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Essential Cytoplasmic Translocation of a Cytokine Receptor–Assembled Signaling Complex
Open accessAbstract
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), IκB kinase regulatory subunit IKKγ (also called NEMO), and mitogen-activated protein kinase (MAPK) kinase kinase MEKK1 upon ligation. TRAF2, Ubc13, and IKKγ 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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Micheau, O., & Tschopp, J. (2003) · Cell · doi:10.1016/s0092-8674(03)00521-x · Cited by 2,738
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Keats, J. J., Fonseca, R., Chesi, M., Schop, R., Baker, A., Chng, W.-J., Van Wier, S., Tiedemann, R., Shi, C.-X., Sebag, M., et al. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.07.003 · Cited by 983
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A cell biological view of Toll-like receptor function: regulation through compartmentalization
Barton, G. M., & Kagan, J. C. (2009) · Nature Reviews Immunology · doi:10.1038/nri2587 · Cited by 709
Vallabhapurapu, S., Matsuzawa, A., Zhang, W., Tseng, P.-H., Keats, J. J., Wang, H., Vignali, D. A. A., Bergsagel, P. L., & Karin, M. (2008) · Nature Immunology · doi:10.1038/ni.1678 · Cited by 608
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Metadata
- Authors
- Matsuzawa, A., Tseng, P.-H., Vallabhapurapu, S., Luo, J.-L., Zhang, W., Wang, H., Vignali, D. A. A., Gallagher, E., & Karin, M.
- Venue
- Science
- Published
- 2008-08
- Volume
- 321
- Issue
- 5889
- Pages
- 663-668
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2050437677
- Cited by
- 217
- References
- 2
- FWCI
- 8.39
- Type
- journal article
- Language
- en
- Open access
- green
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- Matsuzawa, A., Tseng, P.-H., Vallabhapurapu, S., Luo, J.-L., Zhang, W., Wang, H., Vignali, D. A. A., Gallagher, E., & Karin, M. (2008). Essential Cytoplasmic Translocation of a Cytokine Receptor–Assembled Signaling Complex. Science. https://doi.org/10.1126/science.1157340
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