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VAV1 (vav 1 oncogene)

Identity

Other namesVAV
HGNC (Hugo) VAV1
LocusID (NCBI) 7409
Location 19p13.3
Location_base_pair Starts at 6772679 and ends at 6857377 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Transcription 2535 mRNA complete codons

Protein

Note Vav1 was discovered when DNA from five esophageal carcinomas were tested for their transforming activity. This newly identified gene represented the sixth oncogene detected in Dr. Barbacid's laboratory and it was thus designated Vav1, after the sixth letter of the Hebrew alphabet. Vav1 was activated as an oncogene in vitro by replacement of 67 amino-acid residues of its amino-terminus (CH region) with 19 amino-acids residues of pSV2neo sequences, co-transfected as a selectable marker. Wild-type Vav1 produces minimal transformation of NIH3T3 murine fibroblasts only when the protein is grossly over-expressed. Removal of its amino terminus sequences (65 residues), thus mimicking its original mode of activation, is sufficient to induce Vav1 transformation.
 
Description Vav1 encodes a highly unique protein that contains numerous modular motifs known to play a role in tyrosine-mediated signal transduction cascades, such as a dbl homology (DH) region, which exhibits a guanine nucleotide exchange factor (GEF) activity towards the Rho family GTPases; a pleckstrin homology (PH) domain which interacts with polyphosphoinositides; a Src Homology 2 (SH2) and two Src Homology 3 (SH3) domains that mediate protein-protein interactions; a proline- rich motif that enables binding to SH3 -containing proteins, an acidic-rich (Ac) region and a 'calponin-homology' (CH) region, which functions as an actin-binding domain in other proteins and two nuclear localization signals(NLS). In fact, Vav1 is the only known Rho GEF that combines in the same protein the DH/PH motifs and the structural hallmark of signal transducer proteins, the SH2 and SH3 domains.
Expression Vav1 is specifically expressed in the hematopoietic system.
Function The Vav1 protein (95 kDa) is rapidly tyrosine-phosphorylated following stimulation of various receptors on hematopoietic cells (TCR, BCR, IgE, etc). Vav1 can then function in various signaling cascades. First, as a tyrosine-phosphorylated protein, Vav1 operates as a guanine nucleotide exchange factor (GEF) for Rac1, Rac2 and RhoG. It is the only known GEF protein whose activity is regulated by tyrosine phosphorylation. As a regulator of activation of the Rho/Rac GTPases, Vav1 participates in several processes that require cytoskeletal reorganization, such as the formation of the immunological synapse (IS), phagocytosis, platelet aggregation and spreading. Vav1 can also function in GEF-independent pathways through its association with other proteins such as ZAP-70, SLP-76, Ly-GDI (an inhibitor of Rho/RacGTPases), Grb2 and cytoseketal proteins such as Zyxin. Vav1 plays a critical role in stimulation of NFAT (Nuclear Factor of Activated T cells), culminating in the production of numerous vital cytokines. Vav1 also leads to the induction of an intracellular calcium flux by regulating the activation of phospholipase Cg1 (PLCg1) via phosphoinositide 3-kinase (PI3K) dependent and -independent pathways. The activity of Vav1 also leads to the activation of NF-kB and the extracellular signal regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling cascade. There is compelling evidence from studies of gene-targeted mice to indicate that Vav1 participates in the development and function of many types of immune cell such as the positive- and negative-selection events that are imposed on double-positive thymocytes
Homology Vav1 is one of a larger family of proteins that include Vav2 and Vav3 which unlike Vav1 are also ubiquitously expressed and the Vav homologues in Drosophila Melanogaster and in the nematode, C. elegans. These proteins are similar in their structure to Vav1, thus also functioning as signal transducer proteins.

Mutations

Somatic Although, no mutants of Vav1 have been reported thus far in "real" human tumors, it was recently found that Vav1 is expressed in the majority of 42 specimens of human neuroblastoma, suggesting a possible involvement of this protein in the neoplastic process in a subset of neuroblastomas. Furthermore, it was recently found to be involved in a large number of Pancreatic tumors.

