Positive and negative regulation of RTK-Ras signaling

描述（由申请人提供）：信号转导是使细胞能够从细胞外环境获取信息并对该信息做出适当反应的基本过程。这个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（RTK）是响应于调节细胞增殖和分化的细胞外信号的信号传递的关键介质。 人们普遍认为，RTK依赖性信号的持续时间和强度的差异构成了决定它们引起的生物反应性质的重要决定因素。然而，相对知之甚少的监管原则，管理的定量输出的信号产生的RTK激活。本申请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的信号库做出贡献。为了实现这一目标，拟议的研究将分别关注Son of sevenless（Sos）和Spry（Spry）对EGFR-Ras信号轴的正向和负向调节。实验计划包括两个广泛的目标：（1）定义EGFR与Ras活化的Sos依赖性偶联的分子框架。(2)确定Spry和EGFR信号传导之间的功能界面。这些研究应该促进我们对控制RTK信号通路响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.