ERK regulation of the cell fate decision network

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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.