Regulation of Ras through the Ras GRF exchange factor

通过 Ras GRF 交换因子调节 Ras

• 批准号: 6724912
• 负责人: RAYMOND R MATTINGLY
• 金额: $ 19.88万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6724912
• 关键词: G protein; biological signal transduction; calcium ion; calmodulin; cerebral cortex; enzyme activity; guanine nucleotide binding protein; guanine nucleotide exchange factors; guanosine triphosphate; hippocampus; intermolecular interaction; laboratory rabbit; laboratory rat; mass spectrometry; mitogen activated protein kinase; phosphorylation; receptor coupling; serine; site directed mutagenesis

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.

申请人的描述：RAS的异常激活是主要的贡献者 人类癌。 RAS-GRF1交换系数，该系数激活RAS。 G蛋白偶联受体，在中央神经元中高度表达 在建立记忆中的重要作用。 RAS-GRF1的过表达 在人类肿瘤中，这种交换因子在癌变中。活动 Ras-grf1的of至少部分通过其改变。 磷酸化状态，但其调节的详细图表尚未 成就了。该项目的远程目标是获得详细的 了解生理和药理意义 RAS-GRF交换因子。该提议的目的是确定如何 RAS-GRF1交换因子由磷酸化控制。中央 假设是RAS-GRF1充当信号转导的关键积分器 通过调节其活性通过磷酸化和与 钙/钙调蛋白。该提议的理由是，通过定义 在控制Ras-Grf1的机制中，我们将对 RAS激活的新的和生理上重要的途径。这个项目将 在以成功的环境中进行的环境 通过出色的大学互动完成和实质性的完成 机构承诺。该提议的目的将得以实现 通过在三个特定目的中测试中心假设：1）。 RAS-GRFI中调节磷酸化的位点。要检验的假设是 G需要组合磷酸化事件 Ras-Grf1的蛋白质依赖性激活。 2）。定义控制的集成 通过磷酸化和钙信号传导的RAS-GRF1。 RAS-GRF1的能力 将测试将多个信号集成到RAS的激活中。 3）。在丝氨酸916上召集Ras-Grfi磷酸化的双重作用。这 工作假设是丝氨酸-916是一个具有生理意义的部位 受调节的磷酸化既有助于激活和 交换因子的下调。 拟议的研究具有创新性，因为它们解决了重要的机制 对于中枢神经系统中的RAS激活，经过较少的研究。这 结果将是重要的，因为他们将提供对 G蛋白偶联受体对RAS的控制，因此可能导致 鉴定新的治疗靶标在癌症中进行干预。这 结果对于我们对我们的理解至关重要 RAS/MAP激酶系统在学习和记忆中的作用。