Cell signaling by G protein-coupled receptors

G 蛋白偶联受体的细胞信号传导

• 批准号: 10623554
• 负责人: Joann Trejo
• 金额: $ 53.09万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623554
• 关键词: Adaptor Signaling Protein; Arrestins; Biological; Cell membrane; Cell physiology; Cells; Development; Disease; Disease Progression; Drug Targeting; Endosomes; FDA approved; Family; Funding; Future; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Goals; Homeostasis; Human body; Knowledge; Laboratories; Mediating; Mediator; Molecular; Pathway interactions; Pharmaceutical Preparations; Process; Proteins; Receptor Signaling; Regulation; Research; Signal Transduction; System; Technology; Ubiquitin; Ubiquitination; druggable target; improved; innovation; new therapeutic target; p38 Mitogen Activated Protein Kinase; programs; receptor function; response; therapeutic development; trafficking; tumor progression; ubiquitin isopeptidase; vascular inflammation; virtual

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.

抽象的 哺乳动物 G 蛋白偶联受体 (GPCR) 介导大量的生物反应，并且已被 GPCR 与许多疾病有关，具有高度的药物性，并且是大约三分之一的 FDA 的目标。 目前，所有针对 GPCR 的药物均已开发用于调节 GPCR 转导的信号。 然而，我们和其他人已经证明 GPCR 在细胞内保持活跃并发出信号。 来自质膜和内体的 GPCR 信号传导的协调至关重要。 为了实现适当的细胞反应，这些途径的失调，通过异常的增加或 我们的实验室长期以来一直致力于了解信号传导的减少导致疾病进展。 在 MIRA 最近资助的项目中，我们发现了控制 GPCR 信号传导的调节机制。 GPCR 子集的泛素化驱动 p38 丝裂原激活蛋白激酶 (MAPK) 内体信号转导 和血管炎症的分子机制。 GPCR-p38 内体信号传导的调节尚不清楚，并且在未来 5 年内我们仍存在知识空白。 实验室将重点了解两种关键的去泛素化酶如何通过以下方式调节 GPCR 刺激的 p38 信号传导： 识别关键底物并阐明血管炎症的调节和功能机制。 我们还发现，α-抑制蛋白抑制蛋白相关结构域含有蛋白 3 (ARRDC3) 是一种内体 多功能接头蛋白，通过项目中的不同机制控制 GPCR 信号传导和运输 与经典的抑制蛋白不同，我们对 α- 的调节机制几乎一无所知。 抑制蛋白活性以及 α-抑制蛋白如何控制哺乳动物 GPCR 功能以及知识的主要空白。 未来5年，我们将定义控制GPCR刺激的ARRDC3活性的分子机制，并 我们将整合假设驱动的机制，阐明癌症进展中的调节和功能机制。 和公正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传导和 ARRDC3 活动和功能。 了解控制 GPCR 信号传导的时空调节机制对于改善 GPCR 信号传导至关重要 开发针对 GPCR 的新药物。