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Gene Review

Vav1  -  vav 1 oncogene

Mus musculus

Synonyms: Proto-oncogene vav, Vav, p95vav, vav-T
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Disease relevance of Vav1


High impact information on Vav1


Chemical compound and disease context of Vav1


Biological context of Vav1


Anatomical context of Vav1

  • Second, Vav1-deficient thymocytes show defective assembly of a signaling complex containing PLCgamma1 and the adaptor molecule Src homology 2 domain-containing leukocyte phosphoprotein 76 [18].
  • These defects are not attributable to a lack of initial beta2 activation as Vav1/3ko neutrophils undergo chemoattractant-induced arrest on intercellular adhesion molecule-1 under flow [19].
  • Accordingly, in vivo, Vav1/3ko leukocytes arrest on venular endothelium yet are unable to sustain adherence [19].
  • Vav1/2-mutant B cells fail to divide extensively in vitro in response to LPS or CD180, while deficiency of Vav1 alone impairs CD180-but not LPS-driven proliferation [20].
  • Vav1 regulates phospholipase cgamma activation and calcium responses in mast cells [1].

Associations of Vav1 with chemical compounds

  • Among downstream signaling mediators, the guanine nucleotide exchange factor Vav1 carries out a key role in activation [21].
  • Vav1 transduces T cell receptor signals to the activation of phospholipase C-gamma1 via phosphoinositide 3-kinase-dependent and -independent pathways [18].
  • The hematopoietic cell-specific protein Vav1 is a substrate of tyrosine kinases activated following engagement of many receptors, including FcepsilonRI [1].
  • In particular, Vav1 is required for efficient TCR-induced conjugate formation with antigen presenting cells (APCs), activation of the integrin leukocyte function-associated antigen-1 (LFA-1) and cell polarization [22].
  • Using Vav1-deficient mice, we further demonstrate the importance of Vav1 for efficient proliferation, IL-2 production, and Ca(2+) flux [23].
  • Vav proteins specifically couple FcgammaR signaling to NADPH oxidase function through a Rac-dependent as well as an unexpected Rac-independent signal that is proximal to NADPH oxidase activation and does not require actin polymerization [24].
  • Taken together, our data indicate that integrin-dependent signals generated during neutrophil adhesion contribute to the activation of NADPH oxidase by a variety of distinct effector pathways, all of which require Vav [25].
  • We identify the Vav family of Rho guanine nucleotide exchange factors (GEFs) as critical mediators of LPS-induced MyD88-dependent activation of Rac2, NADPH oxidase, and ROI production using mice deficient in Vav1, Vav2, and Vav3 [26].

Physical interactions of Vav1

  • Ephrin-A1 stimulation recruits the binding of Vav proteins to the activated EphA2 receptor [27].
  • Proto-oncoprotein Vav interacts with c-Cbl in activated thymocytes and peripheral T cells [28].
  • The surface of Vav N-terminal SH3 which binds to Grb2 C-terminal SH3 was elucidated by chemical shift mapping experiments using NMR [29].
  • Constitutive CD19/Lyn/Vav complex signaling may therefore be responsible for the establishment of baseline signaling thresholds in B cells before Ag receptor ligation, in addition to accelerating signaling following BCR engagement or other transmembrane signals [30].
  • Co-immunoprecipitation experiments showed, moreover, that a small amount of Vav is engaged in the multimolecular complex that includes elements of the T cell receptor and the T cell specific ZAP-70 tyrosine kinase [31].

Enzymatic interactions of Vav1

  • Interaction with Cbl also induced the loss of phosphorylated Vav [32].
  • Consistently, Vav was strongly phosphorylated in Lck-deficient JCAM-1 cells after CD28 ligation [33].
  • Our data show that direct contact of NK cells with a panel of sensitive tumor targets leads to a rapid and transient tyrosine phosphorylation of Vav and to its association with tyrosine-phosphorylated Syk [34].

Regulatory relationships of Vav1


Other interactions of Vav1

  • It is also possible that two other Vav family molecules, Vav2 and Vav3, are involved in NK cell activation [21].
  • In addition to its known role as an activator of Rac1 GTPases, these findings demonstrate a novel function for Vav1 as a regulator of PLCgamma-activated calcium signals [1].
  • Deficient IL-4 production was restored by retrovirus-mediated Vav1 expression, but only partially by retroviral c-Maf expression [39].
  • Second, Vav1 is required for recruitment of Sos1 and -2 to the transmembrane adapter protein LAT [40].
  • Requirements for Vav guanine nucleotide exchange factors and Rho GTPases in FcgammaR- and complement-mediated phagocytosis [17].

