Sphingosine kinase interacts with TRAF2 and dissects tumor necrosis factor-alpha signaling.
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.
Xia
Pu
P
Division of Human Immunology, The Hanson Institute, Institute of Medical and Veterinary Science and University of Adelaide, Frome Road, Adelaide SA 5000, Australia. pu.xia@imvs.sa.gov
Wang
Lijun
L
Moretti
Paul A B
PA
Albanese
Nathaniel
N
Chai
Fugui
F
Pitson
Stuart M
SM
D'Andrea
Richard J
RJ
Gamble
Jennifer R
JR
Vadas
Mathew A
MA
D017209:Apoptosis; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D004789:Enzyme Activation; D005799:Genes, Dominant; D017930:Genes, Reporter; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry* / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D014471:Umbilical Veins / Q000166:cytology; D000099157:Sphingosine Kinase
D018076:DNA, Complementary; D005982:Glutathione Transferase; D016328:NF-kappa B; D017853:Phosphotransferases (Alcohol Group Acceptor); D011506:Proteins; D011993:Recombinant Fusion Proteins; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D000099157:Sphingosine Kinase