Publications
For a complete listing of Dr.
Bokoch's publications, search the 
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Search PubMed: Bokoch
G or Bokoch GM
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Highlighted
Publications
1.
Knaus, U.G., Heyworth, P.G., Evans, T.,
Curnutte, J.T. and Bokoch, G.M.
Regulation of Phagocyte Oxygen Radical Production by the GTP-binding
Protein
Rac2. Science
254:1512-1515, 1991.
2.
Bokoch, G.M., Quilliam, L.A., Bohl, B.P.,
Jesaitis, A.J. and Quinn, M.T.
Inhibition of Rap1A Binding to Cytochrome b558 of
the NADPH
Oxidase
by
Phosphorylation of Rap1A. Science
254:1794-1796, 1991.
3. Knaus,
U.G., Morris, S., Dong, H-J.,
Chernoff, J., Bokoch, G.M. Regulation of p21-activated Kinases
by Human
Leukocyte G Protein-coupled Receptors.
Science 269:221-223, 1995.
4. Rudel,
T. and Bokoch, G.M.
Membrane and Morphological Changes in Apoptotic Cells Regulated by
Caspase-medicated Activation of PAK2. Science.
276:1571-1574, 1997.
5. Sanders,
L.C., Matsumura, F., Bokoch,
G.M. and de Lanerolle, P. Inhibition of Myosin Light Chain Kinase
by
p21-Activated Kinase (PAK). Science
283:2083-2085, 1999.
6. Edwards,
D.C., Sanders, L.C., Bokoch,
G.M. and Gill, G.N. Activation of LIM Kinase by Pak1 Couples
Rac/Cdc42
GTPase Signaling to Actin Cytoskeletal Dynamics. Nature
Cell Biol., 1(5):253-259, 1999.
7. Diebold,
B.A. and Bokoch, G.M. Molecular
Basis for Rac2 Regulation of
Oxidant Production by the Phagocyte NADPH Oxidase.
Nature
Immunol., 2 (3):211-215, 2001.
8. Krendel,
M.,* Zenke, F.T.*, Bokoch, G.M. Nucleotide
Exchange Factor GEF-H1 Mediates Cross-Talk between Microtubules and the
Actin
Cytoskeleton. Nature Cell Biol., 4:
294-301, 2002. (*Equal contributions) (cover)
9.
DerMardirossian, C., Schnelzer, A., Bokoch,
G.M. Phosphorylation
of RhoGDI by PAK1 mediates dissociation of Rac
GTPase. Mol.
Cell 15: 117-127, 2004.
10.
Gohla A., Birkenfeld J., Bokoch
G.M.
Chronophin, a novel HAD-type serine protein phosphatase, regulates
cofilin-
dependent
actin dynamics. Nat.
Cell Biol. 7(1): 21-29, 2005.
Research
Accomplishments
Gary M. Bokoch, Ph.D
The research in my group has centered
around two major themes: cellular regulation by Rho GTPases, and signal
transduction in human neutrophils.
Human neutrophils are critical mediators
of innate immunity. Signaling initiated
by the binding of chemoattractants and chemokines to cell surface
receptors
induces the chemotactic migration of neutrophils to inflammatory sites
and,
ultimately, bacterial killing via the generation of reactive oxygen
species
(ROS) through the NADPH oxidase. My
laboratory has been at the forefront of elucidating chemoattractant
signaling
in human neutrophils, particularly signaling via Rho GTPases in these
cells,
for many years. Of particular note, our
work has played a seminal role in defining the regulation of neutrophil
NADPH
oxidase by Rac2 GTPase. We initially identified Rac2 as, at the time,
the
missing cytosolic regulatory component of the NADPH oxidase. We
elucidated the regulation of the oxidase
and of Rac2 itself in a series of studies.
More recently, we demonstrated a direct regulatory interaction of Rac2
with the cytochrome b component of the oxidase, leading to a completely
novel
paradigm for oxidase regulation by Rac.
Furthermore, we showed that under physiological conditions, Rac2 was
the
key regulator of NADPH oxidase output.
This body of work has greatly advanced our understanding of this aspect
of the immune response.
We have also contributed
substantially to
current understanding of how Rho GTPases regulate the actin and
microtubule
cytoskeletons during process such as cell motility.
Our work on the Rac/Cdc42 effectors, the
p21-activated kinases (Paks) has established them as key mediators of
Rac
signaling to control actin dynamics. Our
studies identified roles of Paks in modulating cytoskeletal remodeling
induced
by Rho GTPases, and identified a number of key effector targets of Pak
action,
including Lim kinase (LIMK) and myosin light chain kinase (MLCK), among
others. Additionally, our work was
critical in identifying many of the other biological systems modulated
through
Pak action on specific target proteins. Recently, we used a biochemical
approach to identify a novel class of cofilin phosphatase capable of
regulating
actin dynamics downstream of Rho GTPases. Ongoing studies are
investigating the
regulation and biological roles of this novel phosphatase.
Our research has provided a molecular
basis for understanding crosstalk between the actin and microtubule
cytoskeletons. We showed that Pak was an important regulator of
microtubule
dynamics through phosphorylation of stathmin.
We identified the Rho GEF, GEF-H1, as a microtubule
binding-regulated
exchange factor that coupled microtubule dynamics to actin remodeling
in both
motility and cell division. Our current
research is attempting to understand how GEF-H1 is regulated by
phosphorylation,
and how it contributes to a number of biological activities critical
for normal
cell function. An overall theme of our
current research in this area is to relate Rho GTPase signaling both
spatially
and temporally in real time to cellular events, particularly those
involved in
cell motility. With this goal in mind,
we are investigating the basic regulation of the GTPase activation
cycle using
molecular and biophysical (imaging) approaches to investigate current
dogma
underlying Rho GTPase signaling.