AGS1 and signal processing by G-proteins

描述(由申请人提供)：总体假设：异源三聚体G蛋白系统的信号效率/特异性部分由辅助蛋白决定，这些辅助蛋白调节从G蛋白偶联受体(GPCRs)到G蛋白的信号传递的效率和/或特异性，将信号复合体分离到细胞的微域，调节系统的基本活性和/或向独立于典型GPCR的G蛋白信号系统提供替代的信号输入模式。我们的目标是确定这些辅助蛋白，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质(G-蛋白信号转导激活因子(AGS)1-8)，它们不依赖于GPCR而直接影响G-蛋白的激活状态。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，选择性地调节不同类型的G蛋白。这项建议侧重于AGS1，它在AGS家族成员中是独一无二的。AGS1是一种RAS相关蛋白，调节三聚体G蛋白信号转导，为小三聚体和大(异三聚体)G蛋白家族之间的串扰提供了一种令人惊讶的机制。我们对AGS1如何整合到细胞和器官的功能知之甚少，这项应用的一个主要目标就是解决这个问题。特定的AIM#1定义了AGS1的亚细胞位置和调控。特定的AIM#2识别和表征AGS1的下游信号机制。特异性AIM#3决定了AGS1在细胞分化中的功能作用。AGS1和相关的辅助蛋白为G蛋白激活周期的调控提供了意想不到的机制，并开辟了与G蛋白作为信号转导蛋白的细胞角色及其调节的细胞功能相关的新的研究领域。因此，这些蛋白质和随着他们的发现而提出的概念提供了意想不到的途径；用于治疗开发和增加对疾病机制的理解。

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 tieterotrimeric G-protein signaling providing a surprising mechanism for cross talk between small and large (heterotrimeric) G-protein families. We have little understanding of how AGS1 integrates into cell and organ function and a major goal of this application is to address this issue. SPECIFIC AIM #1 Define the subcellular location and regulation of AGS1. SPECIFIC AIM #2 Identify and characterize downstream signaling mechanisms of AGS1. SPECIFIC AIM #3 Determine the functional role of AGS1 in cell differentiation. 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 avenue; for therapeutic development and increased understanding of disease mechanisms.