Journal
CELLULAR SIGNALLING
Volume 19, Issue 10, Pages 2056-2067Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2007.05.016
Keywords
RIP3; kinase; cleavage; apoptosis; caspase-independent; caspase-8
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RIP3 (Receptor Interacting Protein 3), a member of the Ser/Thr kinase family, is able to induce apoptosis and activate NF-kappa B in various cell types. However, the detailed mechanism of RIP3-induced apoptosis is largely unknown. In this study, we show that RIP3 is cleaved at Asp328 by caspase-8 under apoptotic stimuli, which is blocked by pan-caspase inhibitor Z-VAD-FMK. In addition, full-length RIP3 induces both caspase-dependent and-independent apoptosis, as well as activates NF-kappa B. However, after cleavage, the C-terminus of RIP3 (aa 329-518) that lacks the kinase domain can form punctuate or filaments-like structures in cytoplasm, which induces only caspase-dependent apoptosis and exhibits a markedly higher NF-kappa B-activating activity than full-length RIP3. More importantly, the cleaved product of RIP3 (aa 329-518) displays better stability than wild type RIP3. Additionally, RIP3(K50A), a kinase-dead RIP3 mutant, also induces only caspase-dependent apoptosis along with an increased NF-kappa B-activating activity compared to RIP3, which further demonstrates that kinase activity of RIP3 is essential for its caspase-independent apoptotic activity. These results will help us to understand the mechanism underlying RIP3-induced apoptosis and the different roles of kinase domain and unique domain of RIP3, (c) 2007 Elsevier Inc. All rights reserved.
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