γ-Catenin is regulated by the APC tumor suppressor and its oncogenic activity is distinct from that of β-catenin

  1. Frank T. Kolligs1,
  2. Barbara Kolligs1,
  3. Karen M. Hajra1,4,
  4. Gang Hu1,5,
  5. Masachika Tani1,
  6. Kathleen R. Cho1,3, and
  7. Eric R. Fearon1,2,3,4,6
  1. Division of Medical Genetics and the Cancer Center, Departments of1Internal Medicine, 2Human Genetics, and 3Pathology and the 4Program in Cellular and Molecular Biology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109 USA

Abstract

β-Catenin and γ-catenin (plakoglobin), vertebrate homologs of Drosophila armadillo, function in cell adhesion and the Wnt signaling pathway. In colon and other cancers, mutations in the APC tumor suppressor protein orβ-catenin's amino terminus stabilizeβ-catenin, enhancing its ability to activate transcription of Tcf/Lef target genes. Thoughβ- and γ-catenin have analogous structures and functions and like binding to APC, evidence that γ-catenin has an important role in cancer has been lacking. We report here that APC regulates bothβ- and γ-catenin andγ-catenin functions as an oncogene. In contrast to β-catenin, for which only amino-terminal mutated forms transform RK3E epithelial cells, wild-type and several amino-terminal mutated forms of γ-catenin had similar transforming activity. γ-Catenin's transforming activity, like β-catenin's, was dependent on Tcf/Lef function. However, in contrast toβ-catenin, γ-catenin strongly activated c-Myc expression and c-Myc function was crucial for γ-catenin transformation. Our findings suggest APC mutations alter regulation of bothβ- and γ-catenin, perhaps explaining why the frequency of APC mutations in colon cancer far exceeds that of β-catenin mutations. Elevated c-Myc expression in cancers with APC defects may be due to altered regulation of both β- andγ-catenin. Furthermore, the data implyβ- and γ-catenin may have distinct roles in Wnt signaling and cancer via differential effects on downstream target genes.

Keywords

Footnotes

  • 5 Present address: Parke-Davis Research Division of Warner-Lambert, Ann Arbor, Michigan 48105 USA.

  • 6 Corresponding author.

  • E-MAIL fearon{at}umich.edu; FAX (734) 647-7979.

    • Received January 12, 2000.
    • Accepted April 6, 2000.
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