Sphingosine kinase interacts with TRAF2 and dissects tumor necrosis factor-alpha signaling

J Biol Chem. 2002 Mar 8;277(10):7996-8003. doi: 10.1074/jbc.M111423200. Epub 2002 Jan 2.


Tumor necrosis factor-alpha (TNF) receptor-associated factor 2 (TRAF2) is one of the major mediators of TNF receptor superfamily transducing TNF signaling to various functional targets, including activation of NF-kappa B, JNK, and antiapoptosis. We investigated how TRAF2 mediates differentially the distinct downstream signals. We now report a novel mechanism of TRAF2-mediated signal transduction revealed by an association of TRAF2 with sphingosine kinase (SphK), a lipid kinase that is responsible for the production of sphingosine 1-phosphate. We identified a TRAF2-binding motif of SphK that mediated the interaction between TRAF2 and SphK resulting in the activation of the enzyme, which in turn is required for TRAF2-mediated activation of NF-kappa B but not JNK. In addition, by using a kinase inactive dominant-negative SphK and a mutant SphK that lacks TRAF2-binding motif we show that the interaction of TRAF2 with SphK and subsequent activation of SphK are critical for prevention of apoptosis during TNF stimulation. These findings show a role for SphK in the signal transduction by TRAF2 specifically leading to activation of NF-kappa B and antiapoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Blotting, Western
  • Cell Line
  • Cell Survival
  • Cells, Cultured
  • DNA, Complementary / metabolism
  • Endothelium, Vascular / cytology
  • Enzyme Activation
  • Genes, Dominant
  • Genes, Reporter
  • Glutathione Transferase / metabolism
  • Humans
  • Models, Biological
  • Mutagenesis, Site-Directed
  • Mutation
  • NF-kappa B / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / chemistry*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Plasmids / metabolism
  • Precipitin Tests
  • Protein Binding
  • Proteins / chemistry
  • Proteins / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction*
  • TNF Receptor-Associated Factor 2
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism*
  • Umbilical Veins / cytology


  • DNA, Complementary
  • NF-kappa B
  • Proteins
  • Recombinant Fusion Proteins
  • TNF Receptor-Associated Factor 2
  • Tumor Necrosis Factor-alpha
  • Glutathione Transferase
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase