Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1RLD24)

• DOT Name: Proto-oncogene vav
• Gene Name: VAV1
• UniProt ID: VAV_HUMAN
• PDB ID: 2CRH; 2LCT; 2MC1; 2ROR; 3BJI; 3KY9; 6NEW; 6NF1; 6NFA
• Pfam ID: PF00130 ; PF11971 ; PF00169 ; PF00621 ; PF00017 ; PF00018
• Sequence:
  MELWRQCTHWLIQCRVLPPSHRVTWDGAQVCELAQALRDGVLLCQLLNNLLPHAINLREV
  NLRPQMSQFLCLKNIRTFLSTCCEKFGLKRSELFEAFDLFDVQDFGKVIYTLSALSWTPI
  AQNRGIMPFPTEEESVGDEDIYSGLSDQIDDTVEEDEDLYDCVENEEAEGDEIYEDLMRS
  EPVSMPPKMTEYDKRCCCLREIQQTEEKYTDTLGSIQQHFLKPLQRFLKPQDIEIIFINI
  EDLLRVHTHFLKEMKEALGTPGAANLYQVFIKYKERFLVYGRYCSQVESASKHLDRVAAA
  REDVQMKLEECSQRANNGRFTLRDLLMVPMQRVLKYHLLLQELVKHTQEAMEKENLRLAL
  DAMRDLAQCVNEVKRDNETLRQITNFQLSIENLDQSLAHYGRPKIDGELKITSVERRSKM
  DRYAFLLDKALLICKRRGDSYDLKDFVNLHSFQVRDDSSGDRDNKKWSHMFLLIEDQGAQ
  GYELFFKTRELKKKWMEQFEMAISNIYPENATANGHDFQMFSFEETTSCKACQMLLRGTF
  YQGYRCHRCRASAHKECLGRVPPCGRHGQDFPGTMKKDKLHRRAQDKKRNELGLPKMEVF
  QEYYGLPPPPGAIGPFLRLNPGDIVELTKAEAEQNWWEGRNTSTNEIGWFPCNRVKPYVH
  GPPQDLSVHLWYAGPMERAGAESILANRSDGTFLVRQRVKDAAEFAISIKYNVEVKHIKI
  MTAEGLYRITEKKAFRGLTELVEFYQQNSLKDCFKSLDTTLQFPFKEPEKRTISRPAVGS
  TKYFGTAKARYDFCARDRSELSLKEGDIIKILNKKGQQGWWRGEIYGRVGWFPANYVEED
  YSEYC
• Function: Couples tyrosine kinase signals with the activation of the Rho/Rac GTPases, thus leading to cell differentiation and/or proliferation.
• Tissue Specificity: Widely expressed in hematopoietic cells but not in other cell types.
• KEGG Pathway:
  Rap1 sig.ling pathway (hsa04015)
  cAMP sig.ling pathway (hsa04024)
  Chemokine sig.ling pathway (hsa04062)
  Focal adhesion (hsa04510)
  .tural killer cell mediated cytotoxicity (hsa04650)
  T cell receptor sig.ling pathway (hsa04660)
  B cell receptor sig.ling pathway (hsa04662)
  Fc epsilon RI sig.ling pathway (hsa04664)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Leukocyte transendothelial migration (hsa04670)
  Regulation of actin cytoskeleton (hsa04810)
  Yersinia infection (hsa05135)
  Proteoglycans in cancer (hsa05205)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  PIP3 activates AKT signaling (R-HSA-1257604)
  Signaling by SCF-KIT (R-HSA-1433557)
  NRAGE signals death through JNK (R-HSA-193648)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  FCERI mediated MAPK activation (R-HSA-2871796)
  FCERI mediated Ca+2 mobilization (R-HSA-2871809)
  CD28 dependent Vav1 pathway (R-HSA-389359)
  G alpha (12/13) signalling events (R-HSA-416482)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  Interleukin-3, Interleukin-5 and GM-CSF signaling (R-HSA-512988)
  VEGFR2 mediated vascular permeability (R-HSA-5218920)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  RHOA GTPase cycle (R-HSA-8980692)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RHOG GTPase cycle (R-HSA-9013408)
  Erythropoietin activates RAS (R-HSA-9027284)
  Regulation of signaling by CBL (R-HSA-912631)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  Potential therapeutics for SARS (R-HSA-9679191)
  Azathioprine ADME (R-HSA-9748787)
  Antigen activates B Cell Receptor (BCR) leading to generation of second messengers (R-HSA-983695)
  GPVI-mediated activation cascade (R-HSA-114604)

Molecular Interaction Atlas (MIA) of This DOT

6 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 Proto-oncogene vav.	[1]
Azathioprine	DMMZSXQ	Approved	Azathioprine increases the expression of Proto-oncogene vav.	[3]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Proto-oncogene vav.	[4]
Mercaptopurine	DMTM2IK	Approved	Mercaptopurine increases the expression of Proto-oncogene vav.	[3]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Proto-oncogene vav.	[5]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Proto-oncogene vav.	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Proto-oncogene vav.	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Proto-oncogene vav.	[6]
Fmet-leu-phe	DMQ391A	Investigative	Fmet-leu-phe increases the phosphorylation of Proto-oncogene vav.	[8]

References

• [1] 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.
• [2] Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood. Epigenetics. 2014 May;9(5):774-82. doi: 10.4161/epi.28153. Epub 2014 Feb 13.
• [3] CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes. J Clin Invest. 2003 Apr;111(8):1133-45. doi: 10.1172/JCI16432.
• [4] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [5] Induction of class II major histocompatibility complex expression in human multiple myeloma cells by retinoid. Haematologica. 2007 Jan;92(1):115-20.
• [6] 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.
• [7] 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.
• [8] The anti-inflammatory effect of 2-(4-hydroxy-3-prop-2-enyl-phenyl)-4-prop-2-enyl-phenol by targeting Lyn kinase in human neutrophils. Chem Biol Interact. 2015 Jul 5;236:90-101. doi: 10.1016/j.cbi.2015.05.004. Epub 2015 May 14.