TAK1 MEDIATES THE CERAMIDE SIGNALING TO STRESS-ACTIVATED PROTEIN-KINASE C-JUN N-TERMINAL KINASE

Ceramide has been proposed as a second messenger molecule implicated i n a variety of biological processes. It has recently been reported tha t ceramide activates stress-activated protein kinase (SAPK, also known as c-Jun NH2-terminal kinase JNK), a subfamily member of mitogen-acti vated protein kinase superfamily molecules and that the ceramide/SAPK/ JNK signaling pathway is required for stress-induced apoptosis. Howeve r, the molecular mechanism by which ceramide induces SAPK/JNK activati on is unknown. Here we show that TAK1, a member of the mitogen-activat ed protein kinase kinase kinase family, is activated by treatment of c ells with agents and stresses that induce an increase in ceramide. Cer amide itself stimulated the kinase activity of TAK1. Expression of a c onstitutively active form of TAK1 resulted in activation of SAPK/JNK a nd SEK1/MKK4, a direct activator of SAPK/JNK, Furthermore, expression of a kinase-negative form of TAK1 interfered with the activation of SA PK/JNK induced by ceramide. These results indicate that TAK1 may funct ion as a mediator of ceramide signaling to SAPK/JNK activation.