Molecular Mechanisms Underlying E-cadherin Mechanotransduction

E-钙粘蛋白机械转导的分子机制

基本信息

批准号：
10623237
负责人：
Kris A DeMali
金额：
$ 38.16万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
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

项目摘要

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.

项目摘要所有细胞和生物都受到机械力。这些力是通过细胞表面受体感测的例如上皮（E） - 钙粘蛋白，将细胞与邻居联系起来。电子辅助蛋白对武力作出反应激活电池内的信号通路。这些途径触发了新细胞细胞粘附的形成并刺激肌动蛋白细胞骨架的重排和增强。这些肌动蛋白细胞骨架重排的能量成本高昂。我们最近发现，加油所需的能量细胞骨架重排由AMP激活的蛋白激酶（AMPK）提供。 AMPK是主监管机构代谢。当将力施加到E-钙粘蛋白和ATP信号时，它会被激活。 ATP产生的燃料细胞抵抗外力所需的细胞骨架变化。因此，AMPK是机械敏感的，并且将电子 - 钙粘蛋白机械转移与能量稳态联系起来。使用生化，生物物理和细胞生物学方法，在此提案中，我们将开发一个范式，以实现机械转移和代谢是协调的。我们将确定：（1）响应力的葡萄糖被吸收到细胞中，（2）肌动蛋白细胞骨架的代谢和增强在空间上是协调的，（3）不同的幅度力撞击细胞力学和（4）从电子钙黏着蛋白中继的力调节全球细胞代谢。通过这项工作，我们打算提供有关管理的相互联系的途径的根本新图片机械转导。这种新范式可以应用于更好地理解其他机械敏感的系统。此外，它将为疾病缺陷的性质提供信息，并定义防止代谢的策略干扰。