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Sci. Signal., 30 March 2010
Vol. 3, Issue 115, p. re4
[DOI: 10.1126/scisignal.3115re4]


The Role of the Kinases RIP1 and RIP3 in TNF-Induced Necrosis

Peter Vandenabeele1,2*, Wim Declercq1,2, Franky Van Herreweghe1,2, and Tom Vanden Berghe1,2

1 Molecular Signaling and Cell Death Unit, Department for Molecular Biomedical Research, VIB, 9052 Zwijnaarde, Belgium.
2 Department of Biomedical Molecular Biology, Ghent University, 9052 Zwijnaarde, Belgium.

Abstract: Tumor necrosis factor (TNF) is a pleiotropic molecule with a crucial role in cellular stress and inflammation during infection, tissue damage, and cancer. TNF signaling can lead to three distinct outcomes, each of which is initiated by different signaling complexes: the gene induction or survival mode, the apoptosis mode, and the necrosis mode. The kinases receptor-interacting protein 1 (RIP1) and RIP3 are key signaling molecules in necrosis and are regulated by caspases and ubiquitination. Moreover, TNF stimulation induces the formation of a necrosome in which RIP3 is activated and interacts with enzymes that control glycolytic flux and glutaminolysis. The necrosome induces mitochondrial complex I–mediated production of reactive oxygen species (ROS) and cytotoxicity, which suggest a functional link between increased bioenergetics and necrosis. In addition, other effector mechanisms also contribute to TNF-induced necrosis, such as recruitment of NADPH (the reduced form of nicotinamide adenine dinucleotide phosphate) oxidases and subsequent ROS production at the membrane-associated TNF receptor complex I; calcium mobilization; activation of phospholipase A2, lipoxygenases, and acid sphingomyelinases; and lysosomal destabilization. However, the link between RIP1 and RIP3 and these subcellular events remains to be established. The regulation of RIP1 and RIP3 and their downstream signaling cascades opens new therapeutic avenues for treatment of pathologies associated with cell loss, such as ischemia-reperfusion damage and neurodegeneration, and ways to stimulate alternative immunogenic cell death pathways in cancer.

* Corresponding author. E-mail, Peter.Vandenabeele{at}

Citation: P. Vandenabeele, W. Declercq, F. Van Herreweghe, T. Vanden Berghe, The Role of the Kinases RIP1 and RIP3 in TNF-Induced Necrosis. Sci. Signal. 3, re4 (2010).

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