PTEN Suppresses Glycolysis by Dephosphorylating and Inhibiting Autophosphorylated PGK1.,Molecular Cell

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PTEN Suppresses Glycolysis by Dephosphorylating and Inhibiting Autophosphorylated PGK1.
Molecular Cell ( IF 14.5 ) Pub Date : 2019-09-03 , DOI: 10.1016/j.molcel.2019.08.006
Xu Qian ₁ , Xinjian Li ₂ , Zhumei Shi ₃ , Yan Xia ₄ , Qingsong Cai ₄ , Daqian Xu ₄ , Lin Tan ₅ , Linyong Du ₆ , Yanhua Zheng ₄ , Dan Zhao ₇ , Chuanbao Zhang ₈ , Philip L Lorenzi ₅ , Yongping You ₉ , Bing-Hua Jiang ₁₀ , Tao Jiang ₈ , Haitao Li ₇ , Zhimin Lu ₁₁

Affiliation

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Institute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention, and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Bioinformatics & Computational Biology, Proteomics and Metabolomics Core Facility, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China.
Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China.
Institute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention, and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China; Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan 450052, China; Department of Pathology, University of Iowa, Iowa City, IA 52242, USA.
Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China.

The PTEN tumor suppressor is frequently mutated or deleted in cancer and regulates glucose metabolism through the PI3K-AKT pathway. However, whether PTEN directly regulates glycolysis in tumor cells is unclear. We demonstrate here that PTEN directly interacts with phosphoglycerate kinase 1 (PGK1). PGK1 functions not only as a glycolytic enzyme but also as a protein kinase intermolecularly autophosphorylating itself at Y324 for activation. The protein phosphatase activity of PTEN dephosphorylates and inhibits autophosphorylated PGK1, thereby inhibiting glycolysis, ATP production, and brain tumor cell proliferation. In addition, knockin expression of a PGK1 Y324F mutant inhibits brain tumor formation. Analyses of human glioblastoma specimens reveals that PGK1 Y324 phosphorylation levels inversely correlate with PTEN expression status and are positively associated with poor prognosis in glioblastoma patients. This work highlights the instrumental role of PGK1 autophosphorylation in its activation and PTEN protein phosphatase activity in governing glycolysis and tumorigenesis.

中文翻译：

PTEN通过去磷酸化和抑制自磷酸化的PGK1抑制糖酵解。

PTEN抑癌基因在癌症中经常发生突变或缺失，并通过PI3K-AKT途径调节葡萄糖代谢。然而，尚不清楚PTEN是否直接调节肿瘤细胞中的糖酵解。我们在这里证明PTEN直接与磷酸甘油酸激酶1（PGK1）相互作用。PGK1不仅起糖酵解酶的作用，而且还作为蛋白激酶在Y324分子间自身磷酸化以激活。PTEN的蛋白质磷酸酶活性会去磷酸化并抑制自身磷酸化的PGK1，从而抑制糖酵解，ATP产生和脑肿瘤细胞增殖。此外，PGK1 Y324F突变体的敲入表达抑制了脑肿瘤的形成。对人胶质母细胞瘤标本的分析表明，PGK1 Y324磷酸化水平与PTEN表达状态呈负相关，与胶质母细胞瘤患者的不良预后呈正相关。这项工作强调了PGK1自磷酸化在其活化和PTEN蛋白磷酸酶活性中在控制糖酵解和肿瘤发生中的工具作用。

更新日期：2019-09-03

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