State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 200031, Shanghai, China.
Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 200031, Shanghai, China.
Nat Commun. 2019 Mar 1;10(1):991. doi: 10.1038/s41467-019-08921-8.
6-Phosphogluconate dehydrogenase (6PGD) is a key enzyme that converts 6-phosphogluconate into ribulose-5-phosphate with NADP as cofactor in the pentose phosphate pathway (PPP). 6PGD is commonly upregulated and plays important roles in many human cancers, while the mechanism underlying such roles of 6PGD remains elusive. Here we show that upon EGFR activation, 6PGD is phosphorylated at tyrosine (Y) 481 by Src family kinase Fyn. This phosphorylation enhances 6PGD activity by increasing its binding affinity to NADP and therefore activates the PPP for NADPH and ribose-5-phosphate, which consequently detoxifies intracellular reactive oxygen species (ROS) and accelerates DNA synthesis. Abrogating 6PGD Y481 phosphorylation (pY481) dramatically attenuates EGF-promoted glioma cell proliferation, tumor growth and resistance to ionizing radiation. In addition, 6PGD pY481 is associated with Fyn expression, the malignancy and prognosis of human glioblastoma. These findings establish a critical role of Fyn-dependent 6PGD phosphorylation in EGF-promoted tumor growth and radiation resistance.
6-磷酸葡萄糖酸脱氢酶（6PGD）是一种关键酶，它在戊糖磷酸途径（PPP）中以 NADP 为辅因子将 6-磷酸葡萄糖酸转化为核酮糖-5-磷酸。6PGD 在许多人类癌症中普遍上调并发挥重要作用，但其作用的机制尚不清楚。在这里，我们发现，在 EGFR 激活后，Src 家族激酶 Fyn 将 6PGD 磷酸化酪氨酸（Y）481 。这种磷酸化通过增加其与 NADP 的结合亲和力来增强 6PGD 的活性，从而激活 PPP 产生 NADPH 和核糖-5-磷酸，从而减少细胞内的活性氧（ROS）并加速 DNA 合成。消除 6PGD Y481 磷酸化（pY481）可显著抑制 EGF 促进的神经胶质瘤细胞增殖、肿瘤生长和对电离辐射的抵抗。此外，6PGD pY481 与 Fyn 表达、人类胶质母细胞瘤的恶性程度和预后相关。这些发现确立了 Fyn 依赖性 6PGD 磷酸化在 EGF 促进肿瘤生长和辐射抵抗中的关键作用。
