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Click on the image above to see some cells in motion and learn what makes them go.
A direct link between coronins and metastasis has not been confirmed, nor have migrastatin-type drugs been tested in a clinical setting. But two exciting concepts emerge from these studies: One is that actin accessory proteins modulate cytoskeletal rearrangements related to the motility of either healers or invaders. More significantly, these factors are diverse in the way they bind to and mold actin filaments, suggesting it may be possible to tinker with one interaction without perturbing another.
Targeting actin accessory proteins such as coronins might be a viable strategy in some immune disorders. In their coronin 1A mouse mutants, Cyster’s team showed that the signaling apparatus that lymphocytes use to find their way out of the thymus, a receptor called S1PR1, was intact. Yet cells remained paralyzed, as they couldn’t move their lamellipodia because of coronin defects, a situation analogous to the crippled chemotaxis displayed by Bear’s lamellipodia-less fibroblasts. These experiments suggest that the converse may also be true—the motility of cells with a perfectly normal cytoskeleton could be halted if the signals regulating it are blocked.
The signal detected by the S1PR1 receptor is a lipid called sphingosine-1-phosphate (S1P), present in blood and lymph. Cyster’s group has shown that when mature immune cells are ready to leave lymph nodes to travel to target sites, they move toward node exit doors by detecting faint traces of S1P in the circulation via the S1PR1 receptor. In work published September 30, 2011, in Science, his lab demonstrated the converse: that the receptor temporarily shuts down when immature cells need to get back in to the node.
In 2010, the FDA approved use of a fungal derivative drug called fingolimod (FTY720) to treat multiple sclerosis, a condition characterized by an autoimmune response against cells of the patient’s own nervous system. Chemically, fingolimod resembles S1P and likely works by acting as a decoy and binding to S1PR1, jamming its deployment signals to the cytoskeleton. “The current hypothesis is that FTY720 acts as an immunosuppressant by inhibiting lymphocyte egress from lymph nodes,” Cyster says. But he cautions that other mechanisms are also possible.
Yale University cell biologist Tom Pollard is a pioneer in cytoskeletal research. Not only did his lab group discover the Arp2/3 complex, his team was also the first to image fluorescently labeled actin filaments forming in real time. He remembers his fascination with amoebas in high school in the 1950s. “Back then I wanted to be a gremlin inside cells to see how these things happen.”
Four decades later, just such a gremlin would testify that crawling cells first advance some kind of protrusion, lean forward to extend it (often by actin branching), simultaneously demolish the rear scaffolding, and then let go and scrunch forward.
Lavish attention has been paid to step one, in part because protrusions exhibited by motile cells from amoebas to white blood cells called neutrophils are often big, easy to image, and highly photogenic. But Theriot is addressing the equally critical but much less documented “anti-event”—namely, how the back end of the cell lets go. To do so she studies keratocytes, highly motile cells that are found in the basal layer of the epidermis. As a model, Theriot uses fish scale keratocytes, which rapidly repair skin lesions.
Like fibroblasts, keratocytes project a lamellipodium filled with branched actin. But in 2010, Theriot reported in Nature that deconstruction of that meshwork, a process necessary to keep the treadmill moving, required recruitment of a form of myosin—a motor protein filament common in muscle—to the actin cytoskeleton at the rear of the cell, which literally ripped the actin fragments apart. Without that destruction, cells couldn’t move because their cytoskeleton was too stable, analogous to how coronin loss slows cells by making the cytoskeleton overly stiff.
How rapidly the cytoskeleton undergoes cycles of construction and demolition directly determines cell speed, which in keratocytes is roughly a fraction of a micron per second. Factoring into that equation is tissue adhesiveness. “If adhesion is too low, myosin activity keeps a cell running in place,” explains Theriot. “But on a surface that is too sticky, keratocytes have difficulty pulling up their backside to glide along.”