Regulation of Ras through the Ras GRF exchange factor

申请人描述：RAS的异常激活是导致 人类癌症。RAS-GRF1交换因子，它激活RAS以响应 G蛋白偶联受体，在中枢神经元中高度表达并发挥作用 在建立记忆的过程中起着至关重要的作用。RAS-GRF1基因的过表达 在人类肿瘤中，这种交换因子与癌症的发生有关。活动 RAS-GRF1的表达至少部分受其基因改变的控制 磷酸化状态，但其调控的详细图景尚未 已实现。这个项目的长期目标是获得一个详细的 对血管紧张素转换酶的生理和药理学意义 RAS-GRF交换系数。这项提案的目标是确定如何 Ras-GRF1交换因子受磷酸化调控。中环 假设RAS-GRF1是信号转导的关键整合因子 通过磷酸化和与之相互作用来调节其活性 钙/钙调蛋白。这项提议的基本原理是，通过定义 在控制RAS-GRF1的机制中，我们将对 新的和生理上重要的RAS激活途径。这个项目将 在非常有利于其成功的环境中演出 通过出色的大学互动和实质性的 机构承诺。这项建议的目的将会达到 通过对中心假设的三个具体目的进行检验：1)确定 RAS-GRFI中受调控的磷酸化位点。需要检验的假设是 G需要一系列磷酸化事件的组合 Ras-GRF1的蛋白依赖性激活。2).定义控制的集成 通过磷酸化和钙信号转导Ras-GRF1。RAS-GRF1的功能 将测试将多个信号集成到RAS的激活。 3).确定Ras-GRFI在丝氨酸-916处的磷酸化的双重作用。这个 工作假说是丝氨酸-916是一个具有生理意义的部位 调节的磷酸化，有助于激活和 下调汇率因素。 拟议的研究具有创新性，因为它们解决了一个重要的机制 对于中枢神经系统中RAS的激活，受到的研究较少。这个 结果将是重要的，因为它们将提供对 通过G蛋白偶联受体控制RAS，从而可能导致 为癌症干预确定新的治疗靶点。这个 结果很可能对我们理解 RAS/MAP激酶系统在学习和记忆中的作用

APPLICANT'S DESCRIPTION: Aberrant activation of Ras is a major contributor to human cancer. The Ras-GRF1 exchange factor, which activates Ras in response to G protein-coupled receptors, is highly expressed in central neurons and plays an essential role in the establishment of memory. Over-expression of Ras-GRF1 in human tumors implicates this exchange factor in carcinogenesis. The activity of Ras-GRF1 is controlled, at least in part, by alterations in its phosphorylation state, but a detailed picture of its regulation has not been achieved. The long-range goal of this project is to obtain a detailed understanding of the physiological and pharmacological significance of the Ras-GRF exchange factors. The objective of this proposal is to determine how the Ras-GRF1 exchange factor is controlled by phosphorylation. The central hypothesis is that Ras-GRF1 serves as a key integrator of signal transduction by regulation of its activity through both phosphorylation and interaction with calcium/calmodulin. The rationale for this proposal is that, through definition of the mechanisms that control Ras-GRF1, we will produce greater insight into a new and physiologically important pathway for Ras activation. This project will be performed in an environment that is very favorable for its successful completion through excellent collegial interactions and substantial institutional commitment. The objective of this proposal will be attained through testing the central hypothesis in three specific aims: 1).Determine the sites of regulated phosphorylation in Ras-GRFI. The hypothesis to be tested is that a combination of phosphorylation events is required for G protein-dependent activation of Ras-GRF1. 2).Define the integration of control of Ras-GRF1 by phosphorylation and calcium signaling. The ability of Ras-GRF1 to integrate multiple signals into the activation of Ras will be tested. 3).Elucidate a dual role for phosphorylation of Ras-GRFI at Serine-916. The working hypothesis is that Serine-916 is a physiologically significant site of regulated phosphorylation that contributes to both activation and down-regulation of the exchange factor. The proposed studies are innovative in that they address an important mechanism for Ras activation in the CNS that has been subject to less investigation. The results will be significant as they will provide key understanding of the control of Ras by G protein-coupled receptors, and thus may potentially lead to the identification of new therapeutic targets for intervention in cancer. The results are likely to be of fundamental importance to our comprehension of the role of the Ras/MAP kinase system in learning and memory.