p38 MAPK and MK2/3 in post-transcriptional regulation of gene expression.

Matthias Gaestel, Hannover Medical University, Hannover, Germany

p38 MAPKs are activated by stress and in innate (and adaptive) immunity and signal via different routes to alter the stability and translation of various mRNAs, enabling cells to respond promptly. This regulation involves mRNA elements, such as AU-rich elements (AREs), mRNA-binding proteins (RBPs), such as tristetraprolin (TTP), HuR, and hnRNPK-homology (KH) type splicing regulatory protein (KSRP) and downstream protein kinases, such as MK2 and MK3. Signal-dependent phosphorylation of mRNA-binding proteins often alters their subcellular localization or RNA-binding affinity. Furthermore, it could lead to an altered interaction with other mRNA-binding proteins and altered scaffolding properties for mRNA-modifying enzymes, such as deadenylases, polyadenylases, decapping enzymes, poly(A) binding proteins, exo- or endonucleases, and proteins of the exosome machinery. In many cases, it results in unstable mRNAs being stabilized, with their translational arrest being released and stress protein and cytokine production being stimulated. An example is the MAPK-dependent phosphorylation-driven exchange of the RBPs TTP and HuR at specific mRNA-AREs. After phosphorylation by MK2 the affinity of the mRNA destabilizing factor TTP for the ARE is reduced and TTP is replaced by HuR, which stabilizes the mRNA and stimulates its transcription. In a later phase, newly synthesized non-phospho TTP can replace HuR again to down-regulate the response. Components of the above post-transcriptional mechanisms are potential targets for the modulation of the stress and inflammatory responses.