Scientists at the Johns Hopkins University School of Medicine say they have learned how individual “molecular muscles” within cells respond to different types of force. They believe their finding may explain how cells “feel” the environment and appropriately adapt their shapes and activities.
The researchers published their discovery (“Molecular mechanisms of cellular mechanosensing”) online on October 20 in Nature Materials. The work specifically sheds light on how forces outside of cells are translated into internal signals, according to the investigators.
“For the first time, we are able to explain what a cell can do through the individual workings of different proteins and because all cells use information about the forces in their environments to direct decisions about migration, division, and cell fate,” notes Douglas Robinson, Ph.D., professor of cell biology at Johns Hopkins. “This work has implications for a whole host of cellular disorders including cancer metastasis and neurodegeneration.”
Cells have a kind of skin through which they sense their environments, continues Dr. Robinson. “The hardness of their surroundings, various pressures, pushing and pulling, all of those forces are ‘felt’ by different proteins underneath the ‘skin’ of cells.”
How cells sense and react to these forces is poorly understood. The details are being filled in by a computer model created by the team. To develop it, the researchers worked with the proteins that feel the environment, part of a network that wraps around the inside edge of the cell, i.e., the cytoskeleton. The most prevalent among the proteins is actin, which forms short rods held together in a crisscross pattern by linker proteins. There are also anchoring proteins that attach the actin rods to the cell’s skin (plasma membrane).
Together, these components act as the molecular muscles, allowing the cell to change its shape when needed as, for example, when it squeezes through small spaces to migrate to a different part of the body, or when it pinches itself in half to divide.
The team linked each of 37 cytoskeletal proteins to a fluorescent tag that marked its position in the cell. They then applied pressure to the cells, using a tiny glass tube to gently suck on the cells, deforming them and creating a neck as might occur if the hose of a vacuum cleaner sucked on a lightly inflated balloon.
As they recorded a protein's movements under the microscope, they analyzed how each protein responded to the deformation of the cell: where each protein moved, how much of it moved, and how quickly it got there.
There were two types of force in play during the experiments, says Tianzhi Luo, Ph.D., the primary author of the report. The tip of the neck experienced dilation: The overall shape was maintained while the area expanded. The elongated portion of the neck experienced shear: The area was maintained but the shape changed, like blocks of gelatin when they shake. What the team discovered were three different linker proteins that responded to these forces by moving into the neck.
“By combining molecular and mechanical experimental perturbations with theoretical multiscale modeling, we decipher cortical mechanosensing from molecular to cellular scales,” wrote the scientists in the Nature Materials article. “We show that forces are shared between myosin II and different actin crosslinkers, with myosin having potentiating or inhibitory effects on certain crosslinkers.”
Unexpectedly, each moved to a different part of the neck in response to the different forces. Myosin II acts like a spring that can pull actin rods together. It responded to dilation and moved in to cover the tip of the neck to help counteract the stretch in that area.
Alpha-actinin, which reinforces the cytoskeleton by forming parallel bundles that stick to actin rods, also responded to dilation but limited its range to the very tip of the neck. Finally, filamin, which acts like a moveable hinge to connect actin rods in V-shaped angles, responded to the shear force and relocated just to the long part of the neck.