Role of Shc scaffold proteins in regulating neuronal differentiation and survival in the mouse nervous system

细胞内受体介导的信号通路的适当调节确保了来自细胞外环境的信号的正确整合和重新分布。调节性对接蛋白确保多种信号分子的调节。这些蛋白质如何组织其靶点的精确空间和时间分布，从而维持各种信号级联之间的平衡，仍有待了解。我将采取系统水平的方法来了解中枢支架蛋白在神经系统中的复杂功能，涉及遗传学，蛋白质组学和成像。我将使用Shc衔接蛋白作为研究这类分子的原型。Shc蛋白家族的成员已经显示出调节几种受体介导的信号传导途径，包括Ras-MAP激酶和磷脂酰肌醇（PI）3 '-激酶-Akt途径。最广泛研究的同种型Shc 1/ShcA在哺乳动物组织中广泛表达，但在很大程度上被排除在成人神经系统之外，而Shc 2/ShcB/Sli，Shc 3/ShcC/Rai/N-Shc和Shc 4/ShcD/RaLP基因产物主要在有丝分裂后神经元中表达。该项目的目的是研究Shc 2，Shc 3和Shc 4在神经元分化和存活中的作用，从而确定不同亚型在神经系统中的冗余和特定功能。

Proper regulation of receptor-mediated signaling pathways within the cell ensures the correct integration and redistribution of signals from the extracellular environment. Modulatory docking proteins secure the regulation of a variety of signaling molecules. How these proteins manage to organize the precise spatial and temporal distribution of their targets, and thus, to maintain the balance between various signaling cascades, remains to be understood. I am going to take a systems level approach to understand the complex functions of hub scaffold proteins in the nervous system, involving genetics, proteomics and imaging. I will use Shc adapter proteins as a prototype to study this class of molecules. Members of the Shc protein family have been shown to regulate several receptor mediated signaling pathways, including the Ras-MAP kinase and the phosphatidylinositol (PI) 3’-kinase-Akt pathway. The most extensively studied isoform Shc1/ShcA is widely expressed in mammalian tissues, but is largely excluded from the adult nervous system, whilst the Shc2/ShcB/Sli, Shc3/ShcC/Rai/N-Shc, and Shc4/ShcD/RaLP gene products are pre-dominantly expressed in postmitotic neurons. The aims of this project are to investigate the roles of Shc2, Shc3 and Shc4 in neuronal differentiation and survival, and thereby identify redundant and specific functions of the different isoforms in the nervous system.