Regulation of Ras-Dependent Signal Transduction Pathways

Ras 依赖性信号转导途径的调节

• 批准号: 7338463
• 负责人: DEBORAH K MORRISON
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7338463
• 关键词: Regulation; Ras; Dependent; Signal; Transduction

The Raf-1 kinase is an important signaling molecule, functioning in the Ras pathway to transmit mitogenic, differentiative, and oncogenic signals to the downstream kinases MEK and ERK. Due to its integral role in cell signaling, Raf-1 activity must be precisely controlled. During this past fiscal year, our reseach identified critical feedback phosphorylation sites that contribute to the downregulation of Raf-1 following mitogen stimulation. This work elucidated a key mechanism contributing to the temporal regulation of Ras/Raf signaling signaling and identified critical molecules involved in this process - ERK, PP2A and Pin1. KSR is a conserved component of the Ras pathway that acts as a molecular scaffold to facilitate signal transmission through the ERK cascade. During the past fiscal year, our studies provided novel insight into the endogenous scaffolding role of KSR1 within the nervous system. This work demonstrated that KSR1 functions biochemically in the hippocampus to scaffold the components of the ERK cascade, specifically regulating the cascade when a membrane fraction of ERK is activated via a PKC-dependent pathway but not via a cAMP/PKA-dependent pathway. Consistent with these findings, mice lacking KSR1 were found to have deficits in associative learning and certain typses of synaptic plasticity.

Raf-1激酶是一个重要的信号分子，在Ras通路中发挥作用，将有丝分裂、分化和致癌信号传递给下游激酶MEK和ERK。由于其在细胞信号传导中不可或缺的作用，必须精确控制Raf-1的活性。在过去的财政年度，我们的研究确定了在有丝分裂原刺激后导致Raf-1下调的关键反馈磷酸化位点。这项工作阐明了Ras/Raf信号转导的时间调控的关键机制，并鉴定了参与该过程的关键分子- ERK， PP2A和Pin1。KSR是Ras通路的一个保守成分，作为分子支架促进ERK级联的信号传递。在过去的财政年度，我们的研究为KSR1在神经系统中的内源性支架作用提供了新的见解。这项研究表明，KSR1在海马体中发挥生物化学作用，支撑ERK级联的组成部分，当ERK的膜部分通过pkc依赖途径激活而不是通过cAMP/ pka依赖途径激活时，特异性地调节级联。与这些发现一致，缺乏KSR1的小鼠被发现在联想学习和某些类型的突触可塑性方面存在缺陷。