Molecular Mechanisms Underlying E-cadherin Mechanotransduction

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 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 fuels the cytoskeletal changes necessary for cells to resist external forces. In this renewal, our goal is to advance the paradigm for how mechanotransduction and metabolism are coordinated. We will address how: (1) force stimulates glucose metabolism, (2) glycolysis localized to regions of the cell where the actin cytoskeleton is reinforced, (3) actin is polymerized to allow for cytoskeletal reinforcement, and (4) the uncoupling of metabolism and mechanotransduction affects physiology. When this work is complete, significant advances in understanding of the linkages between mechanotransduction and metabolism will emerge. Our proposed animal studies examining uncoupling mechanotransduction and metabolism in vivo have the potential to provide new insight into physiology. The use of sophisticated assays will provide a novel understanding of the relationship between metabolic enzymes and the actin cytoskeleton. These studies, combined with our conceptually innovative observation that PFK-M is the only force sensitive PFK1 isoform, have the potential to call for a re-evaluation of published work and are key to informing the nature of the defects that might be present in disease.