Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, China.
Mol Cell. 2018 Apr 19;70(2):197-210.e7. 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.
表皮生长因子受体（EGFR）激活磷脂酰肌醇 3-激酶（PI3K），但这种激活的机制尚不完全清楚。我们在这里证明，EGFR 激活导致赖氨酸乙酰转移酶 5（KAT5）介导的磷酸果糖激酶 1 血小板同工型（PFKP）的 K395 乙酰化，随后 PFKP 易位到质膜，在质膜上 PFKP 被 EGFR 在 Y64 处磷酸化。磷酸化的 PFKP 与 p85α 的 N 端 SH2 结构域结合，与 Gab1 与 p85α 的 C 端 SH2 结构域结合不同，招募 p85α 到质膜导致 PI3K 激活。PI3K 依赖性 AKT 激活导致磷酸果糖激酶 2（PFK2）磷酸化增强和果糖-2,6-二磷酸的产生，这反过来又促进 PFK1 激活。PFKP Y64 磷酸化增强的 PI3K/AKT 依赖性 PFK1 激活和 GLUT1 表达促进了沃伯格效应、肿瘤细胞增殖和脑肿瘤发生。这些发现强调了 PFKP 在 PI3K 激活和通过 PI3K/AKT 依赖性正反馈调节增强糖酵解中的重要作用。
