Abstract
Tumor necrosis factor receptor (TNFR) superfamily members can induce a context-dependent apoptosis or cell activation. However, the mechanisms by which these opposing programs are selected remain unclear. We show that in T cells, TNFR2 (TNFRSF1B) signaling is dramatically affected by the intracellular mediator RIP, a protein Ser/Thr kinase required for NF-kappaB activation by TNFR1 (TNFRSF1A). In the presence of RIP, TNFR2 triggers cell death, whereas in the absence of RIP, TNFR2 activates NF-kappaB. RIP is induced during IL2-driven T cell proliferation, and its inhibition reduces susceptibility to TNF-dependent apoptosis. Evidence that signaling outputs are shaped by intracellular constraints helps reconcile conflicting views of TNFR1 and TNFR2 as apoptotic mediators.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Antigens, CD / genetics
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Antigens, CD / metabolism*
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Apoptosis*
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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DNA-Binding Proteins / genetics
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Fas-Associated Death Domain Protein
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Humans
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I-kappa B Proteins*
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Jurkat Cells
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Lymphocyte Activation
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NF-KappaB Inhibitor alpha
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NF-kappa B / antagonists & inhibitors
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Proteins / genetics
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Proteins / physiology*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Receptor-Interacting Protein Serine-Threonine Kinases
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / metabolism*
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Receptors, Tumor Necrosis Factor, Type I
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Receptors, Tumor Necrosis Factor, Type II
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Serpins / genetics
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Serpins / metabolism
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Signal Transduction*
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T-Lymphocytes / cytology
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T-Lymphocytes / drug effects
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T-Lymphocytes / metabolism
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Viral Proteins*
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bcl-X Protein
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, CD
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BCL2L1 protein, human
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Carrier Proteins
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DNA-Binding Proteins
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FADD protein, human
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Fas-Associated Death Domain Protein
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I-kappa B Proteins
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NF-kappa B
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NFKBIA protein, human
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Proteins
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Type I
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Receptors, Tumor Necrosis Factor, Type II
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Serpins
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Viral Proteins
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bcl-X Protein
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NF-KappaB Inhibitor alpha
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interleukin-1beta-converting enzyme inhibitor
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RIPK1 protein, human
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Receptor-Interacting Protein Serine-Threonine Kinases