Inferring the Sign of Kinase-Substrate Interactions by Combining Quantitative Phosphoproteomics with a Literature-Based Mammalian Kinome Network

TL;DR

This study combines literature-based kinase-substrate networks with quantitative phosphoproteomics data to infer the activating or inhibiting nature of phosphorylation interactions, enhancing understanding of mammalian cell signaling pathways.

Contribution

It introduces a novel method to infer the signs of kinase-substrate interactions by integrating experimental data with existing network information.

Findings

Predicted signs for 321 links and 153 phosphosites

Reconstructed a signed, directed kinase-kinase interaction subnetwork

Enhanced understanding of mammalian cell signaling pathways

Abstract

Protein phosphorylation is a reversible post-translational modification commonly used by cell signaling networks to transmit information about the extracellular environment into intracellular organelles for the regulation of the activity and sorting of proteins within the cell. For this study we reconstructed a literature-based mammalian kinase-substrate network from several online resources. The interactions within this directed graph network connect kinases to their substrates, through specific phosphosites including kinase-kinase regulatory interactions. However, the "signs" of links, activation or inhibition of the substrate upon phosphorylation, within this network are mostly unknown. Here we show how we can infer the "signs" indirectly using data from quantitative phosphoproteomics experiments applied to mammalian cells combined with the literature-based kinase-substrate network. Our inference method was able to predict the sign for 321 links and 153 phosphosites on 120 kinases, resulting in signed and directed subnetwork of mammalian kinase-kinase interactions. Such an approach can rapidly advance the reconstruction of cell signaling pathways and networks regulating mammalian cells.