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.

Protein Tyrosine Phosphatase PTPRS Is an Inhibitory Receptor on Human and Murine Plasmacytoid Dendritic Cells

“…Gen2.2 cells expressed PTPRS protein, which was downregulated after activation with CpG (Figure 3A). We also observed that the induction of p38 kinase phosphorylation, an important event in pDC activation (Takauji et al, 2002; Zaru et al, 2015), mirrored the decrease of PTPRS (Figure 3A). Furthermore, crosslinking of PTPRS on Gen2.2 cells delayed the characteristic induction of both p-p38 and p-Stat1 (Di Domizio et al, 2009) and inhibited CpG-induced nuclear translocation of IRF7 (Figure S2).…”

Pathogenic effect of a cell-penetrating anti-dsDNA autoantibody through p38 signaling pathway and pro-inflammatory cytokine stimulation in mesangial cells

“…In 2C10 IgG and VH treated MES cells, p38-dependent MAPKAPK-2 activation and MAPKAPK-2-dependent RSK-1 activation were induced. Regulation of RSK phosphorylation by p38 through the activation of MAPKAPK-2 we observed is consistent with previous observations (Zaru et al 2007(Zaru et al , 2015Anjum and Blenis 2008). It has been known that RSK-1 may induce inflammatory cytokines by a nuclear factor kappa beta (NF-κB)-independent pathway or triggering cyclooxygenase-2 through the activation of cAMP response element binding protein (Wu 2006;Moens et al 2013).…”

“…Similarly, there have been reports showing that RSK-1 was activated by p38 rather than by ERK1/2 in kidney epithelial or dendritic cells (Zaru et al 2007(Zaru et al , 2015Luo et al 2017). In 2C10 IgG and VH treated MES cells, p38-dependent MAPKAPK-2 activation and MAPKAPK-2-dependent RSK-1 activation were induced.…”

“…It was previously reported that p38-MAPKAPK-2 induced prostaglandin-2 leads to cyclooxygenase-2 activation and gene expression of TNF-α, IL-6 and IL-1β (Bhatia et al 2017). It was also reported that stronger p38 activation is promoted by TLR4 and TLR5 ligands versus stronger ERK1/2 activation by TLR2 (Zaru et al 2007(Zaru et al , 2015. Previous reports have demonstrated the association of TLRs and anti-dsDNA Abs in in vitro and in vivo animal experiments, including transgenic mice (Qing et al 2008;Lee et al 2010Lee et al , 2014; nephrogenic anti-dsDNA Abs upregulate pro-inflammatory gene expression, such as high mobility group protein B1 (HMGB1) and TLR 2/4, in MES cells, and HMGB1 might be a pro-inflammatory mediator in Ab-induced kidney injury in SLE.…”

Focal-adhesion-independent integrin-αv regulation of FAK and c-Myc is necessary for 3D skin formation and tumor invasion

“…5D). Although ERK1/2 has a wellestablished role in phosphorylating p90RSK family members, p38 MAPK family members have also been shown to promote activation of p90RSK indirectly in some cell types (Roux et al, 2007;Zaru et al, 2015). Furthermore, we observed a decrease in phosphorylation of two ribosomal kinase (RSK) translation machinery targets -RPS6 at residue Ser235 (but not Ser240) and eIF4B, upon integrin-αv knockdown (Fig.…”