title: Structural and functional basis for p38-MK2-activated Rsk signaling in toll-like receptor-stimulated dendritic cells.
abstract: 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.
authors.affiliation: Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Rossana
authors.initials: R
authors.lastname: Zaru
authors.affiliation: Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Edgar
authors.affiliation: Institute of Genetics and Molecular and Cellular Biology (IGBMC), Centre National de la Recherche Scientifique (UMR 7104), Institut National de la Santé et de la Recherche Médicale (U 964), University of Strasbourg, Illkirch, France.
authors.forename: André
authors.initials: A
authors.lastname: Hanauer
authors.affiliation: Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dundee, United Kingdom c.watts@dundee.ac.uk.
authors.forename: Colin
authors.initials: C
authors.lastname: Watts
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology*; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D006412:Hematopoietic Stem Cells / Q000166:cytology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D051193:Toll-Like Receptors; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C512964:Rps6ka1 protein, mouse