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

Key Points

  • 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.

Abstract

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. Although there is no known common function for all three MKs, these kinases are involved in important processes: MKs regulate gene expression at the transcriptional and post-transcriptional level, control cytoskeletal architecture and cell-cycle progression, and are implicated in inflammation and cancer.

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Figure 1: Definition and Structure of MKs.
Figure 2: Models for activation and translocation of MKs.
Figure 3: MK2 and MK3 interact with components of the polycomb repressive complex.
Figure 4: 14-3-3-protein-dependent mechanisms of MK action.

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Acknowledgements

I wish to thank H. Holtmann, M. Kracht and A. Kotlyarov for critical reading and discussion of the manuscript. I apologize to all colleagues for the work I could not cite owing to space constrains. The work of my laboratory was, and is, continuously funded by the Deutsche Forschungsgemeinschaft and is also supported by the European Community.

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DATABASES

Saccharomyces genome database

Rck1

Rck2

OMIM

Peutz–Jeghers cancer syndrome

FURTHER INFORMATION

iHOP (information hyperlinked over proteins)

MAPKAPK2/MK2

MK3/3pK

MK5/PRA

Phosphosite

MAPKAPK2/MK2

MK5/PRA

The AfCS signalling gateway

MAPKAPK2/MK2

MK3/3pK

MK5/PRAK

Human AU-rich-element-containing mRNA database

Glossary

SAPKs

Stress-activated protein kinases that consist of the JNK and p38 subgroups.

Kinome

The protein kinase complement of the genome, which contains 518 genes and 106 pseudogenes in humans, and 540 genes and 97 pseudogenes in mice.

Importins

Proteins that facilitate the nuclear import of cargo proteins. In many cases, importin-α binds to the NLS of the cargo protein, and then importin-β binds to and translocates the complex through the nuclear pore. In the nucleus, Ran·GTP displaces importin-β and the cargo protein is released.

Exportins

Proteins that facilitate the nuclear export of proteins and mRNA. Exportins bind to their cargo in the nucleus together with Ran·GTP. After translocation through the nuclear pore, GTP is hydrolysed and the cargo is released.

Src-homology-3 (SH3) domain

A protein domain of approximately 60 amino acids that has homology to an N-terminal region of the protein tyrosine kinase Src. There are more than 250 SH3 domains in the human proteome, which can bind to proline-rich protein regions that form a left-handed helix with the minimal consensus motif P-X-X-P (where X is any amino acid).

Nuclear export signal

(NES). An amino-acid sequence that often contains several leucines or other hydrophobic residues and interacts with CRM/exportin-1, thereby functioning as a signal to facilitate export from the nucleus.

Nuclear localization signal (NLS)

An amino-acid sequence that often consists of a bipartite arrangement of basic amino acids and interacts with importin-α, thereby functioning as a signal to facilitate import into the nucleus.

Anisomycin

An antibiotic that inhibits protein synthesis and, at lower concentrations, stimulates stress signalling.

Homeotic genes

Genes that specify how structures develop in different segments of the body during embryogenesis. Homeotic genes are often organized in clusters and encode DNA-binding proteins.

Chaperone (molecular chaperone)

Proteins that assist the folding of nascent proteins, or the re-folding of partially misfolded proteins, without being part of the final folded protein structure.

Barbed end

The rapidly growing end of the polar actin microfilaments at which globular actin polymerizes.

14-3-3 proteins

A family of 30-kDa proteins that form cup-like structures that bind to discrete phosphoserine-containing motifs. They are present in fungi, plants and mammals and, in mammals, nine structurally related family members have been identified.

Boyden chamber

An experimental setting that was developed by Stephen Boyden in 1961 to test the chemotactic activity of motile cells in vitro. Two compartments are separated by a membrane of such pore size that only actively migrating cells can pass through it; a gradient of the chemotactic substance is applied, and the number of cells that pass through the membrane is determined.

Polycomb repressive complex-1

(PRC1). One of the two subcomplexes (PRC1 and PRC2) that cooperate to form the nuclear polycomb repressive complex (PRC), which has a role in gene silencing during development.

Kaposi's sarcoma

Cancer of the connective tissue that was named after the person who described it — the Hungarian dermatologist Moritz Kaposi (1837–1902) — and is caused by infection with the herpes virus, especially in patients with severe immunodeficiencies.

23-nucleotide GC-rich direct repeats

The kaposin locus of herpes virus contains a small coding region (open reading frame (orf) k12) preceded by two families of 23-nucleotide GC-rich direct repeats (termed DR1 and DR2). It is transcribed as a single mRNA and a complex translational programme generates various proteins from this mRNA. Kaposin B results from translation of the repeats alone and consists of a series of tandemly repeated copies of 23-amino-acid peptides that are derived from translation of the DR2 (HPRNPARRTPGTRRGAPQEPGAA) and DR1 (PGTWCPPPREPGALLPGNLVPSS) repeats.

P-bodies

Cytoplasmic aggregates of translationally inactive ribonucleoproteins (mRNPs), which are sites of mRNA degradation.

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Gaestel, M. MAPKAP kinases — MKs — two's company, three's a crowd. Nat Rev Mol Cell Biol 7, 120–130 (2006). https://doi.org/10.1038/nrm1834

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