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J Biol Chem, Vol. 274, Issue 25, 18055-18059, June 18, 1999
From the Department of Molecular and Structural Biology, Kyushu
University Graduate School of Medical Science, 3-1-1 Maidashi,
Higashi-ku, Fukuoka 812-8582, Japan
The small GTPase Rac participates in various
cellular events such as cytoskeletal reorganization. It has remained,
however, largely unknown about intracellular signaling pathways for Rac activation because of the lack of a simple and reliable assay to
estimate the activation. Here we describe a novel method to detect the
GTP-bound, active Rac in cells by pulling it down with the Rac-binding
domain of the protein kinase PAK. Experiments using this method reveal
that stimulation of human neutrophils with the
Gi-coupled receptor agonists
N-formyl-methionyl-leucyl-phenylalanine (fMLP) and
leukotriene B4 (LTB4) leads to a rapid and
transient increase in the GTP-bound state of Rac2, whereas phorbol
myristate acetate (PMA) causes a slow but more sustained activation of
Rac2. Pretreatment of cells with pertussis toxin results in defective activation of Rac2 in response to fMLP and LTB4, indicating
that coupling of the receptors to Gi plays a crucial role
in the activation. Furthermore, the phosphoinositide 3-kinase (PI3K)
inhibitors wortmannin and LY294002 block Rac2 activation elicited by
the receptor agonists, but not that by PMA. Thus the
Gi-coupled receptors likely mediate Rac2 activation via
PI3K, whereas PMA activates Rac2 in a PI3K-independent manner.
Phosphoinositide 3-Kinase-dependent and
-independent Activation of the Small GTPase Rac2 in Human
Neutrophils
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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