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Sci. Signal., 28 July 2009
Vol. 2, Issue 81, p. ra39
[DOI: 10.1126/scisignal.2000316]


Comparative Analysis Reveals Conserved Protein Phosphorylation Networks Implicated in Multiple Diseases

Chris Soon Heng Tan1,2*, Bernd Bodenmiller3*, Adrian Pasculescu1, Marko Jovanovic4, Michael O. Hengartner4, Claus Jørgensen1, Gary D. Bader1,2, Ruedi Aebersold3,5,6,7, Tony Pawson1,2, and Rune Linding8{dagger}

1 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
2 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
3 Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule (ETH), 8093 Zurich, Switzerland.
4 Institute of Molecular Biology, University of Zurich, 8057 Zurich, Switzerland.
5 Institute for Systems Biology, Seattle, WA 98103, USA.
6 Competence Center for Systems Physiology and Metabolic Diseases, ETH Zurich, 8093 Zurich, Switzerland.
7 Faculty of Science, University of Zurich, 8057 Zurich, Switzerland.
8 Cellular & Molecular Logic Team, Section of Cell and Molecular Biology, The Institute of Cancer Research (ICR), London SW3 6JB, UK.

* These authors contributed equally to this work.

Abstract: 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.

{dagger} To whom correspondence should be addressed. E-mail: linding{at}

Citation: C. S. H. Tan, B. Bodenmiller, A. Pasculescu, M. Jovanovic, M. O. Hengartner, C. Jørgensen, G. D. Bader, R. Aebersold, T. Pawson, R. Linding, Comparative Analysis Reveals Conserved Protein Phosphorylation Networks Implicated in Multiple Diseases. Sci. Signal. 2, ra39 (2009).

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