AGS1 and signal processing by G-proteins

描述（申请人提供）：总体假设：异源三聚体G蛋白系统的信号传导效率/特异性部分由辅助蛋白决定，辅助蛋白调节从G蛋白偶联受体（GPCR）到G蛋白的信号转移的效率和/或特异性，将信号传导复合物分离到细胞的微结构域，调节该系统的基础活性和/或向独立于典型GPCR操作的G蛋白信号传导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。我们最近鉴定了一组蛋白质（G蛋白信号传导激活剂（AGS）1-8），其直接影响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，并选择性地调节不同类型的G蛋白。该提案的重点是AGS 1，这是AGS家族成员中唯一的。AGS 1是一种Ras相关蛋白，其调节异源三聚体G蛋白信号传导，为小和大（异源三聚体）G蛋白家族之间的串扰提供了令人惊讶的机制。该应用程序的主要目标是了解AGS 1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。特异性目的#2定义与异源三聚体G蛋白相互作用和调节所需的AGS 1结构域。具体目标#3定义AGS 1通过GPCR调节信号处理的机制。特定目标#4识别和表征AGS 1调节器和其他AGS 1效应器。AGS 1和相关辅助蛋白提供了意想不到的G蛋白激活周期调节机制，并开辟了一个新的研究领域，涉及G蛋白作为信号转导子的细胞作用及其调节的细胞功能。因此，这些蛋白质和随着它们的发现而提出的概念为治疗开发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.