P-Rex1, a PtdIns(3,4,5)P3- and Gbetagamma-regulated guanine-nucleotide exchange factor for Rac.
Rac, a member of the Rho family of monomeric GTPases, is an integrator of intracellular signaling in a wide range of cellular processes. We have purified a PtdIns(3,4,5)P3-sensitive activator of Rac from neutrophil cytosol. It is an abundant, 185 kDa guanine-nucleotide exchange factor (GEF), which we cloned and named P-Rex1. The recombinant enzyme has Rac-GEF activity that is directly, substantially, and synergistically activated by PtdIns(3,4,5)P3 and Gbetagammas both in vitro and in vivo. P-Rex1 antisense oligonucleotides reduced endogenous P-Rex1 expression and C5a-stimulated reactive oxygen species formation in a neutrophil-like cell line. P-Rex1 appears to be a coincidence detector in PtdIns(3,4,5)P3 and Gbetagamma signaling pathways that is particularly adapted to function downstream of heterotrimeric G proteins in neutrophils.
Welch
Heidi C E
HC
Inositide Laboratory, Cambridge CB2 4AT, United Kingdom.
Coadwell
W John
WJ
Ellson
Christian D
CD
Ferguson
G John
GJ
Andrews
Simon R
SR
Erdjument-Bromage
Hediye
H
Tempst
Paul
P
Hawkins
Phillip T
PT
Stephens
Len R
LR
D000595:Amino Acid Sequence; D000818:Animals; D002458:Cell Fractionation; D002460:Cell Line; D003001:Cloning, Molecular; D003600:Cytosol / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013552:Swine; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
D020662:Guanine Nucleotide Exchange Factors; C453280:PREX1 protein, human; D018129:Phosphatidylinositol Phosphates; D010982:Platelet-Derived Growth Factor; D017382:Reactive Oxygen Species; C060974:phosphatidylinositol 3,4,5-triphosphate; D010744:Phosphoric Monoester Hydrolases; C053153:phosphatidylinositol-3,4-bisphosphate 4-phosphatase; D020962:Heterotrimeric GTP-Binding Proteins; D020744:rac GTP-Binding Proteins