EGF promotes PKM2 O-GlcNAcylation by stimulating O-GlcNAc transferase phosphorylation at Y976 and their subsequent association

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, PKCδ, 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. 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, PKCδ, 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. Epidermal growth factor (EGF) is one of the most well-characterized growth factors and required for cell growth, proliferation, and differentiation (1Arteaga C.L. Engelman J.A. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics.Cancer Cell. 2014; 25: 282-303Abstract Full Text Full Text PDF PubMed Scopus (740) Google Scholar). As a part of the transmembrane receptor tyrosine kinases (RTKs) family, EGF receptor (EGFR) appears to be highly expressed and constitutively activated in multiple cancer types, such as lung cancer and glioblastoma (2Skoulidis F. Heymach J.V. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy.Nat. Rev. Cancer. 2019; 19: 495-509Crossref PubMed Scopus (490) Google Scholar, 3Villa G.R. Mischel P.S. Old player, new partner: EGFRvIII and cytokine receptor signaling in glioblastoma.Nat. Neurosci. 2016; 19: 765-767Crossref PubMed Scopus (14) Google Scholar, 4Arbour K.C. Riely G.J. Systemic therapy for locally advanced and metastatic non-small cell lung cancer: a review.JAMA. 2019; 322: 764-774Crossref PubMed Scopus (661) Google Scholar). EGFR is the first identified RTK functioning as an oncogene and found to regulate cancer development by triggering distinct pathways, including RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, Src kinases, and STAT transcription factors (1Arteaga C.L. Engelman J.A. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics.Cancer Cell. 2014; 25: 282-303Abstract Full Text Full Text PDF PubMed Scopus (740) Google Scholar). Aberrantly regulated EGFR is often associated with poor prognosis. Targeting EGFR with specific inhibitors, antibodies, or vaccines has been extensively explored and recognized as useful strategies for therapeutic treatment against cancers (1Arteaga C.L. Engelman J.A. ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics.Cancer Cell. 2014; 25: 282-303Abstract Full Text Full Text PDF PubMed Scopus (740) Google Scholar, 2Skoulidis F. Heymach J.V. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy.Nat. Rev. Cancer. 2019; 19: 495-509Crossref PubMed Scopus (490) Google Scholar, 4Arbour K.C. Riely G.J. Systemic therapy for locally advanced and metastatic non-small cell lung cancer: a review.JAMA. 2019; 322: 764-774Crossref PubMed Scopus (661) Google Scholar). Emerging evidence revealed that EGF stimulation could trigger metabolic reprogramming in multiple types of cancer cells (5Vander Heiden M.G. Cantley L.C. Thompson C.B. Understanding the Warburg effect: the metabolic requirements of cell proliferation.Science. 2009; 324: 1029-1033Crossref PubMed Scopus (10996) Google Scholar). In rapidly dividing hepatocellular carcinoma cells, EGFR activation upregulated de novo fatty acid synthesis to meet the demand for membrane lipids (6Zhang G. Li X. Chen Q. Li J. Ruan Q. Chen Y.H. et al.CD317 activates EGFR by regulating its association with lipid rafts.Cancer Res. 2019; 79: 2220-2231Crossref PubMed Scopus (16) Google Scholar, 7Dong X.-F. Liu T.-Q. Zhi X.-T. Zuo J. Zhong J.-T. Li T. et al.COX-2/PGE2 Axis regulates HIF2α activity to promote hepatocellular carcinoma hypoxic response and reduce the sensitivity of sorafenib treatment.Clin. Cancer Res. 2018; 24: 3204-3216Crossref PubMed Scopus (65) Google Scholar). Activation in EGF signaling enhanced nutrient uptake, especially glucose, to support the rapid proliferation of non–small cell lung cancer cells (5Vander Heiden M.G. Cantley L.C. Thompson C.B. Understanding the Warburg effect: the metabolic requirements of cell proliferation.Science. 2009; 324: 1029-1033Crossref PubMed Scopus (10996) Google Scholar, 8DeBerardinis R.J. Lum J.J. Hatzivassiliou G. Thompson C.B. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation.Cell Metab. 2008; 7: 11-20Abstract Full Text Full Text PDF PubMed Scopus (3071) Google Scholar). More recent work has demonstrated an important role for EGF in the regulation of aerobic glycolysis, which is prominently featured in tumors as the Warburg effect (8DeBerardinis R.J. Lum J.J. Hatzivassiliou G. Thompson C.B. