期刊
BIOLOGICAL CHEMISTRY
卷 394, 期 10, 页码 1301-1315出版社
WALTER DE GRUYTER GMBH
DOI: 10.1515/hsz-2013-0197
关键词
mitogen-activated protein kinase-activated protein kinase (MAPKAP); mitogen-activated protein kinase-activated protein kinases 2/3 (MK2/3); protein kinase inhibitor; protein phosphorylation
资金
- DFG
Inflammation is normally a fast and transient response to microbial invaders or sterile damage and has to be stringently controlled. The closely-related mitogen-activated protein kinase-activated protein kinases MK2 and MK3 are involved in both up-and down-regulation of inflammation in mammals and govern the inflammatory response at different regulatory levels of gene expression and with different kinetics. In conjunction with their activator MAP kinase p38, MK2 and MK3 stimulate the transcription of immediate-early genes including that of the mRNA-binding protein tristetraprolin (TTP). TTP competes with the constitutively expressed protein human antigen R in binding to the mRNA destabilizing adenylate-uridylate-rich element. MK2 and MK3 also regulate the activity of TTP by direct phosphorylation, determine stability and stimulate the translation of cytokine mRNAs. In addition, TTP controls its own re-synthesis via stability and translation of its mRNA in a phosphorylation-dependent manner. This results in a complex scenario of gene expression and guarantees fast up-regulation and intrinsic feedback control of the inflammatory response of macrophages. Inhibition of MK2/3 by small-molecule pharmaceutical inhibitors is an emerging strategy to manipulate the inflammatory response as a therapeutic option. This strategy could display advantages over the direct inhibition of MAP kinase p38.
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