P-Rex1 regulates neutrophil function.

Heidi C E Welch; Alison M Condliffe; Laura J Milne; G John Ferguson; Kirsti Hill; Louise M C Webb; Klaus Okkenhaug; W John Coadwell; Simon R Andrews; Marcus Thelen; Gareth E Jones; Phillip T Hawkins; Len R Stephens

doi:10.1016/j.cub.2005.09.050

PubMed · 16243035

P-Rex1 regulates neutrophil function.

Heidi C E Welch·Alison M Condliffe·Laura J Milne·G John Ferguson·Kirsti Hill·Louise M C Webb·Klaus Okkenhaug·W John Coadwell·Simon R Andrews·Marcus Thelen·Gareth E Jones·Phillip T Hawkins·Len R Stephens

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Abstract

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.

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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 RAC2 GTP-Binding Protein Comparative Study Journal Article Research Support, Non-U.S. Gov't

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Heidi C E Welch, Alison M Condliffe, Laura J Milne, G John Ferguson, Kirsti Hill, Louise M C Webb, Klaus Okkenhaug, W John Coadwell, Simon R Andrews, Marcus Thelen, Gareth E Jones, Phillip T Hawkins, Len R Stephens. 2005-10-25. P-Rex1 regulates neutrophil function.. https://doi.org/10.1016/j.cub.2005.09.050

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