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Tyrosine phosphorylation activates 6-phosphogluconate dehydrogenase and promotes tumor growth and radiation resistance

Author

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  • Ruilong Liu

    (University of Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Wenfeng Li

    (First Affiliated Hospital of Wenzhou Medical College)

  • Bangbao Tao

    (Shanghai Jiaotong University)

  • Xiongjun Wang

    (Guangzhou University)

  • Zhuo Yang

    (Chinese Academy of Sciences)

  • Yajuan Zhang

    (University of Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Chenyao Wang

    (Cleveland Clinic)

  • Rongzhi Liu

    (State Administration for Market Regulation)

  • Hong Gao

    (University of Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Ji Liang

    (University of Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Weiwei Yang

    (University of Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

Abstract

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.

Suggested Citation

  • Ruilong Liu & Wenfeng Li & Bangbao Tao & Xiongjun Wang & Zhuo Yang & Yajuan Zhang & Chenyao Wang & Rongzhi Liu & Hong Gao & Ji Liang & Weiwei Yang, 2019. "Tyrosine phosphorylation activates 6-phosphogluconate dehydrogenase and promotes tumor growth and radiation resistance," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08921-8
    DOI: 10.1038/s41467-019-08921-8
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