Comparative Analysis Reveals Conserved Protein Phosphorylation Networks Implicated in Multiple Diseases

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Science Signaling  28 Jul 2009:
Vol. 2, Issue 81, pp. ra39
DOI: 10.1126/scisignal.2000316

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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.