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The VAV family of signal transduction molecules
1Department of Pathology, School of Medicine and University Hospital, State University of New York at Stony Brook, 11794, USA.
Abstract:
This review summarizes the current knowledge on the structure, expression, and physiological roles of the Vav family, a novel group of signaling transducers with known representatives in mammalian (Vav and Vav-2) and nematodes (Cel Vav). Vav was the first member of this family identified during the course of gene transfer experiments aimed at characterizing loci involved in human neoplasia. This transforming protein displays a complex array of structural motifs, including calponin-homology, acidic, dbl-homology, pleckstrin-homology, cysteine-rich, SH3, and SH2 domains. After activation of cells with extracellular stimuli, Vav becomes phosphorylated on tyrosine residues and catalyzes the exchange of guanosine nucleotides on the GTP-binding protein Rac-1, thereby allowing the transition of this GTPase from the inactive (GDP-loaded) to the active (GTP-loaded) state. In addition, Vav associates with phosphorylated receptors, protein tyrosine kinases, and intracellular phosphoproteins whose identities are now being determined. Gene targeting experiments indicate that vav gene disruption results in severe signaling defects in lymphoid cells, further reinforcing its role as a key regulator of mitogenic pathways. Vav-2 and C. elegans Vav bear significant structural similarity with Vav, suggesting that they will be important players as well in evolutionarily conserved signal transduction pathways involved in mitogenesis and cellular transformation.
Insights
The Vav family proteins are key signaling molecules regulating cell growth and transformation. Gene disruption studies reveal their critical role in lymphoid cell signaling pathways.
Area of Science:
- Molecular Biology
- Cell Signaling
- Oncology
Background:
- The Vav family comprises novel signaling transducers with representatives in mammals and nematodes.
- Vav, the first identified member, was discovered during studies of human neoplasia loci.
- Vav possesses a complex structure with multiple functional domains.
Purpose of the Study:
- To review current knowledge on the structure, expression, and physiological roles of the Vav family.
- To highlight Vav's function as a signaling transducer in mitogenic pathways.
- To explore the evolutionary conservation and roles of Vav family members.
Main Methods:
- Review of existing literature on Vav family proteins.
- Analysis of structural motifs and domains.
- Discussion of gene targeting experiments and their outcomes.
Main Results:
- Vav acts as a guanine nucleotide exchange factor for Rac-1, regulating GTPase activity.
- Vav is phosphorylated on tyrosine residues upon cellular activation.
- Vav interacts with various signaling molecules, including receptors and kinases.
- Vav gene disruption leads to significant signaling defects in lymphoid cells.
Conclusions:
- The Vav family plays a crucial role in signal transduction pathways regulating cell proliferation and transformation.
- Vav-2 and C. elegans Vav share structural similarities, suggesting conserved functions.
- Vav is a key regulator of mitogenic pathways, essential for lymphoid cell function.