Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

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

REVIEWS

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.

Gloss: The history of tumor necrosis factor (TNF) incorporates many facets of cell biology, immunology, and pathophysiology. The historical name "TNF" emphasizes its capacity to induce hemorrhagic necrosis of tumors, which refers to a histological feature. However, TNF is now known as a multifunctional cytokine that mediates cell death and inflammation following infection or tissue injury. The ability of TNF to cause cachexia and wasting during chronic neoplastic and infectious diseases suggests a link with metabolism. Here, we report on the different signaling pathways that determine whether the cellular outcome of TNF signaling is gene induction and survival, apoptosis, or programmed necrosis. Programmed necrosis is also called necroptosis, a regulated form of necrotic cell death that occurs in the absence of caspase activation and that can be blocked by inhibiting RIP1 (receptor-interacting protein 1). The kinases RIP1 and RIP3, which are regulated by caspases and ubiquitination, are key initiators of programmed necrosis. However, it remains unclear precisely how RIP1 and RIP3 instigate the execution pathways of programmed necrosis, which involve several cellular processes, such as increased bioenergetics, increased reactive oxygen species production, calcium mobilization, activation of phospholipases and acid sphingomyelinases, and destabilization of lysosomes. Because necrosis occurs in different conditions—such as myocardial infarction, stroke, pancreatitis, and viral infections—kinase inhibitors of RIP1 and RIP3 could be used or developed to prevent pathological cell death. This review highlights TNF-induced mechanisms of programmed necrosis mediated by the kinases RIP1 and RIP3, and contains three figures and 102 references.

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

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).

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Potent obatoclax cytotoxicity and activation of triple death mode killing across infant acute lymphoblastic leukemia.
K. A. Urtishak, A. Y. Z. Edwards, L.-S. Wang, A. Hudome, B. W. Robinson, J. S. Barrett, K. Cao, L. Cory, J. S. Moore, A. D. Bantly, et al. (2013)
Blood 121, 2689-2703
   Abstract »    Full Text »    PDF »
TAK1 Is Essential for Osteoclast Differentiation and Is an Important Modulator of Cell Death by Apoptosis and Necroptosis.
B. Lamothe, Y. Lai, M. Xie, M. D. Schneider, and B. G. Darnay (2013)
Mol. Cell. Biol. 33, 582-595
   Abstract »    Full Text »    PDF »
NADPH Oxidase Inhibits the Pathogenesis of Systemic Lupus Erythematosus.
A. M. Campbell, M. Kashgarian, and M. J. Shlomchik (2012)
Science Translational Medicine 4, 157ra141
   Abstract »    Full Text »    PDF »
GRIM-19-mediated translocation of STAT3 to mitochondria is necessary for TNF-induced necroptosis.
N. Shulga and J. G. Pastorino (2012)
J. Cell Sci. 125, 2995-3003
   Abstract »    Full Text »    PDF »
Novel Ser/Thr Protein Phosphatases in Cell Death Regulation.
H. Sun and Y. Wang (2012)
Physiology 27, 43-52
   Abstract »    Full Text »    PDF »
Functional Conservation and Innovation of Amphioxus RIP1-Mediated Signaling in Cell Fate Determination.
J. Li, S. Yuan, L. Qi, S. Huang, G. Huang, M. Yang, L. Xu, Y. Li, R. Zhang, Y. Yu, et al. (2011)
J. Immunol. 187, 3962-3971
   Abstract »    Full Text »    PDF »
Interaction Patches of Procaspase-1 Caspase Recruitment Domains (CARDs) Are Differently Involved in Procaspase-1 Activation and Receptor-interacting Protein 2 (RIP2)-dependent Nuclear Factor {kappa}B Signaling.
K. Kersse, M. Lamkanfi, M. J. M. Bertrand, T. Vanden Berghe, and P. Vandenabeele (2011)
J. Biol. Chem. 286, 35874-35882
   Abstract »    Full Text »    PDF »
Chymase Inhibition Reduces Infarction and Matrix Metalloproteinase-9 Activation and Attenuates Inflammation and Fibrosis after Acute Myocardial Ischemia/Reperfusion.
S. Oyamada, C. Bianchi, S. Takai, L. M. Chu, and F. W. Sellke (2011)
J. Pharmacol. Exp. Ther. 339, 143-151
   Abstract »    Full Text »    PDF »
Requirement of FADD, NEMO, and BAX/BAK for Aberrant Mitochondrial Function in Tumor Necrosis Factor Alpha-Induced Necrosis.
K. M. Irrinki, K. Mallilankaraman, R. J. Thapa, H. C. Chandramoorthy, F. J. Smith, N. R. Jog, R. K. Gandhirajan, S. G. Kelsen, S. R. Houser, M. J. May, et al. (2011)
Mol. Cell. Biol. 31, 3745-3758
   Abstract »    Full Text »    PDF »
Complementary roles of Fas-associated death domain (FADD) and receptor interacting protein kinase-3 (RIPK3) in T-cell homeostasis and antiviral immunity.
J. V. Lu, B. M. Weist, B. J. van Raam, B. S. Marro, L. V. Nguyen, P. Srinivas, B. D. Bell, K. A. Luhrs, T. E. Lane, G. S. Salvesen, et al. (2011)
PNAS 108, 15312-15317
   Abstract »    Full Text »    PDF »
NF-{kappa}B Protects Cells from Gamma Interferon-Induced RIP1-Dependent Necroptosis.
R. J. Thapa, S. H. Basagoudanavar, S. Nogusa, K. Irrinki, K. Mallilankaraman, M. J. Slifker, A. A. Beg, M. Madesh, and S. Balachandran (2011)
Mol. Cell. Biol. 31, 2934-2946
   Abstract »    Full Text »    PDF »
In TNF-stimulated Cells, RIPK1 Promotes Cell Survival by Stabilizing TRAF2 and cIAP1, which Limits Induction of Non-canonical NF-{kappa}B and Activation of Caspase-8.
I. E. Gentle, W. W.-L. Wong, J. M. Evans, A. Bankovacki, W. D. Cook, N. R. Khan, U. Nachbur, J. Rickard, H. Anderton, M. Moulin, et al. (2011)
J. Biol. Chem. 286, 13282-13291
   Abstract »    Full Text »    PDF »
Distinct Roles for the NF-{kappa}B RelA Subunit during Antiviral Innate Immune Responses.
S. H. Basagoudanavar, R. J. Thapa, S. Nogusa, J. Wang, A. A. Beg, and S. Balachandran (2011)
J. Virol. 85, 2599-2610
   Abstract »    Full Text »    PDF »
Drosophila orthologue of WWOX, the chromosomal fragile site FRA16D tumour suppressor gene, functions in aerobic metabolism and regulates reactive oxygen species.
L. V. O'Keefe, A. Colella, S. Dayan, Q. Chen, A. Choo, R. Jacob, G. Price, D. Venter, and R. I. Richards (2011)
Hum. Mol. Genet. 20, 497-509
   Abstract »    Full Text »    PDF »
Receptor interacting protein kinases mediate retinal detachment-induced photoreceptor necrosis and compensate for inhibition of apoptosis.
G. Trichonas, Y. Murakami, A. Thanos, Y. Morizane, M. Kayama, C. M. Debouck, T. Hisatomi, J. W. Miller, and D. G. Vavvas (2010)
PNAS 107, 21695-21700
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882