EGFR-Phosphorylated Platelet Isoform of Phosphofructokinase 1 Promotes PI3K Activation

Jong Ho Lee, Rui Liu, Jing Li, Yugang Wang, Lin Tan, Xin Jian Li, Xu Qian, Chuanbao Zhang, Yan Xia, Daqian Xu, Wei Guo, Zhiyong Ding, Linyong Du, Yanhua Zheng, Qianming Chen, Philip L. Lorenzi, Gordon B. Mills, Tao Jiang, Zhimin Lu

    Research output: Contribution to journalArticle

    18 Scopus citations

    Abstract

    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. Lee et al. demonstrate that KAT5-mediated PFKP acetylation and subsequent EGFR-phosphorylated PFKP bind to the N-terminal SH2 domain of p85α to activate PI3K, leading to enhanced AKT-dependent PFK2 activation, F-2,6-BP-production-dependent PFK1 activation, and GLUT1 expression. Non-metabolic function of PFKP promotes the Warburg effect through PI3K/AKT-dependent positive-feedback regulation.

    Original languageEnglish (US)
    Pages (from-to)197-210.e7
    JournalMolecular Cell
    Volume70
    Issue number2
    DOIs
    StatePublished - Apr 19 2018

    Keywords

    • EGFR
    • PFKP
    • PI3K
    • phosphorylation
    • the Warburg effect

    ASJC Scopus subject areas

    • Molecular Biology
    • Cell Biology

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  • Cite this

    Lee, J. H., Liu, R., Li, J., Wang, Y., Tan, L., Li, X. J., Qian, X., Zhang, C., Xia, Y., Xu, D., Guo, W., Ding, Z., Du, L., Zheng, Y., Chen, Q., Lorenzi, P. L., Mills, G. B., Jiang, T., & Lu, Z. (2018). EGFR-Phosphorylated Platelet Isoform of Phosphofructokinase 1 Promotes PI3K Activation. Molecular Cell, 70(2), 197-210.e7. https://doi.org/10.1016/j.molcel.2018.03.018