Abstract
MotivationPhosphoproteomic experiments are increasingly used to study the changes in signaling occurring across different conditions. It has been proposed that changes in phosphorylation of kinase target sites can be used to infer when a kinase activity is under regulation. However, these approaches have not yet been benchmarked due to a lack of appropriate benchmarking strategies.ResultsWe used curated phosphoproteomic experiments and a gold standard dataset containing a total of 184 kinase-condition pairs where regulation is expected to occur to benchmark and compare different kinase activity inference strategies: Z-test, Kolmogorov Smirnov test, Wilcoxon rank sum test, gene set enrichment analysis (GSEA), and a multiple linear regression model. We also tested weighted variants of the Z-test and GSEA that include information on kinase sequence specificity as proxy for affinity. Finally, we tested how the number of known substrates and the type of evidence (in vivo, in vitro or in silico) supporting these influence the predictions.ConclusionsMost models performed well with the Z-test and the GSEA performing best as determined by the area under the ROC curve (Mean AUC = 0.722). Weighting kinase targets by the kinase target sequence preference improves the results marginally. However, the number of known substrates and the evidence supporting the interactions has a strong effect on the predictions.Availability and ImplementationThe KSEA implementation is available in https://github.com/ evocellnet/ksea. Additional data is available in http://phosfate.comSupplementary information Supplementary data are available at Bioinformatics online.
Highlights
The functional plasticity of the proteome is modulated by specific post-translational modifications (PTMs) such as phosphorylation, glycosylation or ubiquitination
Based on prior knowledge in kinase regulation, we obtained from a previous compilation (Ochoa et al, 2016) a set of human quantitative phosphoproteomic datasets where the assayed perturbations are expected to trigger specific kinase responses
The progress and developments in mass spectrometry (MS) have led to the unbiased exploration of cell signaling changes via phosphoproteomics
Summary
The functional plasticity of the proteome is modulated by specific post-translational modifications (PTMs) such as phosphorylation, glycosylation or ubiquitination. Reversible modification of proteins controls signal transduction and information processing within the cell, mediating molecular processes such as protein enzymatic regulation, complex associations, protein degradation and changes in subcellular localization (Choudhary and Mann, 2010). Through the coordinated regulation of multiple parallel events, the cell is able to integrate all available signals to appropriately respond to environmental stimuli (Francavilla et al, 2016). Reversible phosphorylation of individual residues remains one the most studied PTMs and its status results from the net activity of kinases and phosphatases. Kinases bind covalently a phosphate group onto specific aminoacids, most frequently serine, threonine or tyrosine, while phosphatases catalyze the reverse reaction.
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