Peptides as Signaling Inhibitors for Mammalian MAP Kinase Cascades

Matthias      Gaestel; Michael      Kracht

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 MAPKphosphatases. 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.

Keywords: DVD, CD domain, DEF domain, KIM domain, protein kinase, protein phosphatase, transcription factor, protein phosphorylation