MAPKAP kinases — MKs — two's company, three's a crowd

Abstract

The mitogen-activated protein kinase (MAPK)-activated protein kinase (MAPKAP or MK) subfamily of protein kinases consists of the three structurally related enzymes MK2, MK3 and MK5. Besides the catalytic domain of the Ca²⁺/calmodulin-dependent protein kinase (CaMK) type, MKs contain a C-terminal region that includes nuclear localization signal (NLS)-, nuclear export signal (NES)- and MAPK-docking sites, and might also contain autoinhibitory and proline-rich elements. MKs are activated by Thr phosphorylation at the activation loop and by at least one other Thr phosphorylation in a hinge region between the catalytic domain and the C terminus of MK2 and MK3. This latter phosphorylation leads to unmasking of the NES and activation-coupled nuclear export of MK2 and MK3. MK5 is activated by phosphorylation of a single site in the activation loop after cytoplasmic anchoring by protein kinases, such as exrtacellular signal-regulated kinase-3 (ERK3). MKs are involved in actin remodelling, cell migration, development, cell-cycle regulation, chromatin remodelling and post-transcriptional control of mRNA stability and translation. More than 20 MK substrates have been identified. MK2 and MK3 interact with components of the polycomb transcription-repressive complex and might modulate gene silencing through phosphorylation of the members of the complex. MK2 can function as an ultraviolet light (UV)-induced kinase for cell-cycle-checkpoint control through CDC25B and CDC25C, and can also downregulate p53 by phosphorylating a specific ubiquitin ligase. The control of mRNA stability and translation by MK2 is dependent on AU-rich elements in the 3′ untranslated mRNA region, and on RNA-binding proteins. Deletion of MK2 leads to an impaired inflammatory response, which is mainly due to reduced TNF-mRNA stability or translation. MK5 shows sustained activation in development, which is dependent on the cytoplasmic protein levels of its activator, ERK3, which is mainly regulated by protein-stability mechanisms. The ERK3–MK5 signalling module is of physiological relevance for embryonic development in mice. A molecular mechanism of MK action is the generation of 14-3-3-protein-binding sites in some of its targets. For MK substrates — such as tristetraprolin, small heat-shock protein HSP27, CDC25B, CDC25C and tuberin — binding to 14-3-3 proteins after phosphorylation by MKs could be essential for the regulation of their function.