Mitogenic and Oncogenic Regulation of ERK/RSK Signaling

ERK/RSK 信号传导的促有丝分裂和致癌调控

• 批准号: 6710577
• 负责人: JOHN BLENIS
• 金额: $ 53.84万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-08 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6710577
• 关键词: athymic mouse; biological signal transduction; cell cell interaction; cell growth regulation; cell motility; cell proliferation; cytogenetics; enzyme activity; enzyme substrate; immunocytochemistry; immunoprecipitation; mitogen activated protein kinase; mitogens; monoclonal antibody; oncogenes; phosphorylation; protein binding; protein localization; protein structure function; regulatory gene; site directed mutagenesis; tissue /cell culture; western blottings; yeast two hybrid system

DESCRIPTION (provided by applicant): Ras is known to modulate many biological processes involved in the regulation of cell proliferation, differentiation, development, survival, and motility. Mutations in Ras can lead to a variety of diseases, including cancer. The ERK-MAP kinase cascade plays a major role in Ras-regulated signaling. In this pathway, the ERK and RSK family of protein kinases are key players in signal transmission. Although the regulation of ERKs and their targets have been studied extensively, how RSKs mediate the biological functions of Ras is poorly understood. Our goal is to investigate and define RSK function by characterizing its complex regulation and its downstream targets. During the last grant period we began characterizing the molecular basis of RSK1 activation and some of RSK1's biological functions. We defined a role for RSK1 in cell survival signaling with the discovery of the proapoptotic protein BAD as a RSK substrate. We also continued our characterization of another RSK target, c-Fos, and its role in cell proliferation and oncogenesis. In the continuation of our work on RSK, we propose three major objectives. The first objective of the proposed research is to define at a molecular level how RSK is regulated by multiple protein kinase inputs and site-specific phosphorylation. Given its important role in Ras signaling and the fact that understanding RSK activation would provide the foundation for understanding the regulation of many similar protein kinases, this is an important aim requiring extensive analyses. The second objective is to determine how RSK's multiple protein partners interact at a molecular level, and how they regulate RSK cellular location, activation and downstream signaling. Additional interaction screens are also proposed to provide new insights into the role RSK plays in Ras-mediated signaling. The third objective of this proposal is to begin an extensive characterization of two RSK targets identified in a yeast two-hybrid screen with the RSK C-terminal kinase domain. The first, FLNa, will provide a molecular understanding of how the Ras-ERK pathway contributes to the regulation of cell spreading and motility. The second, RanBP3, will provide novel information regarding a potential role for RSK in regulating nucleocytoplasmic transport.

描述（由申请人提供）：已知Ras调节参与细胞增殖、分化、发育、存活和运动调节的许多生物学过程。Ras突变可导致多种疾病，包括癌症。ERK-MAP激酶级联在Ras调节的信号传导中起主要作用。在该途径中，ERK和RSK蛋白激酶家族是信号传递的关键参与者。虽然ERK及其靶点的调控已被广泛研究，但RSK如何介导Ras的生物学功能却知之甚少。我们的目标是通过表征RSK的复杂调控及其下游靶点来研究和定义RSK功能。在上一个资助期间，我们开始表征RSK 1激活的分子基础和RSK 1的一些生物学功能。我们确定了RSK 1在细胞存活信号传导中的作用，并发现了促凋亡蛋白BAD作为RSK底物。我们还继续研究了另一个RSK靶点c-Fos及其在细胞增殖和肿瘤发生中的作用。 在继续我们关于RSK的工作时，我们提出三个主要目标。这项研究的第一个目标是在分子水平上确定RSK是如何被多个蛋白激酶输入和位点特异性磷酸化调节的。鉴于其在Ras信号传导中的重要作用以及了解RSK活化将为了解许多类似蛋白激酶的调控提供基础的事实，这是一个需要广泛分析的重要目标。第二个目标是确定RSK的多个蛋白伴侣如何在分子水平上相互作用，以及它们如何调节RSK细胞定位，激活和下游信号传导。还提出了额外的交互屏幕，以提供新的见解RSK在Ras介导的信号传导中发挥的作用。该建议的第三个目标是开始广泛的表征两个RSK目标中确定的酵母双杂交筛选与RSK C-末端激酶结构域。第一个，FLNa，将提供Ras-ERK通路如何有助于调节细胞扩散和运动的分子理解。第二，RanBP 3，将提供新的信息RSK在调节核质运输的潜在作用。