ERK regulation of the cell fate decision network

描述（由申请人提供）：细胞外信号调节激酶（ERK）是细胞命运的主要决定因素。在生长因子的激活下，ERK促进不同的细胞反应，包括增殖、分化和凋亡。人们早就认识到ERK信号动力学与独特的细胞命运有关。在上皮细胞和神经元细胞中，EGF刺激ERK的瞬时激活以促进增殖，而HRG或NGF刺激ERK的持续激活以促进分化。最近，我们发现了两个ERK突变体，它们忠实地促进乳腺上皮细胞的增殖或分化。促进增殖的ERK突变体有利于激活核糖体S6激酶（RSK），而驱动分化的ERK突变体则激活即时早期基因产物（IEG），包括Fra1。这个独特的系统提供了一个机会来研究与每个细胞命运专门相关的信号事件。因此，我们进行了初步的定量磷蛋白组学筛选，以确定与每个细胞命运相关的独特调节因子。我在此提议：目标1。系统地识别决定细胞命运的ERK信号网络组件。目的2：确定RSK活性在促进细胞增殖中的作用为了全面了解癌症的发展，我们必须首先了解控制增殖或分化决策的复杂信号网络。这一建议旨在绘制与每个细胞命运相关的分子信号事件。这项工作将揭示一个复杂的调控网络如何控制基本的生物学变化，并提供一个模型，说明这个网络是如何在癌症中受到干扰的。

DESCRIPTION (provided by applicant): Extracellular signal regulated kinase (ERK) is a primary determinant of cell fate. Upon activation by growth factors ERK promotes distinctive cellular responses including proliferation, differentiation and apoptosis. It has been long appreciated that ERK signal dynamics are associated with unique cell fates. In epithelial and neuronal cells EGF stimulates transient ERK activation to promote proliferation, while HRG or NGF stimulates sustained ERK activation to promote differentiation. Recently we identified two mutants of ERK that faithfully promote either proliferation or differentiation in mammary epithelial cells. ERK mutants that promote proliferation favor activation of the ribosomal S6 kinase (RSK), while ERK mutants that drive differentiation activate immediate early gene products (IEG), including Fra1. This unique system provides an opportunity to study signaling events that are exclusively related to each cell fate. Thus we performed a preliminary quantitative phosphoproteomic screen to identify unique regulators of associated with each cell fate. Here I propose to: Aim 1. Systematically identify ERK signaling network components that determine cell fate. Aim 2: Determine the role of RSK activity in promoting cell proliferation To gain a comprehensive understanding of cancer development, we must first understand the complex signaling network controlling the decision to proliferate or differentiate. This proposal seeks to map the molecular signaling events associated with each cell fate. This work will reveal how a complex regulatory network controls fundamental biological changes and provide a model of how this network is perturbed in cancer.