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation.Cell Metab. 2008; 7: 11-20Abstract Full Text Full Text PDF PubMed Scopus (3071) Google Scholar). The activation of EGFR could turn on both PI3K-AKT and tyrosine kinase signaling to mediate the phosphorylation of several key enzymes controlling glycolysis, including hexokinase, phosphofructokinase, and pyruvate kinase (PK) (5Vander Heiden M.G. Cantley L.C. Thompson C.B. Understanding the Warburg effect: the metabolic requirements of cell proliferation.Science. 2009; 324: 1029-1033Crossref PubMed Scopus (10996) Google Scholar). As a consequence, functions of these enzymes were orchestrated, leading to enhanced glucose uptake as well as metabolic reprogramming that in turn support macromolecular synthesis and NADPH production (5Vander Heiden M.G. Cantley L.C. Thompson C.B. Understanding the Warburg effect: the metabolic requirements of cell proliferation.Science. 2009; 324: 1029-1033Crossref PubMed Scopus (10996) Google Scholar). As pyruvate kinase M2 (PKM2) is the rate-limiting enzyme controlling the final step of glycolysis and serves as a major regulator of the Warburg effect in different cancer cells, the regulation of PKM2 by EGF, particularly in high EGFR–expressing cells, is thus of great importance (9Cairns R.A. Harris I.S. Mak T.W. Regulation of cancer cell metabolism.Nat. Rev. Cancer. 2011; 11: 85-95Crossref PubMed Scopus (3778) Google Scholar, 10Yang W. Zheng Y. Xia Y. Ji H. Chen X. Guo F. et al.ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect.Nat. Cell Biol. 2012; 14: 1295-1304Crossref PubMed Scopus (609) Google Scholar, 11Yang W. Xia Y. Ji H. Zheng Y. Liang J. Huang W. et al.Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation.Nature. 2011; 480: 118-122Crossref PubMed Scopus (762) Google Scholar, 12Lv L. Xu Y.P. Zhao D. Li F.L. Wang W. Sasaki et and stimulation of promotes PKM2 kinase activity and nuclear Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, W. Xia Y. D. Li X. Liang J. D. et and promotes transcription and 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). has been reported that activation PKM2 phosphorylation in W. Zheng Y. Xia Y. Ji H. Chen X. Guo F. et al.ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect.Nat. Cell Biol. 2012; 14: 1295-1304Crossref PubMed Scopus (609) Google Scholar). As a consequence, the activity of PKM2 was and PKM2 was the to promote glucose and W. Zheng Y. Xia Y. Ji H. Chen X. Guo F. et al.ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect.Nat. Cell Biol. 2012; 14: 1295-1304Crossref PubMed Scopus (609) Google Scholar). Moreover, PKM2 was found to be by in cancer cells upon EGF PKM2 its activity and glycolysis L. Xu Y.P. Zhao D. Li F.L. Wang W. Sasaki et and stimulation of promotes PKM2 kinase activity and nuclear Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). More highly PKM2 was observed in a of cells and Y. Liu J. X. D. Li D. F. et the PKM2 to promote the Warburg PubMed Scopus Google Scholar, J. X. et pyruvate kinase M2 to regulate PubMed Scopus Google Scholar). As a posttranslational modification O-GlcNAcylation is by O-GlcNAc transferase (OGT) and and recognized as a G. between O-GlcNAcylation and in and Rev. 2011; PubMed Scopus Google Scholar, X. and Rev. Cell Biol. PubMed Scopus Google Scholar, of on PubMed Scopus Google Scholar, O-GlcNAc for cancer cell Rev. Cancer. 2011; 11: PubMed Scopus Google Scholar). O-GlcNAcylation PKM2 by regulating PKM2 and glycolysis to Y. Liu J. X. D. Li D. F. et the PKM2 to promote the Warburg PubMed Scopus Google Scholar). In we also observed that O-GlcNAcylation PKM2 T405/S406 was in response to EGF stimulation Y. Liu J. X. D. Li D. F. et the PKM2 to promote the Warburg PubMed Scopus Google Scholar). However, the mechanism for the regulation of PKM2 O-GlcNAcylation by EGF still remains In this we showed that EGF the phosphorylation of OGT Y976 and in turn promoted OGT binding to As a consequence, PKM2 O-GlcNAcylation and detetramerization were leading to a significant in PKM2 activity. PKM2, additional phosphotyrosine-binding proteins Heiden M.G. Cantley L.C. Pyruvate kinase M2 is a phosphotyrosine-binding 2008; PubMed Scopus Google Scholar, D. H. et of cells 2019; PubMed Scopus Google Scholar, X. Li L. W. et promotes phosphorylation by OGT and against PubMed Scopus Google Scholar, Liu L. Wang F. of O-GlcNAcylation modification in and with phosphorylation of in 2018; PubMed Scopus Google Scholar, G. The of transcription with the of Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, et of and kinase in and of fatty PubMed Scopus Google Scholar, X. F. et O-GlcNAc transferase to 2008; PubMed Scopus Google Scholar, R.J. O-GlcNAc a metabolic between and Full Text Full Text PDF PubMed Scopus Google including STAT1, STAT3, STAT5, PKCδ, and p85, which are known to be were also recognized and associated with OGT Together, we showed that EGF-dependent Y976 phosphorylation is critical for OGT-PKM2 interaction and this might be important for the substrate selection of OGT. We upregulated PKM2 T405/S406 O-GlcNAcylation upon EGF stimulation in cancer cells Y. Liu J. X. D. Li D. F. et the PKM2 to promote the Warburg PubMed Scopus Google Scholar). EGFR is in cancers, such as lung cancer and glioblastoma in glioblastoma the to the Rev. 14: PubMed Scopus Google Scholar, Full Text Full Text PDF PubMed Scopus Google Scholar, H. et genomic of Full Text Full Text PDF PubMed Scopus Google Scholar). EGFR signaling has a role in cancer in glioblastoma the to the Rev. 14: PubMed Scopus Google Scholar, Full Text Full Text PDF PubMed Scopus Google Scholar, H. et genomic of Full Text Full Text PDF PubMed Scopus Google Scholar). we found this mark was also enhanced by EGF in non–small cell lung cancer and glioblastoma cells T405/S406 was PKM2 O-GlcNAcylation markedly as and to to EGF stimulation is known that PKM2 or to regulate metabolic cell functions of the key regulator PKM2 in 2012; Full Text Full Text PDF PubMed Scopus Google Scholar, W. Emerging of PKM2 in cell and cancer Metab. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar, Heiden M.G. Harris et M2 of pyruvate kinase is important for cancer and 2008; PubMed Scopus Google Scholar). O-GlcNAcylation on PKM2 T405/S406 the and its activity Y. Liu J. X. D. Li D. F. et the PKM2 to promote the Warburg PubMed Scopus Google Scholar). PKM2 O-GlcNAcylation was upregulated by EGF, the of PKM2 from and T405/S406 PKM2 detetramerization the important role of T405/S406 O-GlcNAcylation in the regulation of of the activity of PKM2 to alterations in PKM2 O-GlcNAcylation and The of EGF, which enhanced PKM2 O-GlcNAcylation and detetramerization in and cells, the activity of PKM2 the PKM2 we the of the PKM2 which is of PKM2 in its X. W. Wang Y. Liu J. F. Liu Y. et kinase M2 promotes the activation of cells by Full Text Full Text PDF Scopus Google Scholar, D. Y. et kinase M2 promote and Biol. 2012; PubMed Scopus Google Scholar). The of in PKM2 activity These showed that in PKM2 O-GlcNAcylation and detetramerization the activity of PKM2 O-GlcNAcylation was regulated by EGF, we PKM2 association with OGT and enzymes which and of O-GlcNAc modification on proteins G. between O-GlcNAcylation and in and Rev. 2011; PubMed Scopus Google Scholar, X. and Rev. Cell Biol. PubMed Scopus Google Scholar). are of including and and of and X. and Rev. Cell Biol. PubMed Scopus Google Scholar). and are the most and X. and Rev. Cell Biol. PubMed Scopus Google which we in this In cells PKM2 O-GlcNAcylation, and activity to be to EGF in the cell we found that EGF the binding of to PKM2 the of OGT and Moreover, of the constitutively EGFRvIII also to enhanced OGT association with PKM2 that EGF signaling promoted OGT association with PKM2 to its In we also the of substrate for O-GlcNAcylation, for showed that was by EGF Together, EGF OGT association with PKM2 to PKM2 PKM2 is a phosphotyrosine-binding Heiden M.G. Cantley L.C. Pyruvate kinase M2 is a phosphotyrosine-binding 2008; PubMed Scopus Google and OGT multiple tyrosine of which and Y976 in and and in were reported to phosphorylation the in OGT upon EGF stimulation we EGF OGT-PKM2 interaction by phosphorylation. this we and and OGT as to the part between and OGT showed that or OGT tyrosine phosphorylation Y976 interaction between OGT and PKM2 for OGT from cells the phosphorylation of OGT Y976 the of OGT Y976 we an that OGT Y976 phosphorylation the from OGT a from an was recognized by this and in the for cell the could OGT Y976 phosphorylation in and of OGT Y976 phosphorylation by the of the new we observed that EGF stimulation upregulated OGT Y976 phosphorylation and Y976 was to this was Moreover, and with OGT and PKM2 from we showed that OGT association with PKM2 was by the was enhanced Y976 was by and and that phosphorylation Q. X. F. Y. Liu X. et the of by reprogramming Scopus Google Scholar, H. T. Wang H. et receptor kinase activation of 2018; PubMed Scopus Google Scholar, de Y. et phosphorylation of by tyrosine kinase signaling Cell. 2018; Full Text Full Text PDF PubMed Scopus (16) Google Scholar). These the important role of Y976 phosphorylation in OGT-PKM2 Y976 phosphorylation is important for PKM2 of OGT membrane was with different of OGT OGT Y976 OGT and with OGT of Y976 phosphorylation in and OGT. cells with or were with or EGF for The phosphorylation was for of OGT and PKM2 were to with by of Y976 phosphorylation in OGT. proteins were from cells with or EGF for by and with OGT was with or OGT Y976 for the in of OGT and PKM2 were to OGT. with by for OGT-PKM2 PKM2 and OGT proteins were from and were on and with or to of was to with by for was the for PKM2 binding by and as well as the associated were of was EGF, growth EGF O-GlcNAc OGT Y976 to in PKM2 O-GlcNAcylation However, when OGT Y976 was by the of PKM2 O-GlcNAcylation was of the of EGF and in PKM2 O-GlcNAcylation were to OGT activity upon we of the X. X. W. Li X. Li Li Q. et of promotes the and PubMed Scopus Google Scholar, L. F. Li J. X. Wang enzyme for transferase activity 2009; 11: PubMed Scopus Google with a to and to the for O-GlcNAcylation by OGT. In OGT J.A. J. et of O-GlcNAc transferase 2018; PubMed Scopus Google OGT activity as different to in the or of this between OGT to a or the and activity in this In of OGT detetramerization and in PKM2 activity, OGT PKM2 detetramerization and in PKM2 activity we that OGT Y976 phosphorylation an role in EGF-dependent regulation of As a phosphotyrosine-binding PKM2 and to such as Src and which tyrosine Heiden M.G. Cantley L.C. Pyruvate kinase M2 is a phosphotyrosine-binding 2008; PubMed Scopus Google Scholar). acid in PKM2 has been to be important for PKM2 association with proteins Heiden M.G. Cantley L.C. Pyruvate kinase M2 is a phosphotyrosine-binding 2008; PubMed Scopus Google Scholar). As PKM2 also PKM2 interaction with OGT upon EGF stimulation Y976 phosphorylation of OGT that associated with PKM2 was that in PKM2 OGT These the important role of in PKM2 interaction with the of PKM2 association with OGT upon PKM2 was additional might be also in the regulation of PKM2, a of phosphotyrosine-binding proteins have also been found to be Heiden M.G. Cantley L.C. Pyruvate kinase M2 is a phosphotyrosine-binding 2008; PubMed Scopus Google Scholar, D. H. et of cells 2019; PubMed Scopus Google Scholar, X. Li L. W. et promotes phosphorylation by OGT and against PubMed Scopus Google Scholar, Liu L. Wang F. of O-GlcNAcylation modification in and with phosphorylation of in 2018; PubMed Scopus Google Scholar, G. The of transcription with the of Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, et of and kinase in and of fatty PubMed Scopus Google Scholar, X. F. et O-GlcNAc transferase to 2008; PubMed Scopus Google Scholar, R.J. O-GlcNAc a metabolic between and Full Text Full Text PDF PubMed Scopus Google Scholar). the critical role of Y976 phosphorylation in OGT interaction with PKM2 and we this is also important for OGT by a of phosphotyrosine-binding this phosphotyrosine-binding proteins that O-GlcNAcylation, including factor STAT1, STAT3, STAT5, kinase PKCδ, and D. H. et of cells 2019; PubMed Scopus Google Scholar, X. Li L. W. et promotes phosphorylation by OGT and against PubMed Scopus Google Scholar, Liu L. Wang F. of O-GlcNAcylation modification in and with phosphorylation of in 2018; PubMed Scopus Google Scholar, G. The of transcription with the of Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, et of and kinase in and of fatty PubMed Scopus Google Scholar, X. F. et O-GlcNAc transferase to 2008; PubMed Scopus Google Scholar, R.J. O-GlcNAc a metabolic between and Full Text Full Text PDF PubMed Scopus Google were for the interaction with OGT. EGF the of factors of the of or binding of STAT1, STAT3, STAT5, PKCδ, and to OGT was upregulated by EGF treatment association