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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
Peptides as signaling inhibitors for mammalian MAP kinase cascades
Matthias Gaestel1, Michael Kracht
1Department of Biochemistry, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. gaestel.matthias@mh-hannover.de
Abstract:
Mammalian MAPK cascades are essential for cellular signaling in response to mitogenic signals and stress-stimuli to regulate proliferation, differentiation and apoptosis. The three major MAPK cascades, ERK1/2-, JNK- and p38, maintain signaling specificity by scaffolding proteins and by specific docking interactions between pathway components. The structures mediating these interactions include the domain of versatile docking (DVD) responsible for MAP3K-MAP2K-interaction and the common docking (CD)-domain and the ED (glutamate/aspartate)-site of MAPKs together with the various docking (D) motifs in MAP2Ks, MAPK substrates and MAPK-phosphatases. Several of these interactions have been studied in great detail. First approaches to use this knowledge to develop peptides that specifically inhibit MAPK signaling in disease models have been reported. It becomes obvious that specificity of peptides competing with kinase-docking is comparable to or even superior to small molecule ATP-competitive inhibitors. In addition to specifically targeting protein-protein interactions, the ultimate efficacy of these peptide inhibitors in vivo also depends on their delivery, stability and toxicity in living cells and in the whole organism.
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