Structure and Mechanism of G-proteins and cell adhesion proteins in regulation of cell growth and motility

G蛋白和细胞粘附蛋白调节细胞生长和运动的结构和机制

• 批准号: 10389437
• 负责人: Sharon L Campbell
• 金额: $ 3.07万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10389437
• 关键词: Actins; Binding; Biochemical; Cardiomyopathies; Cardiovascular Diseases; Cell Adhesion Molecules; Cellular Morphology; Cellular biology; Codon Nucleotides; Defect; F-Actin; GTP-Binding Proteins; Guanine Nucleotides; Heart; Heart Diseases; Heterotrimeric GTP-Binding Proteins; Individual; Investigation; Malignant Neoplasms; Mediating; Membrane; Modeling; Mutation; Nucleotides; Oncogenic; Play; Post-Translational Protein Processing; Protein Isoforms; Proteins; Regulation; Role; Signal Transduction; Signaling Protein; Structure; Vinculin; Work; cell growth regulation; cell motility; guanine nucleotide binding protein; multidisciplinary; novel; precision medicine; protein activation; protein structure; transmission process; tumorigenesis

Contact PD/PI: Campbell, Sharon Abstract This project focuses on two themes: 1) elucidation of novel mechanisms that drive guanine nucleotide binding (G)-protein signaling and tumorigenesis and 2) investigation of individual and coordinated roles of cell adhesion proteins in regulating cell morphology, force transmission and cell motility. Our work on G-proteins is centered on RAS and heterotrimeric G-proteins. Recent findings from our lab challenge a long-held dogma in the field that oncogenic activation of G-proteins is primarily driven by defects in nucleotide cycling. However, it is becoming increasingly clear that codon and residue specific activating mutations in G-proteins can drive tumorigenesis by distinct mechanisms. In other words, not all activating mutations are created equal. We propose studies aimed at understanding how residue specific activating mutations uniquely alter G-protein structure, nucleotide cycling, protein recognition and signaling, that may be key to developing precision medicine approaches to antagonize G-protein mediated tumorigenesis. Our lab has also uncovered novel mechanisms of G-protein activation by post-translational modification and pH regulation. We propose highly integrated multidisciplinary structural, biochemical and cell biology approaches to interrogate the role of these novel posttranslational modifications in signaling and tumorigenesis. Our second theme is focused on the cell adhesion proteins, vinculin and metavinculin. These cell adhesion proteins are isoforms that play a key role in regulation of cell morphology, differentiation, force transmission and directed cell migration. We propose studies to experimentally examine new models for vinculin and metavinculin-mediated filamentous actin assembly and membrane insertion, conduct cellular studies to elucidate how metavinculin coordinately regulates vinculin function, and elucidate how metavinculin cardiomyopathy mutations dysregulate contractile force in heart disease. We will also investigate how vinculin and metavinculin engage filamentous actin in a force dependent manner to regulate directed cell motility. Page 6 Project Summary/Abstract

联系人 PD/PI：Campbell、Sharon 抽象的 该项目重点关注两个主题：1）阐明驱动鸟嘌呤核苷酸的新机制 结合 (G)-蛋白信号传导和肿瘤发生以及 2) 细胞个体和协调作用的研究 粘附蛋白在调节细胞形态、力传递和细胞运动方面的作用是 G 蛋白。 我们实验室的最新发现挑战了长期以来的教条。 在该领域，G 蛋白的致癌激活主要是由核苷酸循环缺陷驱动的。 越来越清楚的是，G 蛋白中的密码子和残基特异性激活突变可以驱动 换句话说，并非所有的激活突变都是相同的。 提出旨在了解残基特异性激活突变如何独特地改变 G 蛋白的研究 结构、核苷酸循环、蛋白质识别和信号传导，这可能是开发精度的关键 我们的实验室还发现了对抗 G 蛋白介导的肿瘤发生的新药物方法。 我们强烈建议通过翻译后修饰和 pH 调节来激活 G 蛋白的机制。 综合多学科结构、生化和细胞生物学方法来探讨这些作用 我们的第二个主题是细胞。 粘附蛋白、纽蛋白和美纽蛋白这些细胞粘附蛋白是在细胞粘附中发挥关键作用的亚型。 我们提出细胞形态、分化、力传递和定向细胞迁移的调节。 实验检验纽蛋白和元纽蛋白介导的丝状肌动蛋白新模型的研究 组装和膜插入，进行细胞研究以阐明美维库林如何协调 调节纽蛋白功能，并阐明美纽蛋白心肌病突变如何导致收缩失调 我们还将研究纽蛋白和美纽蛋白如何与丝状肌动蛋白结合。 力依赖方式调节定向细胞运动。 第6页 项目概要/摘要