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EGF promotes PKM2 O-GlcNAcylation by stimulating O-GlcNAc transferase phosphorylation at Y976 and their subsequent association.
- Source :
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The Journal of biological chemistry [J Biol Chem] 2022 Sep; Vol. 298 (9), pp. 102340. Date of Electronic Publication: 2022 Aug 03. - Publication Year :
- 2022
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Abstract
- Epidermal growth factor (EGF) is one of the most well-characterized growth factors and plays a crucial role in cell proliferation and differentiation. Its receptor EGFR has been extensively explored as a therapeutic target against multiple types of cancers, such as lung cancer and glioblastoma. Recent studies have established a connection between deregulated EGF signaling and metabolic reprogramming, especially rewiring in aerobic glycolysis, which is also known as the Warburg effect and recognized as a hallmark in cancer. Pyruvate kinase M2 (PKM2) is a rate-limiting enzyme controlling the final step of glycolysis and serves as a major regulator of the Warburg effect. We previously showed that PKM2 T405/S406 O-GlcNAcylation, a critical mark important for PKM2 detetramerization and activity, was markedly upregulated by EGF. However, the mechanism by which EGF regulates PKM2 O-GlcNAcylation still remains uncharacterized. Here, we demonstrated that EGF promoted O-GlcNAc transferase (OGT) binding to PKM2 by stimulating OGT Y976 phosphorylation. As a consequence, we found PKM2 O-GlcNAcylation and detetramerization were upregulated, leading to a significant decrease in PKM2 activity. Moreover, distinct from PKM2, we observed that the association of additional phosphotyrosine-binding proteins with OGT was also enhanced when Y976 was phosphorylated. These proteins included STAT1, STAT3, STAT5, PKCĪ“, and p85, which are reported to be O-GlcNAcylated. Together, we show EGF-dependent Y976 phosphorylation is critical for OGT-PKM2 interaction and propose that this posttranslational modification might be important for substrate selection by OGT.<br />Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.<br /> (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- ErbB Receptors genetics
ErbB Receptors metabolism
Humans
Neoplasms metabolism
Phosphorylation
Phosphotyrosine metabolism
STAT5 Transcription Factor metabolism
Epidermal Growth Factor metabolism
N-Acetylglucosaminyltransferases genetics
N-Acetylglucosaminyltransferases metabolism
Pyruvate Kinase metabolism
Tyrosine metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 298
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 35931120
- Full Text :
- https://doi.org/10.1016/j.jbc.2022.102340