Mitogen-activated protein kinase-activated protein kinase 2 (MK2; MAPKAPK2), EC 184.108.40.206, is a member of the MAPKAPK family of kinases, which also consists of MK3 and MK5 (PRAK). The MAPKAPK family are activated by MAPK signaling, with MK2 being a downstream substrate of p38.
MK2 is ubiquitously expressed, with its highest expression in the heart, kidney and skeletal muscle. In quiescent cells MK2 is predominantly localized to the nucleus. In response to stress stimuli (such as UV irradiation, heat shock and oxidative stress), as well as LPS and Toll-like receptor signaling, p38 is activated and subsequently phosphorylates MK2, which is exported from the nucleus into the cells cytoplasm. Substrates for MK2 include AU-rich element-binding (ARE) proteins; the chaperone Hsp27; the cell cycle phosphatase cdc25; the transcription factor AATF; and LIMK. MK2 has a role in a number of physiological processes including, inflammation, actin remodeling, cell cycle arrest and apoptosis.
Activation of ARE proteins by MK2 results in the stabilization and translation of mRNA, including that of TNF-α, IL-6 and IL-8, therefore increasing proinflammatory cytokine production and secretion. MK2 has been shown to be essential for LPS-induced TNF-α production, so may be of therapeutic interest for the treatment of chronic inflammatory diseases, such as rheumatoid arthritis. MK2 may also have a role in the neuroinflammation exhibited in neurodegenerative disorders such as Alzheimer's and Parkinson's disease. For example MK2-deficient mice have been shown to exhibit attenuated neuroinflammation in a mouse model of Parkinson's disease.
MK2 is also a potential therapeutic target for the treatment of cancer. It is activated by DNA damage, before phosphorylating cdc25, causing cell cycle arrest at G2/M phase. This gives the cell time to repair the damage to its DNA. MK2 depletion has been shown to enhance the effectiveness of chemotherapeutics against cancer cells in vitro. MK2 also phosphorylates the transcription factor AATF, which suppresses the expression of p53 pro-apoptotic target genes. Furthermore the phosphorylation of Hsp27 by MK2, inhibits its chaperone activity, resulting in actin polymerization and enhanced cell motility.
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Literature for MK2
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