Dendritic cells have a key role in protecting organisms from infections. These cells detect antigens derived from invading bacteria or viruses and present them to T cells. Zaru et al. explored the roles of protein kinases activated in response to mitogen-activated protein kinases (MAPKs) and not only demonstrate the importance of various MAPK-activated protein kinases (MKs)--the MKs known as MK2 and MK3 and the p90 ribosomal S6 kinases (Rsks)--but also reveal a previously unrecognized regulatory network for control of downstream kinases in a MAPK system. The authors monitored Toll-like receptor-activated endocytosis by detecting uptake of fluorescently labeled dextran and observed that dendritic cells lacking both MK2 and MK3 had a reduced response. They also observed that pharmacological inhibition of Rsk family members with two structurally distinct inhibitors inhibited Toll-like receptor-induced endocytosis. The surprise was that inhibition of ERK1 and ERK2, the MAPKs known to activate Rsks, could not block receptor-induced Rsk activation in this system. Inhibition of ERKs only blocked Rsk activation in cells lacking MK2 and MK3, kinases that are activated by the MAPK p38 rather then ERKs. Rsks have two kinase domains, and the C-terminal kinase domain of Rsk proteins is phosphorylated by ERKs and autophosphorylates a serine residue located between the two kinase domains [thus recruiting yet another kinase (PDK1) to complete the activation]. Zaru et al. realized, however, that this critical serine residue in Rsk fits the consensus for recognition by MK2 and MK3 and showed that MK2 could phosphorylate Rsk2 at this site in vitro. Thus, the p38 MAPK provides an alternative mechanism for activating Rsks that bypasses the mechanism used for their activation by the ERK MAPKs, a mechanism that appears to be restricted to dendritic cells. The authors and Karin (in associated commentary) speculate on ways in which this modified regulatory scheme might be advantageous in these particular cells.
R. Zaru, N. Ronkina, M. Gaestel, J. S. C. Arthur, C. Watts, 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). [PubMed]
M. Karin, Rsk Tolls the bell for endocytosis in DCs. Nat. Immunol. 8, 1197-1199 (2007). [PubMed]