The effects of different amplitudes of force on AMPK signaling

All cells experience forces throughout their lifetimes. To survive cells need to sense and respond to these forces. Irregularities in a cell’s response to force can contribute to a variety of diseases such as cancer, asthma, and cardiovascular disease. The mechanisms cells use to respond to force are not fully understood. Gaining a better understanding of how cells respond to force can help further our understanding of how disruptions to this process lead to disease and provide insights to develop novel treatments.

In epithelial cells force is sensed by adhesion receptors like E-cadherin. To withstand the force, E-cadherin triggers energetically costly rearrangements of the actin cytoskeleton and growth adhesion complexes. Key to this process is AMPK, which continues the signaling pathway, leading to cytoskeletal rearrangements and an increase in glucose uptake to fuel the rearrangements. Much of the research done to date focuses on a narrow range of amplitudes of force; however, cells can experience a wide range of forces.

In this thesis, I investigate how cells respond to different amplitudes of force. More specifically, how AMPK signaling is altered by different amplitudes of force. In Chapter 1 I show AMPK alpha isoforms are not uniquely activated in response to different amplitudes of force. In Chapter 2 I demonstrate another AMPK activator, CAMKKβ, is important to cells’; ability to respond to force. These studies begin to extend our understanding of how cells sense and respond to force and provide insight as to defects in this process results in disease.