Alternative titles; symbols
HGNC Approved Gene Symbol: MAPKAPK2
Cytogenetic location: 1q32.1 Genomic coordinates (GRCh38): 1:206,684,905-206,734,281 (from NCBI)
MAPKAPK2, a downstream target of p38 MAPK (MAPK14; 600289), is a major regulator of stress- and cytokine-induced gene expression with roles in gene transcription, mRNA stabilization, and translation of target transcripts (summary by Menon et al., 2013).
Stokoe et al. (1993) described a protein kinase, which they designated MAPKAP kinase-2, that was active only after phosphorylation by mitogen-activated protein kinase (MAP kinase). They identified several features that distinguish MAPKAP kinase-2 from the MAPKAP kinase-1 family (e.g., RPS6KA1; 601684). Stokoe et al. (1993) stated that MAPKAP kinase-2 was identified based on its in vitro phosphorylation of glycogen synthase; however, its phosphorylation of glycogen synthase had not been shown in vivo.
Stokoe et al. (1993) cloned a partial human MAPKAP kinase-2 cDNA from a teratocarcinoma cell line cDNA library. The cDNA sequence revealed the following features (in 5-prime to 3-prime order): a proline-rich region containing 2 putative SH3-binding sites, a kinase catalytic domain, a threonine residue phosphorylated by MAP kinase, and a nuclear localization signal. By Northern analysis, Stokoe et al. (1993) demonstrated that the gene is expressed as a 3.3-kb transcript in all of the 6 human tissues tested.
Stumpf (2022) mapped the MAPKAPK2 gene to chromosome 1q32.1 based on an alignment of the MAPKAPK2 sequence (GenBank BC036060) with the genomic sequence (GRCh38).
Stokoe et al. (1993) stated that one physiologic target of MAPKAP kinase-2 is the small heat-shock protein HSP27 (HSPB1; 602195).
Maizels et al. (2001) investigated the activation in vivo and regulation of the expression of components of the p38 mitogen-activated protein kinase (p38 MAPK; 600289) pathway during gonadotropin-induced formation and development of the rat corpus luteum. They postulated that the p38 MAPK pathway could serve to promote phosphorylation of key substrates during luteal maturation, since maturing luteal cells, thought to be cAMP-nonresponsive, nevertheless maintain critical phosphoproteins. The p38 MAPK downstream protein kinase target MAPK-activated protein kinase-3 (MAPKAPK3; 602130) was newly induced at both mRNA and protein levels during luteal formation and maturation, while mRNA and protein expression of the closely related MAPKAPK2 diminished.
McCormick and Ganem (2005) showed that a latent Kaposi sarcoma-associated herpesvirus (KSHV) gene product, kaposin B, increased the expression of cytokines by blocking the degradation of their mRNAs. Cytokine transcripts are normally unstable because they contain AU-rich elements in their 3-prime noncoding regions that target them for degradation. Kaposin B reversed this instability by binding to and activating MAPKAPK2, a target of the p38 MAPK signaling pathway and a known inhibitor of AU-rich element-mRNA decay. McCormick and Ganem (2005) concluded that their findings define an important mechanism linking latent KSHV infection to cytokine production and illustrate a distinctive mode by which viruses can selectively modulate mRNA turnover.
Using phosphoproteomics, Menon et al. (2013) identified mouse and human UBE2J1 (616175) as a potential substrate of MK2. Under cytosolic stress conditions, mouse Ube2j1 was phosphorylated at ser184, which also occurs under endoplasmic reticulum (ER) stress. Phosphorylation under cytosolic stress, but not ER stress, was sensitive to MK2, MK5 (MAPKAP5; 606723), and p38 inhibitors and was abrogated in Mk2 and Mk3 (MAPKAPK3) double-knockout mouse cells, but not in Mk5-knockout mouse cells. Pull-down analysis in transfected human embryonic kidney cells demonstrated interaction of MK2 and mouse Ube2j1. MK2 phosphorylated recombinant mouse Ube2j1, but not a ser184-to-ala Ube2j1 mutant, in an in vitro kinase assay. However, the mutant protein could ubiquitinate the ER-synthesized TCRA (see TRAC, 186880) substrate, similar to wildtype Ube2j1. Ube2j1 was also phosphorylated in response to lipopolysaccharide stimulation of macrophages and contributed to Tnf (191160) biosynthesis. Treatment of mouse macrophages with small interfering RNA to Ube2J1 blocked Tnf secretion. Menon et al. (2013) concluded that UBE2J1 is involved in MK2-dependent translational control of TNF synthesis.
For a discussion of an association between a functional copy number variant at the MAPKAPK2 locus and susceptibility to lung cancer, see 211980.
