2. Academic Validation
  3. 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

  • Nat Commun. 2019 Mar 1;10(1):991. doi: 10.1038/s41467-019-08921-8.
Ruilong Liu 1 2,  Wenfeng Li 3,  Bangbao Tao 4,  Xiongjun Wang 5,  Zhuo Yang 6,  Yajuan Zhang 1 2,  Chenyao Wang 7,  Rongzhi Liu 8,  Hong Gao 1 2,  Ji Liang 1 2,  Weiwei Yang 9 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 200031, Shanghai, China.
  • 2 Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 200031, Shanghai, China.
  • 3 Department of Radiation Oncology, First Affiliated Hospital of Wenzhou Medical College, Wenzhou, 325000, Zhejiang, China.
  • 4 Department of Neurosurgery, XinHua Hospital School of Medicine, Shanghai Jiaotong University, 200092, Shanghai, China.
  • 5 Precise Genome Engineering Center, School of Life Sciences, Guangzhou University, 510006, Guangzhou, China.
  • 6 Chemical Biology Core Facility, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031, Shanghai, China.
  • 7 Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, 441195, USA.
  • 8 Center for Medical Device Evaluation, China Drug Administration, State Administration for Market Regulation, 100081, Beijing, China.
  • 9 State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 200031, Shanghai, China. wyang@sibcb.ac.cn.
  • 10 Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 200031, Shanghai, China. wyang@sibcb.ac.cn.
PMID: 30824700 DOI: 10.1038/s41467-019-08921-8
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.

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