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Signaling requirements for translocation of P‐Rex1, a key Rac2 exchange factor involved in chemoattractant‐stimulated human neutrophil function
Author(s) -
Zhao Tieming,
Nalbant Perihan,
Hoshino Mikio,
Dong Xuemei,
Wu Dianqing,
Bokoch Gary M.
Publication year - 2007
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0406251
Subject(s) - biology , microbiology and biotechnology , guanine nucleotide exchange factor , chemotaxis , heterotrimeric g protein , rac gtp binding proteins , signal transduction , g protein , receptor , biochemistry , rac1
PI 3,4,5‐trisphosphate [PI(3,4,5)P 3 ; PIP 3 ]‐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 PIP 3 and βγ 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 βγ subunit‐ and PIP 3 ‐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.