Arachidonic acid induces the activation of the stress-activated protein kinase, membrane ruffling and H2O2 production via a small GTPase Rac1

Arachidonic acid (AA) is generated via Rac-mediated phospholipase A2 (PLA2) activation in response to growth factors and cytokines and is implicated i n cell growth and gene expression, In this study, we show that AA activates the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in a time- and dose-dependent manner, Indomethacin and nordihydroguaiaretic ac id, potent inhibitors of cyclooxygenase and lipoxygenase, respectively, did not exert inhibitory effects on AA-induced SAPK/JNK. activation, thereby i ndicating that AA itself could activate SAPK/JNK. As Rac mediates SAPK/JNK activation in response to a variety of stressful stimuli, we examined wheth er the activation of SAPK/JNK by AA is mediated by Rac1, We observed that A A-induced SAPK/JNK activation was significantly inhibited in Rat2-Rac1N17 d ominant-negative mutant cells. Furthermore, treatment of AA induced membran e ruffling and production of hydrogen peroxide, which could be prevented by Rac1N17. These results suggest that AA acts as an upstream signal molecule of Rac, whose activation leads to SAPK/JNK activation, membrane ruffling a nd hydrogen peroxide production. (C) 1999 Federation of European Biochemica l Societies.