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VAV2  -  vav 2 guanine nucleotide exchange factor

Homo sapiens

Synonyms: Guanine nucleotide exchange factor VAV2, VAV-2
 
 
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Disease relevance of VAV2

  • We show that melanoma cells express Vav1 and Vav2, which are activated by CXCL12 involving Jak activity [1].
  • Here we show that mutation of the RGD sequence to RGE in the human P2Y(2)R expressed in 1321N1 astrocytoma cells completely prevented UTP-induced chemotaxis as well as activation of G(o), Rac, and Vav2, a guanine nucleotide exchange factor for Rac [2].
  • P2Y(2)R-mediated chemotaxis, Rac and Vav2 activation, and vitronectin up-regulation were inhibited by pretreatment of the cells with anti-alpha(v)beta(5) integrin antibodies, alpha(v) integrin antisense oligonucleotides, or the G(i/o) inhibitor, pertussis toxin [2].
 

High impact information on VAV2

  • This process is initiated by the activation of the small GTPase Rac by VEGFR-2 through the Src-dependent phosphorylation of Vav2, a guanine nucleotide-exchange factor [3].
  • Although the exact in vivo function of Vav3 is unknown, evidence from several studies indicates a role distinct from Vav2 or Vav1 [4].
  • We evaluated the contribution of the PH domain and the CRD to Vav2 guanine nucleotide exchange, signaling, and transforming activity [5].
  • Vav1, but not Vav2, contributes to platelet aggregation by CRP and thrombin, but neither is required for regulation of phospholipase C [6].
  • Overexpression of either wild-type or constitutively active Vav2 resulted in prominent membrane ruffles and enhanced stress fibers [7].
 

Biological context of VAV2

 

Anatomical context of VAV2

 

Associations of VAV2 with chemical compounds

  • In this study we initially examined the interaction between CD44v3 (a hyaluronan (HA) receptor) and Vav2 (a guanine nucleotide exchange factor) in human ovarian tumor cells (SK-OV-3.ipl cell line) [8].
  • Activation of guanosine triphosphatase Rac-1 in Chinese hamster ovary transfectants required both Nek3 and Vav2 and was inhibited by the overexpression of a kinase inactivating Nek3 mutant [12].
  • Finally, we present evidence indicating the VAV2 can be regulated by integrin-mediated adhesion [13].
  • Using glutathione S-transferase fusion proteins, we observed that the Src homology 2 domain of Vav2 binds tyrosine-phosphorylated proteins from TCR-stimulated Jurkat T cell lysates, including c-Cbl and SLP-76 [9].
  • Introducing a point mutation into the Vav2 pleckstrin homology domain or treatment of cells with the phosphatidylinositol 3-kinase inhibitor LY294002 prior to EGF stimulation inhibits Vav2 exchange activity [14].
 

Enzymatic interactions of VAV2

 

Regulatory relationships of VAV2

  • Hyaluronan promotes CD44v3-Vav2 interaction with Grb2-p185(HER2) and induces Rac1 and Ras signaling during ovarian tumor cell migration and growth [8].
  • However, in contrast to Vav1, Vav2 dramatically suppressed TCR signals leading to nuclear factor of activated T cells (NF-AT)-dependent transcription and induction of the interleukin-2 promoter [9].
  • These results suggest that EGF regulates Vav2 activity basically through phosphatidylinositol 3-kinase activation, whereas tyrosine phosphorylation of Vav2 may rather be necessary for mediating protein-protein interactions [14].
  • Membrane-targeting is critical for the phosphorylation of Vav2 by activated EGF receptor [15].
 

Other interactions of VAV2

  • By using recombinant fragments of Vav2 and in vitro binding assays, we have detected a specific binding interaction between the SH3-SH2-SH3 domain of Vav2 and the cytoplasmic domain of CD44 [8].
  • A conceptual translation of the cDNA indicates that VAV3 is between 40 and 77% identical to VAV and VAV2 at the amino acid level in all identified functional motifs [16].
  • VAV2 is likely to serve a similar role more generally in mammalian cells, but is not the TSC1 gene [10].
  • Like Vav1, Vav2 cooperated with TCR stimulation to increase extracellular signal-regulated kinase activation and to promote c-fos serum response element transcriptional activity [9].
  • Moreover, we demonstrate that the activities of VAV2 and p190RhoGAP are regulated by PTP-PEST [13].

