VAV FAMILY PROTEINS AND CELL SIGNALING AND CANCER

描述：vav原癌基因编码一种95 kDa多肽Vav， 广泛分布于造血细胞类型中。 此外，Vav 包含几个结构基序，如富含亮氨酸的结构域， DBL相关区，一个Pleckstrin结构域，一个富含半胱氨酸的锌蝴蝶 结构域，一个SH 2和两个SH 3结构域，所有这些都表明， 参与信号转导。 申请人最近的研究 表明Vav可能作为GDP/GTP交换因子向Rac-1 GTP转移 结合蛋白，酪氨酸磷酸化影响这种活性， 瓦此外，研究人员已经开始表征另一种蛋白质， 它与Vav高度同源，即Vav-2， 分布在造血和非造血细胞中。 鉴于这种 背景，本提案的总体目标是建立 vav癌基因家族（Vav和Vav-2）诱导细胞凋亡的机制 增殖和转化。 因此，以下具体目标 提出：1）为了验证酪氨酸磷酸化的假设， Vav和/或其膜缔合对于Vav活化是必不可少的。 2)到 检查Vav功能是否通过与GTP结合的相互作用介导 蛋白质和其他信号分子如Cbl-2。 3)要评估，请使用 差异显示和消减DNA文库是否激活 Vav导致基因的上调和下调，这些基因对 vav介导的转化 4)通过PCR筛查和基因检测， Vav是否属于一个癌蛋白家族， 在发育和细胞信号传导中发挥重要作用。

DESCRIPTION: 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.