PTEN Suppresses Glycolysis by Dephosphorylating and Inhibiting Autophosphorylated PGK1.

Abstract

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.

• Authors: Xu Qian, Xinjian Li, Zhumei Shi, Yan Xia, Qingsong Cai, Daqian Xu, Lin Tan, Linyong Du, Yanhua Zheng, Dan Zhao, Chuanbao Zhang, Philip L Lorenzi, Yongping You, Bing-Hua Jiang, Tao Jiang, Haitao Li, Zhimin Lu
• Journal: Molecular cell (Mol Cell) Vol. 76 Issue 3 Pg. 516-527.e7 (11 07 2019) ISSN: 1097-4164 [Electronic] United States
• PMID: 31492635 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Tyrosine
• Adenosine Triphosphate
• PGK1 protein, human
• Pgk1 protein, mouse
• Phosphoglycerate Kinase
• PTEN Phosphohydrolase
• PTEN protein, human
• Pten protein, mouse
• Glucose

Topics

• Adenosine Triphosphate (metabolism)
• Animals
• Brain Neoplasms (enzymology, genetics, pathology)
• Cell Line, Tumor
• Cell Proliferation
• Female
• Glioblastoma (enzymology, genetics, pathology)
• Glucose (metabolism)
• Glycolysis
• HEK293 Cells
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• PTEN Phosphohydrolase (genetics, metabolism)
• Phosphoglycerate Kinase (genetics, metabolism)
• Phosphorylation
• Prognosis
• Signal Transduction
• Time Factors
• Tumor Burden
• Tyrosine