VAV FAMILY PROTEINS AND CELL SIGNALING AND CANCER

描述：Vav原癌基因编码一个95 kDa的多肽Vav， 在造血细胞类型中广泛分布。此外，Vav 包含几个结构基序，如富含亮氨酸的结构域、 DBL相关区域，pleckstrin结构域，富含半胱氨酸的锌蝴蝶 域，一个SH2和两个SH3域，所有这些都表明它 参与信号转导。申请人最近的研究 提示Vav可作为RAC-1 GTP的GDP/GTP交换因子 结合蛋白和酪氨酸磷酸化影响这一活性 Vav.此外，研究人员已经开始对另一种蛋白质进行表征 这与Vav高度同源，即Vav-2，它普遍存在 分布于造血细胞和非造血细胞中。鉴于此， 背景，本提案的总体目标是建立 Vav癌基因家族(Vav和Vav-2)诱导细胞的机制 增殖和转化。因此，以下是具体目标 建议：1)检验酪氨酸磷酸化的假设 Vav和/或其膜结合是激活Vav所必需的。2)至 检查Vav功能是否通过与GTP结合的相互作用来调节 蛋白质和其他信号分子，如Cbl-2。3)使用以下方法进行评估 差异显示和消减DNA文库是否被激活 Vav导致基因的上调和下调，这些基因对 Vav介导的转化。4)用聚合酶链式反应筛查和基因检测进行评估 靶向研究Vav是否属于癌蛋白家族 在发育和细胞信号转导中起着重要作用。

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.