with OGT for these factors was when Y976 in OGT was in to PKM2, phosphotyrosine-binding proteins might also Y976 phosphorylation to with OGT. which is a known regulated by a phosphotyrosine-binding was included in interaction as a that interaction was by Y976 phosphorylation in the of EGF, of enhanced the O-GlcNAcylation of STAT1, STAT3, STAT5, PKCδ, and these that Y976 phosphorylation is important for OGT interaction with phosphotyrosine-binding In this we have a mechanism by which EGF regulates PKM2 OGT phosphorylation EGF signaling OGT interaction with PKM2 and promoted PKM2 O-GlcNAcylation and detetramerization As a key enzyme regulating glycolysis, PKM2 is highly in types of cells and and in the regulation of the Warburg effect Y. Liu J. X. D. Li D. F. et the PKM2 to promote the Warburg PubMed Scopus Google Scholar). We previously showed on one PKM2 detetramerization in activity, leading to the rewiring of metabolic for rapid cell proliferation Y. Liu J. X. D. Li D. F. et the PKM2 to promote the Warburg PubMed Scopus Google Scholar). the PKM2 nuclear translocation and in turn and to promote the Warburg effect Y. Liu J. X. D. Li D. F. et the PKM2 to promote the Warburg PubMed Scopus Google Scholar). PKM2 O-GlcNAcylation and detetramerization are to cell proliferation by both metabolic and nuclear functions of The of Y976 phosphorylation with EGF signaling the for cancer cell proliferation as well as growth by PKM2 we also that the of OGT Y976 phosphorylation in to PKM2 O-GlcNAcylation, or activity EGF that additional be in the of PKM2 especially an O-GlcNAcylation is a and which the of to and G. between O-GlcNAcylation and in and Rev. 2011; PubMed Scopus Google Scholar, X. and Rev. Cell Biol. PubMed Scopus Google Scholar). O-GlcNAc regulates a of and G. between O-GlcNAcylation and in and Rev. 2011; PubMed Scopus Google Scholar, X. and Rev. Cell Biol. PubMed Scopus Google Scholar, et regulates cancer and signaling regulation of the Cell. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar). The is the of nutrient and the which glucose, fatty and G. between O-GlcNAcylation and in and Rev. 2011; PubMed Scopus Google Scholar). O-GlcNAcylation on proteins that is recognized as a is with O-GlcNAc as well as nutrient More recent studies revealed that O-GlcNAcylation is also to different such as and growth factors X. and Rev. Cell Biol. PubMed Scopus Google Scholar). the mechanism for the regulation of PKM2 by OGT Y976 phosphorylation could be useful for cells to to or with types of in to EGF, remains to be of including transcription and metabolic have been found to be X. and Rev. Cell Biol. PubMed Scopus Google Scholar). O-GlcNAc and O-GlcNAcylation are associated with and cancers X. and Rev. Cell Biol. PubMed Scopus Google Scholar). OGT and substrate proteins for O-GlcNAcylation has been a in the of from substrate proteins for OGT has been and of the of OGT have different X. and Rev. Cell Biol. PubMed Scopus Google distinct proteins that different to OGT in a an important role in OGT substrate selection X. and Rev. Cell Biol. PubMed Scopus Google the in which is an of to has been reported to as a for the and of distinct Y. J. of O-GlcNAc transferase and its with a 2011; PubMed Scopus Google a that OGT proteins in or has also been Y. J. of O-GlcNAc transferase and its with a 2011; PubMed Scopus Google Scholar). of these of the for the of OGT substrate selection is still We demonstrated that phosphorylation of OGT Y976 the association of PKM2 with OGT. the regulation of OGT by Y976 phosphorylation to be important for the association of a of phosphotyrosine-binding proteins as that OGT Y976 phosphorylation is a with important in substrate on OGT regulate substrate is an of stimulating OGT Y976 EGF OGT-PKM2 interaction and enhanced PKM2 O-GlcNAcylation and These O-GlcNAcylation as a EGF signaling with metabolic regulation and on the of O-GlcNAcylation in therapeutic treatment against EGF receptor cancer cells, lung cancer cells, and glioblastoma cells were in with and cell were from the Cell of of of EGF was from and was from PKM2 was or was by W. of W. J. J. G. O-GlcNAc modification of proteins in response to response of Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). 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