MAPPINGS v1.0, a tool for network analysis of large phospho-signalling datasets: application to host erythrocyte response to Plasmodium infection

Phosphorylation-based signalling implicates a complex and intertwined series of pathways and is critical to all domains of life. The interconnectivity between pathways results in the emergence of complex networks whose elucidation present a serious challenge. Large datasets of phosphorylation interactions through the activity of kinases on their numerous substrates are constantly being generated, however deciphering the complex network structure hidden in these datasets remains challenging. Many phosphorylation interactions occurring in human cells have been identified and constitute the basis for the known phosphorylation interaction network. We overlayed onto this network phosphorylation datasets obtained from an antibody microarray approach aimed at determining changes in phospho-signalling of host erythrocytes to infection with the malaria parasite Plasmodium falciparum. To analyse the datasets now mapped into the interaction network, we designed a pathway analysis tool denoted MAPPINGS that uses random walks to identify chains of phosphorylation events occurring much more or much less frequently than expected. MAPPINGS highlights pathways of phosphorylation that work synergistically, providing a rapid interpretation of the most critical pathways in each dataset. MAPPINGS confirmed several signalling interactions previously shown to be modulated by infection, and revealed additional interactions which could form the basis of numerous future studies. The MAPPINGS analysis strategy described here is widely applicable to comparative phosphorylation datasets in any context (e.g. response of cells to infection, treatment, or comparison between differentiation stages of any cell populations) and provides a rapid and reliable analysis to guide validation studies.