Understanding Ras effector switching and roles of Ras>RalGEF>Ral in development

总结 Ras是突变最多的癌蛋白，在进化上保守的 在遗传性发育障碍的RAS病谱中突变的蛋白质网络。 Ras生物学的某些方面，如Raf和PI3K致癌基因下游的信号级联， 效应子，是所有生物学中研究得最好和最有针对性的信号之一。然而 Ras如何在不同效应子之间切换以及致癌RalGEF>Ral效应子的作用 在开发过程中，由于冗余、技术限制， 更复杂的系统，以及Ral使用外囊复合物作为信号传导的障碍 中介该实验室的研究重点是了解其组成， 组织原理和体内信号转导网络的功能。这项建议会 支持一系列项目，以回答Ras如何在不同的效应器之间切换， 发展背景下，探索意想不到的信号关系与其他特征 信号级联，解开了Ral和 胞吐复合物在信号转导与胞吐作用中的作用，并识别和理解胞吐复合物的新功能。 Ral在发育和生理学中的信号传导，令人惊讶的是，对此知之甚少。 该实验室已经开发了几项关键的技术进步，以克服 这一领域的进展。拟议的项目建立在实验室的能力，剖析复杂的网络， 利用遗传学原理进行信号转导，辅之以细胞生物学和生物化学 接近。拟议中的研究有望发现新的原理， 信号转导的组成部分。

SUMMARY Ras is the most mutated oncoprotein and functions at the center of an evolutionarily conserved network of proteins mutated in the RASopathy spectrum of heritable developmental disorders. Certain facets of Ras biology, like signaling cascades downstream of the Raf and PI3K oncogenic effectors, are among the best studied and pharmacologically targeted signals in all of biology. Yet how Ras switches between different effectors and the roles of the oncogenic RalGEF>Ral effector during development are poorly understood due to paralog redundancy, technical limitations in more complex systems, and the roadblock of Ral using the exocyst complex as a signaling intermediary. Research in this laboratory focuses on understanding the composition, organizational principles, and functions of signal transduction networks in vivo. This proposal will support a series of projects to answer how Ras switches between effectors in different developmental contexts, explore unexpected signaling relationships with other characterized signaling cascades, untangle the apparently paradoxical relationship between Ral and the exocyst complex in signaling vs. exocytosis, and to identify and understand novel functions of RalGEF>Ral signaling in development and physiology, about which surprisingly little is known. The laboratory has developed several crucial technical advances to overcome barriers to progress in this field. The proposed projects build on the lab’s ability dissect complex webs of signal transduction using genetic principles, complemented by cell biological and biochemical approaches. The proposed research is reasonably expected to discover novel principles and components in signal transduction.