Disease relevance of Mapkapk2

• Our data propose a role for MK2 in AD brain pathology, for which neuroinflammation involving cytokines and chemokines and overt neuronal loss have been documented [1].
• Mice that lack MK2 show increased stress resistance and survive LPS-induced endotoxic shock [2].
• MK2(-/-) mice subjected to focal ischemia markedly reduced infarct size by 64 and 76% after transient and permanent ischemia, respectively, compared with wild-type mice [3].
• In the present study, we investigated the role of MK2 in immune defense against Listeria monocytogenes infection [4].
• The marked neuroprotection from ischemic brain injury in MK2(-/-) mice was not associated with the alteration of hemodynamic or systemic variables, activation of caspase-3, or apoptosis [3].

High impact information on Mapkapk2

• In contrast, p38alpha(1/+) ES cells and primary embryonic fibroblasts responded to stress stimuli and phosphorylated p38alpha, and activated MAPKAP kinase 2 [5].
• MAPKAP kinase 2 (MK2) is one of several kinases that are regulated through direct phosphorylation by p38 MAP kinase [2].
• We have identified the region responsible for nuclear export in MK2 which is partially overlapping with and C-terminal to the autoinhibitory motif [6].
• This region contains a cluster of hydrophobic amino acids in the characteristic spacing of a leucine-rich Rev-type NES which is necessary to direct GFP-MK2 to the cytoplasm [6].
• Molecular mimicry of MK2 phosphorylation at T317 in GFP-MK2 led to a mutant which is located almost exclusively in the cytoplasm of the cell, whereas the mutant T317A shows no stress-induced redistribution [6].

Chemical compound and disease context of Mapkapk2

• TLR7 ligand prevents allergen-induced airway hyperresponsiveness and eosinophilia in allergic asthma by a MYD88-dependent and MK2-independent pathway [7].

Biological context of Mapkapk2

• The increase in Mapkapk2 occurs following short term (5-60 min) stimulation of ERK1/2 activity by OGP-(10-14); phosphorylation of p38 remains unaffected [8].
• We conclude that the differences between the phenotypes of MK5- and MK2-deficient mice result from clearly different functional properties of both enzymes [9].
• MK2 and PRAK in turn suppressed Ras-induced gene expression and cell proliferation, whereas two mutant PRAKs, unresponsive to Ras, had little effect [10].
• In contrast, MK2 deficiency had no effect on macrophage generation of NO or on oxidative burst activity in response to L. moocytogenes [4].
• MK2 regulates LPS-induced TNF mRNA translation, and targeted mutation of the MK2 gene renders mice more resistant to D-galactosamine plus LPS-induced liver damage [4].

Anatomical context of Mapkapk2

• These data define a novel mitogenic signaling pathway in osteoblasts whereby ERK1/2 stimulation of CREB phosphorylation and transcriptional activity as well as DNA synthesis are critically dependent on de novo Mapkapk2 synthesis [8].
• It was interesting to find that the interaction disappeared in the cells from MK2-knock-out mice or the cells treated with lemptomycin B that blocks export of MK2 from nucleus to cytosol [11].
• MAPK-activated protein kinase 2 deficiency in microglia inhibits pro-inflammatory mediator release and resultant neurotoxicity. Relevance to neuroinflammation in a transgenic mouse model of Alzheimer disease [1].
• In spleen cells and macrophages where TNF biosynthesis is restored as a result of this deletion, interleukin (IL)-6 biosynthesis is still dependent on MK2 [12].
• We conclude that MK2, similar to p38MAPK, is involved in transmitting the death signal to the ischemic myocardium [13].

Associations of Mapkapk2 with chemical compounds

• In contrast, arsenite treatment enhanced stress granule localization of the MK2 mutant, consistent with the involvement of additional pathways regulating this event [14].
• MK2 activation and expression were increased in lipopolysaccharide (LPS) + interferon gamma-stimulated microglial cells, implicating a role for MK2 in eliciting a pro-inflammatory response [1].
• Leptomycin B-sensitive nuclear export of MAPKAP kinase 2 is regulated by phosphorylation [6].
• Here, we show that MAPKAP kinase 2 (MK2) can phosphorylate HDM2 on serine 157 and 166 in vitro [15].
• Although the role of MK2 in cytokine expression depends mainly on catalytic activity, its role in cell migration is also dependent on a proline-rich N-terminal motif [16].

Regulatory relationships of Mapkapk2

• ERK1/2-activated de novo Mapkapk2 synthesis is essential for osteogenic growth peptide mitogenic signaling in osteoblastic cells [8].
• The OGP-(10-14) stimulation of CREB transcriptional activity and DNA synthesis is also blocked by Mapkapk2 siRNA [8].
• Mitogen-activated protein (MAP) kinase-activated protein kinase 2 (MK2) is one of several kinases directly regulated by p38 MAP kinase [3].
• In contrast, the acute activation of p70 S6 kinase in C2C12 myoblasts induced by phorbol esters was unaffected by SB 203580 and the acute activation of MAPKAP kinase-2 induced by anisomycin was unaffected by rapamycin [17].

Other interactions of Mapkapk2

• Downstream of Mapkapk2, CREB is phosphorylated on Ser(133) leading to its enhanced transcriptional activity [8].
• AgC10 was found to inhibit both the activation and the activity of p38 MAPK, since MAPK activated protein kinase-2 (MAPKAP-K2 or MK-2) phosphorylation was also strongly inhibited [18].
• Real-time PCR analysis identified a significantly lower expression in interleukin-1beta mRNA (53% reduction) but not in tumor necrosis factor-alpha mRNA in MK2(-/-) mice over wild-type animals after ischemic injury [3].
• Three IgM monoclonal antibodies (MoAb) designated as MK2, MK3 and MK5 and specific for the Vi antigen of Salmonella typhi have been produced [19].
• We demonstrate that lipopolysaccharide-induced tumor necrosis factor (TNF) biosynthesis becomes independent of MAPKAP kinase 2 (MK2) when the AU-rich element (ARE) of the TNF gene is deleted [12].

Analytical, diagnostic and therapeutic context of Mapkapk2

• MAPKAP kinase 2-deficient mice are resistant to collagen-induced arthritis [20].
• The significant reduction in interleukin-1beta was also confirmed in MK2(-/-) mice by enzyme-linked immunosorbent assay [3].
• MK2-/- gene knockout mouse hearts carry anti-apoptotic signal and are resistant to ischemia reperfusion injury [13].
• To further understand the signaling pathway of MAPKAP kinase 2, we have purified p60 from a heat-treated neutrophil lysate by DEAE-cellulose chromatography and SDS-polyacrylamide gel electrophoresis [21].
• Elevating the cAMP in cultured Schwann cells by forskolin, which mimics axonal contact but not myelination, did not induce detectable levels of MK1 and MK2 mRNA by Northern blot analysis [22].

References