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  • Original Paper
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A comparative evaluation of β-catenin and plakoglobin signaling activity

Oncogene volume 19, pages 5720–5728 (2000)Cite this article

Abstract

Vertebrates have two Armadillo-like proteins, β-catenin and plakoglobin. Mutant forms of β-catenin with oncogenic activity are found in many human tumors, but plakoglobin mutations are not commonly found. In fact, plakoglobin has been proposed to suppress tumorigenesis. To assess differences between β-catenin and plakoglobin, we compared several of their biochemical properties. After transient transfection of 293T cells with an expression vector encoding either of the two proteins, soluble wild type β-catenin does not significantly accumulate, whereas soluble wild type plakoglobin is readily detected. As anticipated, β-catenin is stabilized by the oncogenic mutation S37A; however, the analogous mutation in plakoglobin (S28A) does not alter its half-life. S37A-β-catenin activates a TCF/LEF-dependent reporter 20-fold more potently than wild type β-catenin, and ∼5-fold more potently than wild type or S28A plakoglobin. These differences may be attributable to an enhanced affinity of S37A β-catenin for LEF1 and TCF4, as observed here by immunoprecipitation assays. We show that the carboxyl-terminal domain is largely responsible for the difference in signaling and that the Armadillo repeats account for the remainder of the difference. The relatively weak signaling by plakoglobin and the failure of the S28A mutation to enhance its stability, may explain why plakoglobin mutations are infrequent in malignancies.

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Acknowledgements

We would like to thank Mario Chamorro for advice on the pulse/chase analysis and other members of the Varmus laboratory for helpful discussions. BO Williams was a post-doctoral fellow of the Damon Runyon-Walter Winchell Cancer Research Fund. GD Barish was a Howard Hughes Medical Institute-NIH Research Scholar. MW Klymkowsky was supported by NIH grant GM54001.

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  1. Bart O Williams

    Present address: Van Andel Research Institute, 333 Bostwick NE Grand Rapids, MI 49503, USA

  2. Bart O Williams and Grant D Barish: BO Williams and GO Barish contributed equally to this work

Authors and Affiliations

  1. Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, Maryland, USA

    Bart O Williams, Grant D Barish & Harold E Varmus

  2. Molecular, Cellular & Developmental Biology, University of Colorado Boulder, Boulder, CO 80309-0347, Colorado, USA

    Michael W Klymkowsky

  3. Memorial Sloan-Kettering Cancer Center, 75 York Avenue, New York, NY 10021, USA

    Harold E Varmus

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Williams, B., Barish, G., Klymkowsky, M. et al. A comparative evaluation of β-catenin and plakoglobin signaling activity. Oncogene 19, 5720–5728 (2000). https://doi.org/10.1038/sj.onc.1203921

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