Essential cytoplasmic translocation of a cytokine receptor-assembled signaling complex

Atsushi Matsuzawa, Ping Hui Tseng, Sivakumar Vallabhapurapu, Jun Li Luo, Weizhou Zhang, Haopeng Wang, Dario A.A. Vignali, Ewen Gallagher, Michael Karin

Research output: Contribution to journalArticlepeer-review

190 Scopus citations


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), IκB kinase regulatory subunit IKKγ (also called NEMO), and mitogen-activated protein kinase (MAPK) kinase kinase MEKK1 upon ligation. TRAF2, Ubc13, and IKKγ 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.

Original languageEnglish
Pages (from-to)663-668
Number of pages6
Issue number5889
StatePublished - 1 Aug 2008
Externally publishedYes


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