
• UniProt ID: GRP4_HUMAN
• PDB ID: 6AXG
• Pfam ID: PF00130 ; PF00617
• Sequence:
  MNRKDSKRKSHQECTGKIGGRGRPRQVRRHKTCPSPREISKVMASMNLGLLSEGGCSEDE
  LLEKCIQSFDSAGSLCHEDHMLNMVLAMHSWVLPSADLAARLLTSYQKATGDTQELRRLQ
  ICHLVRYWLMRHPEVMHQDPQLEEVIGRFWATVAREGNSAQRRLGDSSDLLSPGGPGPPL
  PMSSPGLGKKRKVSLLFDHLETGELAQHLTYLEFRSFQAITPQDLRSYVLQGSVRGCPAL
  EGSVGLSNSVSRWVQVMVLSRPGPLQRAQVLDKFIHVAQRLHQLQNFNTLMAVTGGLCHS
  AISRLKDSHAHLSPDSTKALLELTELLASHNNYARYRRTWAGCAGFRLPVLGVHLKDLVS
  LHEAQPDRLPDGRLHLPKLNNLYLRLQELVALQGQHPPCSANEDLLHLLTLSLDLFYTED
  EIYELSYAREPRCPKSLPPSPFNAPLVVEWAPGVTPKPDRVTLGRHVEQLVESVFKNYDP
  EGRGTISQEDFERLSGNFPFACHGLHPPPRQGRGSFSREELTGYLLRASAICSKLGLAFL
  HTFHEVTFRKPTFCDSCSGFLWGVTKQGYRCRECGLCCHKHCRDQVKVECKKRPGAKGDA
  GPPGAPVPSTPAPHASCGSEENHSYTLSLEPETGCQLRHAWTQTESPHPSWETDTVPCPV
  MDPPSTASSKLDS
• Function: Functions as a cation- and diacylglycerol (DAG)-regulated nucleotide exchange factor activating Ras through the exchange of bound GDP for GTP. May function in mast cells differentiation.
• Tissue Specificity: Expressed by mast cells and their progenitors (at protein level). Specifically expressed in mononuclear leukocytes. Highly expressed in myeloid cells compared to lymphoid cells. Also detected in heart, skeletal muscle, spleen, liver, placenta and lung. Not detected in brain. Isoform 1 is the major isoform in normal individuals. Isoform 2 is more significantly expressed in a patient with asthma. Isoform 3 is more significantly expressed in a patient with asthma and a mastocytosis patient.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  RAF/MAP kinase cascade (R-HSA-5673001)
  FCERI mediated NF-kB activation (R-HSA-2871837)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell lymphoma	DISIH1YQ	Strong	Altered Expression	[1]
Mast cell leukaemia	DIS7VQW9	Strong	Genetic Variation	[2]
Mastocytosis	DIS1TEE0	Strong	Genetic Variation	[2]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[3]
Asthma	DISW9QNS	moderate	Biomarker	[4]
Advanced cancer	DISAT1Z9	Disputed	Biomarker	[5]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Disputed	Biomarker	[5]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[6]

2 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 4 (RASGRP4).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of RAS guanyl-releasing protein 4 (RASGRP4).	[8]

References

• [1] The critical role of RasGRP4 in the growth of diffuse large B cell lymphoma.Cell Commun Signal. 2019 Aug 13;17(1):92. doi: 10.1186/s12964-019-0415-6.
• [2] RasGRP4, a new mast cell-restricted Ras guanine nucleotide-releasing protein with calcium- and diacylglycerol-binding motifs. Identification of defective variants of this signaling protein in asthma, mastocytosis, and mast cell leukemia patients and demonstration of the importance of RasGRP4 in mast cell development and function.J Biol Chem. 2002 Jul 12;277(28):25756-74. doi: 10.1074/jbc.M202575200. Epub 2002 Apr 15.
• [3] Possible involvement of RasGRP4 in leukemogenesis.Int J Hematol. 2009 May;89(4):470-481. doi: 10.1007/s12185-009-0299-0. Epub 2009 Apr 7.
• [4] Antisense- and RNA interference-based therapeutic strategies in allergy.J Cell Mol Med. 2005 Oct-Dec;9(4):840-53. doi: 10.1111/j.1582-4934.2005.tb00383.x.
• [5] Aberrant expression of RasGRP1 cooperates with gain-of-function NOTCH1 mutations in T-cell leukemogenesis.Leukemia. 2012 May;26(5):1038-45. doi: 10.1038/leu.2011.328. Epub 2011 Nov 25.
• [6] RasGRP4 is a novel Ras activator isolated from acute myeloid leukemia.J Biol Chem. 2002 Aug 23;277(34):30508-14. doi: 10.1074/jbc.M111330200. Epub 2002 Mar 5.
• [7] 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.
• [8] Genome-wide transcriptional and functional analysis of human T lymphocytes treated with benzo[alpha]pyrene. Int J Mol Sci. 2018 Nov 17;19(11).