Kotlyarov et al. (1999) generated viable and fertile Mk2 -/- mice. Mk2 -/- mice showed increased stress resistance and survived toxic shock induced by lipopolysaccharide (LPS), but Tnf, with little or no phosphorylation of Hsp25 (HSPB1). Serum Tnf and nitric oxide were nearly absent in LPS-challenged Mk2-deficient mice due to a posttranslational mechanism, as Tnf and Ifng (147570) mRNA levels were not reduced. In contrast, Il6 (147620) mRNA expression was significantly downregulated. Kotlyarov et al. (1999) proposed that MK2 contributes to regulation of several cytokines at the posttranscriptional level.
Wang et al. (2002) subjected Mapkapk2-deficient mice to focal cerebral ischemia and found that the mice had markedly reduced infarct sizes after both transient and permanent ischemia compared to wildtype mice. The Mapkapk2 -/- mice also had significant reductions in both neurologic deficits and expression of Il1b (147720) mRNA, but not in Tnf. The marked neuroprotection from ischemic brain injury in Mapkapk2 -/- mice was not associated with the alteration of hemodynamic or systemic variables, activation of caspase-3, or apoptosis. These data provided evidence for the involvement of the MAP kinase pathway in focal ischemic brain injury and suggested that this effect might be associated with the expression of IL1B in ischemic brain tissue.
Hegen et al. (2006) found that Mk2 -/- mice were protected against collagen-induced arthritis (CIA) and that Mk2 +/- mice had intermediate protection. Both Mk2 -/- and Mk2 +/- mice had decreased serum Tnf and Il6. Levels of Il6 mRNA in mouse paws correlated with CIA disease status. Hegen et al. (2006) proposed that an MK2 inhibitor could be of therapeutic value in treatment of inflammatory diseases, such as rheumatoid arthritis (180300).
Hegen, M., Gaestel, M., Nickerson-Nutter, C. L., Lin, L.-L., Telliez, J.-B. MAPKAP kinase 2-deficient mice are resistant to collagen-induced arthritis. J. Immun. 177: 1913-1917, 2006. [PubMed: 16849504] [Full Text: https://doi.org/10.4049/jimmunol.177.3.1913]
Kotlyarov, A., Neininger, A., Schubert, C., Eckert, R., Birchmeier, C., Volk, H.-D., Gaestel, M. MAPKAP kinase 2 is essential for LPS-induced TNF-alpha biosynthesis. Nature Cell Biol. 1: 94-97, 1999. [PubMed: 10559880] [Full Text: https://doi.org/10.1038/10061]
Maizels, E. T., Mukherjee, A., Sithanandam, G., Peters, C. A., Cottom, J., Mayo, K. E., Hunzicker-Dunn, M. Developmental regulation of mitogen-activated protein kinase-activated kinases-2 and -3 (MAPKAPK-2/-3) in vivo during corpus luteum formation in the rat. Molec. Endocr. 15: 716-733, 2001. [PubMed: 11328854] [Full Text: https://doi.org/10.1210/mend.15.5.0634]
McCormick, C., Ganem, D. The kaposin B protein of KSHV activates the p38/MK2 pathway and stabilizes cytokine mRNAs. Science 307: 739-741, 2005. [PubMed: 15692053] [Full Text: https://doi.org/10.1126/science.1105779]
Menon, M. B., Tiedje, C., Lafera, J., Ronkina, N., Konen, T., Kotlyarov, A., Gaestel, M. Endoplasmic reticulum-associated ubiquitin-conjugating enzyme Ube2j1 is a novel substrate of MK2 (MAPKAP kinase-2) involved in MK2-mediated TNF-alpha production. Biochem. J. 456: 163-172, 2013. Note: Erratum: Biochem. J. 457: 229 only, 2014. [PubMed: 24020373] [Full Text: https://doi.org/10.1042/BJ20130755]
Stokoe, D., Caudwell, B., Cohen, P. T. W., Cohen, P. The substrate specificity and structure of mitogen-activated protein (MAP) kinase-activated protein kinase-2. Biochem. J. 296: 843-849, 1993. [PubMed: 8280084] [Full Text: https://doi.org/10.1042/bj2960843]
Stumpf, A. M. Personal Communication. Baltimore, Md. 09/09/2022.
Wang, X., Xu, L., Wang, H., Young, P. R., Gaestel, M., Feuerstein, G. Z. Mitogen-activated protein kinase-activated protein (MAPKAP) kinase 2 deficiency protects brain from ischemic injury in mice. J. Biol. Chem. 277: 43968-43972, 2002. [PubMed: 12215446] [Full Text: https://doi.org/10.1074/jbc.M206837200]