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 A(2) (cPLA(2)) in human neutrophils remain obscure. In a previous study, we showed that the activation of cPLA(2) 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 cPLA(2) activity by OZ is mediated by Fc gamma receptors (Fc gamma Rs) and not by complement receptors for the C3b protein. Cross-linking of Fc gamma RILA or Fc gamma RIIIB induces p38 mitogen-activated protein (MAP) kinase and extracellular regulated kinase (ERK) phosphorylation. The kinetics of cPLA(2) activity stimulated by either of the Fc gamma Rs 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 cPLA(2) 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 cPLA(2) activity by occupancy of a single receptor, Fc gamma RILA or Fc gamma RIIIB.