Regulated commitment of TNF receptor signaling: a molecular switch for death or activation

Immunity. 1999 Dec;11(6):783-93. doi: 10.1016/s1074-7613(00)80152-1.


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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Apoptosis*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • DNA-Binding Proteins / genetics
  • Fas-Associated Death Domain Protein
  • Humans
  • I-kappa B Proteins*
  • Jurkat Cells
  • Lymphocyte Activation
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors
  • Proteins / genetics
  • Proteins / physiology*
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Serpins / genetics
  • Serpins / metabolism
  • Signal Transduction*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism
  • Viral Proteins*
  • bcl-X Protein


  • Adaptor Proteins, Signal Transducing
  • Antigens, CD
  • BCL2L1 protein, human
  • Carrier Proteins
  • DNA-Binding Proteins
  • FADD protein, human
  • Fas-Associated Death Domain Protein
  • I-kappa B Proteins
  • NF-kappa B
  • NFKBIA protein, human
  • Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Serpins
  • Viral Proteins
  • bcl-X Protein
  • NF-KappaB Inhibitor alpha
  • interleukin-1beta-converting enzyme inhibitor
  • RIPK1 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases