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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}

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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J. Zinngrebe, A. Montinaro, N. Peltzer, and H. Walczak (2014)
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   Abstract »    Full Text »    PDF »
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C. Alexia, K. Poalas, G. Carvalho, N. Zemirli, J. Dwyer, S. M. Dubois, E. M. Hatchi, N. Cordeiro, S. S. Smith, C. Castanier, et al. (2013)
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   Abstract »    Full Text »    PDF »
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J. L. Johnson, G. Napolitano, J. Monfregola, C. J. Rocca, S. Cherqui, and S. D. Catz (2013)
Mol. Cell. Biol. 33, 2950-2962
   Abstract »    Full Text »    PDF »
T Cell Costimulation with Anti-CD137 Monoclonal Antibodies Is Mediated by K63-Polyubiquitin-Dependent Signals from Endosomes.
I. Martinez-Forero, A. Azpilikueta, E. Bolanos-Mateo, E. Nistal-Villan, A. Palazon, A. Teijeira, G. Perez-Chacon, A. Morales-Kastresana, O. Murillo, M. Jure-Kunkel, et al. (2013)
J. Immunol. 190, 6694-6706
   Abstract »    Full Text »    PDF »
Agonistic CD40 Antibodies and Cancer Therapy.
R. H. Vonderheide and M. J. Glennie (2013)
Clin. Cancer Res. 19, 1035-1043
   Abstract »    Full Text »    PDF »
Chlamydia pneumoniae Impairs the Innate Immune Response in Infected Epithelial Cells by Targeting TRAF3.
K. Wolf and K. A. Fields (2013)
J. Immunol. 190, 1695-1701
   Abstract »    Full Text »    PDF »
Inhibitor of Apoptosis (IAP) Proteins-Modulators of Cell Death and Inflammation.
J. Silke and P. Meier (2013)
Cold Spring Harb Perspect Biol 5, a008730
   Abstract »    Full Text »    PDF »
Mammalian MAPK Signal Transduction Pathways Activated by Stress and Inflammation: A 10-Year Update.
J. M. Kyriakis and J. Avruch (2012)
Physiol Rev 92, 689-737
   Abstract »    Full Text »    PDF »
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E. Varfolomeev, T. Goncharov, H. Maecker, K. Zobel, L. G. Komuves, K. Deshayes, and D. Vucic (2012)
Science Signaling 5, ra22
   Abstract »    Full Text »    PDF »
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Z. Chen, L. Sheng, H. Shen, Y. Zhao, S. Wang, R. Brink, and L. Rui (2012)
Diabetes 61, 566-573
   Abstract »    Full Text »    PDF »
No one can whistle a symphony alone - how different ubiquitin linkages cooperate to orchestrate NF-{kappa}B activity.
A. C. Schmukle and H. Walczak (2012)
J. Cell Sci. 125, 549-559
   Abstract »    Full Text »    PDF »
The Emerging Role of Linear Ubiquitination in Cell Signaling.
C. H. Emmerich, A. C. Schmukle, and H. Walczak (2011)
Science Signaling 4, re5
   Abstract »    Full Text »    PDF »
Novel Phosphorylation-dependent Ubiquitination of Tristetraprolin by Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase Kinase Kinase 1 (MEKK1) and Tumor Necrosis Factor Receptor-associated Factor 2 (TRAF2).
Y. M. Schichl, U. Resch, C. E. Lemberger, D. Stichlberger, and R. de Martin (2011)
J. Biol. Chem. 286, 38466-38477
   Abstract »    Full Text »    PDF »
Induction of the Alternative NF-{kappa}B Pathway by Lymphotoxin {alpha}{beta} (LT{alpha}{beta}) Relies on Internalization of LT{beta} Receptor.
C. Ganeff, C. Remouchamps, L. Boutaffala, C. Benezech, G. Galopin, S. Vandepaer, F. Bouillenne, S. Ormenese, A. Chariot, P. Schneider, et al. (2011)
Mol. Cell. Biol. 31, 4319-4334
   Abstract »    Full Text »    PDF »
Deletion of cIAP1 and cIAP2 in murine B lymphocytes constitutively activates cell survival pathways and inactivates the germinal center response.
S. Gardam, V. M. Turner, H. Anderton, S. Limaye, A. Basten, F. Koentgen, D. L. Vaux, J. Silke, and R. Brink (2011)
Blood 117, 4041-4051
   Abstract »    Full Text »    PDF »
CD40 Pathway Activation Status Predicts Response to CD40 Therapy in Diffuse Large B Cell Lymphoma.
B. Burington, P. Yue, X. Shi, R. Advani, J. T. Lau, J. Tan, S. Stinson, J. Stinson, T. Januario, S. de Vos, et al. (2011)
Science Translational Medicine 3, 74ra22
   Abstract »    Full Text »    PDF »
The death domain kinase RIP1 links the immunoregulatory CD40 receptor to apoptotic signaling in carcinomas.
