Ras/ERK control of cell fates

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DESCRIPTION (provided by applicant): The Ras-stimulated Raf-MEK-ERK kinase cascade is used over and over again to control many aspects of normal, and abnormal, animal development. How this common signaling cascade elicits specific responses is still poorly understood. ERK is thought to phosphorylate multiple targets that may differ among cell types and that act combinatorially with ERK-independent factors to elicit the appropriate response. However, the relative importance of different ERK targets in vivo and how ERK chooses targets appropriate for a given tissue or circumstance is still poorly understood, as are the more downstream gene regulatory networks that ultimately control cellular responses. We are studying this problem in the simple model organism C. elegans, where Ras-ERK specifies the fates of the excretory duct, P12 ectoblast, vulva and other tissues. One "general" target of ERK in all three tissues is the Elk1-related Ets transcription factor LIN-1. We've discovered two other potential general targets, the BTB/Zinc finger protein EOR-1 and the novel (but conserved) protein EOR-2. In Aim 1 we will use a combination of protein interaction studies, worm genetics and DNA binding assays to determine how EOR-1 and EOR-2 cooperate with LIN-1 to control downstream responses to Ras/ERK. In Aim 2 we will focus on how Ras/ERK promotes one specific cell fate, that of the excretory duct, an essential component of the worm's primitive renal system. We will test the roles of two candidate duct-specific Ras-ERK targets, an Nkx5/Hmx-family homeodomain protein and a conserved bromodomain protein, to understand how they promote tissue-appropriate responses to Ras-ERK. Finally we will continue our RNAi-based screens to identify additional genes that are important for the excretory duct fate. These studies will help to answer the question of how the commonly used Ras-ERK signaling pathway elicits different biological responses in different cell types. All of the candidate ERK targets we'll study are conserved in humans. Since several proteins we'll study are causative agents in human cancers, these studies may suggest strategies for treating those cancers. The control of excretory duct cell development also may be a simple model relevant for understanding kidney development and malfunction in humans. Public Health Relevance: These studies will help to answer the question of how a commonly used signaling pathway elicits different biological responses in different cell types. Since several proteins we'll study are causative agents in human cancers and developmental syndromes, these studies may suggest strategies for treating those disorders.