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.
Highlights
Rsk kinases play important roles in several cellular processes such as proliferation, metabolism, and migration
The cells were 91% positive when stained with allophycocyanin (APC)-labeled anti-CD19. plasmacytoid DC (pDC) were generated from bone marrow in the presence of 100 ng/ml Flt3 ligand (Flt3-L) (Peprotech) in complete RPMI medium (cRPMI) for 10 days. pDC (B200ϩ) were sorted on an Influx cell sorter (BD Biosciences)
We previously identified a novel configuration of the mitogenactivated protein (MAP) kinase pathway in dendritic cells (DC) whereby the p38-activated kinase MK2 or MK3 activates Rsk, bypassing the canonical mode of Rsk activation which requires the C-terminal kinase domain (CTKD)
Summary
Rsk kinases play important roles in several cellular processes such as proliferation, metabolism, and migration. Rsk activation was thought to be exclusively initiated by Erk1/2, but in dendritic cells (DC) Rsk is activated by p38 mitogenactivated 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 demonstrated an important exception to this rule in Toll-like receptor (TLR)-stimulated murine dendritic cells (DC) by showing that Rsk is activated downstream of p38 signaling via the intermediate kinases MK2/3 [3]. What are the structural requirements for activation of Rsk when the CTKD is apparently bypassed? Does the C-terminal region of Rsk still play a role? Do Erk1/2-activated Rsk and p38-activated Rsk have the same downstream substrates? since p38-MK2 signaling is intact in the many cell types that activate Rsk exclusively via Erk1/2, what pre-
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