Small GTPases Coincidence detector for Rac activation

The monomeric guanosine triphosphatase Rac controls major aspects of neutrophil function including chemotaxis, phagocytosis, and production of reactive oxygen species. However the guanine-nucleotide exchange factors or GEFs that regulate Rac activity are not well described. Welch et al. purified a phosphatidylinositol(3,4,5) trisphopsphate [PtdIns(3,4,5)P₃]-activated Rac-GEF from pig neutrophils and then cloned the respective human gene encoding the protein they named P-Rex1. In vitro, P-Rex1 was not only directly activated by PtdIns(3,4,5)P₃, but it was synergistically activated by direct interaction with G protein (heterotrimeric guanine nucleotide-binding protein) β subunits. Similar synergistic activation was observed in transfected insect SF9 cells. Such regulation of P-Rex fits nicely with its proposed role as a coincidence detector monitoring signals from G_i-coupled receptors in neutrophils, which release G_βsubunits and activate G_β-sensitive phophoinositide-3 kinase to generate PtdIns(3,4,5)P₃. The authors anticipate the P-Rex1 may also function in other cells by stimuli that cause coinicident activation of type 1A phosphoinositide 3-kinase and G_i or G_o proteins.

H. C. E. Welch, W. J. Coadwell, C. D. Ellson, G. J. Ferguson, S. R. Andrews, H. Erdjument-Bromage, P. Tempst, P. T. Hawkins, L. R. Stephens, P-Rex1, a PtdIns(3,4,5)P₃- and G_β-regulated guanine-nucleotide exchange factor for Rac. Cell 108, 809-821 (2002). [Online Journal]