ountered numerous actin-binding or microtubule-binding proteins, molecular motors as well as small G protein partners. Docking motifs were even found on proteins localized to centrosomes, basal bodies, or those involved in the formation of primary cilia. Several other highscoring hits suggest that JNK is intimately involved in the regulation of endo- and exocytosis. The presence of insulin signaling pathway components in the lists may also explain many previous observations on the causative role of JNK in type II diabetes. Interaction with tissuespecific protein isoforms may thus cause LGX818 price highly cell-type-specific regulation by MAPKs. The analysis of the best 100 hits for the NFAT4 class yielded results similar to the JIP1-type motifs, with some differences. In contrast, members of the greater MEF2A class were markedly dissimilar from those of the JIP1 class. Here, the proportion of cytoskeletal proteins was minimal, while the fraction of transcription factors was considerably higher. Proteins involved in other functions related to gene expression, such as chromatin remodeling or histone methylation, were also present in higher numbers. When comparing distributions of protein functions, the NFAT4 class appeared to lie between the two extremes represented by the JIP1 types 
and greater MEF2A types . The similarity of NFAT4-type motif-containing proteins to JIP1-type bearing ones is easy to understand: Both primarily interact with JNK1. In certain protein families, one can discover closely related pairs in which one protein contains a JIP1-type docking motif and the other contains a likely independently evolved NFAT4-type docking motif. On the other hand, the NFAT4-type motifs are structurally compatible with MEF2A types; thus, some of the predicted best binders are shared between the latter two lists. Our dot-blot experiments indeed corroborated that the overlapping motif definitions result in a naturally overlapping set of interactors for JNK1 and p38a. Evolutionary analysis of D-motifs MAPK pathways are found in almost every eukaryotic organism, and the three-tiered kinase cascade architecture of the MAPK module core is well conserved from yeast PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19844160 to human. Therefore, one would naturally expect the downstream targets of these pathways to be conserved as well. However, our results do not support this and in fact suggest the opposite. Although evolutionary conservation is considered to be a predictive feature of a functional linear motif, this did hold through for D-motifs. There was no correlation between FoldX and any of the evolutionary conservation scores. The maximum traceable distance of a motif in evolutionarily related species could be calculated from the eggNOG alignments. Here, we also noted that most of the motifs were traceable to vertebrates only. A more thorough search, using p-Blast searches in the UniProt database, revealed that some motifs are actually more ancient than what eggNOG data would suggest. Still, a high number of experimentally validated motifs were found to be relatively recent evolutionary inventions. After mapping the most distant organisms in which the motif in question is already present, we were able to compile an evolutionary histogram of MAPK-docking motif emergence. Despite the fact that MAPK pathways are an eukaryotic common heritage, very few human docking motifs had an ancestry among unicellular organisms. This latter was only true for the MAPK kinases or MAPK-activated kinases and a few truly ancient s
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