Positive and Negative Regulation of RTK-RAS Signaling

受体酪氨酸激酶(RTK)是调节细胞增殖、分化和存活等基本过程的细胞外信号转导的重要介质。RTK启动的信号转导的一个中心途径涉及小鸟嘌呤核苷酸结合蛋白RAS的激活。激活的RAS通过刺激多条效应通路进而诱导广泛的细胞反应。现在有大量的遗传和生化证据表明，RTK-RAS途径引发的细胞内信号持续时间和强度的变化可以导致生物学结果的深刻变化。此外，去调控的RTK-RAS信号与许多人类恶性肿瘤和发育障碍有因果关系。该项目的广泛目标是定义管理RTK-RAS信号的量化输出的监管原则。建议的研究将集中在RAS与其鸟核苷酸交换因子SOS之间的相互作用，因为这种相互作用构成了从RTK到RAS的信号传递的速率限制步骤。我们自己十多年的工作，以及其他小组的研究表明，SOS的功能是通过分子间和分子内相互作用的复杂网络来控制的。本申请中描述的实验旨在加深我们对这些相互作用的身份和功能意义的理解。我们将采取多管齐下的策略，包括最先进的生化和细胞生物学方法，以实现四个具体目标：(1)建立SOS介导的RAS激活的时空动力学；(2)确定SOS介导的RAS激活是如何终止的；(3)确定SOS在RAS驱动的肿瘤中的作用；(4)开发RAS-SOS相互作用的抑制剂。因此，这些研究收集的信息将为解释RTK-RAS信号的适当细胞适应以及放松调控的RTK-RAS信号的不利后果的调控范式提供新的见解。

Receptor tyrosine kinases (RTK) are essential mediators of signal transmission in response to extracellular cues that regulate fundamental processes such as cell proliferation, differentiation and survival. A central route by which RTK-initiated signals are transduced involves the activation of the small guanine nucleotide binding protein Ras. Activated Ras in turn induces a broad spectrum of cellular responses through the stimulation of multiple effector pathways. There is now ample genetic and biochemical evidence indicating that changes in the duration and intensity of intracellular signals elicited by the RTK-Ras pathway can lead to profound alterations in the biological outcome. Moreover, deregulated RTK-Ras signaling has been causally linked to a number of human malignancies and developmental disorders. The broad objective of this project is to define regulatory principles that govern the quantitative output of RTK-Ras signaling. The proposed studies will focus on the interaction between Ras and its guanine nucleotide exchange factor Sos as this interaction constitutes the rate limiting step in signal propagation from RTK to Ras. Our own work carried out for over a decade, as well as studies by other groups have indicated that Sos function is controlled through a complex network of inter- and intra-molecular interactions. Experiments described in this application are designed to further our understanding of the identity and functional significance of these interactions. We will undertake a multipronged strategy consisting of state-of-the-art biochemical and cell biological approaches to achieve four specific goals: (1) To establish the spatio-temporal dynamics of Sos-mediated Ras activation (2) To define how Sos-mediated Ras activation is terminated (3) To determine the role of Sos in Ras-driven tumors (4) To develop inhibitors of Ras-Sos interactions The information gathered from these studies should therefore furnish new insights into the regulatory paradigms that account for appropriate cellular adaptation in response to RTK-Ras signaling as well as the adverse consequences of deregulated RTK-Ras signaling.