机构：[1]Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA[2]State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China[3]Department of Bioinformatics and Computational Biology and The Proteomics and Metabolomics Core Facility, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA[4]Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China首都医科大学附属天坛医院[5]Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA[6]Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA[7]Cancer Biology Program, MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, The University of Texas, Houston, Texas 77030, USA
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.
Published by Elsevier Inc.
基金：
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.
第一作者机构：[1]Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
共同第一作者：
通讯作者：
通讯机构：[1]Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA[6]Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA[7]Cancer Biology Program, MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, The University of Texas, Houston, Texas 77030, USA
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