References

  1. Activation of Vav/Rho GTPase signaling by CXCL12 controls membrane-type matrix metalloproteinase-dependent melanoma cell invasion. Bartolomé, R.A., Molina-Ortiz, I., Samaniego, R., Sánchez-Mateos, P., Bustelo, X.R., Teixidó, J. Cancer Res. (2006) [Pubmed]
  2. The P2Y2 nucleotide receptor interacts with alphav integrins to activate Go and induce cell migration. Bagchi, S., Liao, Z., Gonzalez, F.A., Chorna, N.E., Seye, C.I., Weisman, G.A., Erb, L. J. Biol. Chem. (2005) [Pubmed]
  3. VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin. Gavard, J., Gutkind, J.S. Nat. Cell Biol. (2006) [Pubmed]
  4. Vav3 is regulated during the cell cycle and effects cell division. Fujikawa, K., Inoue, Y., Sakai, M., Koyama, Y., Nishi, S., Funada, R., Alt, F.W., Swat, W. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  5. Critical but distinct roles for the pleckstrin homology and cysteine-rich domains as positive modulators of Vav2 signaling and transformation. Booden, M.A., Campbell, S.L., Der, C.J. Mol. Cell. Biol. (2002) [Pubmed]
  6. 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]
  7. Vav2 activates Rac1, Cdc42, and RhoA downstream from growth factor receptors but not beta1 integrins. Liu, B.P., Burridge, K. Mol. Cell. Biol. (2000) [Pubmed]
  8. Hyaluronan promotes CD44v3-Vav2 interaction with Grb2-p185(HER2) and induces Rac1 and Ras signaling during ovarian tumor cell migration and growth. Bourguignon, L.Y., Zhu, H., Zhou, B., Diedrich, F., Singleton, P.A., Hung, M.C. J. Biol. Chem. (2001) [Pubmed]
  9. Vav2 activates c-fos serum response element and CD69 expression but negatively regulates nuclear factor of activated T cells and interleukin-2 gene activation in T lymphocyte. Tartare-Deckert, S., Monthouel, M.N., Charvet, C., Foucault, I., Van Obberghen, E., Bernard, A., Altman, A., Deckert, M. J. Biol. Chem. (2001) [Pubmed]
  10. Identification of VAV2 on 9q34 and its exclusion as the tuberous sclerosis gene TSC1. Henske, E.P., Short, M.P., Jozwiak, S., Bovey, C.M., Ramlakhan, S., Haines, J.L., Kwiatkowski, D.J. Ann. Hum. Genet. (1995) [Pubmed]
  11. Vav proteins, masters of the world of cytoskeleton organization. Hornstein, I., Alcover, A., Katzav, S. Cell. Signal. (2004) [Pubmed]
  12. Novel association of Vav2 and Nek3 modulates signaling through the human prolactin receptor. Miller, S.L., DeMaria, J.E., Freier, D.O., Riegel, A.M., Clevenger, C.V. Mol. Endocrinol. (2005) [Pubmed]
  13. PTP-PEST Couples Membrane Protrusion and Tail Retraction via VAV2 and p190RhoGAP. Sastry, S.K., Rajfur, Z., Liu, B.P., Cote, J.F., Tremblay, M.L., Burridge, K. J. Biol. Chem. (2006) [Pubmed]
  14. Mechanism of epidermal growth factor regulation of Vav2, a guanine nucleotide exchange factor for Rac. Tamás, P., Solti, Z., Bauer, P., Illés, A., Sipeki, S., Bauer, A., Faragó, A., Downward, J., Buday, L. J. Biol. Chem. (2003) [Pubmed]
  15. Membrane-targeting is critical for the phosphorylation of Vav2 by activated EGF receptor. Tamás, P., Solti, Z., Buday, L. Cell. Signal. (2001) [Pubmed]
  16. Major transcript variants of VAV3, a new member of the VAV family of guanine nucleotide exchange factors. Trenkle, T., McClelland, M., Adlkofer, K., Welsh, J. Gene (2000) [Pubmed]
 
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