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Science 296 (5573): 1634-1635

Copyright © 2002 by the American Association for the Advancement of Science

TNF-R1 Signaling: A Beautiful Pathway

Guoqing Chen, David V. Goeddel*

Tumor necrosis factor (TNF) is a major mediator of apoptosis as well as inflammation and immunity, and it has been implicated in the pathogenesis of a wide spectrum of human diseases, including sepsis, diabetes, cancer, osteoporosis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel diseases. The interaction of TNF with TNF receptor-1 (TNF-R1) activates several signal transduction pathways. A common feature of each pathway is the TNF-induced formation of a multiprotein signaling complex at the cell membrane. Over the past decade, many of the components and mechanisms of these signaling pathways have been elucidated. We provide an overview of current knowledge of TNF signaling and introduce an STKE Connections Map that depicts a canonical view of this process.

Tularik Inc., Two Corporate Drive, South San Francisco, CA 94080, USA.
*   To whom correspondence should be addressed. E-mail: goeddel{at}

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FASEB J 25, 2221-2233
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   Abstract »    Full Text »    PDF »
The Adaptor Protein TRADD Is Essential for TNF-Like Ligand 1A/Death Receptor 3 Signaling.
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TNF{alpha} Is Required for Late BRB Breakdown in Diabetic Retinopathy, and Its Inhibition Prevents Leukostasis and Protects Vessels and Neurons from Apoptosis.
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Invest. Ophthalmol. Vis. Sci. 52, 1336-1344
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Antigen-independent signalosome of CARMA1, PKC{theta}, and TNF receptor-associated factor 2 (TRAF2) determines NF-{kappa}B signaling in T cells.
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PNAS 108, 2903-2908
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Apoptosis in Mouse Amniotic Epithelium Is Induced by Activated Macrophages Through the TNF Receptor Type 1/TNF Pathway.
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Tumor Necrosis Factor {alpha} Represses Bone Morphogenetic Protein (BMP) Signaling by Interfering with the DNA Binding of Smads through the Activation of NF-{kappa}B.
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Leukocyte Ig-like Receptor B4 (LILRB4) Is a Potent Inhibitor of Fc{gamma}RI-mediated Monocyte Activation via Dephosphorylation of Multiple Kinases.
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TNF{alpha} shedding and epidermal inflammation are controlled by Jun proteins.
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J. Immunol. 183, 6282-6295
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NF-{kappa}B activity is constitutively elevated in c-Abl null fibroblasts.
R. A. Liberatore, S. P. Goff, and I. Nunes (2009)
PNAS 106, 17823-17828
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Tumor Necrosis Factor-{alpha}-mediated Regulation of the Inositol 1,4,5-Trisphosphate Receptor Promoter.
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Obesity and Cancer: The Role of Dysfunctional Adipose Tissue.
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Cancer Epidemiol. Biomarkers Prev. 18, 2569-2578
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Licochalcone A Potently Inhibits Tumor Necrosis Factor {alpha}-Induced Nuclear Factor-{kappa}B Activation through the Direct Inhibition of I{kappa}B Kinase Complex Activation.
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Mol. Pharmacol. 76, 745-753
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Cigarette Smoking, STAT4 and TNFRSF1B Polymorphisms, and Systemic Lupus Erythematosus in a Japanese Population.
J Rheumatol 36, 2195-2203
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Bcl3 Interacts Cooperatively with Peroxisome Proliferator-Activated Receptor Gamma (PPAR{gamma}) Coactivator 1{alpha} To Coactivate Nuclear Receptors Estrogen-Related Receptor {alpha} and PPAR{alpha}.
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Am J Physiol Renal Physiol 297, F125-F137
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WISP1, a Pro-mitogenic, Pro-survival Factor, Mediates Tumor Necrosis Factor-{alpha} (TNF-{alpha})-stimulated Cardiac Fibroblast Proliferation but Inhibits TNF-{alpha}-induced Cardiomyocyte Death.
K. Venkatachalam, B. Venkatesan, A. J. Valente, P. C. Melby, S. Nandish, J. E. B. Reusch, R. A. Clark, and B. Chandrasekar (2009)
J. Biol. Chem. 284, 14414-14427
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PRMT5, a Novel TRAIL Receptor-Binding Protein, Inhibits TRAIL-Induced Apoptosis via Nuclear Factor-{kappa}B Activation.
H. Tanaka, Y. Hoshikawa, T. Oh-hara, S. Koike, M. Naito, T. Noda, H. Arai, T. Tsuruo, and N. Fujita (2009)
Mol. Cancer Res. 7, 557-569
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Poxvirus MC160 Protein Utilizes Multiple Mechanisms To Inhibit NF-{kappa}B Activation Mediated via Components of the Tumor Necrosis Factor Receptor 1 Signal Transduction Pathway.
D. B. Nichols and J. L. Shisler (2009)
