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Inhibition of Wnt signaling by Dishevelled PDZ peptides

Nature Chemical Biology volume 5, pages 217–219 (2009)Cite this article

Abstract

Dishevelled proteins are key regulators of Wnt signaling pathways that have been implicated in the progression of human cancers. We found that the binding cleft of the Dishevelled PDZ domain is more flexible than those of canonical PDZ domains and enables recognition of both C-terminal and internal peptides. These peptide ligands inhibit Wnt/β-catenin signaling in cells, showing that Dishevelled PDZ domains are potential targets for small-molecule cancer therapeutics.

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Figure 1: Comparison of ligand recognition by Erbin-PDZ and Dvl2-PDZ.
Figure 2: Pen-N3 inhibits Wnt/β-catenin signaling by recognizing Dvl protein.

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Acknowledgements

We thank the oligonucleotide synthesis and DNA sequencing groups at Genentech, Inc., C. Quan (Genentech, Inc.) for peptide synthesis and J. Gunzner (Genentech, Inc.) for synthesis of FJ9. We also thank L. Lasky for advice and discussions.

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Author notes

  1. Brent A Appleton & Sachdev S Sidhu

    Present address: Present addresses: Department of Structural Chemistry, Novartis Institutes for Biomedical Research, Emeryville, California, USA (B.A.A.) and Banting and Best Department of Medical Research and the Terrence Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada (S.S.S.).,

  2. Yingnan Zhang and Brent A Appleton: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Protein Engineering, Genentech, Inc., South San Francisco, California, USA

    Yingnan Zhang, Brent A Appleton, Christian Wiesmann, Rami N Hannoush & Sachdev S Sidhu

  2. Department of Cancer Targets and Pathways, Genentech, Inc., South San Francisco, California, USA

    Ted Lau & Mike Costa

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  1. Yingnan Zhang
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Contributions

Y.Z., B.A.A., C.W., R.N.H. and S.S.S. designed the experiments and analyzed the results. Y.Z., B.A.A. and R.N.H. performed experiments. T.L. and M.C. designed, performed and analyzed the TOPbrite experiments. Y.Z., B.A.A., R.N.H. and S.S.S. wrote the manuscript.

Corresponding authors

Correspondence to Rami N Hannoush or Sachdev S Sidhu.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7, Supplementary Tables 1–3 and Supplementary Methods (PDF 11026 kb)

Supplementary Movie 1

Cellular internalization of fluorescently-labelled pen-N3 (MOV 498 kb)

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Zhang, Y., Appleton, B., Wiesmann, C. et al. Inhibition of Wnt signaling by Dishevelled PDZ peptides. Nat Chem Biol 5, 217–219 (2009). https://doi.org/10.1038/nchembio.152

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