Analytical, diagnostic and therapeutic context of Vav1


  1. Vav1 regulates phospholipase cgamma activation and calcium responses in mast cells. Manetz, T.S., Gonzalez-Espinosa, C., Arudchandran, R., Xirasagar, S., Tybulewicz, V., Rivera, J. Mol. Cell. Biol. (2001) [Pubmed]
  2. Functional dichotomy in natural killer cell signaling: Vav1-dependent and -independent mechanisms. Colucci, F., Rosmaraki, E., Bregenholt, S., Samson, S.I., Di Bartolo, V., Turner, M., Vanes, L., Tybulewicz, V., Di Santo, J.P. J. Exp. Med. (2001) [Pubmed]
  3. Vav1-deficient mice are resistant to MOG-induced experimental autoimmune encephalomyelitis due to impaired antigen priming. Korn, T., Fischer, K.D., Girkontaite, I., Köllner, G., Toyka, K., Jung, S. J. Neuroimmunol. (2003) [Pubmed]
  4. Detection and identification of Vav1 protein in primary cultured murine cerebellar neurons and in neuroblastoma cells (SH-SY5Y and Neuro-2a). Betz, R., Sandhoff, K., Fischer, K.D., van Echten-Deckert, G. Neurosci. Lett. (2003) [Pubmed]
  5. Vav proteins regulate peripheral B-cell survival. Vigorito, E., Gambardella, L., Colucci, F., McAdam, S., Turner, M. Blood (2005) [Pubmed]
  6. Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation. Aghazadeh, B., Lowry, W.E., Huang, X.Y., Rosen, M.K. Cell (2000) [Pubmed]
  7. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Bachmaier, K., Krawczyk, C., Kozieradzki, I., Kong, Y.Y., Sasaki, T., Oliveira-dos-Santos, A., Mariathasan, S., Bouchard, D., Wakeham, A., Itie, A., Le, J., Ohashi, P.S., Sarosi, I., Nishina, H., Lipkowitz, S., Penninger, J.M. Nature (2000) [Pubmed]
  8. Cbl-b regulates the CD28 dependence of T-cell activation. Chiang, Y.J., Kole, H.K., Brown, K., Naramura, M., Fukuhara, S., Hu, R.J., Jang, I.K., Gutkind, J.S., Shevach, E., Gu, H. Nature (2000) [Pubmed]
  9. Defective T-cell receptor signalling and positive selection of Vav-deficient CD4+ CD8+ thymocytes. Fischer, K.D., Zmuldzinas, A., Gardner, S., Barbacid, M., Bernstein, A., Guidos, C. Nature (1995) [Pubmed]
  10. A perspective: regulation of IgE receptor-mediated mast cell responses by a LAT-organized plasma membrane-localized signaling complex. Rivera, J., Arudchandran, R., Gonzalez-Espinosa, C., Manetz, T.S., Xirasagar, S. Int. Arch. Allergy Immunol. (2001) [Pubmed]
  11. Kinase-independent functions for Itk in TCR-induced regulation of Vav and the actin cytoskeleton. Dombroski, D., Houghtling, R.A., Labno, C.M., Precht, P., Takesono, A., Caplen, N.J., Billadeau, D.D., Wange, R.L., Burkhardt, J.K., Schwartzberg, P.L. J. Immunol. (2005) [Pubmed]
  12. Dephosphorylation of Vav is associated with the induction of mouse erythroleukemia cell differentiation: effects of orthovanadate and levamisole. Scher, B.M., Wei, X.J., Waxman, S., Scher, W. Int. J. Oncol. (1998) [Pubmed]
  13. Vav-family proteins in T-cell signalling. Tybulewicz, V.L. Curr. Opin. Immunol. (2005) [Pubmed]
  14. Vav1, but not Vav2, contributes to platelet aggregation by CRP and thrombin, but neither is required for regulation of phospholipase C. Pearce, A.C., Wilde, J.I., Doody, G.M., Best, D., Inoue, O., Vigorito, E., Tybulewicz, V.L., Turner, M., Watson, S.P. Blood (2002) [Pubmed]
