Alternative titles; symbols
HGNC Approved Gene Symbol: VAV1
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38): 19:6,772,708-6,857,361 (from NCBI)
The VAV oncogene was generated by genomic rearrangement that replaced the 5-prime domain of the VAV protooncogene by sequences from a bacterial gene present in the cotransfecting DNA used as a selectable marker during gene transfer assay. A high level of expression of the VAV oncogene leads to morphologic transformation of NIH 3T3 cells in culture and to the efficient induction of tumors in immunocompromised mice. The VAV gene directs the synthesis of a 3.0-kb transcript that is specifically expressed in cells of hematopoietic origin, including those of erythroid, lymphoid, and myeloid lineages. The predicted amino acid sequence of the gene product exhibits motifs characteristic of transcriptional factors, including a highly acidic amino-terminal region, separated from 2 putative nuclear localization signals by a proline-rich sequence, and 2 zinc finger-like domains (Katzav et al., 1989).
Bustelo and Barbacid (1992) presented results suggesting that the VAV protooncogene participates in the signaling processes that mediate the antigen-induced activation of B lymphocytes.
Fackler et al. (1999) identified the protooncogene and guanine nucleotide exchange factor VAV as the specific binding partner of Nef proteins from HIV-1. The interaction between Nef and VAV led to increased activity of VAV and its downstream effectors. Both cytoskeletal changes and the activation of c-Jun N-terminal kinase (see 602896) were observed. Fackler et al. (1999) concluded that the interaction between Nef and VAV initiates a signaling cascade that changes structural and physiologic parameters in the infected cell.
Studies by Tarakhovsky et al. (1995), Zhang et al. (1995), and Fischer et al. (1995) demonstrated functional consequences of VAV gene deletion. The investigators used homologous recombination to introduce a null mutation into embryonic stem (ES) cells. Tarakhovsky et al. (1995) reported that in the absence of VAV antigen, receptor mediated proliferative responses of B and T cells are severely reduced. Fischer et al. (1995) demonstrated that VAV-dependent signaling pathways regulate the maturation of T cells. The studies reported by Zhang et al. (1995) confirmed that VAV plays a role in T- and B-cell development and activation.
Moores et al. (2000) expressed VAV1, VAV2 (600428), and VAV3 (605541) at equivalent levels and found that each responds to similar surface receptor tyrosine kinases. Integrin-induced phosphorylation required the presence of SYK (600085). Only VAV1 could efficiently cooperate with T-cell receptor (TCR; see 186880) signaling to enhance NFAT (600489)-dependent transcription, while only VAV1 and VAV3 could enhance nuclear factor kappa-B (NFKB; see 164011)-dependent transcription.
Bustelo (2000) presented a comprehensive review of the regulatory and signaling properties of the VAV family.
Using genomic sequence analysis, Denkinger et al. (2000) determined that the VAV1 gene contains 27 exons and spans 77 kb on chromosome 19. Its overall exon organization is similar to that of VAV2 (600428). They identified several differences from the original VAV cDNA sequence, notably, that there is an isoleucine at position 718 rather than a threonine, which changes the classification of the VAV SH2 domain from type 3 to type 2. Promoter analysis indicated that a 23-bp segment that includes a potential CBF/AML1 (see 151385)-binding site is essential for VAV expression in a monocytoid cell line.
By analysis of a rodent-human hybrid DNA panel and by chromosomal in situ hybridization, Martinerie et al. (1990) assigned the VAV locus to chromosome 19p13.2-p12. VAV and INSR, the insulin receptor gene (147670), appeared to be closely linked; INSR and VAV migrated together in high molecular weight DNA fragments created with rare cutting restriction enzymes that were subjected to pulsed field gel electrophoresis. By fluorescence in situ hybridization, Trask et al. (1993) assigned the VAV gene to 19p13.3-p13.2.
Zenker et al. (2014) found that Vav1 -/- mice had exacerbated disease, decreased survival, and evidence of pronounced organ damage in an experimental lipopolysaccharide (LPS)-induced toxemia model compared with controls. Reconstitution of wildtype mice with Vav1 -/- macrophages led to higher susceptibility to LPS. Vav1 -/- macrophages, but not T cells, produced increased Il6 (147620), but not Tnf (191160), in response to LPS in vitro and in vivo. Antibody to IL6r (147880) abrogated hypersensitivity to LPS endotoxemia. The authors showed that Il6 promoter activity was controlled by nuclear Vav1 interacting with Hsf1 (140580) at the heat shock element-2 (HSE2) region of the Il6 promoter. Zenker et al. (2014) suggested that targeting VAV1 may lead to better treatment of shock.
