Mitogen-Activated Protein Kinase–Activated Protein Kinase 2 in Neuroinflammation, Heat Shock Protein 27 Phosphorylation, and Cell Cycle: Role and Targeting

Abstract

Mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MAPKAPK-2 or MK2) is a downstream substrate of the p38 MAPK responsible for the signaling events influencing inflammation, cell division and differentiation, apoptosis, and cell motility in response to a wide range of extracellular stimuli. After the failure of p38 MAPK inhibitors in clinical trials, MK2 was unveiled as a potential target to regulate inflammatory cytokines' mRNA stability and translation. Recent work suggests that this mechanism may underlie the pathophysiology of brain disorders associated with inflammation. In addition, MK2 is a prominent kinase that phosphorylates heat shock protein 27 (Hsp27), an intensively investigated biomarker of cancer progression. This phosphorylation decreases the chaperone properties of Hsp27, making MK2 an endogenous inhibitor of Hsp27. MK2 is also one of the major players in the signal transduction pathways activated in response to DNA damage. Experimental evidence highlights the role of MK2 in G 2 /M and the mitotic spindle checkpoints, two mechanisms by which MK2 contributes to the maintenance of genomic stability. Thus, MK2 is considered a good molecular target to increase, in combination with chemotherapeutic agents, the sensitivity of treatment, especially in p53-mutated tumors. This review looks at the functions of MK2 in inflammation, Hsp27 regulation, and cell cycle checkpoint control with a focus on brain pathologies. Analysis of MK2 signaling in various disease models and a summary of the data on MK2 inhibitors suggest novel indications for MK2 inhibitors in addition to their mainstream use against peripheral inflammatory disorders.

Maternal Immune Activation Induces Changes in Myelin and Metabolic Proteins, Some of Which Can Be Prevented with Risperidone in Adolescence

“…In addition, based on our finding of upregulated MAPK1, which we validated, we also quantified its related kinases pMAPK1 and pMAPKAPK2 [52] by Western blotting. We found these proteins to be upregulated following prenatal inflammation, in agreement with the current literature [68][69][70] , and decreased following preventative treatment. The MAPK pathway is known to be highly implicated in the cellular response to inflammation [71] , and it has been linked to myelin formation where gain of MAPK1 function promotes central nervous system developmental myelination [40] .…”

Squalene targets pro- and anti-inflammatory mediators and pathways to modulate over-activation of neutrophils, monocytes and macrophages

“…MAPKs include extracellular signal-regulated kinases (ERK-1 and -2), JNKs and p38 (Gurgis, Ziaziaris, & Munoz, 2014). Previous studies have recognized that JNK and p38 MAPK are primarily involved in LPS-induced expression of iNOS and COX-2 in macrophages (Kwon, Ju, Youn, Choi, & Park, 2013;Kyriakis & Avruch, 2012).…”

Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts To Lead Small Molecule Inhibitors to Clinical Trials

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