  15. Vav1 and vav3 have critical but redundant roles in mediating platelet activation by collagen. Pearce, A.C., Senis, Y.A., Billadeau, D.D., Turner, M., Watson, S.P., Vigorito, E. J. Biol. Chem. (2004) [Pubmed]
  16. Activated c-Fms recruits Vav and Rac during CSF-1-induced cytoskeletal remodeling and spreading in osteoclasts. Sakai, H., Chen, Y., Itokawa, T., Yu, K.P., Zhu, M.L., Insogna, K. Bone (2006) [Pubmed]
  17. Requirements for Vav guanine nucleotide exchange factors and Rho GTPases in FcgammaR- and complement-mediated phagocytosis. Hall, A.B., Gakidis, M.A., Glogauer, M., Wilsbacher, J.L., Gao, S., Swat, W., Brugge, J.S. Immunity (2006) [Pubmed]
  18. Vav1 transduces T cell receptor signals to the activation of phospholipase C-gamma1 via phosphoinositide 3-kinase-dependent and -independent pathways. Reynolds, L.F., Smyth, L.A., Norton, T., Freshney, N., Downward, J., Kioussis, D., Tybulewicz, V.L. J. Exp. Med. (2002) [Pubmed]
  19. Vav GEFs are required for beta2 integrin-dependent functions of neutrophils. Gakidis, M.A., Cullere, X., Olson, T., Wilsbacher, J.L., Zhang, B., Moores, S.L., Ley, K., Swat, W., Mayadas, T., Brugge, J.S. J. Cell Biol. (2004) [Pubmed]
  20. Vav proteins are required for B-lymphocyte responses to LPS. Hebeis, B., Vigorito, E., Kovesdi, D., Turner, M. Blood (2005) [Pubmed]
  21. Differential requirements for Vav proteins in DAP10- and ITAM-mediated NK cell cytotoxicity. Cella, M., Fujikawa, K., Tassi, I., Kim, S., Latinis, K., Nishi, S., Yokoyama, W., Colonna, M., Swat, W. J. Exp. Med. (2004) [Pubmed]
  22. Vav1: a key signal transducer downstream of the TCR. Tybulewicz, V.L., Ardouin, L., Prisco, A., Reynolds, L.F. Immunol. Rev. (2003) [Pubmed]
  23. Mitogenic CD28 Signals Require the Exchange Factor Vav1 to Enhance TCR Signaling at the SLP-76-Vav-Itk Signalosome. Dennehy, K.M., Elias, F., Na, S.Y., Fischer, K.D., Hünig, T., Lühder, F. J. Immunol. (2007) [Pubmed]
  24. Vav proteins in neutrophils are required for FcgammaR-mediated signaling to Rac GTPases and nicotinamide adenine dinucleotide phosphate oxidase component p40(phox). Utomo, A., Cullere, X., Glogauer, M., Swat, W., Mayadas, T.N. J. Immunol. (2006) [Pubmed]
  25. Neutrophil-mediated oxidative burst and host defense are controlled by a Vav-PLCgamma2 signaling axis in mice. Graham, D.B., Robertson, C.M., Bautista, J., Mascarenhas, F., Diacovo, M.J., Montgrain, V., Lam, S.K., Cremasco, V., Dunne, W.M., Faccio, R., Coopersmith, C.M., Swat, W. J. Clin. Invest. (2007) [Pubmed]
  26. Vav proteins control MyD88-dependent oxidative burst. Miletic, A.V., Graham, D.B., Montgrain, V., Fujikawa, K., Kloeppel, T., Brim, K., Weaver, B., Schreiber, R., Xavier, R., Swat, W. Blood (2007) [Pubmed]
  27. Essential role of Vav family guanine nucleotide exchange factors in EphA receptor-mediated angiogenesis. Hunter, S.G., Zhuang, G., Brantley-Sieders, D., Swat, W., Cowan, C.W., Chen, J. Mol. Cell. Biol. (2006) [Pubmed]
  28. Proto-oncoprotein Vav interacts with c-Cbl in activated thymocytes and peripheral T cells. Marengère, L.E., Mirtsos, C., Kozieradzki, I., Veillette, A., Mak, T.W., Penninger, J.M. J. Immunol. (1997) [Pubmed]
  29. Solution structure of N-terminal SH3 domain of Vav and the recognition site for Grb2 C-terminal SH3 domain. Ogura, K., Nagata, K., Horiuchi, M., Ebisui, E., Hasuda, T., Yuzawa, S., Nishida, M., Hatanaka, H., Inagaki, F. J. Biomol. NMR (2002) [Pubmed]
