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.