G-PROTEIN-COUPLED CHEMOATTRACTANT RECEPTORS REGULATE LYN TYROSINE KINASE-CENTER-DOT-SHC ADAPTER PROTEIN SIGNALING COMPLEXES

Receptors for chemoattractants that direct the migration of phagocytic leukocytes to sites of injury/infection also modulate many other leuk ocyte functions that are critical to the inflammatory response, These chemoattractant receptors, members of the G protein-coupled heptahelic al receptor family, have been classically linked to cell activation vi a phospholipase C, calcium, and protein kinase C. We show here that ac tivation of the N-formyl peptide chemoattractant receptor stimulates a n additional protein kinase C-independent pathway through the Src-rela ted tyrosine kinase, Lyn, in human neutrophils. We demonstrate that ac tivation of Lyn is associated with binding to the She adapter protein, which becomes phosphorylated on tyrosine residues. This interaction a ppears to be mediated via the She SH2 domain, Complexes of phosphoryla ted Lyn and She with phosphatidylinositol 3-kinase are rapidly formed in stimulated neutrophils, correlating with phosphatidylinositol 1,4,5 -trisphosphate formation and cell activation. This signaling pathway i nvolving a Src-related kinase and the She adapter protein provides a p otential mechanism linking chemoattractant receptors to downstream eve nts involving Rac activation and NADPH oxidase, Regulation of She by G protein-coupled receptors may also allow these receptors to modulate the activity of the Ras/mitogen-activated protein kinase cascade.