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Science 321 (5889): 663-668

Copyright © 2008 by the American Association for the Advancement of Science

Essential Cytoplasmic Translocation of a Cytokine Receptor–Assembled Signaling Complex

Atsushi Matsuzawa,1* Ping-Hui Tseng,1* Sivakumar Vallabhapurapu,1 Jun-Li Luo,1 Weizhou Zhang,1 Haopeng Wang,2 Dario A. A. Vignali,2 Ewen Gallagher,3 Michael Karin1{dagger}

Abstract: 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.

1 Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093–0723, USA.
2 Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105–2794, USA.
3 Department of Immunology, Imperial College, London, Faculty of Medicine, Norfolk Place, London W2 1PG, UK.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: karinoffice{at}ucsd.edu

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