The RaLGTPase Regulatory Network

描述（由申请方提供）：来自细胞和动物模型系统的累积证据表明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分。最近，我们已经建立了这些高度相关的G蛋白对癌症和细胞增殖和存活的调节的离散但互锁的贡献。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是偏转细胞死亡检查点激活所必需的。该提案旨在定义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效应途径。我们的具体目标是1）鉴定介导RalA支持锚定非依赖性增殖的效应子途径，2）定义RalB信号传导对癌细胞存活的机制贡献，和3）评估RalA/RalB信号传导网络中的扰动对异种移植物和器官型模型系统中肿瘤起始和/或进展的后果。

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.