ERK regulation of the cell fate decision network

描述(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。在被生长因子激活后，ERK促进独特的细胞反应，包括增殖、分化和凋亡。长期以来，人们一直认为ERK信号动力学与独特的细胞命运有关。在上皮和神经细胞中，EGF刺激短暂的ERK激活以促进增殖，而HRG或NGF刺激持续的ERK激活以促进分化。最近，我们发现了两个ERK的突变体，它们能够忠实地促进乳腺上皮细胞的增殖或分化。促进增殖的ERK突变体有利于核糖体S6激酶(RSK)的激活，而促进分化的ERK突变体激活包括Fra1在内的即刻早期基因产物(IEG)。这个独特的系统提供了一个研究信号事件的机会，这些信号事件专门与每个细胞的命运有关。因此，我们进行了初步的定量磷酸蛋白质组筛选，以确定与每个细胞命运相关的独特调控因子。在这里，我建议：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肿瘤的发生发展，我们必须首先了解控制细胞增殖或分化的复杂信号网络。这项提议试图绘制与每个细胞命运相关的分子信号事件图。这项工作将揭示复杂的调控网络如何控制基本的生物变化，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.