VAV1 (vav 1 oncogene)

2005-01-01   Shulamit Katzav 

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





2535 mRNA complete codons



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. Barbacids 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.
Atlas Image


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.


Vav1 is specifically expressed in the hematopoietic system.


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


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.



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



Pubmed IDLast YearTitleAuthors
116078392001Vav proteins, adaptors and cell signaling.Bustelo XR et al
13114231992Product of vav proto-oncogene defines a new class of tyrosine protein kinase substrates.Bustelo XR et al
89901211997Phosphotyrosine-dependent activation of Rac-1 GDP/GTP exchange by the vav proto-oncogene product.Crespo P et al
156527482005Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis.Fernandez-Zapico ME et al
146072702004Vav proteins, masters of the world of cytoskeleton organization.Hornstein I et al
125550962003Adaptors as central mediators of signal transduction in immune cells.Jordan MS et al
145928212004Vav1: an oncogene that regulates specific transcriptional activation of T cells.Katzav S et al
24772411989vav, a novel human oncogene derived from a locus ubiquitously expressed in hematopoietic cells.Katzav S et al
113401692001Vav1 regulates phospholipase cgamma activation and calcium responses in mast cells.Manetz TS et al
15316991992Tyrosine phosphorylation of vav proto-oncogene product containing SH2 domain and transcription factor motifs.Margolis B et al
22539391990The human VAV proto-oncogene maps to chromosome region 19p12----19p13.2.Martinerie C et al
119944162002Vav1 transduces T cell receptor signals to the activation of phospholipase C-gamma1 via phosphoinositide 3-kinase-dependent and -independent pathways.Reynolds LF et al
120942222002VAV proteins as signal integrators for multi-subunit immune-recognition receptors.Turner M et al
76238281995A functional T-cell receptor signaling pathway is required for p95vav activity.Wu J et al

Other Information

Locus ID:

NCBI: 7409
MIM: 164875
HGNC: 12657
Ensembl: ENSG00000141968


dbSNP: 7409
ClinVar: 7409
TCGA: ENSG00000141968


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Focal adhesionKEGGko04510
Natural killer cell mediated cytotoxicityKEGGko04650
T cell receptor signaling pathwayKEGGko04660
B cell receptor signaling pathwayKEGGko04662
Fc epsilon RI signaling pathwayKEGGko04664
Leukocyte transendothelial migrationKEGGko04670
Regulation of actin cytoskeletonKEGGko04810
Focal adhesionKEGGhsa04510
Natural killer cell mediated cytotoxicityKEGGhsa04650
T cell receptor signaling pathwayKEGGhsa04660
B cell receptor signaling pathwayKEGGhsa04662
Fc epsilon RI signaling pathwayKEGGhsa04664
Leukocyte transendothelial migrationKEGGhsa04670
Regulation of actin cytoskeletonKEGGhsa04810
Chemokine signaling pathwayKEGGko04062
Chemokine signaling pathwayKEGGhsa04062
Fc gamma R-mediated phagocytosisKEGGko04666
Fc gamma R-mediated phagocytosisKEGGhsa04666
cAMP signaling pathwayKEGGhsa04024
cAMP signaling pathwayKEGGko04024
Diseases of signal transductionREACTOMER-HSA-5663202
PI3K/AKT Signaling in CancerREACTOMER-HSA-2219528
Constitutive Signaling by Aberrant PI3K in CancerREACTOMER-HSA-2219530
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Costimulation by the CD28 familyREACTOMER-HSA-388841
CD28 co-stimulationREACTOMER-HSA-389356
CD28 dependent Vav1 pathwayREACTOMER-HSA-389359
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Antigen activates B Cell Receptor (BCR) leading to generation of second messengersREACTOMER-HSA-983695
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
PIP3 activates AKT signalingREACTOMER-HSA-1257604
Negative regulation of the PI3K/AKT networkREACTOMER-HSA-199418
Innate Immune SystemREACTOMER-HSA-168249
Fcgamma receptor (FCGR) dependent phagocytosisREACTOMER-HSA-2029480
Regulation of actin dynamics for phagocytic cup formationREACTOMER-HSA-2029482
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
FCERI mediated Ca+2 mobilizationREACTOMER-HSA-2871809
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Regulation of signaling by CBLREACTOMER-HSA-912631
Platelet activation, signaling and aggregationREACTOMER-HSA-76002
GPVI-mediated activation cascadeREACTOMER-HSA-114604
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GAB1 signalosomeREACTOMER-HSA-180292
Signalling by NGFREACTOMER-HSA-166520
p75 NTR receptor-mediated signallingREACTOMER-HSA-193704
Cell death signalling via NRAGE, NRIF and NADEREACTOMER-HSA-204998
NRAGE signals death through JNKREACTOMER-HSA-193648
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
PI3K/AKT activationREACTOMER-HSA-198203
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFR2 mediated vascular permeabilityREACTOMER-HSA-5218920
Signaling by SCF-KITREACTOMER-HSA-1433557
Signaling by Rho GTPasesREACTOMER-HSA-194315
Rho GTPase cycleREACTOMER-HSA-194840
Signaling by GPCRREACTOMER-HSA-372790
GPCR downstream signalingREACTOMER-HSA-388396
G alpha (12/13) signalling eventsREACTOMER-HSA-416482
PI5P, PP2A and IER3 Regulate PI3K/AKT SignalingREACTOMER-HSA-6811558

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
94388481998Role of substrates and products of PI 3-kinase in regulating activation of Rac-related guanosine triphosphatases by Vav.191
129173492003Vav1 dephosphorylation by the tyrosine phosphatase SHP-1 as a mechanism for inhibition of cellular cytotoxicity.93
156527482005Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis.87
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
201418382010Structural and energetic mechanisms of cooperative autoinhibition and activation of Vav1.70
167284002006Fibrillar beta-amyloid-stimulated intracellular signaling cascades require Vav for induction of respiratory burst and phagocytosis in monocytes and microglia.60
205628272010Cooperative interactions at the SLP-76 complex are critical for actin polymerization.56
201894812010Synergistic signals for natural cytotoxicity are required to overcome inhibition by c-Cbl ubiquitin ligase.51
190180072008Differential expression and molecular associations of Syk in systemic lupus erythematosus T cells.48
128858702003Vav1 phosphorylation is induced by beta2 integrin engagement on natural killer cells upstream of actin cytoskeleton and lipid raft reorganization.44


Shulamit Katzav

VAV1 (vav 1 oncogene)

Atlas Genet Cytogenet Oncol Haematol. 2005-01-01

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