Disease relevance of VAV1

• Ectopic expression of VAV1 reveals an unexpected role in pancreatic cancer tumorigenesis [1].
• We show that melanoma cells express Vav1 and Vav2, which are activated by CXCL12 involving Jak activity [2].
• Because Vav1 inducibly associates with further proteins including phospholipase C (PLC)gamma1 and Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76), we investigated their role for NF-kappaB activation in Jurkat leukemia T cell lines deficient for expression of these two proteins [3].
• We also analysed the expression of Vav1 in 42 specimens of human neuroblastoma [4].
• Overexpression was not observed in B-ALL or CMD, but 13% of B-NHL and 34.4% of B-CLL patients (P = 0.002) overexpressed VAV [5].

High impact information on VAV1

• In this issue of Cell, Norman, Maricq, and colleagues (Norman et al., 2005) show that VAV-1, a guanine nucleotide exchange factor for Rho-family GTPases, is necessary for three rhythmic behaviors in the nematode Caenorhabditis elegans: feeding, defecation, and ovulation [6].
• CD28 signaling via VAV/SLP-76 adaptors: regulation of cytokine transcription independent of TCR ligation [7].
• CD28 signaling is dependent on VAV/SLP-76 complex formation and induces membrane localization of these complexes [7].
• Introduction of the cbl-b mutation into a vav1-/- background relieved the functional defects of vav1-/- T cells and caused spontaneous autoimmunity [8].
• T cell antigen receptor (TCR) stimulation induces tyrosine phosphorylation of many intracellular proteins, including the proto-oncogene Vav, which is expressed exclusively in hematopoietic and trophoblast cells [9].

Chemical compound and disease context of VAV1

• When another, AVP-antagonist, d(CH2)5-D-Tyr (Et) VAVP, which blocks vascular and renal tubular AVP-receptors, was administered chronically, the development of DOCA/salt hypertension was prevented at the expense of severe and persistent hypernatremia [10].

Biological context of VAV1

• CXCL12 activates the GTPase Rac, as well as Vav1, a guanine-nucleotide exchange factor for Rac, concomitant with up-regulation of alpha4beta1-dependent adhesion [11].
• In this study, we have investigated the mechanisms by which Vav1 can regulate c-fos serum response element transcriptional activity [12].
• Importantly, inhibition of Vav1 expression by RNA interference resulted in a blockade of Rac activation in response to CXCL12 [11].
• Phosphorylation of Tyr(183) is required for the interaction with Vav1, the guanine nucleotide exchanging factor of Rac1 [13].
• Vav1, the 95-kDa protein encoded by the vav1 proto-oncogene, is expressed exclusively in haematopoietic cells, where it becomes phosphorylated on tyrosine residues in response to antigen receptor ligation [14].

Anatomical context of VAV1

• The actin cytoskeleton defect could be reversed by reconstitution of Vav1 expression in the patients' T cells [15].
• The adaptor protein 3BP2 associates with VAV guanine nucleotide exchange factors to regulate NFAT activation by the B-cell antigen receptor [16].
• The guanine nucleotide exchange factor Vav1 regulates actin polymerization and contributes to cytotoxicity by natural killer (NK) cells [17].
• Because Vav1 becomes tyrosine phosphorylated and activated following integrin engagement in hematopoietic cells, we investigated the tyrosine phosphorylation of Vav2 in response to integrin-mediated adhesion in fibroblasts and epithelial cells [18].
• Upon organization of the immunological synapse, both Ly-GDI and Vav1 relocalize to T cell extensions in contact with the antigen-presenting cell [19].

Associations of VAV1 with chemical compounds

• Vav1 is expressed exclusively in hematopoietic cells and tyrosine phosphorylated in response to activation of multiple cell surface receptors [20].
• Vav1 and Rac control chemokine-promoted T lymphocyte adhesion mediated by the integrin alpha4beta1 [11].
• However, coengagement of 2B4 with LFA-1 resulted in an enhancement of Vav1 phosphorylation that was sensitive to cholesterol depletion and to inhibition of actin polymerization [17].
• We conclude therefore that in Jurkat or related T cells, signalling via PARs that can affect VAV1 phosphorylation is mediated via PAR 1 or 2, or both, and that distinct serine proteinases may potentially differentially affect T-cell function in the settings of inflammation [21].
• Previous studies suggest that Vav1 regulates NADPH oxidase activity elicited by the chemoattractant formyl-Met-Leu-Phe (fMLP) [22].

Physical interactions of VAV1

• Vav1 couples T cell receptor to serum response factor-dependent transcription via a MEK-dependent pathway [12].
• Here we show that Vav1 also induces transcription factors that bind to the CD28RE/AP element contained in the interleukin-2 promoter [23].

Regulatory relationships of VAV1

• Vav1 overexpression activated JNK1 in COS7 and 293T cells but not in Jurkat T lymphocytes [14].
• In contrast, Vav1 did not cooperate with calcineurin to activate either extracellular signal-regulated kinase 2 or p38 [14].
• In contrast, Vav1-induced NF-kappaB activation was normal in SLP-76(-) cells, but absent in PLCgamma1(-) cells [3].
• Moreover, Ly-GDI does not alter the regulation of these phenomena when coexpressed with oncogenic Vav1 [19].
• Vav1 phosphorylation is induced by beta2 integrin engagement on natural killer cells upstream of actin cytoskeleton and lipid raft reorganization [17].

Other interactions of VAV1

• Adhesions in flow chambers and soluble binding assays using these transfectants indicated that initial ligand binding and adhesion strengthening mediated by alpha4beta1 were dependent on Vav1 and Rac activation by CXCL12 [11].
• Although the role of Vav1 in T cells is well documented, the role of Vav3 is less clear [24].
• Recognition and activation of Rho GTPases by Vav1 and Vav2 guanine nucleotide exchange factors [25].
• Distinct functions of Vav1 in JNK1 activation in Jurkat T cells versus non-haematopoietic cells [14].
• Binding of activation receptor 2B4 to its ligand CD48 was not sufficient for Vav1 phosphorylation [17].

Analytical, diagnostic and therapeutic context of VAV1

• Recent data suggest that the activation of PARs 1, 2 and 3 in Jurkat T-leukaemic cells induces tyrosine phosphorylation of the haematopoietic signal transducer protein, VAV1 [21].
• Gel filtration experiments revealed the existence of constitutively associated Vav1/PKCtheta heterodimers in extracts from unstimulated T-cells, whereas T-cell costimulation induced the recruitment of Vav1 into high molecular weight complexes [26].
• We now report that the VAV locus has been localized in the human genome at chromosome 19p12----19p13.2 by analysis of its segregation pattern in rodent-human somatic cell hybrids and by chromosomal in situ hybridization [27].

References