THE SMALL GTP-BINDING PROTEINS RAC1 AND CDC42 REGULATE THE ACTIVITY OF THE JNK SAPK SIGNALING PATHWAY/

c-Jun amino-terminal kinases (JNKs) and mitogen-activated protein kina ses (MAPKs) are closely related; however, they are independently regul ated by a variety of environmental stimuli. Although molecules linking growth factor receptors to MAPKs have been recently identified, littl e is known about pathways controlling JNK activation. Here, we show th at in COS-7 cells, activated Rac1 effectively stimulates MAPK but poor ly induces JNK activity. In contrast, mutationally activated Rac1. and Cdc42 GTPases potently activate JNK without affecting MAPK, and oncog enic guanine nucleotide exchange factors for these Rho-like proteins s electively stimulate JNK activity. Furthermore, expression of inhibito ry molecules for Rho-related GTPases and dominant negative mutants of Rac1 and Cdc42 block JNK activation by oncogenic exchange factors or a fter induction by inflammatory cytokines and growth factors. Taken tog ether, these findings strongly support a critical role for Rac1 and Cd c42 in controlling the JNK signaling pathway.