O-GlcNAc stabilizes SMAD4 by inhibiting GSK-3β-mediated proteasomal degradation

Yeon Jung Kim, Min Jueng Kang, Eunah Kim, Tae Hyun Kweon, Yun Soo Park, Suena Ji, Won Ho Yang, Eugene C. Yi, Jin Won Cho

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11 Citations (Scopus)


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.

Original languageEnglish
Article number19908
JournalScientific reports
Issue number1
Publication statusPublished - 2020 Dec

Bibliographical note

Funding Information:
This study was supported by National Research Foundation of Korea grants funded by the Korean government (The Ministry of Science, ICT and Future Planning) (NRF-2016R1A5A1010764 and NRF-2015M3A9B6073840) to J.W.C. We thank Prof. Seong-Jin Kim (Seoul National University, Suwon, South Korea) for generously providing plasmids for FLAG-SMAD4 expression and (CAGA)12-Luc reporter genes.

Publisher Copyright:
© 2020, The Author(s).

All Science Journal Classification (ASJC) codes

  • General


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