Cells experience force throughout their lifetimes. Cells sense force via adhesion receptors, such as the cadherins, which anchor cells to neighboring cells, and integrins, which tether cells to the underlying matrix. Both adhesion receptors respond to force by activating signaling pathways inside the cell. These pathways trigger growth of adhesion complexes and reinforcement of the cytoskeleton in order to resist the force. These activities are energetically costly. Thus, mechanisms are needed to couple force transmission and energy production.
In this thesis, I demonstrated force on cadherins activates a master regulator of energy homeostasis known as AMP-activated kinase (AMPK). In response to force, AMPK was recruited to the cadherins. AMPK promoted growth of the adhesion complex and cytoskeletal reinforcement by stimulating energy production in the cell. Additionally, AMPK formed a complex with vinculin—a protein that is recruited to both cadherins and integrins. I observed AMPK activation of vinculin dictates whether vinculin joins the cadherin complex. Conversely, AMPK activation has no bearing on vinculin recruitment to integrins.
This work provides three novel contributions: (1) the first link between energy production and force transmission, (2) a molecular mechanism for how AMPK increases adhesion complex growth, and (3) an explanation for how vinculin discriminates between cadherins and integrins.