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P-Rex1 regulates neutrophil function.

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

Authors

  • Welch HC
  • Condliffe AM
  • Milne LJ
  • Ferguson GJ
  • Hill K
  • Webb LM
  • Okkenhaug K
  • Coadwell WJ
  • Andrews SR
  • Thelen M
  • Jones GE
  • Hawkins PT
  • Stephens LR

Journal

Current biology : CB

Publication Data

October 25, 2005

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
  • Agency: Medical Research Council, Id: G1100041

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