The death domain kinase RIP is essential for TRAIL (Apo2L)-induced activation of I kappa B kinase and c-Jun N-terminal kinase

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) (Apo2 Ligand [Apo2L]) is a member of the TNF superfamily and has been shown to h ave selective antitumor activity. Although it is known that TRAIL (Apo2L) i nduces apoptosis and activates NF-kappa B and Jun N-terminal kinase (JNK) t hrough receptors such as TRAIL-R1 (DR4) and TRAIL-R2 (DR5), the components of its signaling cascade have not been well defined. In this report, we dem onstrated that the death domain kinase RIP is essential for TRAIL-induced I kappa B kinase (IKK) and JNK activation. We found that ectopic expression of the dominant negative mutant RIP, RIP(559-671), blocks TRAIL-induced IKK and JNK activation. In the RIP null fibroblasts, TRAIL failed to activate IKK and only partially activated JNK. The endogenous RIP protein was detect ed by immunoprecipitation in the TRAIL-R1 complex after TRAIL treatment. Mo re importantly, we found that RIP is not involved in TRAIL-induced apoptosi s. In addition, we also demonstrated that the TNF receptor-associated facto r 2 (TRAF2) plays little role in TRAIL-induced IKK activation although it i s required for TRAIL-mediated JNK activation. These results indicated that the death domain kinase RIP, a key factor in TNF signaling, also plays a pi votal role in TRAIL-induced IKK and JNK activation.