New insights into the molecular regulation of mechanotransduction

Project summary
Cells exist in a physical world, and there is often a physical basis for human function and disease.
Mechanotransduction is the molecular process by which cells sense and respond to mechanical signals in their
environment. Abnormal mechanotransduction can contribute to many human diseases including asthma, heart
failure, osteoporosis, and cancer. Thus, it is crucial to understand the molecular basis of mechanotransduction
and how these signaling pathways are disrupted during disease. Integrin receptors are critical regulators of
mechanotransduction at the plasma membrane that signal through the assembly supramolecular complexes
termed “focal adhesions.” Focal adhesions physically connect the actin cytoskeleton to the extracellular
environment, and forces generated in the actin cytoskeleton are transmitted across focal adhesions to drive
tissue morphogenesis, cell movement, and extracellular matrix remodeling. Although the proper regulation of
focal adhesions is essential for integrin-dependent mechanotransduction, important questions about their
formation and function remain unanswered. We do not understand how focal adhesions form, how they grow, or
how their molecular composition is regulated. Cell-based experiments have led to conflicting observations, and
we have limited tools to understand how changing molecular composition can create focal adhesions with
specific chemical or physical characteristics that alter downstream signaling.
To address these important questions, Dr. Case has developed a novel biochemical reconstitution of
focal adhesions using purified proteins on supported lipid bilayers. This work identified seven proteins that are
sufficient to form focal adhesions through liquid-liquid phase separation. Studying integrin-dependent
mechanotransduction through the lens of phase separation could drive significant advances in the field. The
Case Lab will use a variety of experimental strategies to understand different aspects of integrin-dependent
mechanotransduction. They will directly test different models of mechanotransduction with biochemical
reconstitution and confirm the importance of any new in vitro observations with cell-based assays. They will
investigate how focal adhesions mature, how forces are transmitted across focal adhesions, and how the
biochemical composition of focal adhesions is regulated. This project will take advantage of a novel experimental
approach to challenge the current dogma about integrin-dependent mechanotransduction, and will reveal how
specific molecules regulate focal adhesion growth and composition.

Grant Number: 4DP2GM149549-02
NIH Institute/Center: NIH
Principal Investigator: Lindsay Case