Startseite What goes up must come down: molecular basis of MAPKAP kinase 2/3-dependent regulation of the inflammatory response and its inhibition
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What goes up must come down: molecular basis of MAPKAP kinase 2/3-dependent regulation of the inflammatory response and its inhibition

  • Matthias Gaestel

    Matthias Gaestel received his PhD from the Humboldt-Universität zu Berlin, Germany, in 1983. During postdoctoral training, he characterized growth-related heat shock proteins at the Central Institute for Molecular Biology, Berlin, and analyzed translational control of gene expression in the laboratory of George Brawerman at Tufts University, Boston. In 1991, he became a Junior Research Group Leader at the Max-Delbrück-Centrum for Molecular Medicine (MDC), Berlin-Buch, and focused his research on structure and function of small heat shock proteins. As a Heisenberg-Fellow of the German Research Council (DFG), he headed a guest research group at the MDC starting from 1995 and analyzed molecular mechanisms of stress-dependent signal transduction and nucleo-cytoplasmic signaling. In 1997, Matthias Gaestel became Professor of Molecular Genetics at the Martin-Luther-University Halle-Wittenberg, where he characterized the role of the stress-activated protein kinase MK2 in vivo using knockout mouse models. Since 2001, he has been a full Professor and Chair of Biochemistry at the Medical School Hannover. At the moment, his research interest is focused on regulation of gene expression by protein phosphorylation at the post-transcriptional level as well as on function of the new ERK3/MK5 signaling module.

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Veröffentlicht/Copyright: 5. Juli 2013

Abstract

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.


Corresponding author: Matthias Gaestel, Institute of Physiological Chemistry, Hannover Medical University, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany

About the author

Matthias Gaestel

Matthias Gaestel received his PhD from the Humboldt-Universität zu Berlin, Germany, in 1983. During postdoctoral training, he characterized growth-related heat shock proteins at the Central Institute for Molecular Biology, Berlin, and analyzed translational control of gene expression in the laboratory of George Brawerman at Tufts University, Boston. In 1991, he became a Junior Research Group Leader at the Max-Delbrück-Centrum for Molecular Medicine (MDC), Berlin-Buch, and focused his research on structure and function of small heat shock proteins. As a Heisenberg-Fellow of the German Research Council (DFG), he headed a guest research group at the MDC starting from 1995 and analyzed molecular mechanisms of stress-dependent signal transduction and nucleo-cytoplasmic signaling. In 1997, Matthias Gaestel became Professor of Molecular Genetics at the Martin-Luther-University Halle-Wittenberg, where he characterized the role of the stress-activated protein kinase MK2 in vivo using knockout mouse models. Since 2001, he has been a full Professor and Chair of Biochemistry at the Medical School Hannover. At the moment, his research interest is focused on regulation of gene expression by protein phosphorylation at the post-transcriptional level as well as on function of the new ERK3/MK5 signaling module.

The author thanks Dr Christopher Tiedje (Hannover) for critical reading of the manuscript, Stefanie Hall for proofreading and the DFG for financial support.

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Received: 2013-6-6
Accepted: 2013-7-1
Published Online: 2013-07-05
Published in Print: 2013-10-01

©2013 by Walter de Gruyter Berlin Boston

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