Differential interaction of plakoglobin and beta-catenin with the ubiquitin-proteasome system.
Beta-catenin and plakoglobin are closely related armadillo family proteins with shared and distinct properties; Both are associated with cadherins in actin-containing adherens junctions. Plakoglobin is also found in desmosomes where it anchors intermediate filaments to the desmosomal plaques. Beta-catenin, on the other hand, is a component of the Wnt signaling ... pathway, which is involved in embryonic morphogenesis and tumorigenesis. A key step in the regulation of this pathway involves modulation of beta-catenin stability. A multiprotein complex, regulated by Wnt, directs the phosphorylation of beta-catenin and its degradation by the ubiquitin-proteasome system. Plakoglobin can also associate with members of this complex, but inhibition of proteasomal degradation has little effect on its levels while dramatically increasing the levels of beta-catenin. Beta-TrCP, an F-box protein of the SCF E3 ubiquitin ligase complex, was recently shown to play a role in the turnover of beta-catenin. To elucidate the basis for the apparent differences in the turnover of beta-catenin and plakoglobin we compared the handling of these two proteins by the ubiquitin-proteasome system. We show here that a deletion mutant of beta-TrCP, lacking the F-box, can stabilize the endogenous beta-catenin leading to its nuclear translocation and induction of beta-catenin/LEF-1-directed transcription, without affecting the levels of plakoglobin. However, when plakoglobin was overexpressed, it readily associated with beta-TrCP, efficiently competed with beta-catenin for binding to beta-TrCP and became polyubiquitinated. Fractionation studies revealed that about 85% of plakoglobin in 293 cells, is Triton X-100-insoluble compared to 50% of beta-catenin. These results suggest that while both plakoglobin and beta-catenin can comparably interact with beta-TrCP and the ubiquitination system, the sequestration of plakoglobin by the membrane-cytoskeleton system renders it inaccessible to the proteolytic machinery and stabilizes it.
Mesh Terms:
Animals, Biological Transport, CHO Cells, Cell Compartmentation, Cricetinae, Cysteine Endopeptidases, Cytoskeletal Proteins, DNA-Binding Proteins, Desmoplakins, Dexamethasone, GTP-Binding Proteins, Humans, Lymphoid Enhancer-Binding Factor 1, Multienzyme Complexes, Octoxynol, Proteasome Endopeptidase Complex, Recombinant Proteins, Trans-Activators, Transcription Factors, Ubiquitins, beta Catenin, beta-Transducin Repeat-Containing Proteins, gamma Catenin
Animals, Biological Transport, CHO Cells, Cell Compartmentation, Cricetinae, Cysteine Endopeptidases, Cytoskeletal Proteins, DNA-Binding Proteins, Desmoplakins, Dexamethasone, GTP-Binding Proteins, Humans, Lymphoid Enhancer-Binding Factor 1, Multienzyme Complexes, Octoxynol, Proteasome Endopeptidase Complex, Recombinant Proteins, Trans-Activators, Transcription Factors, Ubiquitins, beta Catenin, beta-Transducin Repeat-Containing Proteins, gamma Catenin
Oncogene
Date: Apr. 13, 2000
PubMed ID: 10803460
View in: Pubmed Google Scholar
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