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Sci. Signal., 24 May 2011
Vol. 4, Issue 174, p. ra33
[DOI: 10.1126/scisignal.2001823]

RESEARCH ARTICLES

α-Catenin Is a Tumor Suppressor That Controls Cell Accumulation by Regulating the Localization and Activity of the Transcriptional Coactivator Yap1

Mark R. Silvis1*, Bridget T. Kreger1*, Wen-Hui Lien1*{dagger}, Olga Klezovitch1*, G. Marianna Rudakova1, Fernando D. Camargo2, Dan M. Lantz3, John T. Seykora4, and Valeri Vasioukhin1,5{ddagger}

1 Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
2 Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
3 Dermatopathology Northwest, 2330 130th Avenue NE, Bellevue, WA 98005, USA.
4 Department of Dermatology, University of Pennsylvania Medical School, Philadelphia, PA 19101, USA.
5 Department of Pathology and Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA 98195, USA.

* These authors contributed equally to this work.

{dagger} Present address: Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.

Abstract: The Hippo pathway regulates contact inhibition of cell proliferation and, ultimately, organ size in diverse multicellular organisms. Inactivation of the Hippo pathway promotes nuclear localization of the transcriptional coactivator Yap1, a Hippo pathway effector, and can cause cancer. Here, we show that deletion of αE (α epithelial) catenin in the hair follicle stem cell compartment resulted in the development of skin squamous cell carcinoma in mice. Tumor formation was accelerated by simultaneous deletion of αE-catenin and the tumor suppressor–encoding gene p53. A small interfering RNA screen revealed a functional connection between αE-catenin and Yap1. By interacting with Yap1, αE-catenin promoted its cytoplasmic localization, and Yap1 showed constitutive nuclear localization in αE-catenin–null cells. We also found an inverse correlation between αE-catenin abundance and Yap1 activation in human squamous cell carcinoma tumors. These findings identify αE-catenin as a tumor suppressor that inhibits Yap1 activity and sequesters it in the cytoplasm.

{ddagger} To whom correspondence should be addressed. E-mail: vvasiouk{at}fhcrc.org

Citation: M. R. Silvis, B. T. Kreger, W.-H. Lien, O. Klezovitch, G. M. Rudakova, F. D. Camargo, D. M. Lantz, J. T. Seykora, V. Vasioukhin, α-Catenin Is a Tumor Suppressor That Controls Cell Accumulation by Regulating the Localization and Activity of the Transcriptional Coactivator Yap1. Sci. Signal. 4, ra33 (2011).

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