c-Src facilitates tumorigenesis by phosphorylating and activating G6PD
c-Src facilitates tumorigenesis by phosphorylating and activating G6PD
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c-Src 通过磷酸化和激活 G6PD 促进肿瘤发生
DOI：
10.1038/s41388-021-01673-0
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发表时间：
2021-03-08
期刊：
影响因子：
8
通讯作者：
Li, Qinxi
中科院分区：
文献类型：
--
作者：
Ma, Huanhuan;Zhang, Fengqiong;Li, Qinxi
葡萄糖-6-磷酸脱氢酶（Glucose-6-phosphate dehydrogenase, G6PD）是戊糖磷酸途径（pentose phosphate pathway， PPP）中的第一酶和限速酶，其过度激活被认为与肿瘤发生有关。在这里，我们发现酪氨酸激酶c-Src与G6PD在Tyr 112位点相互作用并磷酸化。这种磷酸化通过显著降低其skmvalue和增加底物葡萄糖-6-磷酸的skcatvalue来增强G6PD的催化活性。因此，激活的G6PD增加了NADPH和核糖-5-磷酸生产的PPP通量，这是细胞内活性氧（ROS）解毒和癌细胞生物合成所必需的，最终有助于肿瘤的发生。在临床结直肠癌样本中，c-Src活化与酪氨酸磷酸化和G6PD活性密切相关。因此，我们揭示了c-Src在促进细胞增殖和肿瘤发生方面的另一个方面，加深了我们对c-Src作为原癌基因的理解。
Glucose-6-phosphate dehydrogenase (G6PD) is the first and rate-limiting enzyme in pentose phosphate pathway (PPP), excessive activation of which has been considered to be involved in tumorigenesis. Here, we show that tyrosine kinase c-Src interacts with and phosphorylates G6PD at Tyr 112. This phosphorylation enhances catalytic activity of G6PD by dramatically decreasing itsKmvalue and increasing itsKcatvalue for substrate glucose-6-phosphate. Activated G6PD therefore augments the PPP flux for NADPH and ribose-5-phosphate production which is required for detoxification of intracellular reactive oxygen species (ROS) and biosynthesis of cancer cells, and eventually contributes to tumorigenesis. Consistently, c-Src activation is closely correlated with tyrosine phosphorylation and activity of G6PD in clinical colorectal cancer samples. We thus uncover another aspect of c-Src in promoting cell proliferation and tumorigenesis, deepening our understanding of c-Src as a proto-oncogene.