Rac Activation and Cell Motility

By Jason Socrates Bardi

Anyone who has ever seen a video of a neutrophil chasing a bacterium cannot help but to be impressed with the persistence of these phagocytic blood cells. Like a cat chasing a mouse, the neutrophil chases the bacterium around the "corners" of cells and other obstacles until it catches, engulfs, and destroys the pathogen as part of the body's innate immune response.

Behind this amazing microscopic drama is the important physiological phenomenon of cell motility. In addition to its crucial role in the innate immune response, cell motility is important for such diverse physiological situations as wound healing, angiogenesis, metastasis in cancer, and neuronal development. Scientists have for years sought the master regulators of cell motility—the molecules driving the process that have their hands on the steering wheels and feet on the gas pedals.

When cells move, their movement is driven by the assembly and polymerization of actin at the leading edge of the cells and the myosin-mediated contraction in the tail of the cells. The dynamics of both of these processes must be highly orchestrated so that the cell can move smoothly, change directions, and stop.

In a recent paper published in the journal Current Biology, Professor Gary Bokoch and his colleagues at The Scripps Research Institute show that one of the molecules that is controlling these dynamics may be Rac, a small GTP-binding protein. Bokoch and his colleagues found that Rac is spatially and temporally regulated to coordinate leading-edge extension and tail contraction during the "chemotactic" motility of human neutrophils.

Using a fluorescence resonance energy transfer-based technique, Bokoch and his colleagues were able to detect the formation of active Rac-GTP and show that Rac is dynamically activated during motility. Specifically, Bokoch and his colleagues showed that Rac is activated at specific times and in specific locations in the extending leading edge. In conjunction with data obtained by introduction of mutant Rac proteins, they propose that Rac establishes and maintains the leading edge of crawling neutrophils.

Surprisingly, the group also found activated Rac in the retracting tail of motile neutrophils, suggesting that Rac might be involved in the contraction events that pull the retracting tail forward. This was verified by demonstrating that an inhibitory form of Rac blocked tail retraction. Bokoch and his colleagues also found that Rac activity is modulated by cell adhesion, suggesting that integrin-mediated signals probably play important roles in regulating Rac activation during motility.

To read the article, "Spatial and Temporal Analysis of Rac Activation during Live Neutrophil Chemotaxis" by Elisabeth M. Gardiner, Kersi N. Pestonjamasp, Benjamin P. Bohl, Chester Chamberlain, Klaus M. Hahn, and Gary M. Bokoch, please see:

http://www.current-biology.com/cgi/content/abstract/12/23/2029/

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These confocal images of human neutrophils stained for F-actin (top) and Rac2 antibody (bottom) show that Rac2 becomes activated and re-localizes to areas of actin polymerization. The relative intensity is shown on the attached color scale from blue (low) to red (high).