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Sci. Signal., 6 September 2011
Vol. 4, Issue 189, p. rs8
[DOI: 10.1126/scisignal.2001699]


A Directed Protein Interaction Network for Investigating Intracellular Signal Transduction

Arunachalam Vinayagam1*{dagger}, Ulrich Stelzl1,2*{ddagger}, Raphaele Foulle1, Stephanie Plassmann1, Martina Zenkner1, Jan Timm1, Heike E. Assmus3, Miguel A. Andrade-Navarro1, and Erich E. Wanker1{ddagger}

1 AG Neuroproteomics and Computational Biology and Data Mining Group, Max Delbrück Centrum for Molecular Medicine, Robert-Rössle-Strasse 10, D-13125 Berlin-Buch, Germany.
2 Otto-Warburg Laboratory, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, D-14195 Berlin, Germany.
3 AG Systems Biology and Bioinformatics, Department of Computer Science, University of Rostock, Ulmenstrasse 69, D-18051 Rostock, Germany.

* These authors contributed equally to this work.

{dagger} Present address: Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.

Abstract: Cellular signal transduction is a complex process involving protein-protein interactions (PPIs) that transmit information. For example, signals from the plasma membrane may be transduced to transcription factors to regulate gene expression. To obtain a global view of cellular signaling and to predict potential signal modulators, we searched for protein interaction partners of more than 450 signaling-related proteins by means of automated yeast two-hybrid interaction mating. The resulting PPI network connected 1126 proteins through 2626 PPIs. After expansion of this interaction map with publicly available PPI data, we generated a directed network resembling the signal transduction flow between proteins with a naïve Bayesian classifier. We exploited information on the shortest PPI paths from membrane receptors to transcription factors to predict input and output relationships between interacting proteins. Integration of directed PPI with time-resolved protein phosphorylation data revealed network structures that dynamically conveyed information from the activated epidermal growth factor and extracellular signal–regulated kinase (EGF/ERK) signaling cascade to directly associated proteins and more distant proteins in the network. From the model network, we predicted 18 previously unknown modulators of EGF/ERK signaling, which we validated in mammalian cell-based assays. This generic experimental and computational approach provides a framework for elucidating causal connections between signaling proteins and facilitates the identification of proteins that modulate the flow of information in signaling networks.

{ddagger} To whom correspondence should be addressed. E-mail: stelzl{at} (U.S.); erich.w{at} (E.E.W.)

Citation: A. Vinayagam, U. Stelzl, R. Foulle, S. Plassmann, M. Zenkner, J. Timm, H. E. Assmus, M. A. Andrade-Navarro, E. E. Wanker, A Directed Protein Interaction Network for Investigating Intracellular Signal Transduction. Sci. Signal. 4, rs8 (2011).

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