Journal
SCIENCE
Volume 321, Issue 5889, Pages 663-668Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1157340
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Funding
- NCI NIH HHS [CA21765] Funding Source: Medline
- NIAID NIH HHS [AI52199, R01 AI043477-12, R01 AI043477, AI043477] Funding Source: Medline
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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), I kappa B kinase regulatory subunit IKK gamma ( also called NEMO), and mitogen- activated protein kinase ( MAPK) kinase kinase MEKK1 upon ligation. TRAF2, Ubc13, and IKK gamma 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.
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