The Key to Cell Motility
By Jason Socrates
Bardi
Scientists at The Scripps Research Institute have described
the regulatory mechanism of an important human protein called
Rac that controls a number of biological processes and is
directly implicated in several human diseases.
Rac is involved in tumor growth and metastasis in cancer;
it is important for the proper functioning of immune cells
and is necessary for the innate immune response; it is required
for neuronal function and has been implicated in neurological
diseases and mental retardation.
"Understanding the basic mechanism of how Rac activation
is regulated," says Professor Gary Bokoch, "is a key to understanding
[these sorts of diseases]."
In an article appearing in the latest issue of the journal
Molecular Cell, Bokoch and his colleagues Celine DerMardirossian
and Andreas Schnelzer at Scripps Research have described the
molecular mechanism whereby Rac activation is regulated by
a molecule called Pak.
The Rac-Pak Connection and Its Relevance to Disease
Rac is one of the most important members of a family of
proteins known as the Rho GTPases. This family of proteins
binds to a small metabolic product called GTP, which acts
as a critical regulator of Rho GTPase activity. This enables
Rac to regulate a wide variety of cellular functions that
span the entire gamut of a cell's life, from its initial growth
and differentiation, to its movement and division, and finally
to its death. They are important for gene expression, and
they play crucial roles in the ability of innate immune cells
to make lethal responses to bacterial infections, of skin
cells to cover wounds during the healing process, of vascular
cells to make new blood vessels, of cancer cells to metastasize,
and of neurons to develop and make proper connections in the
brain.
Two years ago Bokoch and his Scripps Research colleagues
discovered that Rac is one of the master regulators of cell
motility—the molecules driving the process that places
the cell's "hands" on the steering wheels and "feet" on the
gas pedals. They discovered that Rac is spatially and temporally
regulated during leading-edge extension and tail contraction
during the movement of human neutrophils—the phagocytic
blood cells that chase down, engulf, and destroy bacterial
pathogens as part of the body's innate immune response.
One of the big questions that remained unanswered, however,
was how Rac was regulated to become active in the first place.
What were the master switches that control the activity of
Rac and the fundamental cell processes it controls?
All that was known until recently was that inside cells,
Rac is controlled by a protein known as RhoGDI, which is in
the cell's cytosol. Rac is inactive in resting cells because
it is bound to RhoGDI. This keeps the Rac in the cytosol and
away from the cellular membrane, where Rac's molecular targets
reside. When the cell receives activation signals, the Rac
GTPases will dissociate from the RhoGDI in the cytosol and
move to the ruffles at the edges of the cell where they are
needed. Thus, Rac must be released from RhoGDI for Rac to
become active.
"Nobody had any idea how this happened," says DerMardirossian.
Now Bokoch, DerMardirossian, and Schnelzer have discovered
the mechanism whereby Rac is released from RhoGDI. In their
current study, they show in vitro and in vivo
that Rac is released from RhoGDI by an enzyme called p21-activated
kinase (Pak). Pak is a kinase enzyme. Its job in the cell
is phosphorylation—to attach phosphate groups to other
molecules inside the cells in order to modify their function.
Pak attaches its phosphate to two serine residues within
the portion of RhoGDI that Rac normally binds to. These bulky
and negatively charged phosphates disrupt the normally cozy
bond Rac shares with RhoGDI. Freed from the RhoGDI, Rac can
then become activated and move about the cell to act on its
target molecules and regulate cell function.
Interestingly, one of the targets of active Rac is the enzyme
Pak itself. This suggests that Pak and Rac can participate
in a positive feedback loop whereby active Rac stimulates
Pak, and the active Pak then induces more Rac activation.
Such regulation may be important for maintaining continuous
cell movement.
The article, "Phosphorylation of RhoGDI by Pak1 mediates
dissociation of Rac GTPase" by Celine DerMardirossian, Andreas
Schnelzer, and Gary M. Bokoch appears in the July 2, 2004
issue of the journal Molecular Cell. See http://www.molecule.org.
This work was funded through a grant from the National Institutes
of Health, by a German Academic Exchange fellowship, and by
an American Heart Association—Western affiliate fellowship.
Send comments to: jasonb@scripps.edu
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