Implicated in

Disease Neuroblastoma
  
Disease Pancreatic tumors
  

External links

Nomenclature
HGNC (Hugo)VAV1   12657
Cards
AtlasVAV1ID195ch19p13
Entrez_Gene (NCBI)VAV1  7409  vav 1 guanine nucleotide exchange factor
GeneCards (Weizmann)VAV1
Ensembl (Hinxton)ENSG00000141968 [Gene_View]  chr19:6772679-6857377 [Contig_View]  VAV1 [Vega]
ICGC DataPortalENSG00000141968
cBioPortalVAV1
AceView (NCBI)VAV1
Genatlas (Paris)VAV1
WikiGenes7409
SOURCE (Princeton)NM_001258206 NM_001258207 NM_005428
Genomic and cartography
GoldenPath (UCSC)VAV1  -  19p13.3   chr19:6772679-6857377 +  19p13.2   [Description]    (hg19-Feb_2009)
EnsemblVAV1 - 19p13.2 [CytoView]
Mapping of homologs : NCBIVAV1 [Mapview]
OMIM164875   
Gene and transcription
Genbank (Entrez)AK225710 AK301128 AK313307 AW105491 BC013361
RefSeq transcript (Entrez)NM_001258206 NM_001258207 NM_005428
RefSeq genomic (Entrez)AC_000151 NC_000019 NC_018930 NT_011295 NW_001838478 NW_004929412
Consensus coding sequences : CCDS (NCBI)VAV1
Cluster EST : UnigeneHs.116237 [ NCBI ]
CGAP (NCI)Hs.116237
Alternative Splicing : Fast-db (Paris)GSHG0014513
Alternative Splicing GalleryENSG00000141968
Gene ExpressionVAV1 [ NCBI-GEO ]     VAV1 [ SEEK ]   VAV1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP15498 (Uniprot)
NextProtP15498  [Medical]
With graphics : InterProP15498
Splice isoforms : SwissVarP15498 (Swissvar)
Domaine pattern : Prosite (Expaxy)CH (PS50021)    DH_1 (PS00741)    DH_2 (PS50010)    PH_DOMAIN (PS50003)    SH2 (PS50001)    SH3 (PS50002)    ZF_DAG_PE_1 (PS00479)    ZF_DAG_PE_2 (PS50081)   
Domains : Interpro (EBI)CH-domain [organisation]   DH-domain [organisation]   GDS_CDC24_CS [organisation]   PH_like_dom [organisation]   Pleckstrin_homology [organisation]   Prot_Kinase_C-like_PE/DAG-bd [organisation]   SH2 [organisation]   SH3_domain [organisation]   SM22_calponin [organisation]   Vav [organisation]  
Related proteins : CluSTrP15498
Domain families : Pfam (Sanger)C1_1 (PF00130)    CH (PF00307)    PH (PF00169)    RhoGEF (PF00621)    SH2 (PF00017)    SH3_1 (PF00018)   
Domain families : Pfam (NCBI)pfam00130    pfam00307    pfam00169    pfam00621    pfam00017    pfam00018   
Domain families : Smart (EMBL)C1 (SM00109)  CH (SM00033)  PH (SM00233)  RhoGEF (SM00325)  SH2 (SM00252)  SH3 (SM00326)  
DMDM Disease mutations7409
Blocks (Seattle)P15498
PDB (SRS)2CRH    2LCT    2MC1    2ROR    3BJI    3KY9   
PDB (PDBSum)2CRH    2LCT    2MC1    2ROR    3BJI    3KY9   
PDB (IMB)2CRH    2LCT    2MC1    2ROR    3BJI    3KY9   
PDB (RSDB)2CRH    2LCT    2MC1    2ROR    3BJI    3KY9   
Human Protein AtlasENSG00000141968 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasP15498
HPRD01284
IPIIPI00011696   IPI01009756   
Protein Interaction databases
DIP (DOE-UCLA)P15498
IntAct (EBI)P15498
FunCoupENSG00000141968
BioGRIDVAV1
InParanoidP15498
Interologous Interaction database P15498
IntegromeDBVAV1
STRING (EMBL)VAV1
Ontologies - Pathways
