The requirement of both extracellular regulated kinase and p38 mitogen- activated protein kinase for stimulation of cytosolic phospholipase A₂ activity by either FcγRIIA or FcγRIIIB in human neutrophils. A possible role for Pyk2 but not for the Grb2-Sos-Shc complex

The signal transduction pathways initiated by opsonized zymosan (OZ) leading to activation of cytosolic phospholipase A₂ (cPLA₂) in human neutrophils remain obscure. In a previous study, we showed that the activation of cPLA₂ by OZ is tyrosine kinase-dependent. The present study demonstrates that the signals initiated by OZ involve activation of tyrosine kinase Pyk2 but not the formation of the adhesion protein complex, Shc-Grb2- Sos. Stimulation of cPLA₂ activity by OZ is mediated by Fc γ receptors (FcγRs) and not by complement receptors for the C3b protein. Cross-linking of FcγRIIA or FcγRIIIB induces p38 mitogen-activated protein (MAP) kinase and extracellular regulated kinase (ERK) phosphorylation. The kinetics of cPLA₂ activity stimulated by either of the FcγRs or by both is similar to that of p38 MAP kinase and was detected as early as 15 s after stimulation, maintained a plateau for 10 min, and decreased thereafter. ERK activation was detected also within 15 s but decreased significantly 5 min after stimulation. The MEK inhibitor, PD-098059, or the p38 MAP kinase inhibitor, SB-203580, caused a partial inhibition during the time course of cPLA₂ activity, whereas their combination caused a total inhibition. Thus, although ERK activation is significantly shorter than that of p38 MAP kinase, it is equally required for activation and maintenance of cPLA₂ activity by occupancy of a single receptor, FcγRIIA or FcγRIIIB.