Disease relevance of Vav1

• Vav1-deficient mice contain normal numbers of mast cells but respond more weakly than their normal counterparts to a passive systemic anaphylaxis challenge [1].
• Vav1-/- mice produced normal amounts of interferon (IFN)-gamma in response to Listeria monocytogenes and controlled early infection but showed reduced tumor clearance in vivo [2].
• MOG(35-55)-induced experimental autoimmune encephalomyelitis (EAE) was used to test the susceptibility of Vav1(-/-) mice to organ-specific autoimmunity [3].
• Detection and identification of Vav1 protein in primary cultured murine cerebellar neurons and in neuroblastoma cells (SH-SY5Y and Neuro-2a) [4].
• The constitutive nuclear factor-kappaB (NF-kappaB) activity of resting naive B cells required Vav function and expression of cellular reticuloendotheliosis (c-Rel) [5].

High impact information on Vav1

• Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation [6].
• Thus, tyrosine phosphorylation relieves autoinhibition by exposing the GTPase interaction surface of the DH domain, which is obligatory for Vav activation [6].
• Mutation of Cbl-b uncouples T-cell proliferation, interleukin-2 production and phosphorylation of the GDP/GTP exchange factor Vav1 from the requirement for CD28 co-stimulation [7].
• Our findings indicate that Cbl-b may influence the CD28 dependence of T-cell activation by selectively suppressing TCR-mediated Vav activation [8].
• Furthermore, Vav-deficient T lymphocytes showed severely impaired antigen receptor signalling [9].

Chemical compound and disease context of Vav1

• LAT- and Vav1-deficient mice showed reduced blood histamine levels after a systemic anaphylaxis challenge as compared to their normal counterparts [10].
• Reduction of Itk expression via small interfering RNA treatment of the Jurkat human T lymphoma cell line or human peripheral blood T cells disrupted TCR-induced actin polarization, a defect that correlated with decreased recruitment of the Vav guanine nucleotide exchange factor to the site of Ag contact [11].
• Dephosphorylation of Vav is associated with the induction of mouse erythroleukemia cell differentiation: effects of orthovanadate and levamisole [12].

Biological context of Vav1

• Recent evidence suggests that Vav1 might also function in the nucleus, where it undergoes arginine methylation [13].
• The present study has provided evidence for a possible role of Vav1 but not Vav2 in the later stages of platelet aggregation [14].
• The phenotype of Vav1/2/3 triple-deficient platelets is similar to that of Vav1/3 double-deficient cells [15].
• CSF-1-induced osteoclast spreading was not significantly reduced in osteoclasts isolated from Vav1 knock-out mice and Vav1 knock-out mice had normal bone density [16].
• Moreover, constitutively active Rac is able to rescue actin polymerization and complement-mediated phagocytosis in Vav-deficient macrophages [17].

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

• In contrast, Vav is specifically required for complement-mediated phagocytosis, suggesting that Rac is regulated by GEFs other than Vav downstream of the FcgammaR [17].
• Because Vav is activated by the epidermal growth factor receptor and other tyrosine kinases involved in cancer development, defining the role of aberrant Vav signaling may identify activities of receptor tyrosine kinases important for human oncogenesis [35].
• When activated by B-cell receptor (BCR) cross-linking, Vav-deficient B cells failed to activate NF-kappaB [5].
• Further, tyrosine phosphorylation of Vav and the costimulation-dependent activation of Jun N-terminal kinase was blocked in cells defective in CD28/Grb2 binding [36].
• Thus, Vav localization to the plasma membrane is mediated by its SH2 domain and may serve to regulate downstream effectors like JNK1 [37].
• FcgammaR signaling through the Vav and Rac proteins in neutrophils is critical for stimulating immune complex disease while Vav- and Rac-independent pathways promote Mac-1/complement C3-dependent functions [38].

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

• Vav1: a key signal transducer downstream of the TCR [22].
• Here we have used somatic cell gene-targeting technology to generate a Vav-1-deficient Jurkat T-cell line [41].
• The interactions between M2 and Vav proteins were also confirmed in vivo in 293T and WEHI-231 B-cells by co-immunoprecipitation assays [42].
• Beta1 integrin ligation by fibronectin induced Vav1 phosphorylation in peripheral blood lymphocytes and in two different T cell lines [43].
• By using yeast two-hybrid assays, we identified the carboxyl-terminal region of the guanine nucleotide-exchange factor (GEF) Vav1 as a Mer-binding partner [44].

References