Abstract
Most dendritic cell (DC) responses to Toll-like receptor (TLR) ligands depend on the activation of mitogen-activated protein kinases (MAPKs), but the contributions of the many MAPK-activated kinases (MKs) that act 'downstream' of the MAPKs Erk and p38 are not known. Here we sought to determine which MKs are required for acute TLR-driven, MAPK-dependent DC endocytic responses. Two specific and structurally different inhibitors of the MK Rsk suppressed TLR-induced endocytosis, thus defining in DCs a specific requirement for MKs in TLR responses. In addition, we identify in DCs a previously unknown configuration of the MAPK system whereby Rsk is activated not only by Erk but also by p38 through the intermediates MK2 and MK3. Thus, in DCs, p38 contributes to the activation of all known MK families.
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Change history
16 November 2007
In the version of this article initially published, the Author Contributions section was incorrect. The correct author contributions are as follows: R.Z and C.W designed the study, interpreted the data and wrote the manuscript; R.Z. did the experiments; N.R. and M.G. provided MK2-null mice and generated embryonic stem cells carrying a targeted allele of MK3; J.S.C.A. provided advice and MSK1-MSK2-null mice and generated MK3-null mice from the MK3 embryonic stem cells provided by N.R. and M.G. The error has been corrected in the PDF version of the article.
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Acknowledgements
We thank M. Frödin and P. Cohen for suggestions and discussions; N. Shpiro for BI-D1870 synthesis; C. Proud (University of British Columbia), M. Buxade (University of British Columbia) and R. Fukunaga (Osaka University) for cells lacking MNK1 and MNK2; D. Alessi (University of Dundee) for anti-Rsk2 and for comments on the manuscript; B. Collins and J. Hastie for reagents and for help with the Rsk assays; and M. West and P. Mollahan for collaboration and technical assistance. Supported by the Medical Research Council (C.W. and J.C.S.A.) and Deutsche Forschungsgemeinschaft (M.G.).
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R.Z. and C.W. designed the study, interpreted the data and wrote the manuscript; R.Z. did the experiments; N.R. and M.G. provided MK2-null mice and the targeting vector for generation of MK3-null mice; J.S.C.A. generated MK3-null mice and MSK1-MSK2-null mice and gave advice.
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Zaru, R., Ronkina, N., Gaestel, M. et al. The MAPK-activated kinase Rsk controls an acute Toll-like receptor signaling response in dendritic cells and is activated through two distinct pathways. Nat Immunol 8, 1227–1235 (2007). https://doi.org/10.1038/ni1517
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DOI: https://doi.org/10.1038/ni1517
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