The DOI matches its Crossref record; 42 of the 42 references it cites were found in a registry or an index.
The E3 Ubiquitin Ligase Itch Couples JNK Activation to TNFα-induced Cell Death by Inducing c-FLIPL Turnover
Open accessAbstract
The proinflammatory cytokine tumor necrosis factor (TNF) alpha signals both cell survival and death. The biological outcome of TNFalpha treatment is determined by the balance between NF-kappaB and Jun kinase (JNK) signaling; NF-kappaB promotes survival, whereas JNK enhances cell death. Critically, identity of a JNK substrate that promotes TNFalpha-induced apoptosis has been outstanding. Here we show that TNFalpha-mediated JNK activation accelerates turnover of the NF-kappaB-induced antiapoptotic protein c-FLIP, an inhibitor of caspase-8. This is not due to direct c-FLIP phosphorylation but depends on JNK-mediated phosphorylation and activation of the E3 ubiquitin ligase Itch, which specifically ubiquitinates c-FLIP and induces its proteasomal degradation. JNK1 or Itch deficiency or treatment with a JNK inhibitor renders mice resistant in three distinct models of TNFalpha-induced acute liver failure, and cells from these mice do not display inducible c-FLIP(L) ubiquitination and degradation. Thus, JNK antagonizes NF-kappaB during TNFalpha signaling by promoting the proteasomal elimination of c-FLIP(L).
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“JNK targets c-FLIP, an inhibitor for the activation of caspase-8/caspase-10, for proteasomal degradation, thus allowing apoptosis to proceed [105].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [105]
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Self-citationReactive oxygen species, cellular redox systems, and apoptosis
Circu, M. L., & Aw, T. Y. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.12.022 · Cited by 3,340
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Metadata
- Authors
- Chang, L., Kamata, H., Solinas, G., Luo, J.-L., Maeda, S., Venuprasad, K., Liu, Y.-C., & Karin, M.
- Affiliations
- City Of Hope National Medical Center (US)
- University of California San Diego (US)
- La Jolla Institute for Immunology (US)
- Corresponding author
- Karin, Michael
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2006-02
- Volume
- 124
- Issue
- 3
- Pages
- 601-613
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W1990752073
- Cited by
- 706
- References
- 42
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 15 · 2023: 20 · 2022: 18 · 2021: 23 · 2020: 21 · 2019: 22 · 2018: 16 · 2017: 23 · 2016: 25 · 2015: 34 · 2014: 33 · 2013: 45 · 2012: 56
- FWCI
- 30.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2723 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- Itch E3 ubiquitin ligase, c-FLIP, JNK signaling, TNF-α, apoptosis, NF-κB, caspase-8, ubiquitination, proteasomal degradation, acute liver failure, JNK1, cell death
- MeSH terms
- Animals, Enzyme Activation, Female, Mice, Inbred C57BL, Mice, Mutant Strains, Models, Biological, Pregnancy, Tumor Necrosis Factor-alpha, Signal Transduction, Liver Failure, Acute, Apoptosis, Receptors, Tumor Necrosis Factor, Mice, Knockout, Hepatocytes, Ubiquitin-Protein Ligases, Receptors, Tumor Necrosis Factor, Type I, Intracellular Signaling Peptides and Proteins, JNK Mitogen-Activated Protein Kinases, Mice, Tumor Necrosis Factor Decoy Receptors, CASP8 and FADD-Like Apoptosis Regulating Protein
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