Large-scale models of signal propagation in human cells derived from discovery phosphoproteomic data

Abstract

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.

Synthesizing Signaling Pathways from Temporal Phosphoproteomic Data

“…Protein activities are observed with antibody-based assays, and pathways are recovered de novo (Ciaccio et al, 2015;Fröhlich et al, 2009;Kiani and Kaderali, 2014;Molinelli et al, 2013) or by adapting prior pathway knowledge (Morris et al, 2011). The PHONEMeS method is unique for its ability to handle large-scale phosphoproteomic perturbation data (Terfve et al, 2015).…”

Exploiting receptor tyrosine kinase co-activation for cancer therapy

“…Newer methodologies that incorporate high-throughput quantitative phosphoproteomics data which depict signalling alterations in response to drug perturbations are also emerging (76, 77). Each data type provides a different piece of information in relation to kinase dependencies in tumours which together generates a complete portrait of kinase co-dependencies in cancer cells.…”

Logic Modeling in Quantitative Systems Pharmacology

“…However, the application of mass‐spectrometry to the investigation of dynamic signaling pathways has so far been limited by the relatively low number of experimental conditions, due to the expensive and laborious nature of this technology when compared with antibody‐based techniques. Accordingly, modeling efforts with this type of data have been scarce,69 but this is likely to change in the near future with the rapid development of the technology 70…”