Molecular Mechanisms Underlying E-cadherin Mechanotransduction

E-钙粘蛋白机械转导的分子机制

• 批准号: 10406888
• 负责人: Kris A DeMali
• 金额: $ 37.81万
• 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: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406888
• 关键词: 5' -AMP-activated protein kinase; Actins; Biochemical; Biological; Biophysics; Cell Surface Receptors; Cell-Cell Adhesion; Cells; Cellular Metabolic Process; Cytoskeleton; Defect; Disease; E-Cadherin; Glucose; Homeostasis; Link; Malignant Neoplasms; Mechanics; Metabolic; Metabolism; Molecular; Muscular dystrophy cardiomyopathy; Nature; Organism; Pathway interactions; Process; Protein Kinase; Psychological reinforcement; Signal Pathway; Signal Transduction; System; Work; cost; insight; mechanical force; mechanotransduction; prevent; response

PROJECT SUMMARY All cells and organisms are subjected to mechanical forces. These forces are sensed by cell surface receptors, such as the epithelial (E)-cadherin, which links cells to their neighbors. E-cadherin responds to force by activating signaling pathways inside the cell. These pathways trigger the formation of new cell-cell adhesions and stimulate the rearrangement and reinforcement of the actin cytoskeleton. These actin cytoskeletal rearrangements are energetically costly. We recently discovered that the energy required to fuel the cytoskeletal rearrangements is provided by AMP-activated protein kinase (AMPK). AMPK is a master regulator of metabolism. It is activated when force is applied to E-cadherin and signals for ATP. The ATP produced fuels the cytoskeletal changes necessary for cells to resist external forces. Thus, AMPK is mechanosensitive and links E-cadherin mechanotransduction to energy homeostasis. Using biochemical, biophysical, and cell biological approaches, in this proposal we will develop a paradigm for how mechanotransduction and metabolism are coordinated. We will identify how: (1) glucose is taken up into the cell in response to force, (2) metabolism and reinforcement of the actin cytoskeletal are spatially coordinated, (3) different magnitudes of force impact cell mechanics, and (4) forces relayed from E-cadherin adjust global cellular metabolism. Through this work, we intend to provide a fundamentally new picture of the interconnected pathways that govern mechanotransduction. This new paradigm can be applied to better understand other mechanosensitive systems. Additionally, it will inform the nature of disease defects and define strategies to prevent metabolic disturbances.

项目概要 所有细胞和生物体都受到机械力的作用。这些力被细胞表面受体感知， 例如上皮 (E)-钙粘蛋白，它将细胞与其相邻细胞连接起来。 E-钙粘蛋白通过以下方式响应力 激活细胞内的信号通路。这些途径触发新的细胞间粘附的形成 并刺激肌动蛋白细胞骨架的重排和强化。这些肌动蛋白细胞骨架 重新安排的成本非常高昂。我们最近发现，提供燃料所需的能量 细胞骨架重排由 AMP 激活蛋白激酶 (AMPK) 提供。 AMPK 是一个主调节器 的新陈代谢。当对 E-钙粘蛋白施加力并发出 ATP 信号时，它就会被激活。 ATP 产生燃料 细胞抵抗外力所必需的细胞骨架变化。因此，AMPK 是机械敏感的并且 将E-钙粘蛋白机械转导与能量稳态联系起来。利用生物化学、生物物理和细胞 生物学方法，在本提案中，我们将开发一个范式来说明机械传导和 新陈代谢是协调的。我们将确定如何：(1) 葡萄糖在力的作用下被吸收到细胞中，(2) 肌动蛋白细胞骨架的代谢和强化在空间上是协调的，（3）不同程度的 力影响细胞力学，(4) E-钙粘蛋白传递的力调节整体细胞代谢。通过 在这项工作中，我们打算提供一幅全新的图景，展示治理的相互关联的路径 力传导。这种新的范式可以用于更好地理解其他机械敏感的 系统。此外，它将告知疾病缺陷的性质并确定预防代谢的策略 干扰。