Molecular Determinants of Kinase Pathway Activation by Apo2 Ligand/Tumor Necrosis Factor-related Apoptosis-inducing Ligand

Eugene Varfolomeev,Heather Maecker,Darcie Sharp,David Lawrence,Mark Renz,Domagoj Vucic,Avi Ashkenazi

doi:10.1074/jbc.m509560200

Eugene Varfolomeev, Heather Maecker + Show 5 more

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https://doi.org/10.1074/jbc.m509560200

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Abstract

Apo2 ligand/tumor necrosis factor (TNF)-related apoptosis-inducing ligand (Apo2L/TRAIL) mainly activates programmed cell death through caspases. By contrast, TNF primarily induces gene transcription through the inhibitor of kappaB kinase (IKK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathways. Apo2L/TRAIL also can stimulate these kinases, albeit less strongly; however, the underlying mechanisms of this stimulation and its relation to apoptosis are not well understood. Here we show that Apo2L/TRAIL activates kinase pathways by promoting the association of a secondary signaling complex, subsequent to assembly of a primary, death-inducing signaling complex (DISC). The secondary complex retained the DISC components FADD and caspase-8, but recruited several factors involved in kinase activation by TNF, namely, RIP1, TRAF2, and NEMO/IKKgamma. Secondary complex formation required Fas-associated death domain (FADD), as well as caspase-8 activity. Apo2L/TRAIL stimulation of JNK and p38 further depended on RIP1 and TRAF2, whereas IKK activation required NEMO. Apo2L/TRAIL induced secretion of interleukin-8 and monocyte chemoattractant protein-1, augmenting macrophage migration. Thus, Apo2L/TRAIL and TNF organize common molecular determinants in distinct signaling complexes to stimulate similar kinase pathways. One function of kinase stimulation by Apo2L/TRAIL may be to promote phagocytic engulfment of apoptotic cells.

Highlights

Contain an amino acid sequence motif that mediates interaction with TNFR-associated factors (TRAFs)
In contrast to the apoptosis-initiating events triggered by binding of Fas ligand (FasL) and Apo2L/TRAIL to their corresponding death receptors, TNF binding to TNFR1 leads to activation of the IKK/NF-␬B, Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) signaling pathways [13]
Apo2L/TRAIL induced ϳ60fold up-regulation of c-IAP2 mRNA, as compared with induction of ϳ950-fold by TNF (Fig. 1D). These results show that Apo2L/ TRAIL is capable of stimulating the JNK, p38, and IKK kinase pathways, albeit less rapidly and much less potently than TNF

Summary

Introduction

Contain an amino acid sequence motif that mediates interaction with TNFR-associated factors (TRAFs). Death requires further amplification of the apoptosis signal This augmentation can be initiated by caspase-8-mediated cleavage of the proximal pro-apoptotic Bcl-2 family member Bid. The truncated form of Bid activates the distal pro-apoptotic Bcl-2 family members Bax and Bak, which trigger mitochondrial release of factors that promote activation of the apical protease caspase-9. In contrast to the apoptosis-initiating events triggered by binding of FasL and Apo2L/TRAIL to their corresponding death receptors, TNF binding to TNFR1 leads to activation of the IKK/NF-␬B, JNK, and p38 mitogen-activated protein kinase (MAPK) signaling pathways [13]. TRADD in turn binds two other adpators: RIP1, which contains a death domain and mediates activation of the IKK and p38 pathways, and TRAF2, which supports activation of IKK and JNK. Apoptosis initiation by TNF relies on the formation of a secondary intracellular signaling complex, composed of TRADD, RIP1, and TRAF2, as well as FADD and caspase-8 [17]

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