Large-scale models of signal propagation in human cells derived from discovery phosphoproteomic data.
Mass spectrometry is widely used to probe the proteome and its modifications in an untargeted manner, with unrivalled coverage. Applied to phosphoproteomics, it has tremendous potential to interrogate phospho-signalling and its therapeutic implications. However, this task is complicated by issues of undersampling of the phosphoproteome and challenges stemming from its high-content but low-sample-throughput nature. Hence, methods using such data to reconstruct signalling networks have been limited to restricted data sets and insights (for example, groups of kinases likely to be active in a sample). We propose a new method to handle high-content discovery phosphoproteomics data on perturbation by putting it in the context of kinase/phosphatase-substrate knowledge, from which we derive and train logic models. We show, on a data set obtained through perturbations of cancer cells with small-molecule inhibitors, that this method can study the targets and effects of kinase inhibitors, and reconcile insights obtained from multiple data sets, a common issue with these data.
European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
Camille D A
CD
Terfve
Integrative Cell Signalling and Proteomics, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
Edmund H
EH
Wilkes
Integrative Cell Signalling and Proteomics, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
Pedro
P
Casado
Integrative Cell Signalling and Proteomics, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK.
Pedro R
PR
Cutillas
European Molecular Biology Laboratory-European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
Julio
http://orcid.org/0000-0002-8552-8976
J
Saez-Rodriguez
D002853:Chromatography, Liquid; D003627:Data Interpretation, Statistical; D006801:Humans; D061986:MCF-7 Cells; D008954:Models, Biological; D015233:Models, Statistical; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D040901:Proteomics / Q000379:methods*; D015398:Signal Transduction; D053719:Tandem Mass Spectrometry
D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D010770:Phosphotransferases