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Comparative Analysis Reveals Conserved Protein Phosphorylation Networks Implicated in Multiple Diseases

Comparing the human phosphoproteome to that of flies, worms, and yeast reveals insight into evolution and disease. Phosphorylation Networks in Disease and Evolution Insights into the evolution of protein phosphorylation were revealed by combining the results from two computational analyses—a sequence-alignment approach and a kinase-substrate network alignment approach. The two approaches yielded different, but somewhat overlapping, sets of conserved phosphoproteins among humans and the model organisms. The first provided a set of genes encoding phosphoproteins that had positionally conserved phosphorylation sites, whereas the second included many functionally conserved phosphoproteins that lacked this positional conservation. Enrichment analysis of the genes identified through the kinase-substrate network approach suggested that genes encoding phosphorylated signaling hubs were enriched in disease-associated genes (defined by Online Mendelian Inheritance in Man), and both approaches showed that genes encoding conserved phosphoproteins were enriched in genes associated with cancer. The functional annotation of the two gene sets suggested that positional conservation is common in regions that are structurally constrained, such as those regulated by allosteric interactions, and that the kinase-substrate network method may aid in analyzing fast-evolving signaling processes, where functional conservation does not require positional conservation. The analysis also suggests that conserved regulatory networks may be involved in different diseases. Protein kinases enable cellular information processing. Although numerous human phosphorylation sites and their dynamics have been characterized, the evolutionary history and physiological importance of many signaling events remain unknown. Using target phosphoproteomes determined with a similar experimental and computational pipeline, we investigated the conservation of human phosphorylation events in distantly related model organisms (fly, worm, and yeast). With a sequence-alignment approach, we identified 479 phosphorylation events in 344 human proteins that appear to be positionally conserved over ~600 million years of evolution and hence are likely to be involved in fundamental cellular processes. This sequence-alignment analysis suggested that many phosphorylation sites evolve rapidly and therefore do not display strong evolutionary conservation in terms of sequence position in distantly related organisms. Thus, we devised a network-alignment approach to reconstruct conserved kinase-substrate networks, which identified 778 phosphorylation events in 698 human proteins. Both methods identified proteins tightly regulated by phosphorylation as well as signal integration hubs, and both types of phosphoproteins were enriched in proteins encoded by disease-associated genes. We analyzed the cellular functions and structural relationships for these conserved signaling events, noting the incomplete nature of current phosphoproteomes. Assessing phosphorylation conservation at both site and network levels proved useful for exploring both fast-evolving and ancient signaling events. We reveal that multiple complex diseases seem to converge within the conserved networks, suggesting that disease development might rely on common molecular networks.