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

Abstract

BackgroundProtein phosphorylation is a post-translational modification that is essential for a wide range of eukaryotic physiological processes, such as transcription, cytoskeletal regulation, cell metabolism, and signal transduction. Although more than 200,000 phosphorylation sites have been reported in the human genome, the physiological roles of most remain unknown. In this study, we provide some useful datasets for the assessment of functional phosphorylation signaling using a comparative genome analysis of phosphorylation motifs.FindingsWe described the evolutionary patterns of conservation of these and comparative genomic data for 93,101 phosphosites and 1,003,756 potential phosphosites in human phosphomotifs, using 178 phosphomotifs identified in a previous study that occupied 69% of known phosphosites in public databases. Comparative genomic analyses were performed using genomes from nine species from yeast to humans. Here we provide an overview of the evolutionary patterns of phosphomotif acquisition and indicate the dependence on motif structures. Using the data from our previous study, we describe the interaction networks of phosphoproteins, identify the kinase substrates associated with phosphoproteins, and perform gene ontology enrichment analyses. In addition, we show how this dataset can help to elucidate the function of phosphomotifs.ConclusionsOur characterizations of motif structures and assessments of evolutionary conservation of phosphosites reveal physiological roles of unreported phosphosites. Thus, interactions between protein groups that share motifs are likely to be helpful for inferring kinase-substrate interaction networks. Our computational methods can be used to elucidate the relationships between phosphorylation signaling and cellular functions.Electronic supplementary materialThe online version of this article (doi:10.1186/s13742-015-0057-6) contains supplementary material, which is available to authorized users.

Evolutionary Divergence of Phosphorylation to Regulate Interactive Protein Networks in Lower and Higher Species

“…This suggests that regulation via phosphorylation occurred late in prokaryotic evolution from the split between yeast and higher eukaryotes. This might explain why eucharyotic species far remote in the phylogenetic tree share some common features regarding the kinone [61,[65][66][67][68]].…”

“…In this scenario, the proteins authorizing chemical modification due to the phosphate addition are multi-phasic, allowing fine regulation [8]. In this report, we tried to address when an ordered apparition of kinases took place in the evolutionary timing of living organisms, and some major events of phosphorylation could explain the primate status [67,68].…”

“…In the massive background and noise of phosphate addition, only a few highly conserved phosphorylation hotspot regions have been documented with functional importance [69]. If 90% of human proteins are found phosphorylated, only 5% have a reported regulatory function situated mostly in the catalytic domain or the protein-protein interaction domain [67][68][69].…”

An Integrated Proteomic Strategy to Identify SHP2 Substrates

“…Perturbation of protein phosphorylation has been implicated in many human diseases, including different types of cancers, , diabetes, and autoimmune diseases, , etc. It is estimated that approximately 1 million phosphorylation sites are present in the human proteome, most of which are phosphorylated on serine and threonine residues, with less than 2% on tyrosine residues. , …”

“…It is estimated that approximately 1 million phosphorylation sites are present in the human proteome, most of which are phosphorylated on serine and threonine residues, with less than 2% on tyrosine residues. 7,8 Despite the rarity of phosphotyrosine (pTyr)-mediated signaling, the role of protein tyrosine kinases as protein oncogenes is widely recognized. For instance, a mutation in the receptor tyrosine kinase, epidermal growth factor receptor (EGFR), leads to its overexpression in 35−70% of glioblastomas 9 and more than 43% of lung cancers.…”