Regulation of Ras through the Ras GRF exchange factor

通过 Ras GRF 交换因子调节 Ras

• 批准号: 6513528
• 负责人: RAYMOND R MATTINGLY
• 金额: $ 19.89万
• 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/6513528
• 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.

申请人描述：Ras的异常激活是 人类癌症Ras-GRF 1交换因子，其激活Ras以响应 G蛋白偶联受体，在中枢神经元中高度表达， 在记忆的建立中起着至关重要的作用。Ras-GRF 1的过表达 在人类肿瘤中，这种交换因子与致癌作用有关。活动 Ras-GRF 1的表达至少部分地受其 磷酸化状态，但其调节的详细情况尚未得到 办妥了一批该项目的长期目标是获得详细的 了解的生理和药理学意义， Ras-GRF交换因子。本提案的目的是确定如何 Ras-GRF 1交换因子由磷酸化控制。中央 假设Ras-GRF 1是信号转导的关键整合子 通过磷酸化和与 钙/钙调素。提出这一建议的理由是，通过定义， 控制Ras-GRF 1的机制，我们将产生更大的洞察力， 新的和生理上重要的途径Ras激活。该项目将 在一个非常有利于其成功的环境中进行 通过优秀的学院互动和实质性的 体制承诺。这项建议的目的将会达到 通过在三个具体目标中测试中心假设：1）.确定 Ras-GRFI中受调节的磷酸化位点。待检验的假设是 G蛋白的合成需要磷酸化事件的组合， Ras-GRF 1的蛋白依赖性激活。2).定义控制的集成 Ras-GRF 1通过磷酸化和钙信号传导。Ras-GRF 1的能力 将多种信号整合到Ras的激活中。 3).阐明Ras-GRFI在丝氨酸-916处磷酸化的双重作用。的 工作假设是丝氨酸-916是一个生理上重要的位点， 调节磷酸化，有助于激活和 下调汇率因素。 拟议的研究是创新的，因为它们涉及一个重要的机制， 对于CNS中Ras激活的研究较少。的 结果将是重要的，因为它们将提供关键的理解， 通过G蛋白偶联受体控制Ras，因此可能导致 确定新的治疗靶点以干预癌症。的 结果可能对我们理解 Ras/MAP激酶系统在学习和记忆中的作用