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| 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. |
| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| Vav proteins, adaptors and cell signaling. |
| Bustelo XR |
| Oncogene. 2001 ; 20 (44) : 6372-6381. |
| PMID 11607839 |
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| 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 |
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| 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 |
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| 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 |
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| 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 |
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| Vav proteins, masters of the world of cytoskeleton organization. |
| Hornstein I, Alcover A, Katzav S |
| Cellular signalling. 2004 ; 16 (1) : 1-11. |
| PMID 14607270 |
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| Vav1: an oncogene that regulates specific transcriptional activation of T cells. |
| Katzav S |
| Blood. 2004 ; 103 (7) : 2443-2451. |
| PMID 14592821 |
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| 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 |
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