Downstream of mitogen-activated protein kinases (MAPKs), three structurally related MAPK-activated protein kinases (MAPKAPKs or MKs) — MK2, MK3 and MK5 — signal to diverse cellular targets. MK2 and MK3 are phosphorylated and activated by p38MAPK-α/β and, in turn phosphorylate various substrates involved in diverse cellular processes. In addition to forwarding of the p38-signal by MK2/3, protein complex formation between MK2/3 and p38 mutually stabilizes these enzymes and affects p38 signaling in general. Among the substrates of MK2/3, there are mRNA-AU-rich-element (ARE)-binding proteins, such as tristetraprolin (TTP), which regulate mRNA-stability and translation in a phosphorylation-dependent manner. Phosphorylation by MK2 stabilizes TTP and ARE-mRNAs by their exclusion from a default degradation pathway and facilitates the TTP-HuR-exchange at the ARE to stimulate translation of pro-TNF. MK2/3 also contribute to the de novo synthesis of TTP and of further immediate early genes by stimulating SRF-dependent transcription.
Both p38 MAPK-α and MK2/3 are elements of TLR- and cytokine-signaling and are therefore preferential targets to treat chronic inflammation involved in by orally available small molecules. Inhibitors against p38 MAPK have been tested in animal models and in the clinics, block acute and chronic inflammation efficiently, but show side effects such as liver toxicity and skin rash which might result from “on target”-effects. Thus, targets downstream to p38 MAPK-α, such as MK2/3, become more interesting for anti-inflammatory therapy.
The related protein kinase, MK5/PRAK, is predominantly regulated by the atypical MAPK ERK3 (MAPK6). The MK5/ERK3 signaling module regulates septin function and neuronal morphogenesis. Hence, MKs are of diverse, but essential biological importance.