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Sadot, E., Dept. of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
Simcha, I., Dept. of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
Iwai, K., Dept. of Molec. and System Biology, Kyoto University, Yoshida-Konoe-ChoSakyo-ku, Kyoto 606-8501, Japan
Ciechanover, A., Faculty of Medicine, Rappaport Inst. for Res. in the M., Technion-Israel Inst. of Technology, Haifa 31096, Israel
Geiger, B., Dept. of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
Ben-Ze'ev, A., Dept. of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
β-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. β-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 β-catenin stability. A multiprotein complex, regulated by Wnt, directs the phosphorylation of β-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 β-catenin. β-TrCP, an F-box protein of the SCF E3 ubiquitin ligase complex, was recently shown to play a role in the turnover of β-catenin. To elucidate the basis for the apparent differences in the turnover of β-catenin and plakoglobin we compared the handling of these two proteins by the ubiquitin-proteasome system. We show here that a deletion mutant of β-TrCP, lacking the F-box, can stabilize the endogenous β-catenin leading to its nuclear translocation and induction of β-catenin/LEF-1-directed transcription, without affecting the levels of plakoglobin. However, when plakoglobin was overexpressed, it readily associated with β-TrCP, efficiently competed with β-catenin for binding to β-TrCP and became polyubiquitinated. Fractionation studies revealed that about 85% of plakoglobin in 293 cells, is Triton X-100-insoluble compared to 50% of β-catenin. These results suggest that while both plakoglobin and β-catenin can comparably interact with β-TrCP and the ubiquitination system, the sequestration of plakoglobin by the membrane-cytoskeleton system renders it inaccessible to the proteolytic machinery and stabilizes it.
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Differential interaction of plakoglobin and β-catenin with the ubiquitin-proteasome system
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Sadot, E., Dept. of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
Simcha, I., Dept. of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
Iwai, K., Dept. of Molec. and System Biology, Kyoto University, Yoshida-Konoe-ChoSakyo-ku, Kyoto 606-8501, Japan
Ciechanover, A., Faculty of Medicine, Rappaport Inst. for Res. in the M., Technion-Israel Inst. of Technology, Haifa 31096, Israel
Geiger, B., Dept. of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
Ben-Ze'ev, A., Dept. of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel
Differential interaction of plakoglobin and β-catenin with the ubiquitin-proteasome system
β-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. β-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 β-catenin stability. A multiprotein complex, regulated by Wnt, directs the phosphorylation of β-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 β-catenin. β-TrCP, an F-box protein of the SCF E3 ubiquitin ligase complex, was recently shown to play a role in the turnover of β-catenin. To elucidate the basis for the apparent differences in the turnover of β-catenin and plakoglobin we compared the handling of these two proteins by the ubiquitin-proteasome system. We show here that a deletion mutant of β-TrCP, lacking the F-box, can stabilize the endogenous β-catenin leading to its nuclear translocation and induction of β-catenin/LEF-1-directed transcription, without affecting the levels of plakoglobin. However, when plakoglobin was overexpressed, it readily associated with β-TrCP, efficiently competed with β-catenin for binding to β-TrCP and became polyubiquitinated. Fractionation studies revealed that about 85% of plakoglobin in 293 cells, is Triton X-100-insoluble compared to 50% of β-catenin. These results suggest that while both plakoglobin and β-catenin can comparably interact with β-TrCP and the ubiquitination system, the sequestration of plakoglobin by the membrane-cytoskeleton system renders it inaccessible to the proteolytic machinery and stabilizes it.
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