Role of cytosolic phospholipase A(2) 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 kina se (JNK) activation in response to stress and cytokines. However, the signa ling events that mediate the activation of JNK by Rac are not yet well char acterized. To broaden our understanding of downstream mediators that link R ac signals to the JNK pathway, we investigated whether cytosolic phospholip ase A(2) (cPLA(2)) is involved in Rac activation of JNK. In this report we demonstrate that either co-transfection with antisense cPLA(2) oligonucleot ide or pretreatment with arachidonyltrifluoromethyl ketone (AACOCF3), a pot ent and specific inhibitor of cPLA(2), inhibits Rac-mediated JNK activation , implying a potential role of cPLA(2) in Rac-signaling to JNK activation. In accordance with this observation, we demonstrate that the addition of ex ogenous arachidonic acid (AA), a principal product of Rac-activated cPLA(2) , or leukotrienes, products of 5-lipoxygenase (5-LO) of AA, caused a specif ic stimulation of JNK. Together, our findings suggest that cPLA(2) mediates , at least partly, the signaling cascade by which Rac stimulates JNK. (C) 2 000 Academic Press.