J. Virol. 83, 3162-3174
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ROS and Innate Immunity.
Anticancer Res 29, 817-821
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Cannabinoid Receptor Activation Induces Apoptosis through Tumor Necrosis Factor {alpha}-Mediated Ceramide De novo Synthesis in Colon Cancer Cells.
F. Cianchi, L. Papucci, N. Schiavone, M. Lulli, L. Magnelli, M. C. Vinci, L. Messerini, C. Manera, E. Ronconi, P. Romagnani, et al. (2008)
Clin. Cancer Res. 14, 7691-7700
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Parkin Deficiency Increases Vulnerability to Inflammation-Related Nigral Degeneration.
T. C. Frank-Cannon, T. Tran, K. A. Ruhn, T. N. Martinez, J. Hong, M. Marvin, M. Hartley, I. Trevino, D. E. O'Brien, B. Casey, et al. (2008)
J. Neurosci. 28, 10825-10834
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The Interaction between Human Papillomavirus Type 16 and FADD Is Mediated by a Novel E6 Binding Domain.
S. S. Tungteakkhun, M. Filippova, J. W. Neidigh, N. Fodor, and P. J. Duerksen-Hughes (2008)
J. Virol. 82, 9600-9614
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Role of NF-{kappa}B and PI 3-kinase/Akt in TNF-{alpha}-induced cytotoxicity in microvascular endothelial cells.
Z. Zhou, P. Gengaro, W. Wang, X.-q. Wang, C. Li, S. Faubel, C. Rivard, and R. W. Schrier (2008)
Am J Physiol Renal Physiol 295, F932-F941
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Functional genetic screening reveals the role of mitochondrial cytochrome b as a mediator of FAS-induced apoptosis.
A. P. Komarov, O. W. Rokhlin, C.-A. Yu, and A. V. Gudkov (2008)
PNAS 105, 14453-14458
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cAMP-dependent Protein Kinase A (PKA) Signaling Induces TNFR1 Exosome-like Vesicle Release via Anchoring of PKA Regulatory Subunit RII{beta} to BIG2.
A. Islam, H. Jones, T. Hiroi, J. Lam, J. Zhang, J. Moss, M. Vaughan, and S. J. Levine (2008)
J. Biol. Chem. 283, 25364-25371
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c-IAP1 and c-IAP2 Are Critical Mediators of Tumor Necrosis Factor {alpha} (TNF{alpha})-induced NF-{kappa}B Activation.
E. Varfolomeev, T. Goncharov, A. V. Fedorova, J. N. Dynek, K. Zobel, K. Deshayes, W. J. Fairbrother, and D. Vucic (2008)
J. Biol. Chem. 283, 24295-24299
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Beyond tumor necrosis factor receptor: TRADD signaling in toll-like receptors.
N.-J. Chen, I. I. C. Chio, W.-J. Lin, G. Duncan, H. Chau, D. Katz, H.-L. Huang, K. A. Pike, Z. Hao, Y.-W. Su, et al. (2008)
PNAS 105, 12429-12434
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Diesel exhaust particles induce oxidative stress, proinflammatory signaling, and P-glycoprotein up-regulation at the blood-brain barrier.
A. M. S. Hartz, B. Bauer, M. L. Block, J.-S. Hong, and D. S. Miller (2008)
FASEB J 22, 2723-2733
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Essential Cytoplasmic Translocation of a Cytokine Receptor-Assembled Signaling Complex.
A. Matsuzawa, P.-H. Tseng, S. Vallabhapurapu, J.-L. Luo, W. Zhang, H. Wang, D. A. A. Vignali, E. Gallagher, and M. Karin (2008)
Science 321, 663-668
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Uniocular Anterior Chamber Inoculation of a Tumor Necrosis Factor Alpha-Expressing Recombinant of Herpes Simplex Virus Type 1 Results in More Rapid Destruction and Increased Viral Replication in the Retina of the Uninoculated Eye.
M. A. Fields, M. Zheng, P. Wall, S. Oberg, and S. S. Atherton (2008)
J. Virol. 82, 5068-5078
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Simvastatin antagonizes tumor necrosis factor-{alpha} inhibition of bone morphogenetic proteins-2-induced osteoblast differentiation by regulating Smad signaling and Ras/Rho-mitogen-activated protein kinase pathway.
M. Yamashita, F. Otsuka, T. Mukai, H. Otani, K. Inagaki, T. Miyoshi, J. Goto, M. Yamamura, and H. Makino (2008)
J. Endocrinol. 196, 601-613
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Transglutaminase Type II Is Involved in the Pathogenesis of Endotoxic Shock.
L. Falasca, M. G. Farrace, A. Rinaldi, L. Tuosto, G. Melino, and M. Piacentini (2008)
J. Immunol. 180, 2616-2624
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Dissecting "stress" in Fanconi anemia.
I. Dokal (2008)
Blood 111, 1756-1757
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Aberrant activation of stress-response pathways leads to TNF-{alpha} oversecretion in Fanconi anemia.
D. Briot, G. Mace-Aime, F. Subra, and F. Rosselli (2008)
Blood 111, 1913-1923
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Creation and X-ray Structure Analysis of the Tumor Necrosis Factor Receptor-1-selective Mutant of a Tumor Necrosis Factor-{alpha} Antagonist.
H. Shibata, Y. Yoshioka, A. Ohkawa, K. Minowa, Y. Mukai, Y. Abe, M. Taniai, T. Nomura, H. Kayamuro, H. Nabeshi, et al. (2008)
J. Biol. Chem. 283, 998-1007
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Activation of Rho Kinase by TNF-{alpha} Is Required for JNK Activation in Human Pulmonary Microvascular Endothelial Cells.
P. Y. Mong, C. Petrulio, H. L. Kaufman, and Q. Wang (2008)
J. Immunol. 180, 550-558
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