Essential cytoplasmic translocation of a cytokine receptor-assembled signaling complex

Science. 2008 Aug 1;321(5889):663-8. doi: 10.1126/science.1157340. Epub 2008 Jul 17.


Cytokine signaling is thought to require assembly of multicomponent signaling complexes at cytoplasmic segments of membrane-embedded receptors, in which receptor-proximal protein kinases are activated. Indeed, CD40, a tumor necrosis factor receptor (TNFR) family member, forms a complex containing adaptor molecules TRAF2 and TRAF3, ubiquitin-conjugating enzyme Ubc13, cellular inhibitor of apoptosis proteins 1 and 2 (c-IAP1/2), IkappaB kinase regulatory subunit IKKgamma (also called NEMO), and mitogen-activated protein kinase (MAPK) kinase kinase MEKK1 upon ligation. TRAF2, Ubc13, and IKKgamma were required for complex assembly and activation of MEKK1 and MAPK cascades. However, these kinases were not activated unless the multicomponent signaling complex translocated from CD40 to the cytosol upon c-IAP1/2-induced degradation of TRAF3. This two-stage signaling mechanism may apply to other innate immune receptors, accounting for spatial and temporal separation of MAPK and IKK signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism*
  • CD40 Antigens / metabolism*
  • Cell Membrane / metabolism
  • Cytoplasm / metabolism*
  • Enzyme Activation
  • I-kappa B Kinase / metabolism
  • Inhibitor of Apoptosis Proteins / metabolism
  • Lymphocyte Activation*
  • MAP Kinase Kinase Kinase 1 / metabolism
  • MAP Kinase Kinase Kinases / metabolism
  • MAP Kinase Signaling System*
  • Mice
  • Proteasome Endopeptidase Complex / metabolism
  • Signal Transduction*
  • TNF Receptor-Associated Factor 2 / metabolism
  • TNF Receptor-Associated Factor 3 / metabolism
  • TNF Receptor-Associated Factor 6 / metabolism
  • Ubiquitin-Conjugating Enzymes / metabolism
  • Ubiquitination


  • CD40 Antigens
  • Inhibitor of Apoptosis Proteins
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 3
  • TNF Receptor-Associated Factor 6
  • Ube2n protein, mouse
  • Ubiquitin-Conjugating Enzymes
  • I-kappa B Kinase
  • MAP Kinase Kinase Kinase 1
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Proteasome Endopeptidase Complex