MK2-TNF-Signaling Comes Full Circle.

MK2 (p38MAPK-activated protein kinase 2) is essential for tumor necrosis factor (TNF) biosynthesis, mainly operating by post-transcriptional regulation. Deletion of the gene encoding MK2 strongly reduced serum TNF and protected against endotoxic shock, demonstrating the positive role of p38MAPK/MK2 in TNF signaling at the level of ligand expression. Recent evidence indicates that MK2 directly phosphorylates the TNF receptor interactor RIPK1 and suppresses its activity, thereby limiting TNF-mediated apoptosis and necroptosis - pointing to a more complex, double-edged role of MK2 in TNF signaling. In addition, novel MK2 substrates have emerged in the DNA damage response, autophagy, and obesity, making MK2 a multifunctional kinase at the crossroads of stress response and cell death. We therefore propose a more general role of p38MAPK/MK2 signaling in the timely coordinated onset and resolution of inflammation and beyond.