The vav proto-oncogene encodes a 95 kDa polypeptide, Vav, that is widely distributed among hematopoietic cell types. Furthermore, Vav contains several structural motifs, such as a leucine-rich domain, a Dbl-related region, a pleckstrin domain, a cysteine-rich zinc-butterfly domain, one SH2 and two SH3 domains, all of which suggest that it participates in signal transduction. Recent studies by the applicant suggest that Vav may act as a GDP/GTP exchange factor towards the Rac-1 GTP binding protein and that tyrosine phosphorylation affects this activity of Vav. Moreover, the investigator has begun to characterize another protein that is highly homologous to Vav, namely Vav-2, which is ubiquitously distributed among hematopoietic and non-hematopoietic cells. Given this background, the overall aim of the present proposal is to establish the mechanisms by which the vav oncogene family (Vav and Vav-2) induces cell proliferation and transformation. Therefore, the following Specific Aims are proposed: 1) To test the hypothesis that tyrosine phosphorylation of Vav and/or its membrane association are essential for Vav activation. 2) To examine whether Vav function is mediated by interactions with GTP-binding proteins and other signaling molecules such as Cbl-2. 3) To evaluate using differential display and subtracted DNA libraries whether the activation of Vav leads to the up-and down-regulation of genes that are important for vav-mediated transformation. 4) To assess using PCR screening and gene targeting approaches whether Vav belongs to a family of oncoproteins that have important roles in development and cell signaling.
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