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Published online before print January 16, 2007

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(Journal of Leukocyte Biology. 2007;81:1127-1136.)
© 2007 by Society for Leukocyte Biology

Signaling requirements for translocation of P-Rex1, a key Rac2 exchange factor involved in chemoattractant-stimulated human neutrophil function

Tieming Zhao^*, Perihan Nalbant^*, Mikio Hoshino, Xuemei Dong, Dianqing Wu and Gary M. Bokoch^*,1

^* Departments of Immunology and Cell Biology, IMM14, The Scripps Research Institute, La Jolla, California, USA;
Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan; and
Program of Vascular Biology, Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA

¹ Correspondence: Departments of Immunology and Cell Biology, IMM14, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA. E-mail: bokoch{at}scripps.edu

PI 3,4,5-trisphosphate [PI(3,4,5)P₃; PIP₃]-dependent Rac exchanger 1 (P-Rex1) is a Rac-specific guanine nucleotide exchange factor abundant in neutrophils and myeloid cells. As a selective catalyst for Rac2 activation, P-Rex1 serves as an important regulator of human neutrophil NADPH oxidase activity and chemotaxis in response to a variety of extracellular stimuli. The exchange activity of P-Rex1 is synergistically activated by the binding of PIP₃and ß subunits of heterotrimeric G proteins in vitro, suggesting that the association of P-Rex1 with membranes is a prerequisite for cellular activation. However, the spatial regulation of endogenous P-Rex1 has not been well defined, particularly in human neutrophils activated through G protein-coupled receptors. Upon stimulation of neutrophil chemoattractant receptors, we observed that P-Rex1 translocated from cytoplasm to the leading edge of polarized cells in a G protein ß subunit- and PIP₃-dependent manner, where it colocalized with F-actin and its substrate, Rac2. Redistribution of P-Rex1 to the leading edge was also dependent on tyrosine kinase activity and was modulated by cell adhesion. Furthermore, we observed that activation of cAMP-dependent protein kinase A (PKA), which phosphorylates and inactivates P-Rex1, inhibited its translocation. Our data indicate that endogenous P-Rex1 translocates to areas of Rac2 and cytoskeletal activation at the leading edge in response to chemoattractant stimuli in human neutrophils and that this translocation can be negatively modulated by activation of PKA and by cell adhesion.

Key Words: GTPases • chemoattractant receptors • signal transduction • chemotaxis • NADPH oxidase

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