Elucidation of the evolutionary expansion of phosphorylation signaling networks using comparative phosphomotif analysis

Abstract

BackgroundProtein phosphorylation is catalyzed by kinases and is involved in the regulation of a wide range of processes. The phosphosites in protein sequence motifs determine the types of kinases involved. The development of phosphoproteomics has allowed the identification of huge numbers of phosphosites, some of which are not involved in physiological functions.ResultsWe developed a method for extracting phosphosites with important roles in cellular functions and determined 178 phosphomotifs based on the analysis of 34,366 phosphosites. We compared the conservation of serine/threonine/tyrosine residues observed in humans and seven other species. Consequently, we identified 16 phosphomotifs, where the level of conservation increased among species. The highly conserved phosphomotifs in humans and the worm were kinase regulatory sites. The motifs present in the fly were novel phosphomotifs, including zinc finger motifs involved in the regulation of gene expression. Subsequently, we found that this zinc finger motif contributed to subcellular protein localization. The motifs identified in fish allowed us to detect the expansion of phosphorylation signals related to alternative splicing. We also showed that the motifs present in specific species functioned in an additional network that interacted directly with the core signaling network conserved from yeast to humans.ConclusionsOur method may facilitate the efficient extraction of novel phosphomotifs with physiological functions, thereby contributing greatly to the analysis of complex phosphorylation signaling cascades. Our study suggests that the phosphorylation networks acquired during evolution have added signaling network modules to the core signaling networks.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-546) contains supplementary material, which is available to authorized users.

Large-scale analysis of the evolutionary histories of phosphorylation motifs in the human genome

“…Here, we have determined the functions of phosphorylation signaling pathways in cellular processes. We have also investigated the relationships between 178 phosphomotifs and cellular functions, and evolutionary conservation [ 5 ]. Our analyses indicate that highly conserved phosphomotifs are likely to be involved in similar signaling networks with functionally important roles.…”

“…In a previous study, we identified 178 phosphomotifs [ 5 ] and investigated the evolutionary conservation of the phosphosites in each motif to elucidate the physiological roles of the identified motifs. To evaluate evolutionary conservation, we selected model organisms with rich genome information, as follows: Saccharomyces cerevisiae , Schizosaccharomyces pombe , Caenorhabditis elegans , Drosophila melanogaster , Danio rerio , Canis familiaris , Mus musculus , Pan troglodytes , and Homo sapiens .…”

“…Interactions between proteins with the same motif were more likely than reconstructed interactions between randomly selected proteins, allowing enrichment of proteins with similar physiological functions [ 5 ]. Hence, identification of protein networks with the same motifs may facilitate characterizations of phosphorylation interaction networks based on kinase-substrate relationships and may be used to determine the ensuing physiological functions.…”

“…We have previously identified [ 5 ] the likely functional correlations between a wide variety of phosphomotifs, warranting the characterization of phosphomotifs with functional categories, such as gene ontology (GO), to confirm the physiological functions of the ensuing phosphorylation signaling. Thus, correlations between extracted phosphorylation motifs and specific physiological protein functions were identified here using functional enrichment analysis based on GO (Additional file 7 ).…”

Nuclear Prospero allows one-division potential to neural precursors and post-mitotic status to neurons via opposite regulation of Cyclin E

“…These changes can regulate the catalytic activity of a phosphoprotein, thus, can either activate or inactivate them. Phosphorylation can also recruit neighboring proteins that recognize and bind phosphomotifs [ 37 , 38 ]. Since Pros is a phosphoprotein [ 29 ], we sought to re-examine the nuclear versus cytoplasmic localization and the phosphorylation status of Pros.…”