A comparative evaluation of beta-catenin and plakoglobin signaling activity

Vertebrates have two Armadillo-like proteins, beta -catenin and plakoglobin . Mutant forms of beta -catenin with oncogenic activity are found in many h uman tumors, but plakoglobin mutations are not commonly found, In fact, pla koglobin has been proposed to suppress tumorigenesis, To assess differences between beta -catenin and plakoglobin, we compared several of their bioche mical properties, After transient transfection of 293T cells with an expres sion vector encoding either of the two proteins, soluble wild type beta -ca tenin does not significantly accumulate, whereas soluble wild type plakoglo bin is readily detected. As anticipated, beta -catenin is stabilized by the oncogenic mutation S37A; however, the analogous mutation in plakoglobin (S 28A) does not alter its half-life. S37A-beta -catenin activates a TCF/LEF-d ependent reporter 20-fold more potently than wild type beta -catenin, and s imilar to5-fold more potently than wild type or S28A plakoglobin. These dif ferences may be attributable to an enhanced affinity of S37A beta -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 t he 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.