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O-GlcNAc stabilizes SMAD4 by inhibiting GSK-3β-mediated proteasomal degradation
O-linked β-N-acetylglucosamine (O-GlcNAc) is a post-translational modification which occurs on the hydroxyl group of serine or threonine residues of nucleocytoplasmic proteins. It has been reported that the presence of this single sugar motif regulates various biological events by altering the fate...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670456/ https://www.ncbi.nlm.nih.gov/pubmed/33199824 http://dx.doi.org/10.1038/s41598-020-76862-0 |
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author | Kim, Yeon Jung Kang, Min Jueng Kim, Eunah Kweon, Tae Hyun Park, Yun Soo Ji, Suena Yang, Won Ho Yi, Eugene C. Cho, Jin Won |
author_facet | Kim, Yeon Jung Kang, Min Jueng Kim, Eunah Kweon, Tae Hyun Park, Yun Soo Ji, Suena Yang, Won Ho Yi, Eugene C. Cho, Jin Won |
author_sort | Kim, Yeon Jung |
collection | PubMed |
description | O-linked β-N-acetylglucosamine (O-GlcNAc) is a post-translational modification which occurs on the hydroxyl group of serine or threonine residues of nucleocytoplasmic proteins. It has been reported that the presence of this single sugar motif regulates various biological events by altering the fate of target proteins, such as their function, localization, and degradation. This study identified SMAD4 as a novel O-GlcNAc-modified protein. SMAD4 is a component of the SMAD transcriptional complex, a major regulator of the signaling pathway for the transforming growth factor-β (TGF-β). TGF-β is a powerful promoter of cancer EMT and metastasis. This study showed that the amount of SMAD4 proteins changes according to cellular O-GlcNAc levels in human lung cancer cells. This observation was made based on the prolonged half-life of SMAD4 proteins. The mechanism behind this interaction was that O-GlcNAc impeded interactions between SMAD4 and GSK-3β which promote proteasomal degradation of SMAD4. In addition, O-GlcNAc modification on SMAD4 Thr63 was responsible for stabilization. As a result, defects in O-GlcNAcylation on SMAD4 Thr63 attenuated the reporter activity of luciferase, the TGF-β-responsive SMAD binding element (SBE). This study’s findings imply that cellular O-GlcNAc may regulate the TGF-β/SMAD signaling pathway by stabilizing SMAD4. |
format | Online Article Text |
id | pubmed-7670456 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-76704562020-11-18 O-GlcNAc stabilizes SMAD4 by inhibiting GSK-3β-mediated proteasomal degradation Kim, Yeon Jung Kang, Min Jueng Kim, Eunah Kweon, Tae Hyun Park, Yun Soo Ji, Suena Yang, Won Ho Yi, Eugene C. Cho, Jin Won Sci Rep Article O-linked β-N-acetylglucosamine (O-GlcNAc) is a post-translational modification which occurs on the hydroxyl group of serine or threonine residues of nucleocytoplasmic proteins. It has been reported that the presence of this single sugar motif regulates various biological events by altering the fate of target proteins, such as their function, localization, and degradation. This study identified SMAD4 as a novel O-GlcNAc-modified protein. SMAD4 is a component of the SMAD transcriptional complex, a major regulator of the signaling pathway for the transforming growth factor-β (TGF-β). TGF-β is a powerful promoter of cancer EMT and metastasis. This study showed that the amount of SMAD4 proteins changes according to cellular O-GlcNAc levels in human lung cancer cells. This observation was made based on the prolonged half-life of SMAD4 proteins. The mechanism behind this interaction was that O-GlcNAc impeded interactions between SMAD4 and GSK-3β which promote proteasomal degradation of SMAD4. In addition, O-GlcNAc modification on SMAD4 Thr63 was responsible for stabilization. As a result, defects in O-GlcNAcylation on SMAD4 Thr63 attenuated the reporter activity of luciferase, the TGF-β-responsive SMAD binding element (SBE). This study’s findings imply that cellular O-GlcNAc may regulate the TGF-β/SMAD signaling pathway by stabilizing SMAD4. Nature Publishing Group UK 2020-11-16 /pmc/articles/PMC7670456/ /pubmed/33199824 http://dx.doi.org/10.1038/s41598-020-76862-0 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Kim, Yeon Jung Kang, Min Jueng Kim, Eunah Kweon, Tae Hyun Park, Yun Soo Ji, Suena Yang, Won Ho Yi, Eugene C. Cho, Jin Won O-GlcNAc stabilizes SMAD4 by inhibiting GSK-3β-mediated proteasomal degradation |
title | O-GlcNAc stabilizes SMAD4 by inhibiting GSK-3β-mediated proteasomal degradation |
title_full | O-GlcNAc stabilizes SMAD4 by inhibiting GSK-3β-mediated proteasomal degradation |
title_fullStr | O-GlcNAc stabilizes SMAD4 by inhibiting GSK-3β-mediated proteasomal degradation |
title_full_unstemmed | O-GlcNAc stabilizes SMAD4 by inhibiting GSK-3β-mediated proteasomal degradation |
title_short | O-GlcNAc stabilizes SMAD4 by inhibiting GSK-3β-mediated proteasomal degradation |
title_sort | o-glcnac stabilizes smad4 by inhibiting gsk-3β-mediated proteasomal degradation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670456/ https://www.ncbi.nlm.nih.gov/pubmed/33199824 http://dx.doi.org/10.1038/s41598-020-76862-0 |
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