Role of cytosolic phospholipase A₂ as a downstream mediator of Rac in the signaling pathway to JNK stimulation

Rac is an important regulatory molecule implicated in c-jun N-terminal kinase (JNK) activation in response to stress and cytokines. However, the signaling events that mediate the activation of JNK by Rac are not yet well characterized. To broaden our understanding of downstream mediators that link Rac sig nals to the JNK pathway, we investigated whether cytosolic phospholipase A₂ (cPLA₂) is involved in Rac activation of JNK. In this report we demonstrate that either co-transfection with antisense cPLA₂ oligonucleotide or pretreatment with arachidonyltrifluoromethyl ketone (AACOCF3), a potent and specific inhibitor of cPLA₂, inhibits Rac-mediated JNK activation, implying a potential role of cPLA₂ in Rac-signaling to JNK activation. In accordance with this observation, we demonstrate that the addition of exogenous arachidonic acid (AA), a principal product of Rac-activated cPLA₂, or leukotrienes, products of 5-lipoxygenase (5-LO) of AA, caused a specific stimulation of JNK. Together, our findings suggest that cPLA₂ mediates, at least partly, the signaling cascade by which Rac stimulates JNK. (C) 2000 Academic Press.