The RaLGTPase Regulatory Network

描述（由申请人提供）：从细胞和动物模型系统中积累的证据表明，ras样小gtp结合蛋白RalA和RalB是支持致瘤转化的调控框架的核心组成部分。最近，我们已经确定了这些高度相关的g蛋白对癌症和细胞增殖和存活的调节的离散但连锁的贡献。具体来说，RalA的慢性激活是维持锚定非依赖性增殖所必需的，而RalB则是转移细胞死亡检查点激活所必需的。该建议旨在定义由Ral家族g蛋白参与的细胞调节网络的组成、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支持锚定不依赖增殖的效应通路，2)定义RalB信号传导对癌细胞存活的机制贡献，以及3)评估RalA/RalB信号网络的干扰对异种移植和器官型模型系统中肿瘤发生和/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.