Bustelo, X. R., Barbacid, M. Tyrosine phosphorylation of the VAV proto-oncogene product in activated B cells. Science 256: 1196-1199, 1992. [PubMed: 1375396] [Full Text: https://doi.org/10.1126/science.256.5060.1196]
Bustelo, X. R. Regulatory and signaling properties of the Vav family. Molec. Cell. Biol. 20: 1461-1477, 2000. [PubMed: 10669724] [Full Text: https://doi.org/10.1128/MCB.20.5.1461-1477.2000]
Denkinger, D. J., Borges, C. R., Butler, C. L., Cushman, A. M., Kawahara, R. S. Genomic organization and regulation of the vav proto-oncogene. Biochim. Biophys. Acta 1491: 253-262, 2000. [PubMed: 10760587] [Full Text: https://doi.org/10.1016/s0167-4781(00)00008-7]
Fackler, O. T., Luo, W., Geyer, M., Alberts, A. S., Peterlin, B. M. Activation of Vav by Nef induces cytoskeletal rearrangements and downstream effector functions. Molec. Cell 3: 729-739, 1999. [PubMed: 10394361] [Full Text: https://doi.org/10.1016/s1097-2765(01)80005-8]
Fischer, K.-D., Zmuidzinas, A., Gardner, S., Barbacid, M., Bernstein, A., Guidos, C. Defective T-cell receptor signalling and positive selection of Vav-deficient CD4(+) CD8(+) thymocytes. Nature 374: 474-477, 1995. [PubMed: 7700360] [Full Text: https://doi.org/10.1038/374474a0]
Katzav, S., Martin-Zanca, D., Barbacid, M. VAV, a novel human oncogene derived from a locus ubiquitously expressed in hematopoietic cells. EMBO J. 8: 2283-2290, 1989. [PubMed: 2477241] [Full Text: https://doi.org/10.1002/j.1460-2075.1989.tb08354.x]
Martinerie, C., Cannizzaro, L. A., Croce, C. M., Huebner, K., Katzav, S., Barbacid, M. The human VAV proto-oncogene maps to chromosome region 19p12-19p13.2. Hum. Genet. 86: 65-68, 1990. [PubMed: 2253939] [Full Text: https://doi.org/10.1007/BF00205175]
Moores, S. L., Selfors, L. M., Fredericks, J., Breit, T., Fujikawa, K., Alt, F. W., Brugge, J. S., Swat, W. Vav family proteins couple to diverse cell surface receptors. Molec. Cell. Biol. 20: 6364-6373, 2000. [PubMed: 10938113] [Full Text: https://doi.org/10.1128/MCB.20.17.6364-6373.2000]
Tarakhovsky, A., Turner, M., Schaal, S., Mee, P. J., Duddy, L. P., Rajewsky, K., Tybulewicz, V. L. J. Defective antigen receptor-mediated proliferation of B and T cells in the absence of Vav. Nature 374: 467-470, 1995. [PubMed: 7700358] [Full Text: https://doi.org/10.1038/374467a0]
Trask, B., Fertitta, A., Christensen, M., Youngblom, J., Bergmann, A., Copeland, A., de Jong, P., Mohrenweiser, H., Olsen, A., Carrano, A., Tynan, K. Fluorescence in situ hybridization mapping of human chromosome 19: cytogenetic band location of 540 cosmids and 70 genes or DNA markers. Genomics 15: 133-145, 1993. [PubMed: 8432525] [Full Text: https://doi.org/10.1006/geno.1993.1021]
Zenker, S., Panteleev-Ivlev, J., Wirtz, S., Kishimoto, T., Waldner, M. J., Ksionda, O., Tybulewicz, V. L. J., Neurath, M. F., Atreya, I. A key regulatory role for Vav1 in controlling lipopolysaccharide endotoxemia via macrophage-derived IL-6. J. Immun. 192: 2830-2836, 2014. [PubMed: 24532586] [Full Text: https://doi.org/10.4049/jimmunol.1300157]
Zhang, R., Alt, F. W., Davidson, L., Orkin, S. H., Swat, W. Defective signalling through the T- and B-cell antigen receptors in lymphoid cells lacking the vav proto-oncogene. Nature 374: 470-473, 1995. [PubMed: 7700359] [Full Text: https://doi.org/10.1038/374470a0]