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Structural and Functional Basis for p38-MK2-Activated Rsk Signaling in Toll-Like Receptor-Stimulated Dendritic Cells

Rsk kinases play important roles in several cellular processes such as proliferation, metabolism, and migration. Until recently, Rsk activation was thought to be exclusively initiated by Erk1/2, but in dendritic cells (DC) Rsk is also activated by p38 mitogen-activated protein (MAP) kinase via its d...

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Detalles Bibliográficos
Autores principales: Zaru, Rossana, Edgar, Alexander J., Hanauer, André, Watts, Colin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295372/
https://www.ncbi.nlm.nih.gov/pubmed/25332232
http://dx.doi.org/10.1128/MCB.00773-14
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author Zaru, Rossana
Edgar, Alexander J.
Hanauer, André
Watts, Colin
author_facet Zaru, Rossana
Edgar, Alexander J.
Hanauer, André
Watts, Colin
author_sort Zaru, Rossana
collection PubMed
description Rsk kinases play important roles in several cellular processes such as proliferation, metabolism, and migration. Until recently, Rsk activation was thought to be exclusively initiated by Erk1/2, but in dendritic cells (DC) Rsk is also activated by p38 mitogen-activated protein (MAP) kinase via its downstream substrates, MK2/3. How and why this noncanonical configuration of the MAP kinase pathway is adopted by these key immune cells are not known. We demonstrate that the Erk1/2-activated C-terminal kinase domain of Rsk is dispensable for p38-MK2/3 activation and show that compared with fibroblasts, a greater fraction of p38 and MK2/3 is located in the cytosol of DC prior to stimulation, suggesting a partial explanation for the operation of the noncanonical pathway of Rsk activation in these cells. p38/MK2/3-activated Rsk phosphorylated downstream targets and is physiologically important because in plasmacytoid DC (pDC) stimulated with Toll-like receptor 7 (TLR7) agonists, Erk1/2 activation is very weak relative to p38. As a result, Rsk activation is entirely p38 dependent. We show that this unusual configuration of MAP kinase signaling contributes substantially to production of type I interferons, a hallmark of pDC activation.
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spelling pubmed-42953722015-01-15 Structural and Functional Basis for p38-MK2-Activated Rsk Signaling in Toll-Like Receptor-Stimulated Dendritic Cells Zaru, Rossana Edgar, Alexander J. Hanauer, André Watts, Colin Mol Cell Biol Articles Rsk kinases play important roles in several cellular processes such as proliferation, metabolism, and migration. Until recently, Rsk activation was thought to be exclusively initiated by Erk1/2, but in dendritic cells (DC) Rsk is also activated by p38 mitogen-activated protein (MAP) kinase via its downstream substrates, MK2/3. How and why this noncanonical configuration of the MAP kinase pathway is adopted by these key immune cells are not known. We demonstrate that the Erk1/2-activated C-terminal kinase domain of Rsk is dispensable for p38-MK2/3 activation and show that compared with fibroblasts, a greater fraction of p38 and MK2/3 is located in the cytosol of DC prior to stimulation, suggesting a partial explanation for the operation of the noncanonical pathway of Rsk activation in these cells. p38/MK2/3-activated Rsk phosphorylated downstream targets and is physiologically important because in plasmacytoid DC (pDC) stimulated with Toll-like receptor 7 (TLR7) agonists, Erk1/2 activation is very weak relative to p38. As a result, Rsk activation is entirely p38 dependent. We show that this unusual configuration of MAP kinase signaling contributes substantially to production of type I interferons, a hallmark of pDC activation. American Society for Microbiology 2014-12-09 2015-01 /pmc/articles/PMC4295372/ /pubmed/25332232 http://dx.doi.org/10.1128/MCB.00773-14 Text en Copyright © 2015, Zaru et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 3.0 Unported license (http://creativecommons.org/licenses/by/3.0/) .
spellingShingle Articles
Zaru, Rossana
Edgar, Alexander J.
Hanauer, André
Watts, Colin
Structural and Functional Basis for p38-MK2-Activated Rsk Signaling in Toll-Like Receptor-Stimulated Dendritic Cells
title Structural and Functional Basis for p38-MK2-Activated Rsk Signaling in Toll-Like Receptor-Stimulated Dendritic Cells
title_full Structural and Functional Basis for p38-MK2-Activated Rsk Signaling in Toll-Like Receptor-Stimulated Dendritic Cells
title_fullStr Structural and Functional Basis for p38-MK2-Activated Rsk Signaling in Toll-Like Receptor-Stimulated Dendritic Cells
title_full_unstemmed Structural and Functional Basis for p38-MK2-Activated Rsk Signaling in Toll-Like Receptor-Stimulated Dendritic Cells
title_short Structural and Functional Basis for p38-MK2-Activated Rsk Signaling in Toll-Like Receptor-Stimulated Dendritic Cells
title_sort structural and functional basis for p38-mk2-activated rsk signaling in toll-like receptor-stimulated dendritic cells
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295372/
https://www.ncbi.nlm.nih.gov/pubmed/25332232
http://dx.doi.org/10.1128/MCB.00773-14
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