Human 4-1BB (CD137) signals are mediated by TRAF2 and activate nuclear factor-kappa B

Biochem Biophys Res Commun. 1998 Jan 26;242(3):613-20. doi: 10.1006/bbrc.1997.8016.

Abstract

Human 4-1BB (CD137), a member of the tumor necrosis factor receptor (TNFR) superfamily, costimulates T cell activation. No apparent intrinsic kinase activity is seen with 4-1BB, which suggests that 4-1BB-associated molecules may be involved in 4-1BB-mediated signal transduction. We found that tumor necrosis factor receptor-associated factor (TRAF) 1, TRAF2, and TRAF3, all interacted with the cytoplasmic domain of 4-1BB. Mutation analysis showed that TRAF1, TRAF2, and TRAF3 were associated with one of two runs of acidic residues found in the cytoplasmic domain of 4-1BB. In addition, 4-1BB cross-linking with TCR signal in Jurkat cells and overexpression of 4-1BB in 293 cells were able to induce activation of the nuclear factor-kappa B (NF-kappa B). 4-1BB-mediated NF-kappa B activation was inhibited by a dominant negative-TRAF2 or -NF-kappa B-inducing kinase (NIK). These data suggest that 4-1BB functions may be mediated by NF-kappa B activation, which requires a TRAF2/NIK pathway.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Antigens, CD
  • Blotting, Western
  • Cell Line
  • Electrophoresis, Polyacrylamide Gel
  • Genes, Reporter
  • Humans
  • Molecular Sequence Data
  • Mutation / genetics
  • NF-kappa B / metabolism*
  • Protein Binding
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteins / metabolism*
  • Receptors, Nerve Growth Factor / genetics
  • Receptors, Nerve Growth Factor / metabolism*
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Signal Transduction / physiology
  • T-Lymphocytes / metabolism
  • TNF Receptor-Associated Factor 1
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 3
  • Transfection / genetics
  • Tumor Necrosis Factor Receptor Superfamily, Member 9

Substances

  • Antigens, CD
  • NF-kappa B
  • Proteins
  • Receptors, Nerve Growth Factor
  • Receptors, Tumor Necrosis Factor
  • Recombinant Fusion Proteins
  • TNF Receptor-Associated Factor 1
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 3
  • TNFRSF9 protein, human
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Protein-Serine-Threonine Kinases
  • NF-kappa B kinase