Editors' ChoiceSmall GTPases

Coincidence detector for Rac activation

Science's STKE  26 Mar 2002:
Vol. 2002, Issue 125, pp. tw118
DOI: 10.1126/stke.2002.125.tw118

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) βγ 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 Gi-coupled receptors in neutrophils, which release Gβγsubunits and activate Gβγ-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 Gi or Go 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 Gβγ-regulated guanine-nucleotide exchange factor for Rac. Cell 108, 809-821 (2002). [Online Journal]