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c-Src facilitates tumorigenesis by phosphorylating and activating G6PD

Oncogene volume 40, pages 2567–2580 (2021)Cite this article

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Abstract

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 Km value and increasing its Kcat 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.

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Fig. 1: G6PD interacts with c-Src in vivo and in vitro.
Fig. 2: c-Src phosphorylates G6PD at Tyr112.
Fig. 3: c-Src phosphorylation of G6PD promotes its activity.
Fig. 4: c-Src activation of G6PD promotes NADPH and nucleotides synthesis.
Fig. 5: c-Src activation of G6PD promotes tumor growth.
Fig. 6: Expression levels and activities of c-Src and G6PD show clinical correlation.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China, China (U1705287 and 91857102) and the Open Research Fund of State Key Laboratory of Cellular Stress Biology, Xiamen University (SKLCSB2020KF002 and SKLCSB2019KF005).

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Author notes

  1. These authors contributed equally: Huanhuan Ma, Fengqiong Zhang

Authors and Affiliations

  1. State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China

    Huanhuan Ma, Fengqiong Zhang, Lin Zhou, Tingyan Cao, Dachao Sun, Shixiong Wen, Jinpei Zhu, Zhaoqianyu Xiong & Qinxi Li

  2. Metabolomics Core Laboratory, Healthy Aging Research Center, Chang Gung University, Taoyuan City, Taiwan

    Ming-Tong Tsau & Mei-Ling Cheng

  3. Clinical Metabolomics Core Laboratory, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan

    Mei-Ling Cheng

  4. Department and Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan

    Mei-Ling Cheng & Li-Man Hung

  5. Center for Healthy and Aging Research, Chang Gung University, Taoyuan City, Taiwan

    Li-Man Hung

  6. Kidney Research Center, Chang Gung Memorial Hospital, Taoyuan City, Taiwan

    Li-Man Hung

  7. Department of Hepatobiliary & Pancreatovascular Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China

    Yanming Zhou

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Contributions

HM and QL conceived the project. HM, FZ, LZ, TC, DS, SW, JZ, ZX, and MT performed experiments. LH, MT, MC, and YZ helped with data analysis and discussion. QL and HM wrote the manuscript. All authors commented on the manuscript.

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Correspondence to Qinxi Li.

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The authors declare that they have no conflict of interest.

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All animal experiments were carried out with the approval of Animal Care and Use Committee in Xiamen University (Ethics license, XMULAC20170330). The CRC specimens and surrounding nontumor colon tissues used in the current study were obtained from The First Affiliated Hospital of Xiamen University (Xiamen, China) with patient consent and institutional review board approval.

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Ma, H., Zhang, F., Zhou, L. et al. c-Src facilitates tumorigenesis by phosphorylating and activating G6PD. Oncogene 40, 2567–2580 (2021). https://doi.org/10.1038/s41388-021-01673-0

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