@article{9f3a1ecd19b34f79822903c89075d4c2,
title = "EGFR-Phosphorylated Platelet Isoform of Phosphofructokinase 1 Promotes PI3K Activation",
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.",
keywords = "EGFR, PFKP, PI3K, phosphorylation, the Warburg effect",
author = "Lee, {Jong Ho} and Rui Liu and Jing Li and Yugang Wang and Lin Tan and Li, {Xin Jian} and Xu Qian and Chuanbao Zhang and Yan Xia and Daqian Xu and Wei Guo and Zhiyong Ding and Linyong Du and Yanhua Zheng and Qianming Chen and Lorenzi, {Philip L.} and Mills, {Gordon B.} and Tao Jiang and Zhimin Lu",
note = "Funding Information: We thank Tamara Locke in the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for critically reading this manuscript and Dr. Li Li (Mass Spectrometry Specialist) at The University of Texas Health Center at Houston for technical assistance. This work was supported by National Cancer Institute grants 2R01 CA109035 (Z.L.) and 1R0 CA169603 (Z.L.), National Institute of Neurological Disorders and Stroke grant 1R01 NS089754 (Z.L.), NIH/NCI award numbers P30CA016672 and 1S10OD012304-01 , and 2P50 CA127001 (Brain Cancer SPORE), as well as by a Cancer Prevention Research Institute of Texas (CPRIT) Core Facility Award RP130397 (P.L.) and a Sister Institution Network Fund from MD Anderson (Z.L.). Z.L. is a Ruby E. Rutherford Distinguished Professor. Funding Information: We thank Tamara Locke in the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for critically reading this manuscript and Dr. Li Li (Mass Spectrometry Specialist) at The University of Texas Health Center at Houston for technical assistance. This work was supported by National Cancer Institute grants 2R01 CA109035 (Z.L.) and 1R0 CA169603 (Z.L.), National Institute of Neurological Disorders and Stroke grant 1R01 NS089754 (Z.L.), NIH/NCI award numbers P30CA016672 and 1S10OD012304-01, and 2P50 CA127001 (Brain Cancer SPORE), as well as by a Cancer Prevention Research Institute of Texas (CPRIT) Core Facility Award RP130397 (P.L.) and a Sister Institution Network Fund from MD Anderson (Z.L.). Z.L. is a Ruby E. Rutherford Distinguished Professor. Publisher Copyright: {\textcopyright} 2018",
year = "2018",
month = apr,
day = "19",
doi = "10.1016/j.molcel.2018.03.018",
language = "English (US)",
volume = "70",
pages = "197--210.e7",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "2",
}