CDC42 AND PAK-MEDIATED SIGNALING LEADS TO JUN KINASE AND P38 MITOGEN-ACTIVATED PROTEIN-KINASE ACTIVATION

The PAK family of protein kinases has been suggested as a potential ta rget of the Cdc42 and Rac GTPases based on studies in vitro. We show t hat PAK-3 is activated by Cdc42 in vivo. Both, activated (GTPase-defec tive) Cdc42 and a constitutively active PAK-3 mutant stimulated the ac tivity of Jun kinase 1 (JNK1) in transfected cells. Activated Cdc42 al so stimulated the activity of the related p38 mitogen-activated protei n kinase but was a less effective activator of ERK2. The effect of Cdc 42 on JNK activity was similar to that of the potent inflammatory cyto kine interleukin-1 (IL-1). The observation that a dominant-negative Cd c42 mutant inhibited IL-1 activation of JNK1 indicates a role for Cdc4 2 in IL-1 signaling. These results suggest that Cdc42 and PAK may medi ate the effects of cytokines on transcriptional regulation.