State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China.
Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan City, Taiwan.
Oncogene. 2021 Apr;40(14):2567-2580. doi: 10.1038/s41388-021-01673-0. Epub 2021 Mar 8.
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 its K value and increasing its K value 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.
葡萄糖-6-磷酸脱氢酶（G6PD）是磷酸戊糖途径（PPP）的第一个也是限速酶，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 的酪氨酸 112 残基相互作用并使其磷酸化。这种磷酸化通过显著降低 G6PD 的 K 值和增加其葡萄糖-6-磷酸底物 K 值，极大地增强了 G6PD 的催化活性。因此，激活的 G6PD 增加了 PPP 通量，为 NADPH 和核糖-5-磷酸的产生提供了所需的物质，这对于细胞内活性氧（ROS）的解毒和癌细胞的生物合成是必需的，最终有助于肿瘤发生。一致地，c-Src 的激活与临床结直肠癌样本中 G6PD 的酪氨酸磷酸化和活性密切相关。因此，我们揭示了 c-Src 在促进细胞增殖和肿瘤发生中的另一个方面，加深了我们对 c-Src 作为原癌基因的理解。
