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P-Rex1 regulates neutrophil function.

Current biology : CB | Oct 25, 2005

Rac GTPases regulate cytoskeletal structure, gene expression, and reactive oxygen species (ROS) production. Rac2-deficient neutrophils cannot chemotax, produce ROS, or degranulate upon G protein-coupled receptor (GPCR) activation. Deficiency in PI3Kgamma, an upstream regulator of Rac, causes a similar phenotype. P-Rex1, a guanine-nucleotide exchange factor (GEF) for Rac, is believed to link GPCRs and PI3Kgamma 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 TNFalpha-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.

Pubmed ID: 16243035 RIS Download

Mesh terms: Actins | Animals | Cell Degranulation | Chemotaxis | Cloning, Molecular | Enzyme Activation | Guanine Nucleotide Exchange Factors | Mice | Mice, Knockout | Neuropeptides | Neutrophils | Reactive Oxygen Species | Receptors, G-Protein-Coupled | rac GTP-Binding Proteins | rac1 GTP-Binding Protein

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Associated grants

  • Agency: Biotechnology and Biological Sciences Research Council, Id: BBS/E/B/0000M090
  • Agency: Biotechnology and Biological Sciences Research Council, Id: C19943
  • Agency: Medical Research Council, Id: G0100152

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