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Published Online July 17, 2008
Science DOI: 10.1126/science.1157340

Research Articles

Submitted on March 4, 2008
Accepted on June 17, 2008

Essential Cytoplasmic Translocation of a Cytokine Receptor-Assembled Signaling Complex

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

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 and Molecular Pathology, Royal Free and University College Medical School, Windeyer Building, 46 Cleveland Street, London W1T 4JF, UK.

* To whom correspondence should be addressed.
Michael Karin , E-mail: karinoffice{at}ucsd.edu

{dagger}These authors contributed equally to this work.

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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Science. ISSN 0036-8075 (print), 1095-9203 (online)