Cell signaling by G protein-coupled receptors

摘要 哺乳动物G蛋白偶联受体(GPCRs)介导了一系列的生物反应，并已被 与多种疾病有牵连。GPCRs是高度可下药的，约三分之一的FDA 批准的药物。目前，所有靶向GPCRs的药物都已被开发出来，以调制在 质膜。然而，我们和其他人已经证明，GPCRs在细胞内保持活跃，并发出信号 从内吞体内。质膜和内吞体内gpr信号的协调是必不可少的。 为了实现适当的细胞反应，这些通路的失调，通过异常增加或 信号的减少会导致疾病的进展。我们的实验室长期以来一直致力于了解 控制gpr信号的调控机制。在米拉最近资助的项目中，我们发现 GPCRs的泛素化驱动p38丝裂原活化蛋白激酶(MAPK)的内体信号转导 和血管炎症。泛素化的关键调节因子和介体的分子机制 GPCR-p38内体信号的调控目前尚不清楚，也是一个知识空白。在接下来的5年里，我们 实验室将专注于了解两种关键的去泛素酶如何通过以下方式调节GPCR刺激的p38信号 确定关键底物，阐明血管炎症的调节和作用机制。 我们还发现α-arrestin arrestin相关结构域包含蛋白-3(ArrDc3)是一个内体 多功能接头蛋白，通过项目中不同的机制控制GPCR信号和运输 由米拉资助。与经典的逮捕不同，人们对α的调节机制几乎一无所知- Arrestin的活性以及α-arrestins如何控制哺乳动物GPCRs的功能，这是一个重大的知识差距。在 在接下来的5年里，我们将确定控制GPCR刺激的ARRDC3活性的分子机制和 阐明肿瘤进展过程中的调控和作用机制。我们将整合假设驱动的 和无偏见的系统方法来询问控制泛素驱动的GPCR内体的机制 利用创新和尖端技术的信号和ARRDC3活动和功能。一次彻底的 了解控制gpr信号的时空调控机制对于改进 针对GPCRs的新药开发。

Abstract Mammalian G protein coupled receptors (GPCRs) mediate a vast array of biological responses and have been implicated in numerous diseases. GPCRs are highly druggable and the target of about one-third of all FDA approved drugs. Currently, all drugs targeting GPCRs have been developed to modulate signals transduced at the plasma membrane. However, we and others have shown that GPCRs remain active inside the cell and signal from endosomes. The orchestration of GPCR signaling from the plasma membrane and endosomes is essential for achieving proper cellular responses, dysregulation of these pathways, through either aberrant increases or decreases in signaling drives disease progression. Our laboratory has long focused on understanding the regulatory mechanisms that control GPCR signaling. In recent projects funded by MIRA, we discovered that ubiquitination of a subset of GPCRs drives p38 mitogen-activated protein kinase (MAPK) endosomal signaling and vascular inflammation. The molecular mechanisms by which key regulators and mediators of ubiquitination regulate GPCR-p38 endosomal signaling is not known and a gap in knowledge. In the next 5 years, our laboratory will focus on understanding how two key deubiquitinases regulate GPCR-stimulated p38 signaling by identifying key substrates and elucidating the mechanisms of regulation and function in vascular inflammation. We also discovered that the α-arrestin arrestin-related domain containing protein-3 (ARRDC3) is an endosomal multi-functional adaptor protein that controls GPCR signaling and trafficking via distinct mechanisms in projects funded by MIRA. Unlike classical arrestins, virtually nothing is known about the mechanisms that regulate α- arrestin activity and how α-arrestins govern mammalian GPCR function and a major gap in knowledge. In the next 5 years, we will define the molecular mechanisms that control GPCR-stimulated ARRDC3 activity and elucidate the mechanisms of regulation and function in cancer progression. We will integrate hypothesis-driven and unbiased systems approaches to interrogate the mechanisms that control ubiquitin-driven GPCR endosomal signaling and ARRDC3 activity and function utilizing innovative and cutting-edge technologies. A thorough understanding of the spatial-temporal regulatory mechanisms that control GPCR signaling is critical for improving the development of novel drugs targeting GPCRs.