A comparative evaluation of β-catenin and plakoglobin signaling activity

Bart O. Williams*, Grant D. Barish, Michael W. Klymkowsky, Harold E. Varmus

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5720-5728
Number of pages9
JournalOncogene
Volume19
Issue number50
DOIs
StatePublished - Nov 23 2000

Keywords

  • LEF/TCF
  • Plakoglobin
  • Wnt
  • β-catenin

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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