How Cells Turn Force Into Signals

Cells constantly detect physical cues in their environment, but their responses are biochemical. That creates a long-standing question in cell biology: how does mechanical information become a molecular signal? The answer matters for cancer and other diseases, and Gregory M. Alushin’s lab at Rockefeller University has been studying the problem for more than a decade.

In the new study, Alushin and colleagues used technical advances they developed to show for the first time how myosin compression of actin filaments can trigger signaling. Myosin, a motor protein, squeezes actin filaments in the cytoskeleton into coils, and protein sensors associated with cell adhesion detect that change and gather at specific sites inside the cell. The findings, published in Nature, provide what Alushin called “the first snapshot of a mechanical signaling complex in action.”

The cytoskeleton helps cells transmit, receive, and process physical and biochemical information. Actin filaments are a major structural component, and myosin motors tug, twist, and compress them. Earlier work from the lab had shown that pulling on actin filaments with myosin improved binding to alpha-catenin, a protein sensor that helps build physical connections between cells, but the reason for that effect remained unknown.

To investigate further, the team adapted cryo-EM methods so they could secure myosin motors to a grid, add ATP, and flash-freeze the system while myosin interacted with nearby actin filaments. Because myosin motors fire randomly, this approach let the researchers capture several states at once. They also repeated the experiment without ATP to compare active and inactive conditions, allowing them to infer that the structural changes came from motor activity.

The surprise was that compression, not tension, was the key signal. When myosin compressed actin filaments, the filaments formed spirals, and that shape activated the alpha-catenin sensors. The effect was localized, because only some segments of the network were under compression at any given time as the motors operated asynchronously.

First author Xiaoyu Sun also used computer simulations to test tension, torsion, and compression in different directions and at different strengths. “This was also tricky,” Sun said. “It wasn’t computationally difficult, but it required us to figure out how to capture the dynamics of a process that’s happening at an intermediate length scale— between the atomic level and the subcellular scale.”

“What studies like ours do is provide a way to potentially interpret which processes could be going wrong in certain diseases,” Alushin added. “At this level, causes are usually mysterious—for instance, why would having too much of a particular force on a protein be bad? Is it responding to these types of changes in the wrong way? Understanding the correct function of a process allows you to rationally design ways to correct dysfunctions in that process.”