Regulation of beta-catenin signaling by the B56 subunit of protein phosphatase 2A.

Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84132, USA.
Science (Impact Factor: 31.48). 04/1999; 283(5410):2089-91. DOI: 10.1126/science.283.5410.2089
Source: PubMed

ABSTRACT Dysregulation of Wnt-beta-catenin signaling disrupts axis formation in vertebrate embryos and underlies multiple human malignancies. The adenomatous polyposis coli (APC) protein, axin, and glycogen synthase kinase 3beta form a Wnt-regulated signaling complex that mediates the phosphorylation-dependent degradation of beta-catenin. A protein phosphatase 2A (PP2A) regulatory subunit, B56, interacted with APC in the yeast two-hybrid system. Expression of B56 reduced the abundance of beta-catenin and inhibited transcription of beta-catenin target genes in mammalian cells and Xenopus embryo explants. The B56-dependent decrease in beta-catenin was blocked by oncogenic mutations in beta-catenin or APC, and by proteasome inhibitors. B56 may direct PP2A to dephosphorylate specific components of the APC-dependent signaling complex and thereby inhibit Wnt signaling.

  • Source
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The tumor suppressor Adenomatous polyposis coli (APC) is an essential negative regulator of Wnt signaling through its activity in the destruction complex with Axin, GSK3β and CK1 that targets ß-catenin/Armadillo (ß-cat/Arm) for proteosomal degradation. The destruction complex forms macromolecular particles we termed the destructosome. While APC functions in the complex through its ability to bind both ß-cat and Axin, we hypothesize that APC proteins play an additional role in destructosome assembly through self-association. Here we show that a novel N-terminal coil, the APC Self-Association Domain (ASAD), found in vertebrate and invertebrate APCs, directly mediates self-association of Drosophila APC2 and plays an essential role in the assembly and stability of the destructosome that regulates ß-cat degradation in Drosophila and human cells. Consistent with this, removal of the ASAD from the Drosophila embryo results in ß-cat/Arm accumulation and aberrant Wnt pathway activation. These results suggest that APC proteins are required not only for the activity of the destructosome, but also for the assembly and stability of this macromolecular machine.
    Molecular Biology of the Cell 09/2014; 25(21). DOI:10.1091/mbc.E14-04-0885 · 4.55 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Canonical Wnt signaling is altered in most cases of colorectal cancer. Experimental evidence indicates that protein phosphatase 2A (PP2A) may play either positive or negative roles in Wnt signaling but its precise in vivo functions remain elusive. In this work, using colon cultured cell lines we showed that basal PP2A activity is markedly reduced in malignant cells compared to non-malignant counterparts. We found that whereas normal or cancer cells displaying not altered Wnt signaling express mRNAs coding for PP2A-A scaffold a and b isoforms, cancer cells which have altered Wnt signaling do not express the Ab isoform mRNA. Remarkably, we found that the Ab protein levels are lost in all colon cancer cells, and in patients' tumor biopsies. In addition, all cancer cells exhibit higher levels of RalA activity, compared to non-malignant cells. Rescue experiments to restore Ab expression in malignant RKO cells, diminished the RalGTPase activation and cell proliferation, indicating that the Ab isoform acts as tumor suppressor in colon cancer cells. Reciprocal co-immunoprecipitation and immunofluorescence studies showed that the PP2A-C and -Aa subunits, expressed in all colon cells, interact in vivo with b-catenin only in malignant cells. Selective inhibition of PP2A did not significantly affect cellular apoptosis but induced dose-dependent negative effects in b-catenin-mediated transcriptional activity and in cell proliferation of malignant cells, indicating that the residual PP2A activity found in malignant cells, mediated by –C and Aa core subunits, is essential to maintain active Wnt signaling and cell proliferation in colon cancer cells.
    Molecular Carcinogenesis 09/2014; DOI:10.1002/mc.22217 · 4.77 Impact Factor