TNF-Dependent Recruitment of the Protein Kinase RIP to the TNF Receptor-1 Signaling Complex

Abstract

The death domain of tumor necrosis factor (TNF) receptor-1 (TNFR1) triggers distinct signaling pathways leading to apoptosis and NF-kappa B activation through its interaction with the death domain protein TRADD. Here, we show that TRADD interacts strongly with RIP, another death domain protein that was shown previously to associate with Fas antigen. We also show that RIP is a serine-threonine kinase that is recruited by TRADD to TNFR1 in a TNF-dependent process. Overexpression of the intact RIP protein induces both NF-kappa B activation and apoptosis. However, expression of the death domain of RIP Induces apoptosis, but potently inhibits NF-kappa B activation by TNF. These results suggest that distinct domains of RIP participate in the TNF signaling cascades leading to apoptosis and NF-kappa B activation.

Modulation of life and death by the TNF receptor superfamily

“…Interestingly, these cells retain TNF-mediated JNK activation, suggesting that RIP may not be directly involved in the activation of JNK (Kelliher et al, 1998). This observation poses a problem in explaining earlier results, where Hsu et al (1996) have shown that dominant negative mutants of RIP block activation of both NF-kB and JNK. This model also does not explain how a kinase-defective RIP mutant restores the NF-kB inducibility in a RIPde®cient JURKAT clone (Ting et al, 1996).…”

RIP kinases: key decision makers in cell death and innate immunity

“…The stimulation of TNF-R1 with TNF leads to the interaction of TNF-R1-associated death domain protein (TRADD) 19 and RIP1 20 with the TNF-R1 signalling complex (Figure 2). This is followed by the recruitment of a number of E3 ubiquitin ligases to RIP1, including TNF receptor-associated factor 2 (TRAF2) or TRAF5 and the cellular inhibitor of apoptosis proteins (cIAPs) cIAP1 and cIAP2 resulting in the formation of Complex I.…”

From receptors to stress-activated MAP kinases

“…TNF binding induces receptor aggregation, which results in the recruitment of a number of cytoplasmic signaling proteins to two distinct TNFR complexes (Rothe et al, 1994(Rothe et al, , 1995bHsu et al, 1995Hsu et al, , 1996aShu et al, 1996). One of these molecules is TNF receptor associated factor 2 Figure 1 The mammalian stress-activated MAP kinase modules.…”