Abstract:

Cells need to constantly adapt to changes in conditions and use different mechanisms to transfer information from sensors to the effectors of cellular responses. One of the fastest mechanisms is the reversible post-translational modification of proteins such as protein phosphorylation. Advances in mass-spectrometry now allow us to identify phosphosites in large scale and quantify their changes across different conditions. However, little is know about how the thousands of recently discovered phosphosites evolve, how they modulate protein function or how they act in coordinate fashion to dictate a cellular response. I will describe recent progress from our group in addressing these issues. We are developing methods to infer the most likely age of phosphosites by combining phosphorylation data from multiple species, protein sequences and phylogenetic trees. We have observed that only a small fraction of phosphosites are ancient in origin and that these are more likely to cause deleterious consequences when mutated. In parallel we are analysing changes in phosphosite abundances under different conditions. We have compiled a dataset of 150 perturbations in human cell lines where we can estimate the activities of approximately 200 kinases. These data allows to characterize cell signalling states across conditions and to infer associations between kinase activities and the phosphorylation levels of protein complexes.