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Sci. Signal., 11 November 2008
Vol. 1, Issue 45, p. ra12
[DOI: 10.1126/scisignal.2000037]

RESEARCH ARTICLES

New Regulators of Wnt/β-Catenin Signaling Revealed by Integrative Molecular Screening

Michael B. Major1*, Brian S. Roberts2*, Jason D. Berndt1, Shane Marine3, Jamie Anastas1, Namjin Chung3, Marc Ferrer3, XianHua Yi4, Cristi L. Stoick-Cooper1, Priska D. von Haller5, Lorna Kategaya1, Andy Chien1, Stephane Angers6, Michael MacCoss4, Michele A. Cleary2, William T. Arthur2{dagger}, and Randall T. Moon1{dagger}

1 Howard Hughes Medical Institute, Department of Pharmacology, and Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Box 357370, Seattle, WA 98195, USA.
2 Rosetta Inpharmatics, LLC, Merck & Co Inc., 401 Terry Avenue N, Seattle, WA 98109, USA.
3 Merck Research Labs, Department of Automated Biotechnology, North Wales, PA 19454, USA.
4 Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
5 Proteomics Resource, University of Washington, Seattle, WA 98109, USA.
6 Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada M5S 3M2.

* These authors contributed equally to this work.

Abstract: The identification and characterization of previously unidentified signal transduction molecules has expanded our understanding of biological systems and facilitated the development of mechanism-based therapeutics. We present a highly validated small interfering RNA (siRNA) screen that functionally annotates the human genome for modulation of the Wnt/β-catenin signal transduction pathway. Merging these functional data with an extensive Wnt/β-catenin protein interaction network produces an integrated physical and functional map of the pathway. The power of this approach is illustrated by the positioning of siRNA screen hits into discrete physical complexes of proteins. Similarly, this approach allows one to filter discoveries made through protein-protein interaction screens for functional contribution to the phenotype of interest. Using this methodology, we characterized AGGF1 as a nuclear chromatin-associated protein that participates in β-catenin–mediated transcription in human colon cancer cells.

{dagger} To whom correspondence should be addressed. E-mail: william_arthur{at}merck.com (W.T.A.) and rtmoon{at}u.washington.edu (R.T.M.)

Citation: M. B. Major, B. S. Roberts, J. D. Berndt, S. Marine, J. Anastas, N. Chung, M. Ferrer, X. Yi, C. L. Stoick-Cooper, P. D. von Haller, L. Kategaya, A. Chien, S. Angers, M. MacCoss, M. A. Cleary, W. T. Arthur, R. T. Moon, New Regulators of Wnt/β-Catenin Signaling Revealed by Integrative Molecular Screening. Sci. Signal. 1, ra12 (2008).

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