  30. CD19 amplifies B lymphocyte signal transduction by regulating Src-family protein tyrosine kinase activation. Fujimoto, M., Poe, J.C., Jansen, P.J., Sato, S., Tedder, T.F. J. Immunol. (1999) [Pubmed]
  31. The proto-oncogene Vav product is constitutively tyrosine-phosphorylated in normal human immature T cells. Gouy, H., Debré, P., Bismuth, G. Eur. J. Immunol. (1995) [Pubmed]
  32. Cbl-mediated ubiquitinylation and negative regulation of Vav. Miura-Shimura, Y., Duan, L., Rao, N.L., Reddi, A.L., Shimura, H., Rottapel, R., Druker, B.J., Tsygankov, A., Band, V., Band, H. J. Biol. Chem. (2003) [Pubmed]
  33. Fyn and ZAP-70 are required for Vav phosphorylation in T cells stimulated by antigen-presenting cells. Michel, F., Grimaud, L., Tuosto, L., Acuto, O. J. Biol. Chem. (1998) [Pubmed]
  34. Role for the Rac1 exchange factor Vav in the signaling pathways leading to NK cell cytotoxicity. Galandrini, R., Palmieri, G., Piccoli, M., Frati, L., Santoni, A. J. Immunol. (1999) [Pubmed]
  35. Vav transformation requires activation of multiple GTPases and regulation of gene expression. Palmby, T.R., Abe, K., Karnoub, A.E., Der, C.J. Mol. Cancer Res. (2004) [Pubmed]
  36. Growth factor receptor-bound protein 2 SH2/SH3 domain binding to CD28 and its role in co-signaling. Kim, H.H., Tharayil, M., Rudd, C.E. J. Biol. Chem. (1998) [Pubmed]
  37. The Src homology 2 domain of Vav is required for its compartmentation to the plasma membrane and activation of c-Jun NH(2)-terminal kinase 1. Arudchandran, R., Brown, M.J., Peirce, M.J., Song, J.S., Zhang, J., Siraganian, R.P., Blank, U., Rivera, J. J. Exp. Med. (2000) [Pubmed]
  38. Requirement for Vav proteins in post-recruitment neutrophil cytotoxicity in IgG but not complement C3-dependent injury. Utomo, A., Hirahashi, J., Mekala, D., Asano, K., Glogauer, M., Cullere, X., Mayadas, T.N. J. Immunol. (2008) [Pubmed]
  39. Impaired IL-4 and c-Maf expression and enhanced Th1-cell development in Vav1-deficient mice. Tanaka, Y., So, T., Lebedeva, S., Croft, M., Altman, A. Blood (2005) [Pubmed]
  40. Vav1 transduces T cell receptor signals to the activation of the Ras/ERK pathway via LAT, Sos, and RasGRP1. Reynolds, L.F., de Bettignies, C., Norton, T., Beeser, A., Chernoff, J., Tybulewicz, V.L. J. Biol. Chem. (2004) [Pubmed]
  41. Pleiotropic defects in TCR signaling in a Vav-1-null Jurkat T-cell line. Cao, Y., Janssen, E.M., Duncan, A.W., Altman, A., Billadeau, D.D., Abraham, R.T. EMBO J. (2002) [Pubmed]
  42. Murine gamma-herpesvirus 68 latency protein M2 binds to Vav signaling proteins and inhibits B-cell receptor-induced cell cycle arrest and apoptosis in WEHI-231 B cells. Madureira, P.A., Matos, P., Soeiro, I., Dixon, L.K., Simas, J.P., Lam, E.W. J. Biol. Chem. (2005) [Pubmed]
  43. Guanine exchange-dependent and -independent effects of Vav1 on integrin-induced T cell spreading. del Pozo, M.A., Schwartz, M.A., Hu, J., Kiosses, W.B., Altman, A., Villalba, M. J. Immunol. (2003) [Pubmed]
  44. An SH2 domain-dependent, phosphotyrosine-independent interaction between Vav1 and the Mer receptor tyrosine kinase: a mechanism for localizing guanine nucleotide-exchange factor action. Mahajan, N.P., Earp, H.S. J. Biol. Chem. (2003) [Pubmed]
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