Regulation of Ras-Dependent Signal Transduction Pathways

Raf-1是一种重要的信号分子，在RAS途径中发挥作用，将有丝分裂、分化和致癌信号传递给下游的MEK和ERK。由于Raf-1在细胞信号转导中起着不可或缺的作用，因此必须对其活性进行精确控制。在过去的财政年度中，我们的研究确定了关键的反馈磷酸化位点，这些位点有助于在有丝分裂原刺激后下调Raf-1的表达。本工作阐明了RAS/Raf信号的时间调控的一个关键机制，并确定了参与这一过程的关键分子-ERK、PP2A和Pin1。KSR是RAS途径中的保守成分，它作为分子支架促进ERK级联信号的传递。在过去的一年里，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。这项工作证明了KSR1在海马区以生物化学的方式发挥作用，以支架ERK级联的组成部分，当ERK的膜部分通过依赖PKC的途径而不是通过cAMP/PKA依赖的途径被激活时，KSR1特异性地调节该级联。与这些发现一致的是，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。

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.