Positive and negative regulation of RTK-Ras signaling

描述（由申请人提供）：信号转导是一个基本的过程，使细胞能够从细胞外环境获取信息并对这些信息做出适当的反应。这一过程中的分子缺陷现在被认为是许多人类疾病的主要原因。受体酪氨酸激酶（RTKs）是响应细胞外信号传递的关键介质，调节细胞增殖和分化。人们普遍认为，rtk依赖信号的持续时间和强度的差异是决定它们引发的生物反应性质的重要决定因素。然而，对于控制响应RTK激活所产生的信号定量输出的调控原理，我们所知相对较少。这种应用的动机是需要精确地阐明这些原理，并了解它们如何在细胞水平上对rtk的信号传导库做出贡献。为了实现这一目标，拟议的研究将分别关注七子子（Sos）和Spry （Spry）对EGFR-Ras信号轴的正向和负向调节。实验计划包括两个主要目标：(1)定义依赖于sos的EGFR与Ras激活耦合的分子框架。(2)确定Spry与EGFR信号传导之间的功能接口。这些研究将促进我们对控制RTK信号通路反应能力的基本机制的理解，并提供对导致人类疾病的分子决定因素的见解。

DESCRIPTION (provided by applicant): Signal transduction is a fundamental process that enables cells to acquire information from the extracellular environment and respond to this information appropriately. Molecular defects in this process are now recognized as a leading cause of a host of human diseases. Receptor tyrosine kinases (RTKs) are key mediators of signal transmission in response to extracellular cues that regulate cell proliferation and differentiation. It is widely accepted that differences in the duration and intensity of RTK-dependent signals constitute important determinants in dictating the nature of the biological response they elicit. However, relatively little is known about the regulatory principles that govern the quantitative output of signals generated in response to RTK activation. This application is motivated by the need to elucidate these principles with precision and to understand how they contribute to the signaling repertoire of RTKs at the cellular level. To accomplish this objective, the proposed studies will focus on the positive and negative modulation of the EGFR-Ras signaling axis by Son of sevenless (Sos) and Spry (Spry), respectively. The experimental plans consist of two broad aims: (1) To define the molecular framework for Sos-dependent coupling of EGFR to Ras activation. (2) To determine the functional interface between Spry and EGFR signaling. These investigations should advance our understanding of fundamental mechanisms that control the response capabilities of RTK signaling pathways and provide insights into molecular determinants that contribute to human disease.