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EGFR activates phosphatidylinositide 3-kinase (PI3K), but the mechanism underlying this activation is not completely understood. We demonstrated here that EGFR activation resulted in lysine acetyltransferase 5 (KAT5)-mediated K395 acetylation of the platelet isoform of phosphofructokinase 1 (PFKP) and subsequent translocation of PFKP to the plasma membrane, where the PFKP was phosphorylated at Y64 by EGFR. Phosphorylated PFKP binds to the N-terminal SH2 domain of p85α, which is distinct from binding of Gab1 to the C-terminal SH2 domain of p85α, and recruited p85α to the plasma membrane resulting in PI3K activation. PI3K-dependent AKT activation results in enhanced phosphofructokinase 2 (PFK2) phosphorylation and production of fructose-2,6-bisphosphate, which in turn promotes PFK1 activation. PFKP Y64 phosphorylation-enhanced PI3K/AKT-dependent PFK1 activation and GLUT1 expression promoted the Warburg effect, tumor cell proliferation, and brain tumorigenesis. These findings underscore the instrumental role of PFKP in PI3K activation and enhanced glycolysis through PI3K/AKT-dependent positive-feedback regulation.

PD-L1 up-regulation in cancer contributes to immune evasion by tumor cells. Here, we show that Wnt ligand and activated EGFR induce the binding of the β-catenin/TCF/LEF complex to the CD274 gene promoter region to induce PD-L1 expression, in which AKT activation plays an important role. β-Catenin depletion, AKT inhibition, or PTEN expression reduces PD-L1 expression in tumor cells, enhances activation and tumor infiltration of CD8+ T cells, and reduces tumor growth, accompanied by prolonged mouse survival. Combined treatment with a clinically available AKT inhibitor and an anti–PD-1 antibody overcomes tumor immune evasion and greatly inhibits tumor growth. In addition, AKT-mediated β-catenin S552 phosphorylation and nuclear β-catenin are positively correlated with PD-L1 expression and inversely correlated with the tumor infiltration of CD8+ T cells in human glioblastoma specimens, highlighting the clinical significance of β-catenin activation in tumor immune evasion.

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Highlights d PGK1, functioning as a protein kinase, autophosphorylates itself at Y324 d PGK1 autophosphorylation enhances its glycolytic activity via promoting ATP release d PTEN, functioning as a protein phosphatase, dephosphorylates PGK1 pY324 d PGK1 Y324 autophosphorylation promotes brain tumor formation

Cancer cells often encounter oxidative stress. However, it is unclear whether normal and cancer cells differentially respond to oxidative stress. Here, we demonstrated that under oxidative stress, hepatocellular carcinoma (HCC) cells exhibit increased antioxidative response and survival rates compared to normal hepatocytes. Oxidative stimulation induces HCC-specifically expressed fructokinase A (KHK-A) phosphorylation at S80 by 5′-adenosine monophosphate-activated protein kinase. KHK-A in turn acts as a protein kinase to phosphorylate p62 at S28, thereby blocking p62 ubiquitination and enhancing p62’s aggregation with Keap1 and Nrf2 activation. Activated Nrf2 promotes expression of genes involved in reactive oxygen species reduction, cell survival, and HCC development in mice. In addition, phosphorylation of KHK-A S80 and p62 S28 and nuclear accumulation of Nrf2 are positively correlated in human HCC specimens and with poor prognosis of patients with HCC. These findings underscore the role of the protein kinase activity of KHK-A in antioxidative stress and HCC development.

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