Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Originally published in Science Express on 17 July 2008
Science 1 August 2008:
Vol. 321. no. 5889, pp. 663 - 668
DOI: 10.1126/science.1157340
Prev | Table of Contents | Next

Research Articles

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}

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

Read the Full Text

ADVERTISEMENT
Click Me!

ADVERTISEMENT
Click Me!

To Advertise     Find Products

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