K. Shirakabe et al., TAK1 MEDIATES THE CERAMIDE SIGNALING TO STRESS-ACTIVATED PROTEIN-KINASE C-JUN N-TERMINAL KINASE, The Journal of biological chemistry, 272(13), 1997, pp. 8141-8144
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.