A TYROSINE KINASE SIGNALING PATHWAY ACCOUNTS FOR THE MAJORITY OF PHOSPHATIDYLINOSITOL 3,4,5-TRISPHOSPHATE FORMATION IN CHEMOATTRACTANT-STIMULATED HUMAN NEUTROPHILS

The signaling pathway leading from G protein-coupled chemoattractant r eceptors to the generation of oxidants by NADPH oxidase in human neutr ophils requires the formation of the lipid mediator phosphatidylinosit ol 3,4,5-trisphosphate (PIP3). Two mechanisms through which PIP3 can b e generated have been described in human leukocytes. One pathway invol ves the coupling of the src-related tyrosine kinase Lyn to the ''class ical'' p85/p110 form of phosphatidylinositol 3-kinase. The second para digm utilizes a novel form of phosphatidylinositol 3-kinase whose acti vity is directly regulated by G protein beta gamma subunits. In this p aper, we show that formation of PIP3 in chemoattractant-stimulated neu trophils is substantially attenuated by inhibitors that specifically b lock tyrosine kinase activity. These data suggest that the Lyn activat ion pathway plays a major role in the formation of this important lipi d messenger during chemoattractant stimulation of human neutrophils.