The RaLGTPase Regulatory Network

描述(申请人提供)：来自细胞和动物模型系统的积累证据表明，RAS样小GTP结合蛋白Rala和RalB是支持肿瘤形成转化的调控框架的核心组件。最近，我们已经确定了这些高度相关的G蛋白对癌症、细胞增殖和生存的调节作用是离散的，但又是相互关联的。具体地说，Rala的慢性激活是维持锚定非依赖性增殖所必需的，而RalB则需要转移细胞死亡检查点的激活。这项建议旨在定义由Ral家族G蛋白参与的细胞调控网络的组成、组织和功能。我们的重点是直接参与致癌转化的主要Rala和RalB效应通路。我们的具体目标是1)确定介导Rala支持锚定非依赖增殖的效应通路(S)，2)确定RalB信号对癌细胞存活的机制贡献，以及3)在异种移植和器官模型系统中评估Rala/RalB信号网络的扰动对肿瘤启动和/或进展的影响。

DESCRIPTION (provided by applicant): Accumulating evidence from both cell and animal-based model systems indicates the Ras-like small GTP-binding proteins RalA and RalB are core components of a regulatory framework supporting tumorigenic transformation. Recently we have established discrete but interlocking contributions of these highly related G-proteins to the regulation of both cancer and cell proliferation and survival. Specifically, chronic activation of RalA is required to maintain anchorage-independent proliferation, while RalB is required to deflect cell-death checkpoint activation. This proposal is directed at defining the composition, organization, and function of cell regulatory networks engaged by Ral family G-proteins. Our focus is on the dominant RalA and RalB effector pathways that directly participate in oncogenic transformation. Our specific aims are 1) identification of the effector pathway(s) mediating RalA support of anchorage-independent proliferation, 2) defining the mechanistic contribution of RalB signaling to cancer cell survival, and 3) evaluating the consequences of perturbations in RalA/RalB signaling networks to tumor initiation and/or progression in xenograft and organotypic model systems.