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.

摘要 哺乳动物G蛋白偶联受体（GPCR）介导大量的生物学应答，并且已经被广泛应用于哺乳动物中。 与多种疾病有关。GPCR是高度可药物化的，并且是所有FDA药物的三分之一的目标。 批准的药物。目前，已经开发了所有靶向GPCR的药物来调节在GPCR处转导的信号。 质膜。然而，我们和其他人已经表明，GPCR在细胞内保持活跃，并发出信号， 来自内体。来自质膜和内体的GPCR信号的协调是必不可少的 为了实现适当的细胞反应，这些途径的失调，通过异常增加或 信号传导的减少驱动疾病进展。我们的实验室长期以来一直致力于了解 控制GPCR信号传导的调节机制。在最近由MIRA资助的项目中，我们发现， GPCR亚群的泛素化驱动p38丝裂原活化蛋白激酶（MAPK）内体信号传导 和血管炎症。泛素化的关键调节因子和介质的分子机制 调节GPCR-p38内体信号传导的机制尚不清楚，这是一个知识空白。未来5年，我们 实验室将重点了解两种关键的去泛素化酶如何通过以下途径调节GPCR刺激的p38信号传导： 确定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-arrestin arrestin相关结构域蛋白3（ARRDC 3）是一个内体蛋白， 一种多功能衔接蛋白，通过项目中的不同机制控制GPCR信号传导和运输 由MIRA资助。与经典的抑制蛋白不同，人们对调节α-肾上腺素的机制几乎一无所知。 arrestin活性和α-arrestins如何控制哺乳动物GPCR功能以及知识上的重大空白。在 未来5年，我们将确定控制GPCR刺激的ARRDC 3活性的分子机制， 阐明癌症进展中的调节和功能机制。我们将整合假设驱动 和公正的系统方法来询问控制泛素驱动的GPCR内体的机制， 信号和ARRDC 3的活动和功能，利用创新和尖端技术。的透彻 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。