期刊
JOURNAL OF LEUKOCYTE BIOLOGY
卷 81, 期 4, 页码 1127-1136出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1189/jlb.0406251
关键词
GTPases; chemoattractant receptors; signal transduction; chemotaxis; NADPH oxidase
资金
- NHLBI NIH HHS [HL70694, R01 HL080706, R01 HL080706-12, HL48008, HL80706, R01 HL080706-11, R01 HL080706-10] Funding Source: Medline
- NIGMS NIH HHS [GM39434, R01 GM054597] Funding Source: Medline
- Grants-in-Aid for Scientific Research [19670002] Funding Source: KAKEN
PI 3,4,5-trisphosphate [PI(3,415)P-3; PIP3]-dependent Rac exchanger 1 (P-Rex1) is a Rac-specific guanine nucleotide exchange factor abundant in nentrophils and myeloid cells. As a selective catalyst for Rac2 activation, P-Rex1 serves as an important regulator of human nentrophil 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 PIP3 and beta gamma 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 nentrophil chemoattractant receptors, we observed that P-Rex1 translocated from cytoplasm to the leading edge of polarized cells in a G protein beta gamma 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-Rcx1, 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.
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