Ontology : AmiGOsequence-specific DNA binding transcription factor activity  guanyl-nucleotide exchange factor activity  guanyl-nucleotide exchange factor activity  protein binding  cytosol  plasma membrane  regulation of transcription, DNA-templated  epidermal growth factor receptor signaling pathway  integrin-mediated signaling pathway  small GTPase mediated signal transduction  blood coagulation  fibroblast growth factor receptor signaling pathway  platelet activation  Rac guanyl-nucleotide exchange factor activity  T cell costimulation  positive regulation of Rac GTPase activity  Fc-epsilon receptor signaling pathway  Fc-gamma receptor signaling pathway involved in phagocytosis  T cell activation  positive regulation of apoptotic process  positive regulation of GTPase activity  positive regulation of GTPase activity  innate immune response  positive regulation of cell adhesion  metal ion binding  neurotrophin TRK receptor signaling pathway  phosphatidylinositol-mediated signaling  regulation of small GTPase mediated signal transduction  apoptotic signaling pathway  
Ontology : EGO-EBIsequence-specific DNA binding transcription factor activity  guanyl-nucleotide exchange factor activity  guanyl-nucleotide exchange factor activity  protein binding  cytosol  plasma membrane  regulation of transcription, DNA-templated  epidermal growth factor receptor signaling pathway  integrin-mediated signaling pathway  small GTPase mediated signal transduction  blood coagulation  fibroblast growth factor receptor signaling pathway  platelet activation  Rac guanyl-nucleotide exchange factor activity  T cell costimulation  positive regulation of Rac GTPase activity  Fc-epsilon receptor signaling pathway  Fc-gamma receptor signaling pathway involved in phagocytosis  T cell activation  positive regulation of apoptotic process  positive regulation of GTPase activity  positive regulation of GTPase activity  innate immune response  positive regulation of cell adhesion  metal ion binding  neurotrophin TRK receptor signaling pathway  phosphatidylinositol-mediated signaling  regulation of small GTPase mediated signal transduction  apoptotic signaling pathway  
Pathways : BIOCARTARac 1 cell motility signaling pathway [Genes]    Fc Epsilon Receptor I Signaling in Mast Cells [Genes]    Phospholipase C Signaling Pathway [Genes]    T Cell Receptor Signaling Pathway [Genes]    BCR Signaling Pathway [Genes]    Ras-Independent pathway in NK cell-mediated cytotoxicity [Genes]   
Pathways : KEGGChemokine signaling pathway    Focal adhesion    Natural killer cell mediated cytotoxicity    T cell receptor signaling pathway    B cell receptor signaling pathway    Fc epsilon RI signaling pathway    Fc gamma R-mediated phagocytosis    Leukocyte transendothelial migration    Regulation of actin cytoskeleton   
Protein Interaction DatabaseVAV1
Wikipedia pathwaysVAV1
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)VAV1
snp3D : Map Gene to Disease7409
SNP (GeneSNP Utah)VAV1
SNP : HGBaseVAV1
Genetic variants : HAPMAPVAV1
Exome VariantVAV1
1000_GenomesVAV1 
ICGC programENSG00000141968 
Somatic Mutations in Cancer : COSMICVAV1 
CONAN: Copy Number AnalysisVAV1 
Mutations and Diseases : HGMDVAV1
Genomic VariantsVAV1  VAV1 [DGVbeta]
dbVarVAV1
ClinVarVAV1
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM164875   
MedgenVAV1
GENETestsVAV1
Disease Genetic AssociationVAV1
Huge Navigator VAV1 [HugePedia]  VAV1 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneVAV1
Homology/Alignments : Family Browser (UCSC)VAV1
Phylogenetic Trees/Animal Genes : TreeFamVAV1
Chemical/Protein Interactions : CTD7409
Chemical/Pharm GKB GenePA37280
Clinical trialVAV1
Cancer Resource (Charite)ENSG00000141968
Other databases
Probes
Litterature
PubMed207 Pubmed reference(s) in Entrez
CoreMineVAV1
iHOPVAV1
OncoSearchVAV1

