Molecular Mechanisms Underlying E-cadherin Mechanotransduction

项目摘要 所有的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， 如上皮钙粘蛋白，它将细胞与其邻近细胞连接起来。E-cadherin对力的反应是 激活细胞内的信号通路。这些通路触发新的细胞-细胞粘附的形成 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 重排在能量上是昂贵的。我们最近发现， 细胞骨架重排由AMP活化蛋白激酶（AMPK）提供。AMPK是一个主调节器 新陈代谢的过程。当对E-钙粘蛋白施加力并发出ATP信号时，它被激活。ATP产生的燃料 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、生物物理学和细胞 生物学方法，在这个建议中，我们将开发一个范式，如何机械转导和 新陈代谢是协调的。我们将确定如何：（1）葡萄糖被吸收到细胞中以响应力，（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，和（4）从E-钙粘蛋白传递的力调节整体细胞代谢。通过 这项工作，我们打算提供一个从根本上新的图片的相互联系的途径， 机械传导这种新的范例可以应用于更好地理解其他机械敏感性 系统.此外，它将告知疾病缺陷的性质，并确定预防代谢缺陷的策略。 干扰.

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.