A membrane-permeant ester of phosphatidylinositol 3,4,5-trisphosphate (PIP3) is an activator of human neutrophil migration

Activity of phosphatidylinositol (PI) 3-kinase is required for optimal migration of human neutrophils [Niggli and Keller (1999) for. J. Pharmacol. 335, 43-52]. We have tested the direct effect of a product of PI 3-kinase, phosphatidylinositol 3,4,5-trisphosphate (PIP3), on neutrophil migration. To this end, a membrane-permeant ester of PIP3, dilauroyl phosphatidylinositol 3,4,5-trisphosphate-heptakis-(acetooxymethyl)ester (PIP3/AM) was used. PIP3/AM (ED50: 10-17 mu M) induced development of polarity and accumulation of F-actin in the leading lamellae in up to 70%, of the cells. These cells exhibited stimulated random migration, comparable to that observed in uniform concentrations of chemotactic peptide. Evidence is provided for a role of Rho-kinase and for activation of PI 3-kinase in a positive feedback loop in PIP3/AM-induced motility. (C) 2000 Federation of European Biochemical Societies.