Bibliography

vav, a novel human oncogene derived from a locus ubiquitously expressed in hematopoietic cells.
Katzav S, Martin-Zanca D, Barbacid M
The EMBO journal. 1989 ; 8 (8) : 2283-2290.
PMID 2477241
 
The human VAV proto-oncogene maps to chromosome region 19p12----19p13.2.
Martinerie C, Cannizzaro LA, Croce CM, Huebner K, Katzav S, Barbacid M
Human genetics. 1990 ; 86 (1) : 65-68.
PMID 2253939
 
Product of vav proto-oncogene defines a new class of tyrosine protein kinase substrates.
Bustelo XR, Ledbetter JA, Barbacid M
Nature. 1992 ; 356 (6364) : 68-71.
PMID 1311423
 
Tyrosine phosphorylation of vav proto-oncogene product containing SH2 domain and transcription factor motifs.
Margolis B, Hu P, Katzav S, Li W, Oliver JM, Ullrich A, Weiss A, Schlessinger J
Nature. 1992 ; 356 (6364) : 71-74.
PMID 1531699
 
A functional T-cell receptor signaling pathway is required for p95vav activity.
Wu J, Katzav S, Weiss A
Molecular and cellular biology. 1995 ; 15 (8) : 4337-4346.
PMID 7623828
 
Phosphotyrosine-dependent activation of Rac-1 GDP/GTP exchange by the vav proto-oncogene product.
Crespo P, Schuebel KE, Ostrom AA, Gutkind JS, Bustelo XR
Nature. 1997 ; 385 (6612) : 169-172.
PMID 8990121
 
Vav proteins, adaptors and cell signaling.
Bustelo XR
Oncogene. 2001 ; 20 (44) : 6372-6381.
PMID 11607839
 
Vav1 regulates phospholipase cgamma activation and calcium responses in mast cells.
Manetz TS, Gonzalez-Espinosa C, Arudchandran R, Xirasagar S, Tybulewicz V, Rivera J
Molecular and cellular biology. 2001 ; 21 (11) : 3763-3774.
PMID 11340169
 
Vav1 transduces T cell receptor signals to the activation of phospholipase C-gamma1 via phosphoinositide 3-kinase-dependent and -independent pathways.
Reynolds LF, Smyth LA, Norton T, Freshney N, Downward J, Kioussis D, Tybulewicz VL
The Journal of experimental medicine. 2002 ; 195 (9) : 1103-1114.
PMID 11994416
 
VAV proteins as signal integrators for multi-subunit immune-recognition receptors.
Turner M, Billadeau DD
Nature reviews. Immunology. 2002 ; 2 (7) : 476-486.
PMID 12094222
 
Adaptors as central mediators of signal transduction in immune cells.
Jordan MS, Singer AL, Koretzky GA
Nature immunology. 2003 ; 4 (2) : 110-116.
PMID 12555096
 
Vav proteins, masters of the world of cytoskeleton organization.
Hornstein I, Alcover A, Katzav S
Cellular signalling. 2004 ; 16 (1) : 1-11.
PMID 14607270
 
Vav1: an oncogene that regulates specific transcriptional activation of T cells.
Katzav S
Blood. 2004 ; 103 (7) : 2443-2451.
PMID 14592821
 
Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis.
Fernandez-Zapico ME, Gonzalez-Paz NC, Weiss E, Savoy DN, Molina JR, Fonseca R, Smyrk TC, Chari ST, Urrutia R, Billadeau DD
Cancer cell. 2005 ; 7 (1) : 39-49.
PMID 15652748
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written01-2005Shulamit Katzav
Experimental Medicine & Cancer Research, The Hebrew University/Hadassah Medical School, Ein-Karem, P.O.Box 12272, Jerusalem 91120, Israel

Citation

This paper should be referenced as such :
Katzav, S
VAV1 (vav 1 oncogene)
Atlas Genet Cytogenet Oncol Haematol. 2005;9(1):21-22.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/VAV1ID195ch19p13.html

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indexed on : Sat Jul 26 14:53:39 CEST 2014

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