Molecular Mechanisms Underlying E-cadherin Mechanotransduction

项目总结 所有的细胞和有机体都受到机械力的作用。这些力是由细胞表面的感受器感知的， 例如上皮性钙粘附素，它将细胞与它们的邻居联系起来。E-钙粘附素对压力的反应 激活细胞内的信号通路。这些途径触发了新的细胞间黏附的形成 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 重新安排是耗资巨大的。我们最近发现，燃料所需的能量 细胞骨架重排是由AMP激活的蛋白激酶(AMPK)提供的。AMPK是一个主要的监管者 新陈代谢。当用力作用于E-钙粘素并发出ATP信号时，它就会被激活。三磷酸腺苷生产的燃料 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， 将E-钙粘素的机械转导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，在这个建议中，我们将开发一个范例，如何机械转导和 新陈代谢是协调的。我们将确定：(1)葡萄糖是如何被细胞吸收的，(2) 肌动蛋白细胞骨架的新陈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，以及(4)E-钙粘蛋白传递的力调节全球细胞代谢。穿过 在这项工作中，我们打算提供一幅关于相互关联的路径的根本新图景 机械转导。这一新的范式可以应用于更好地理解其他机械敏感 系统。此外，它还将告知疾病缺陷的性质，并确定预防新陈代谢的策略 骚乱。

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.