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: 10551735
• 负责人: Sharon L Campbell
• 金额: $ 59.8万
• 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/10551735
• 关键词: Actins; Binding; Biochemical; Cardiomyopathies; Cardiovascular Diseases; Cell Adhesion Molecules; Cellular Morphology; Cellular biology; Codon Nucleotides; Cytoskeleton; Defect; F-Actin; GTP-Binding Proteins; Guanine Nucleotides; Heart; Heart Diseases; 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

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.

抽象的 该项目侧重于两个主题：1）阐明驱动鸟嘌呤核苷酸的新型机制 结合（G） - 蛋白质信号传导和肿瘤发生以及2）研究细胞的个体和协调作用 调节细胞形态，力传递和细胞运动中的粘附蛋白。我们在G蛋白上的工作是 以Ras和异三聚体G蛋白为中心。我们实验室挑战的最新发现是长期以来的教条 在核苷酸循环中的缺陷中，G蛋白的致癌激活主要驱动。然而， 越来越清楚的是，密码子和残基特异性激活突变可以驱动 肿瘤发生通过不同的机制。换句话说，并非所有激活突变都相等。我们 提案研究旨在了解残留特异性激活突变如何独特地改变G蛋白 结构，核循环，蛋白质识别和信号传导，这可能是发展精度的关键 医学方法与G蛋白介导的肿瘤发生结合。我们的实验室也发现了小说 通过翻译后修饰和pH调节，G蛋白激活的机制。我们提出了高度的建议 综合的多学科结构，生化和细胞生物学方法来询问这些作用 新颖的信号传导和肿瘤发生后翻译后修饰。我们的第二个主题专注于单元格 粘附蛋白，Vinculin和Metavinculin。这些细胞粘附蛋白是同工型，在 调节细胞形态，分化，力传递和定向细胞迁移。我们建议 实验研究的研究，用于检查源自元素和元蛋白介导的丝状肌动蛋白的新模型 组装和膜插入，进行细胞研究，以阐明荟萃蛋白如何协调 调节vinculin功能，并阐明元环蛋白心肌病突变如何失调收缩性 心脏病的力量。我们还将调查Vinculin和Metavinculin如何参与丝状肌动蛋白 依赖性方式调节定向细胞运动。