Cell Adhesion and the Regulation of Rho GTPases

细胞粘附和 Rho GTP 酶的调节

基本信息

批准号：
9040974
负责人：
Keith Burridge
金额：
$ 45.19万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
1981
资助国家：
美国
起止时间：
1981-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9040974
关键词：
Actins Actomyosin Adherens Junction Affect Attention Behavior Cadherins Cell Adhesion Cell Adhesion Molecules Cell Nucleus Cell Shape Cell surface Cell-Matrix Junction Cells Complex Contractile System Cytoskeletal Modeling Cytoskeleton Disease Dominant-Negative Mutation Exhibits Extracellular Matrix Face Family Feedback Fibrosis Functional disorder Future GTPase-Activating Proteins Gene Expression Goals Grant Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Health Homeostasis Integrins Intercellular Junctions JAM protein Lead Link Malignant Neoplasms Mechanics Mediating Membrane Morphogenesis Morphology Movement Muscular dystrophy cardiomyopathy Organelles Pathway interactions Permeability Proteins Regulation Role Signal Pathway Signal Transduction Signaling Protein Source Stretching System Testing Tight Junctions Tissues Work Wound Healing cell behavior cell motility emerin live cell imaging magnetic beads migration response rho rho GTP-Binding Proteins shear stress

项目摘要

DESCRIPTION (provided by applicant): It is well established that cells are frequently exposed to changing levels of mechanical tension, and that they respond to tension through signaling pathways that affect their cytoskeletal organization, their cell shape and often their gene expression. Tension is usually transmitted through membrane-spanning cell adhesion molecules that either mediates attachment to the extracellular matrix or to other cells. At their cytoplasmic face these adhesion molecules connect with the cytoskeleton. Tension on adhesion molecules can derive from external sources or be generated by a cell's own actomyosin contractile system. Many of the signaling pathways initiated by tension on adhesion molecules converge to regulate Rho family GTPases, which in turn, influence many aspects of cell behavior. The goal of this grant is to understand how mechanical tension on different adhesion molecules signal to Rho GTPases, focusing on integrins, cadherins and the tight junction protein JAM-A. Applying tension to these adhesion molecules via magnetic beads, we will identify how tension activates pathways that regulate the activities of guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). Within a tissue as tension increases on one cell there is often a parallel decrease in tension on another, and cells need to be able to respond to both increasing and decreasing levels of mechanical tension. Consequently, we will also investigate how release of tension affects the signaling pathways that regulate Rho GTPase activity. With adherens junctions and tight junctions, tension can either enhance barrier function and junction assembly, or it can increase permeability and promote disassembly. We will test the hypothesis that these divergent effects of tension on junctions derive from the influence of additional signaling pathways that modulate the specific response to tension. Mechanical tension is also relayed from the cell surface to the nucleus, which is linked to the cytoskeleton via multiple connections. We have shown recently that isolated nuclei stiffen in response to tension and that blocking this response affects cytoskeletal organization as well as cell migration. Building on these findings, as well as on the work of others showing similar consequences from disrupting the links between the nucleus and the cytoskeleton, we will explore how the nucleus contributes to the overall tension within the actin cytoskeleton, thereby influencing the activities of Rho GTPases.

描述（由适用提供）：众所周知，细胞经常暴露于机械张力的变化水平，并且它们通过影响其细胞骨架组织，细胞形状以及通常的基因表达的信号通路来应对张力。张力通常是通过跨膜细胞粘附分子传播的，该分子介导附着在细胞外基质或其他细胞上。在它们的细胞质上，这些粘合剂分子与细胞骨架相连。粘合分子的张力可以源自外部来源，也可以由细胞自身的肌动球蛋白收缩系统产生。张力在粘合分子上引发的许多信号通路会融合以调节Rho家族GTPases，这反过来影响细胞行为的许多方面。该赠款的目的是了解不同粘合分子上的机械张力如何向Rho GTPase发出信号，重点是整联蛋白，钙粘蛋白和紧密连接蛋白JAM-A。通过磁珠将张力应用于这些粘合分子，我们将确定张力如何激活调节鸟嘌呤核交换因子（GEFS）和GTPase激活蛋白（GAP）活性的途径。随着一个细胞的张力增加，在组织内通常会平行于另一种细胞的张力降低，并且细胞需要能够响应机械张力水平的增加和降低。因此，我们还将研究张力的释放如何影响调节Rho GTPase活性的信号传导途径。借助粘附连接和紧密的连接，张力可以增强屏障功能和连接组件，也可以提高渗透率并促进拆卸。我们将测试以下假设：张力对连接的这些不同影响来自调节特定响应张力的其他信号通路的影响。机械张力也从细胞表面传递到核us，该核素通过多个连接与细胞骨架有关。我们最近表明，孤立的核对紧张的响应加强，而阻止这种反应会影响细胞骨架组织以及细胞迁移。在这些发现以及其他人的工作的基础上，由于破坏了细胞核与细胞骨架之间的联系所产生的类似后果，我们将探讨核如何促进肌动蛋白细胞骨架内的整体张力，从而影响Rho GTPases的活性。