Stabilization of phosphofructokinase 1 platelet isoform by AKT promotes tumorigenesis

Jong-Ho Lee, Rui Liu, Jing Li, Chuanbao Zhang, Yugang Wang, Qingsong Cai, Xu Qian, Yan Xia, Yanhua Zheng, Yuji Piao, Qianming Chen, John F. Groot, Tao Jiang and Zhimin Lu ()
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Jong-Ho Lee: The University of Texas MD Anderson Cancer Center
Rui Liu: The University of Texas MD Anderson Cancer Center
Jing Li: The University of Texas MD Anderson Cancer Center
Chuanbao Zhang: Capital Medical University
Yugang Wang: The University of Texas MD Anderson Cancer Center
Qingsong Cai: The University of Texas MD Anderson Cancer Center
Xu Qian: The University of Texas MD Anderson Cancer Center
Yan Xia: The University of Texas MD Anderson Cancer Center
Yanhua Zheng: The University of Texas MD Anderson Cancer Center
Yuji Piao: The University of Texas MD Anderson Cancer Center
Qianming Chen: Sichuan University
John F. Groot: The University of Texas MD Anderson Cancer Center
Tao Jiang: Capital Medical University
Zhimin Lu: The University of Texas MD Anderson Cancer Center

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Phosphofructokinase 1 (PFK1) plays a critical role in glycolysis; however, its role and regulation in tumorigenesis are not well understood. Here, we demonstrate that PFK1 platelet isoform (PFKP) is the predominant PFK1 isoform in human glioblastoma cells and its expression correlates with total PFK activity. We show that PFKP is overexpressed in human glioblastoma specimens due to an increased stability, which is induced by AKT activation resulting from phosphatase and tensin homologue (PTEN) loss and EGFR-dependent PI3K activation. AKT binds to and phosphorylates PFKP at S386, and this phosphorylation inhibits the binding of TRIM21 E3 ligase to PFKP and the subsequent TRIM21-mediated polyubiquitylation and degradation of PFKP. PFKP S386 phosphorylation increases PFKP expression and promotes aerobic glycolysis, cell proliferation, and brain tumor growth. In addition, S386 phosphorylation in human glioblastoma specimens positively correlates with PFKP expression, AKT S473 phosphorylation, and poor prognosis. These findings underscore the potential role and regulation of PFKP in human glioblastoma development.

Date: 2017
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DOI: 10.1038/s41467-017-00906-9

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