MAPKAPK2 encodes a member of the Ser/Thr protein kinase regulated through direct phosphorylation by p38 MAP kinase. Inhibition of the p38 MAPK pathway could be a possible target to inflammatory diseases therapy. Unfortunately, blocking p38 MAPK activation "in vivo" implies in high toxicity and it does not have oral bioavailability. MAPKAPK2/MK2 inhibitors acting downstream of p38 could be reasonable solutions to overcome this problem (Duraisamy et al., 2008).

Size 49,338 bases, starts at 204924912 and ends at 204974256 bp from pter with plus strand orientation.

We found some discordant information regarding MAPKAPK2 splice variants. Kervinen et al. 2006, described that the human MAPKAPK2 gene encodes two alternatively spliced transcripts and also that this gene contains 14 different introns (13 gt-ag, 1 gc-ag). Transcription produces 9 different mRNAs, 8 alternatively spliced variants and 1 unspliced form. There are 5 probable alternative promoters and 3 validated alternative polyadenylation sites. The mRNAs appear to differ by truncation of the 5 end, presence or absence of 7 cassette exons, overlapping exons with different boundaries, alternative splicing or retention of 3 introns.

ATF4C - Cyclic AMP-dependent transcription factor ATF-4, localized at chromosome 17, location: 17q25.1.

MAPKAPK2 has two alternatively spliced transcripts, encoding 400 and 370 amino acids, with sequence heterogeneity from Lys-353 to the C-terminus. Crystal structure shows: 1) an autoinhibitory domain, consisting of 328-370 residues; 2) a helix-turn-helix structure that occupies the substrate-binding cleft of the kinase domain and inhibits kinase function (ter Haar et al., 2007).

The 400-residue MAPKAPK2 (isoform 1) consists of an N-terminal Pro-rich region, a kinase domain, an autoinhibitory domains, and C-terminal nuclear export (NES) and nuclear localization (NLS) signals. The 1-370 isoform (isoform 2) lacks NES and NLS, consistent with its presence only in the cytoplasm. MAPKAPK2 also phosphorylates proteins found in both the nucleus (cAMP-response element-binding protein, or CREB) and cytoplasm (HSP25/27 and LSP-1) (Kervinen et al., 2006).

MAPKAPK2 is required for both cytokines production and cell migration (Kotlyarov et al., 2002).
MAPKAPK2 is activated upon stress by p38 MAPK, which binds C terminus of MAPKAPK2, leading to subsequently phosphorylation of its regulatory sites. After activation, MAPKAPK2 is transferred from nucleus to cytoplasm, and cotransport p38 to the new localization. In murine knockout model, MAPKAPK2 blockage leads to a dramatic reduction of tumor necrosis factor (TNF) production in response to lipopolysaccharide (Kotlyarov et al., 2002). One of the major substrates of MAPKAPK2 is the heat shock protein HSP27, which stimulates actin polymerization in order to facilitate recovery from destruction of cytoskeleton during cellular stresses.

Isoform 1 and 2 see figure below.

There is one described mutation: position 804 of mRNA, allele change GCC to GGC. At protein level, residue change A [Ala] to G [Gly].