AGS1 and signal processing by G-proteins

描述（由申请人提供）：异三聚体g蛋白系统的信号传导效率/特异性部分取决于辅助蛋白，这些辅助蛋白调节从g蛋白偶联受体（GPCR）到g蛋白的信号传递的效率和/或特异性，将信号复合物分离到细胞的微结构域，调节系统的基础活性和/或为独立于典型GPCR操作的g蛋白信号系统提供替代的信号输入模式。我们的目标是定义这些辅助蛋白，它们的调节机制，它们在各种疾病中的功能障碍以及它们作为治疗靶点的潜力。我们最近发现了一组蛋白（g蛋白信号激活因子（Activators of G-protein signaling， AGS） 1-8），它们直接影响g蛋白的激活状态，而不依赖于GPCR。AGS蛋白与异源三聚体g蛋白的不同亚基和/或构象相互作用，选择性调节不同类型的g蛋白。本提案的重点是AGS1，它在AGS家族成员中是独一无二的。AGS1是一种Ras相关蛋白，调节异三聚体G-蛋白信号，为小G-蛋白家族和大G-蛋白家族之间的串扰提供了一种令人惊讶的机制。该应用程序的主要目标是了解AGS1如何整合到细胞和器官功能中。明确AGS 1的亚细胞定位以及受体和信号通路激活对其亚细胞定位和核苷酸结合状态的影响。明确与异源三聚体g蛋白相互作用和调控所需的AGS - 1结构域。明确AGS1调控GPCRs信号处理的机制。鉴定和表征AGS 1调节剂和其他AGS 1效应物。AGS1及其附属蛋白为g蛋白激活周期的调控提供了意想不到的机制，并为g蛋白作为信号转导的细胞作用及其调控的细胞功能开辟了一个新的研究领域。因此，这些蛋白质和随着它们的发现而提出的概念为治疗发展和增加对疾病机制的理解提供了意想不到的途径。

DESCRIPTION (provided by applicant): OVERALL HYPOTHESIS: Signaling efficiency/specificity for heterotrimeric G-protein systems is determined in part by accessory proteins which regulate the efficiency and/or specificity of signal transfer from G-protein coupled receptors (GPCRs) to G-proteins, segregate a signaling complex to microdomains of the cell, regulate the basal activity of the system and/or provide alternative modes of signal input to G-protein signaling systems that operate independent of a typical GPCR. Our objectives are to define such accessory proteins, their mechanism of regulation, their dysfunction in various diseases and their potential as therapeutic targets. We recently identified a group of proteins (Activators of G-protein signaling (AGS) 1-8 that directly influence the activation state of G-proteins independent of a GPCR. AGS proteins interact with different subunits and/or conformations of heterotrimeric G-proteins and selectively regulate different types of G-proteins. This proposal focuses on AGS1, which is unique among the AGS family members. AGS1 is a Ras related protein that regulates heterotrimeric G- protein signaling providing a surprising mechanism for cross talk between small and large (heterotrimeric) G- protein families. A major goal of this application is to understand how AGS1 integrates into cell and organ function. SPECIFIC AIM #1 Define the subcellular location of AGS 1 and the influence of receptor and signal pathway activation on its subcellular location and nucleotide binding state. SPECIFIC AIM #2 Define the domains of AGS 1 required for interaction with and regulation of heterotrimeric G-proteins. SPECIFIC AIM #3 Define the mechanism by which AGS1 regulates signal processing by GPCRs. SPECIFIC AIM #4 Identify and characterize AGS 1 regulators and additional AGS 1 effectors. AGS1 and related accessory proteins provide unexpected mechanisms for regulation of the G-protein activation cycle and have opened up a new area of research related to the cellular role of G-proteins as signal transducers and the cellular functions they regulate. As such, these proteins and the concepts advanced with their discovery provide unexpected avenues for therapeutic development and increased understanding of disease mechanisms.