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: 10798511
• 负责人: Sharon L Campbell
• 金额: $ 1.56万
• 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/10798511
• 关键词: Acetylation; Actins; Address; Amino Acids; Apoptosis; Award; Binding; Biochemical; Bundling; Cardiomyopathies; Cardiovascular Diseases; Cell Adhesion Molecules; Cell physiology; Cells; Cellular Morphology; Cellular biology; Codon Nucleotides; Cytoskeleton; DNA; Defect; Dilated Cardiomyopathy; Dimerization; Disease; Embryo Deaths; Enzymatic Biochemistry; Exhibits; F-Actin; GTP Binding; GTP-Binding Proteins; GTPase-Activating Proteins; Glutamine; Guanine Nucleotide Exchange Factors; Guanine Nucleotides; Guanosine Triphosphate Phosphohydrolases; Heart; Heart Diseases; Heterotrimeric GTP-Binding Proteins; Histone Deacetylase Inhibitor; Individual; Intercalated disc; Investigation; KRAS2 gene; Lead; Link; Lysine; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Membrane; Microfilaments; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Conformation; Morphology; Mus; Muscle Cells; Mutation; Nucleotides; Oncogenic; Parents; Patients; Phosphorylation; Play; Point Mutation; Post-Translational Protein Processing; Protein Isoforms; Proteins; RNA Splicing; Regulation; Research; Resistance; Role; Signal Transduction; Signaling Protein; Structure; System; Tail; Testing; Thick; UV Radiation Exposure; Up-Regulation; Vinculin; Work; Yeasts; cell growth regulation; cell motility; crosslink; dimer; directional cell; experience; guanine nucleotide binding protein; mechanical load; melanoma; migration; multidisciplinary; mutant; novel; precision medicine; protein activation; protein protein interaction; protein structure; raf Kinases; response; sensor; structural biology; transmission process; tumorigenesis

Abstract of Parent Award 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 Gα-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.

父母摘要 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，2）研究个体和协调的作用 调节细胞形态，力传递和细胞运动中的细胞粘合剂蛋白。我们在G- 蛋白质以Ras和异三聚体Gα-蛋白质为中心。我们实验室挑战的最新发现 在田间的长期教条，G蛋白的致癌激活主要由缺陷驱动 核苷酸循环。但是，越来越清楚的是密码子和居住的特定激活 G蛋白中的突变可以通过不同的机制驱动肿瘤发生。换句话说，并非全部激活 突变是平等的。我们提出了旨在了解残留特定激活的研究 突变独特地改变了G蛋白结构，核苷酸循环，蛋白质识别和信号传导， 可能是开发拮抗G蛋白介导的精确医学方法的关键 肿瘤发生。我们的实验室还发现了通过后的G蛋白激活的新型机制 翻译修改和pH调节。我们提出了高度综合的多学科结构， 生化和细胞生物学方法来询问这些新型翻译后的作用 信号传导和肿瘤发生的修饰。我们的第二个主题专注于细胞粘附 蛋白质，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，并阐明荟萃的心肌病突变如何失调 心脏病中的收缩力。我们还将研究Vinculin和Metavinculin如何参与 丝状肌动蛋白以依赖性方式调节定向细胞运动。

项目成果

Cardiomyopathy Mutations in Metavinculin Disrupt Regulation of Vinculin-Induced F-Actin Assemblies.

Metavinculin 的心肌病突变破坏了 Vinculin 诱导的 F-肌动蛋白组装的调节。

• DOI: 10.1016/j.jmb.2019.02.024
• 发表时间: 2019
• 期刊: Journal of molecular biology
• 影响因子: 5.6
• 作者: Sarker,Muzaddid;Lee,HyunnaT;Mei,Lin;Krokhotin,Andrey;deLosReyes,SantiagoEspinosa;Yen,Laura;Costantini,LindseyM;Griffith,Jack;Dokholyan,NikolayV;Alushin,GregoryM;Campbell,SharonL
• 通讯作者: Campbell,SharonL