PTEN Suppresses Glycolysis by Dephosphorylating and Inhibiting Autophosphorylated PGK1.

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. • PGK1, functioning as a protein kinase, autophosphorylates itself at Y324 • PGK1 autophosphorylation enhances its glycolytic activity via promoting ATP release • PTEN, functioning as a protein phosphatase, dephosphorylates PGK1 pY324 • PGK1 Y324 autophosphorylation promotes brain tumor formation Qian et al. demonstrate that PGK1 functions as a protein kinase and autophosphorylates itself at Y324, leading to subsequent PGK1 activation. This phosphorylation is dephosphorylated by the protein phosphatase activity of PTEN. Loss of PTEN expression in tumors enhances PGK1 activity, thereby promoting glycolysis and brain tumor growth. [ABSTRACT FROM AUTHOR]