P-Rex1 Regulates Neutrophil Function
| Autor: | Gareth E. Jones, G. John Ferguson, W. John Coadwell, Louise M. C. Webb, Phillip T. Hawkins, Kirsti Hill, Marcus Thelen, Len R. Stephens, Laura Milne, Klaus Okkenhaug, Alison M. Condliffe, Simon Andrews, Heidi C.E. Welch |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
rac1 GTP-Binding Protein
Lipopolysaccharide Neutrophils Regulator RAC1 Biology General Biochemistry Genetics and Molecular Biology Cell Degranulation Receptors G-Protein-Coupled Azurophilic granule chemistry.chemical_compound Mice medicine Animals Guanine Nucleotide Exchange Factors Cloning Molecular Mice Knockout Agricultural and Biological Sciences(all) Biochemistry Genetics and Molecular Biology(all) Chemotaxis Neuropeptides Degranulation PREX1 Neutrophilia Actins Cell biology rac GTP-Binding Proteins Enzyme Activation chemistry medicine.symptom General Agricultural and Biological Sciences Reactive Oxygen Species |
| Zdroj: | Current Biology. 15(20):1867-1873 |
| ISSN: | 0960-9822 |
| DOI: | 10.1016/j.cub.2005.09.050 |
| Popis: | SummaryRac GTPases regulate cytoskeletal structure, gene expression, and reactive oxygen species (ROS) production [1, 2]. Rac2-deficient neutrophils cannot chemotax, produce ROS, or degranulate upon G protein-coupled receptor (GPCR) activation [3–10]. Deficiency in PI3Kγ, an upstream regulator of Rac, causes a similar phenotype [11–13]. P-Rex1, a guanine-nucleotide exchange factor (GEF) for Rac [14], is believed to link GPCRs and PI3Kγ to Rac-dependent neutrophil responses. We have investigated the functional importance of P-Rex1 by generating a P-Rex1−/− mouse. P-Rex1−/− mice are viable and healthy, with apparently normal leukocyte development, but with mild neutrophilia. In neutrophils from P-Rex1−/− mice, GPCR-dependent Rac2 activation is impaired, whereas Rac1 activation is less compromised. GPCR-dependent ROS formation is absent in lipopolysaccharide (LPS)-primed P-Rex1−/− neutrophils, but less affected in unprimed or TNFα-primed cells. Recruitment of P-Rex1−/− neutrophils to inflammatory sites is impaired. Surprisingly, chemotaxis of isolated neutrophils is only slightly reduced, with a mild defect in cell speed, but normal polarization and directionality. Secretion of azurophil granules is unaffected. In conclusion, P-Rex1 is an important regulator of neutrophil function by mediating a subset of Rac-dependent neutrophil responses. However, P-Rex1 is not an essential regulator of neutrophil chemotaxis and degranulation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|