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 motilitythe 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,
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:
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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).