P. G. Knox, C. C. Davies, M. Ioannou, and A. G. Eliopoulos (2011)
J. Cell Biol. 192, 391-399
   Abstract »    Full Text »    PDF »
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P. Xie, Z. J. Kraus, L. L. Stunz, Y. Liu, and G. A. Bishop (2011)
J. Immunol. 186, 143-155
   Abstract »    Full Text »    PDF »
Modulation of experimental autoimmune encephalomyelitis through TRAF3-mediated suppression of interleukin 17 receptor signaling.
S. Zhu, W. Pan, P. Shi, H. Gao, F. Zhao, X. Song, Y. Liu, L. Zhao, X. Li, Y. Shi, et al. (2010)
J. Exp. Med. 207, 2647-2662
   Abstract »    Full Text »    PDF »
The WD40-repeat protein Han11 functions as a scaffold protein to control HIPK2 and MEKK1 kinase functions.
S. Ritterhoff, C. M. Farah, J. Grabitzki, G. Lochnit, A. V. Skurat, and M. L. Schmitz (2010)
EMBO J. 29, 3750-3761
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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S. Stavrou, Z. Feng, S. M. Lemon, and R. P. Roos (2010)
J. Virol. 84, 9181-9189
   Abstract »    Full Text »    PDF »
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A. Tsagaratou, E. Trompouki, S. Grammenoudi, D. L. Kontoyiannis, and G. Mosialos (2010)
J. Immunol. 185, 2032-2043
   Abstract »    Full Text »    PDF »
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G. Solinas and M. Karin (2010)
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   Abstract »    Full Text »    PDF »
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G. Carvalho, A. Le Guelte, C. Demian, A. Vazquez, J. Gavard, and N. Bidere (2010)
J. Cell Sci. 123, 2375-2380
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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R. Feltham, M. Moulin, J. E. Vince, P. D. Mace, W. W. L. Wong, H. Anderton, C. L. Day, D. L. Vaux, and J. Silke (2010)
J. Biol. Chem. 285, 17525-17536
   Abstract »    Full Text »    PDF »
Oncogenic Activation of NF-{kappa}B.
L. M. Staudt (2010)
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   Abstract »    Full Text »    PDF »
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A.-P. Mao, S. Li, B. Zhong, Y. Li, J. Yan, Q. Li, C. Teng, and H.-B. Shu (2010)
J. Biol. Chem. 285, 9470-9476
   Abstract »    Full Text »    PDF »
Low TNF-induced NF-{kappa}B and p38 phosphorylation levels in leucocytes in tumour necrosis factor receptor-associated periodic syndrome.
S. Stjernberg-Salmela, A. Ranki, L. Karenko, S. Siitonen, H. Mustonen, P. Puolakkainen, S. Sarna, T. Pettersson, and H. Repo (2010)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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Y.-H. Ahn and J. M. Kurie (2009)
J. Biol. Chem. 284, 29399-29404
   Abstract »    Full Text »    PDF »
NEMO specifically recognizes K63-linked poly-ubiquitin chains through a new bipartite ubiquitin-binding domain.
E. Laplantine, E. Fontan, J. Chiaravalli, T. Lopez, G. Lakisic, M. Veron, F. Agou, and A. Israel (2009)
EMBO J. 28, 2885-2895
   Abstract »    Full Text »    PDF »
Roles of the TRAF2/3 Binding Site in Differential B Cell Signaling by CD40 and Its Viral Oncogenic Mimic, LMP1.
J. P. Graham, C. R. Moore, and G. A. Bishop (2009)
J. Immunol. 183, 2966-2973
   Abstract »    Full Text »    PDF »
Linear polyubiquitination: a new regulator of NF-{kappa}B activation.
K. Iwai and F. Tokunaga (2009)
EMBO Rep. 10, 706-713
   Abstract »    Full Text »    PDF »
GCK is essential to systemic inflammation and pattern recognition receptor signaling to JNK and p38.
J. Zhong, L. C. Gavrilescu, A. Molnar, L. Murray, S. Garafalo, J. H. Kehrl, A. R. Simon, R. A. Van Etten, and J. M. Kyriakis (2009)
PNAS 106, 4372-4377
   Abstract »    Full Text »    PDF »
Analysis of nondegradative protein ubiquitylation with a monoclonal antibody specific for lysine-63-linked polyubiquitin.
H. Wang, A. Matsuzawa, S. A. Brown, J. Zhou, C. S. Guy, P.-H. Tseng, K. Forbes, T. P. Nicholson, P. W. Sheppard, H. Hacker, et al. (2008)
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   Abstract »    Full Text »    PDF »
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M. Liu, R. Aneja, X. Sun, S. Xie, H. Wang, X. Wu, J.-T. Dong, M. Li, H. C. Joshi, and J. Zhou (2008)
J. Biol. Chem. 283, 35783-35788
   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »

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