Tyrosine phosphorylation activates 6-phosphogluconate dehydrogenase and promotes tumor growth and radiation resistance
Tyrosine phosphorylation activates 6-phosphogluconate dehydrogenase and promotes tumor growth and radiation resistance
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DOI：
10.1038/s41467-019-08921-8
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发表时间：
2019-03-01
影响因子：
16.6
通讯作者：
Yang, Weiwei
中科院分区：
文献类型：
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作者：
Liu, Ruilong;Li, Wenfeng;Yang, Weiwei
6-磷酸葡萄糖酸脱氢酶（6PGD）是戊糖磷酸途径（PPP）中的一个关键酶，它与NADP（+）一起将6-磷酸葡萄糖酸转化为5-磷酸核酮糖。6PGD通常被上调并且在许多人类癌症中起重要作用，而6PGD的这种作用的潜在机制仍然难以捉摸。在这里，我们表明，在EGFR激活，6PGD是磷酸化酪氨酸（Y）481的Src家族激酶Fyn。这种磷酸化通过增加其与NADP（+）的结合亲和力来增强6PGD活性，因此激活NADPH和核糖-5-磷酸的PPP，从而使细胞内活性氧（ROS）解毒并加速DNA合成。消除6PGD Y 481磷酸化（pY 481）显著减弱EGF促进的神经胶质瘤细胞增殖、肿瘤生长和对电离辐射的抗性。此外，6PGD pY 481与Fyn表达、人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促进的肿瘤生长和辐射抗性中的关键作用。
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.