IDENTIFICATION OF C-JUN NH2-TERMINAL PROTEIN-KINASE (JNK)-ACTIVATING KINASE-2 AS AN ACTIVATOR OF JNK BUT NOT P38

c-Jun NH2-terminal protein kinase (JNK), a distant member of the mitog en-activated protein (MAP) kinase family, regulates gene expression in response to various extracellular stimuli. JNK is activated by JNK-ac tivating kinase 1 (JNKK1), a dual specificity protein kinase that phos phorylates JNK on threonine 183 and tyrosine 185 residues. Here we sho w that JNKK2, a novel member of the MAP kinase kinase family, was phos phorylated and activated by MEKK1, a MAP kinase kinase kinase in the J NK signaling cascade. JNKK2 activity was also stimulated by constituti vely active forms of Pac and Cdc42Hs, members of the Rho small GTP-bin ding protein family. Unlike JNKK1 that activates both JNK and p38 MAP kinases, JNKK2 stimulated only JNK. Transient transfection assays demo nstrated that JNKK2 potentiated the stimulation of c-Jun transcription al activity by MEKK1. The existence of multiple JNK-activating kinases may contribute to the specificity of the JNK signaling cascade.