EGFR-Phosphorylated Platelet Isoform of Phosphofructokinase 1 Promotes PI3K Activation

• Published in: Molecular cell Vol. 70; no. 2; pp. 197 - 210.e7
• Main Authors: Lee, Jong-Ho, Liu, Rui, Li, Jing, Wang, Yugang, Tan, Lin, Li, Xin-Jian, Qian, Xu, Zhang, Chuanbao, Xia, Yan, Xu, Daqian, Guo, Wei, Ding, Zhiyong, Du, Linyong, Zheng, Yanhua, Chen, Qianming, Lorenzi, Philip L., Mills, Gordon B., Jiang, Tao, Lu, Zhimin
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.04.2018
• Subjects: 6-phosphofructo-2-kinase; Acetylation; acetyltransferases; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; brain; Brain Neoplasms - enzymology; Brain Neoplasms - genetics; Brain Neoplasms - pathology; carcinogenesis; Cell Line, Tumor; cell proliferation; Class Ia Phosphatidylinositol 3-Kinase; EGFR; Enzyme Activation; ErbB Receptors - genetics; ErbB Receptors - metabolism; Feedback, Physiological; Fructosediphosphates - metabolism; Glioblastoma - enzymology; Glioblastoma - genetics; Glioblastoma - pathology; Glucose Transporter Type 1 - genetics; Glucose Transporter Type 1 - metabolism; Glycolysis; Humans; lysine; Lysine Acetyltransferase 5 - genetics; Lysine Acetyltransferase 5 - metabolism; Male; Mice, Inbred BALB C; Mice, Nude; neoplasm cells; PFKP; phosphatidylinositol 3-kinase; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphofructokinase-1, Type C - genetics; Phosphofructokinase-1, Type C - metabolism; Phosphofructokinase-2 - genetics; Phosphofructokinase-2 - metabolism; Phosphorylation; PI3K; plasma membrane; Protein Binding; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; src Homology Domains; the Warburg effect; PI3K; the Warburg effect; phosphorylation; EGFR; PFKP
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2018.03.018

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. [Display omitted] •KAT5 acetylates PFKP at K395 and promotes the binding of PFKP to EGFR•EGFR-phosphorylated PFKP Y64 binds to p85α SH2 domain and activates PI3K•PFKP-activated AKT enhances GLUT1 expression and PFK2-mediated PFK1 activity•PFKP Y64 phosphorylation enhances the Warburg effect and tumorigenesis 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.