Tyrosine Kinase-Stimulated Guanine Nucleotide Exchange Activity of Vav in T Cell Activation

Abstract

The hematopoietically expressed product of the vav proto-oncogene, Vav, shared homology with guanine nucleotide releasing factors (GRFs) [also called guanosine diphosphate-dissociation stimulators (GDSs)] that activate Ras-related small guanosine triphosphate (GTP)-binding proteins. Human T cell lysates or Vav immunoprecipitates possessed GRF activity that increased after T cell antigen receptor (TCR)-CD3 triggering; an in vitro-translated Vav fragment that contained the putative GRF domain was also active. Vav-associated GRF stimulation after TCR-CD3 ligation paralleled its tyrosine phosphorylation; both were blocked by a protein tyrosine kinase (PTK) inhibitor. Vav also was a substrate for the p56lck PTK. Thus, Vav is a PTK-regulated GRF that may be important in TCR-CD3-initiated signal transduction through the activation of Ras.

Prolactin receptor signal transduction in cells of the immune system

“…Indeed recent data have shown Vav can function as a GEF for Rac-1 in vitro and in vivo, leading to activation of the JNK/Jun signal transduction pathway (Crespo et al 1997). Some data, however, indicate that Vav may also associate and/or activate Ras GEFs during activation of the T-cell receptor and immunoglobulin (Gulbins et al 1993, 1994c, Clevenger et al 1995b. Finally, in the carboxy terminus of Vav reside two SH2 and one SH3 domains, with striking overall homology to the signal transduction adaptor protein Grb-2.…”

“…Marked variations in the expression of Vav mRNA and protein were observed in developing thymic T-lymphocyte populations (Bustelo et al 1993), suggesting that the regulation of this protein may be important during the development and expansion of T cells. The phosphorylation of Vav has been observed after stimulation of the T-cell receptor (Gulbins et al 1993), membrane immunoglobulin (Gulbins et al 1994c), Fc receptor (Margolis et al 1992), interferon receptor (Platanias & Sweet 1994), c-kit (Alai et al 1992), PRLr (Clevenger et al 1995b), and the receptors for IL-1 (Gulbins et al 1994a) and -2 (Evans et al 1993). Antisense experiments have revealed that the inhibition of Vav expression in embryonic stem cells prevents their in vitro differentiation into mature hematopoietic elements (Wulf et al 1993).…”

“…A GEF activity associated with Vav has been demonstrated during stimulation of the T-cell receptor (Gulbins et al 1993) and membrane immunoglobulin (Gulbins et al 1994c). This activity appeared to be regulated by PTKs (Gulbins et al 1993), and by phorbol esters and DAG (Gulbins et al 1994a,b).…”

“…Thus, although these data question the role of Vav during embryonic hematopoiesis, they support its role as an important signaling factor involved in the immune response. Stimulation of both the T-cell receptor and PRLr in T-cell lines and surface immunoglobulin in B cells stimulates Vav-associated GEF activity (Gulbins et al 1993, Clevenger et al 1995b. Taken together, these data indicate that Vav expression contributes to immune system function, mediating critical growth and differentiation signals from ligand-stimulated hematopoietic receptors.…”

Caspase-dependent cleavage and inactivation of the Vav1 proto-oncogene product during apoptosis prevents IL-2 transcription

“…Among the numerous PTK substrate proteins is the Vav1 proto-oncogene product (Gulbins et al, 1993). This 95 kDa protein displays a wide variety of structural motifs including a N-terminal calponin homology (CH) domain, an acidic domain (AD), a Dbl-homology (DH) domain, a putative bipartite nuclear localization signal (NLS), a pleckstrin homology (PH) domain, a cysteine-rich domain (CR) and one SH2-domain anked by two SH3 domains (Romero and Fischer, 1996).…”