Investigating E-cadherin Mechanotransduction

研究 E-钙粘蛋白机械转导

• 批准号: 9907024
• 负责人: Alicia Salvi
• 金额: $ 3.11万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-21 至 2022-01-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9907024
• 关键词: 6-Phosphofructokinase; Actins; Actomyosin; Adhesions; Affect; Aldehyde-Lyases; Area; Binding; Biochemical; Biological; Cadherins; Cell membrane; Cell surface; Cells; Complex; Coupled; Coupling; Cytoskeleton; Data; Diabetes Mellitus; Disease; E-Cadherin; Enzymes; Epithelial; Epithelium; Event; Exposure to; F-Actin; Generations; Glucose; Glucose Transporter; Glycolysis; Goals; Growth; Insulin; Intercellular Junctions; Laboratories; Link; Malignant Neoplasms; Mediating; Metabolic; Molecular; Muscular Dystrophies; Pathway interactions; Physiological; Process; Production; Psychological reinforcement; Research; SLC2A1 gene; Signal Pathway; Signal Transduction; Testing; Transducers; Work; adhesion receptor; base; cost; experience; glucose metabolism; glucose uptake; insight; mechanical force; mechanotransduction; novel; oxidation; recruit; response; rho GTP-Binding Proteins; shear stress; transmission process; virtual

Project Summary/Abstract All cells experience force. These forces are sensed by cell surface adhesion receptors and trigger robust actin cytoskeletal rearrangements and growth of the associated adhesion complex to counter the applied forces. This process is known as cell stiffening or reinforcement. The actin re-arrangements necessary for stiffening are energetically costly suggesting that mechanisms coupling force transduction and energy production exist. Previously our laboratory identified a mechanism for coupling force transmission and energy utilization. We demonstrated that, in response to force, AMPK is recruited and activated at the E-cadherin adhesion complexes, thereby stimulating actomyosin contractility, glucose uptake, and ATP production. This increase in glucose uptake and ATP provides the energy necessary to grow the adhesion complexes and reinforce the actin cytoskeleton. Despite this advancement, how mechanical force modulates glucose uptake and glucose metabolism is not fully understood. This study aims to determine how glucose transporter-1 (GLUT1) affects force-induced metabolic changes and cell stiffening. Here we suggest that GLUT1 is the force-sensitive glucose transporter responsible for the glucose uptake necessary for the growth of adhesion complexes and reinforcement of the actin cytoskeleton. In further support of this notion, we show that GLUT1 is recruited to the cell-cell junctions and forms a complex with E-cadherin in response to force. Furthermore, we present evidence that inhibition of GLUT1 blocks force-induced cell stiffening. A second goal of the proposed work in this study is to assess how glucose metabolism is coupled to E-cadherin mediated cytoskeleton rearrangements. Multiple glycolytic enzymes are bound to filamentous actin (F-actin), such as aldolase and phosphofructokinase-1. Previous studies have demonstrated that F-actin bound aldolase is released upon insulin stimulated actin remodeling. We propose that the application of force to E-cadherin causes the release of F-actin-bound glycolytic enzymes, such as aldolase and PFK. Additionally, we suspect that cytosolic release of these enzymes mediates the increase and localization of glycolysis, necessary for force-induced energy production. This study proposes a novel connection between glucose metabolism and the energy-intensive process of force-induced cell stiffening.

项目概要/摘要 所有细胞都会受到力。这些力被细胞表面粘附受体感知并触发强大的 肌动蛋白细胞骨架重排和相关粘附复合物的生长以对抗所施加的力。 这个过程被称为细胞硬化或强化。硬化所需的肌动蛋白重新排列是 能量消耗巨大，表明存在耦合力传导和能量产生的机制。 此前，我们的实验室确定了一种耦合力传递和能量利用的机制。我们 证明，作为对力的反应，AMPK 在 E-钙粘蛋白粘附复合物上被招募并激活， 从而刺激肌动球蛋白收缩性、葡萄糖摄取和 ATP 产生。这种血糖升高 摄取和 ATP 提供生长粘附复合物和强化肌动蛋白所需的能量 细胞骨架。尽管取得了这一进步，但机械力如何调节葡萄糖摄取和葡萄糖 新陈代谢尚不完全清楚。本研究旨在确定葡萄糖转运蛋白 1 (GLUT1) 如何影响 力引起的代谢变化和细胞僵化。这里我们建议GLUT1是力敏感的葡萄糖 转运蛋白负责粘附复合物生长所需的葡萄糖摄取和 肌动蛋白细胞骨架的强化。为了进一步支持这一观点，我们表明 GLUT1 被招募到 细胞与细胞连接并与 E-钙粘蛋白形成复合物以响应力。此外，我们还提供证据 抑制 GLUT1 可以阻止力诱导的细胞硬化。本研究拟议工作的第二个目标是 评估葡萄糖代谢如何与 E-钙粘蛋白介导的细胞骨架重排耦合。多种的 糖酵解酶与丝状肌动蛋白 (F-肌动蛋白) 结合，例如醛缩酶和磷酸果糖激酶-1。 先前的研究表明，F-肌动蛋白结合醛缩酶在胰岛素刺激肌动蛋白后释放 重塑。我们建议对 E-钙粘蛋白施加力会导致 F-肌动蛋白结合的糖酵解释放 酶，例如醛缩酶和PFK。此外，我们怀疑这些酶的胞质释放介导 糖酵解的增加和局部化，这是力诱导能量产生所必需的。本研究提出 葡萄糖代谢与力诱导细胞能量密集过程之间的新联系 硬化。