title: P-Rex1 regulates neutrophil function.
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.
authors.affiliation: Inositide Laboratory, The Babraham Institute, Babraham Research Campus, Cambridge CB2 4AT, United Kingdom.
authors.forename: Heidi C E
authors.initials: HC
authors.lastname: Welch
authors.forename: Alison M
authors.initials: AM
authors.lastname: Condliffe
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Milne
authors.forename: G John
authors.initials: GJ
authors.lastname: Ferguson
authors.forename: Kirsti
authors.initials: K
authors.lastname: Hill
authors.forename: Louise M C
authors.initials: LM
authors.lastname: Webb
authors.forename: Klaus
authors.initials: K
authors.lastname: Okkenhaug
authors.forename: W John
authors.initials: WJ
authors.lastname: Coadwell
authors.forename: Simon R
authors.initials: SR
authors.lastname: Andrews
authors.forename: Marcus
authors.initials: M
authors.lastname: Thelen
authors.forename: Gareth E
authors.initials: GE
authors.lastname: Jones
authors.forename: Phillip T
authors.initials: PT
authors.lastname: Hawkins
authors.forename: Len R
authors.initials: LR
authors.lastname: Stephens
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015550:Cell Degranulation / Q000502:physiology*; D002633:Chemotaxis / Q000502:physiology*; D003001:Cloning, Molecular; D004789:Enzyme Activation / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism* / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein
chemical_list: D000199:Actins; D020662:Guanine Nucleotide Exchange Factors; D009479:Neuropeptides; D017382:Reactive Oxygen Species; D043562:Receptors, G-Protein-Coupled; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; C511197:PREX1 protein, mouse; C484602:Rac1 protein, mouse