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Molecular Mechanisms coordinating the actin and microtubule cytoskeletons

协调肌动蛋白和微管细胞骨架的分子机制

基本信息

批准号：
9096423
负责人：
JEFF GELLES
金额：
$ 33.87万
依托单位：
BRANDEIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9096423
关键词：
Actins Acute Lymphocytic Leukemia Adenomatous Polyposis Coli Adenomatous Polyposis Coli Protein Advanced Development Affinity Alzheimer&apos s Disease Area Automobile Driving Behavior Binding Binding Proteins Biochemical Biochemistry Biological CLIP-170 gene Cell Shape Cell physiology Cell-Cell Adhesion Cells Cellular Morphology Cellular biology Characteristics Colorectal Cancer Complex Cytoskeleton Defect Development Disease Enzymes Filament Fluorescence Fluorescence Microscopy Funding Gap Junctions Genes Genetic Goals Grant Growth Human Huntington Disease In Vitro Inherited Investigation Kinesin Kinetics Lead Length Life Link MLL gene Malignant Neoplasms Mediating Methods Microfilaments Microtubule Proteins Microtubule-Associated Proteins Microtubules Molecular Morphogenesis Motor Movement Mutation Neurodegenerative Disorders Parkinson Disease Pathway interactions Plus End of the Microtubule Polymers Positioning Attribute Process Proteins Reaction Recruitment Activity Regulation Regulatory Pathway Research Research Personnel Role System Techniques Testing Time Tissues Triad Acrylic Resin Tumor Suppressor Proteins Work actin capping protein cell motility design experience in vitro activity in vivo insight live cell imaging molecular imaging novel polymerization protein complex protein function public health relevance reconstitution research study single molecule tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The goal of this research is to determine how both the dynamics and spatial organization of the actin and microtubule cytoskeletons are coordinated by a group of five interacting mammalian proteins: APC, Dia1, EB1, CLIP-170, and capping protein. This work will define the functions and mechanisms of these proteins in microtubule-actin cross-regulation, and will thereby provide a deeper understanding of the molecular activities and interactions that underlie such processes as cell migration, cell adhesion, and cell and tissue morphogenesis. This project uses bulk biochemical experiments combined with novel multi-wavelength single molecule fluorescence methods that we have tailored to directly observe the mechanisms of complex multi- component regulatory systems in vitro. Further, the mechanisms deduced from the experiments in vitro will be tested in vivo to confirm that they are important for specific cellular functions of these proteins. The Specific Aims are: (1) Test the hypothesis that the microtubule plus end-binding protein EB1 directly regulates nucleation of actin filaments by APC-Dia1; (2) Test the hypothesis that the rate and duration of actin filament elongation is controlled by dynamic binding interactions of Dia1, capping protein, microtubules, and/or EB1 at barbed ends; and (3) Define the roles of APC, Dia1, EB1, and CLIP-170 in controlling microtubule plus end dynamics and in triggering ultrafast actin polymerization from microtubule plus ends.

描述（由申请人提供）：本研究的目标是确定肌动蛋白和微管细胞骨架的动力学和空间组织如何通过一组五种相互作用的哺乳动物蛋白进行协调：APC、Dia1、EB1、CLIP-170 和加帽蛋白。这项工作将定义这些蛋白质在微管-肌动蛋白交叉调节中的功能和机制，从而更深入地了解细胞迁移、细胞粘附以及细胞和组织形态发生等过程中的分子活动和相互作用。该项目使用大量生化实验与我们定制的新型多波长单分子荧光方法相结合，以直接观察体外复杂多组分调节系统的机制。此外，从体外实验推论的机制将在体内进行测试，以确认它们对于这些蛋白质的特定细胞功能很重要。具体目标是：（1）检验微管加末端结合蛋白EB1通过APC-Dia1直接调节肌动蛋白丝成核的假设； (2) 检验肌动蛋白丝伸长率和持续时间受倒刺末端 Dia1、加帽蛋白、微管和/或 EB1 动态结合相互作用控制的假设； (3) 定义 APC、Dia1、EB1 和 CLIP-170 在控制微管加末端动力学和触发微管加末端超快肌动蛋白聚合中的作用。