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（由申请人提供）：众所周知，细胞经常暴露于不断变化的机械张力水平，并且它们通过影响其细胞骨架组织、细胞形状以及通常其基因表达的信号传导途径对张力做出反应。张力通常是其基因表达。通过跨膜细胞粘附分子传递，这些粘附分子介导与细胞外基质或其他细胞的附着，这些粘附分子在细胞质表面与细胞骨架连接。或由细胞自身的肌动球蛋白收缩系统产生，许多由粘附分子张力引发的信号传导途径汇聚以调节 Rho 家族 GTP 酶，从而影响细胞行为的许多方面。这项资助的目标是了解其机械作用。不同粘附分子上的张力向 Rho GTPases 发出信号，重点是整合素、钙粘蛋白和紧密连接蛋白 JAM-A 通过磁珠对这些粘附分子施加张力，我们将识别。张力如何激活调节组织内鸟嘌呤核苷酸交换因子 (GEF) 和 GTP 酶激活蛋白 (GAP) 活性的途径，当一个细胞上的张力增加时，另一个细胞上的张力通常会同时降低，并且细胞需要能够做到这一点。为了响应观察到的机械张力的增加和减少，我们还将研究张力的释放如何影响调节 Rho GTP 酶活性的信号通路，张力可以增强屏障功能和连接组装，或者它可以增加渗透性并促进分解，即张力对连接的这些不同影响源自调节对张力的特定反应的额外信号通路的影响。，我们最近证明，孤立的细胞核会因张力而变硬，并且基于这些发现以及其他人的工作，阻断这种反应会影响细胞骨架组织和细胞迁移。破坏细胞核和细胞骨架之间的联系显示出类似的后果，我们将探索细胞核如何影响肌动蛋白细胞骨架内的整体张力，从而影响 Rho GTPases 的活性。