ERK1-mediated GLYCTK2 phosphorylation promotes fructolysis to sustain glioblastoma survival under glucose deprivation
Abstract Metabolic plasticity sustains glioblastoma (GBM) survival under nutrient stress, yet how fructolytic adaptation compensates for glucose deprivation remains unclear. Here, we identify glycerate kinase 2 (GLYCTK2) as a glucose-sensing metabolic checkpoint that maintains GBM cell viability thr...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-06-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02544-3 |
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| author | Yingping Li Fenna Zhang Fumin Hu Rui Tong Yueqi Wen Guokai Fu Xueli Bian |
| author_facet | Yingping Li Fenna Zhang Fumin Hu Rui Tong Yueqi Wen Guokai Fu Xueli Bian |
| author_sort | Yingping Li |
| collection | DOAJ |
| description | Abstract Metabolic plasticity sustains glioblastoma (GBM) survival under nutrient stress, yet how fructolytic adaptation compensates for glucose deprivation remains unclear. Here, we identify glycerate kinase 2 (GLYCTK2) as a glucose-sensing metabolic checkpoint that maintains GBM cell viability through ERK1-mediated phosphorylation. Mechanistically, glucose deprivation-activated ERK1 phosphorylates GLYCTK2 at serine 220 directly, which prevents STUB1 (ubiquitin E3 ligase) binding, thereby abrogating the ubiquitination and degradation of GLYCTK2. Importantly, Functional studies demonstrated that fructose supplementation rescues glucose deprivation-induced death in wild-type GBM cells, but fails to protect GLYCTK2-depleted cells, establishing GLYCTK2 as the gatekeeper of fructolytic salvage pathways. These findings demonstrate an important mechanism by which GBM cells rewire glucose metabolism to fructose metabolism via phosphorylating and stabilizing GLYCTK2 to maintain GBM cell survival under glucose deprivation condition, underscoring the potential to target GLYCTK2 for the treatment of patients with GBM. |
| format | Article |
| id | doaj-art-84b7c0839a4e44e98ded2c87c077e5c4 |
| institution | OA Journals |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj-art-84b7c0839a4e44e98ded2c87c077e5c42025-08-20T02:30:43ZengNature Publishing GroupCell Death Discovery2058-77162025-06-0111111210.1038/s41420-025-02544-3ERK1-mediated GLYCTK2 phosphorylation promotes fructolysis to sustain glioblastoma survival under glucose deprivationYingping Li0Fenna Zhang1Fumin Hu2Rui Tong3Yueqi Wen4Guokai Fu5Xueli Bian6Department of Clinical Nutrition, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityThe First Affiliated Hospital of Xi’an Medical UniversityThe MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang UniversityThe MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang UniversityThe MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang UniversityThe MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang UniversityDepartment of Clinical Nutrition, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang UniversityAbstract Metabolic plasticity sustains glioblastoma (GBM) survival under nutrient stress, yet how fructolytic adaptation compensates for glucose deprivation remains unclear. Here, we identify glycerate kinase 2 (GLYCTK2) as a glucose-sensing metabolic checkpoint that maintains GBM cell viability through ERK1-mediated phosphorylation. Mechanistically, glucose deprivation-activated ERK1 phosphorylates GLYCTK2 at serine 220 directly, which prevents STUB1 (ubiquitin E3 ligase) binding, thereby abrogating the ubiquitination and degradation of GLYCTK2. Importantly, Functional studies demonstrated that fructose supplementation rescues glucose deprivation-induced death in wild-type GBM cells, but fails to protect GLYCTK2-depleted cells, establishing GLYCTK2 as the gatekeeper of fructolytic salvage pathways. These findings demonstrate an important mechanism by which GBM cells rewire glucose metabolism to fructose metabolism via phosphorylating and stabilizing GLYCTK2 to maintain GBM cell survival under glucose deprivation condition, underscoring the potential to target GLYCTK2 for the treatment of patients with GBM.https://doi.org/10.1038/s41420-025-02544-3 |
| spellingShingle | Yingping Li Fenna Zhang Fumin Hu Rui Tong Yueqi Wen Guokai Fu Xueli Bian ERK1-mediated GLYCTK2 phosphorylation promotes fructolysis to sustain glioblastoma survival under glucose deprivation Cell Death Discovery |
| title | ERK1-mediated GLYCTK2 phosphorylation promotes fructolysis to sustain glioblastoma survival under glucose deprivation |
| title_full | ERK1-mediated GLYCTK2 phosphorylation promotes fructolysis to sustain glioblastoma survival under glucose deprivation |
| title_fullStr | ERK1-mediated GLYCTK2 phosphorylation promotes fructolysis to sustain glioblastoma survival under glucose deprivation |
| title_full_unstemmed | ERK1-mediated GLYCTK2 phosphorylation promotes fructolysis to sustain glioblastoma survival under glucose deprivation |
| title_short | ERK1-mediated GLYCTK2 phosphorylation promotes fructolysis to sustain glioblastoma survival under glucose deprivation |
| title_sort | erk1 mediated glyctk2 phosphorylation promotes fructolysis to sustain glioblastoma survival under glucose deprivation |
| url | https://doi.org/10.1038/s41420-025-02544-3 |
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