FORMYL PEPTIDE RECEPTORS ARE COUPLED TO MULTIPLE MITOGEN-ACTIVATED PROTEIN-KINASE CASCADES BY DISTINCT SIGNAL-TRANSDUCTION PATHWAYS - ROLE IN ACTIVATION OF REDUCED NICOTINAMIDE ADENINE-DINUCLEOTIDE OXIDASE

Formyl peptide receptor activation of three mitogen-activated protein kinase (MAPK) cascades, extracellular signal-regulated kinases (ERKs), N-terminal kinases (JNKs), and p38 MAPK was examined in differentiate d HL-60 granulocytes, FMLP stimulated a concentration-and time-depende nt increase in ERK, JNK, and p38 MAPK activities, all of which were de pendent on a pertussis toxin-sensitive G protein, Pharmacologic inhibi tors were used to examine the roles of tyrosine kinases, phosphatidyli nositol 3-kinase, protein kinase C, and phospholipase C, FMLP-stimulat ed ERK activity was dependent on tyrosine kinases, phosphatidylinosito l 3-kinase, protein kinase C, and phospholipase C; p38 MAPK activation was dependent on phosphatidylinositol 3-kinase and phospholipase C; w hile JNK activation was independent of all of these signaling componen ts. The mitogen-activated protein kinase/ERK kinase inhibitor PD098059 reduced ERK activation by 90%, while an inhibitor of p38 MAPK, 5B2035 80, inhibited p38 MAPK activation by 80%. Both PD098059 and SB203580 i nhibited FMLP-stimulated superoxide release, as did inhibitors directe d against protein kinase C, tyrosine kinases, and phosphatidylinositol 3-kinase. We conclude that formyl peptide receptors are coupled to th ree MAPK cascades by G(i) proteins, ERKs, p38 MAPK, and JNKs are each activated by distinct proximal signal transduction pathways, Activatio n of p38 MAPK is necessary for FMLP stimulation of respiratory burst a ctivity; however, a second signal that may involve ERK is also require d for this activity.