2. Academic Validation
  3. TRIM21 and PHLDA3 negatively regulate the crosstalk between the PI3K/AKT pathway and PPP metabolism

TRIM21 and PHLDA3 negatively regulate the crosstalk between the PI3K/AKT pathway and PPP metabolism

  • Nat Commun. 2020 Apr 20;11(1):1880. doi: 10.1038/s41467-020-15819-3.
Jie Cheng 1,  Yan Huang  # 1,  Xiaohui Zhang  # 2,  Yue Yu 2,  Shumin Wu 3,  Jing Jiao 3,  Linh Tran 3,  Wanru Zhang 1,  Ran Liu 1,  Liuzhen Zhang 1,  Mei Wang 1,  Mengyao Wang 1,  Wenyu Yan 1,  Yilin Wu 1,  Fangtao Chi 4,  Peng Jiang 5,  Xinxiang Zhang 2,  Hong Wu 6 7
Affiliations

Affiliations

  • 1 The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Beijing Advanced Innovation Center for Genomics, Peking University, Beijing, 100871, China.
  • 2 Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China.
  • 3 Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • 4 Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
  • 5 School of Life Sciences, Tsinghua University, Beijing, 100084, China.
  • 6 The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Beijing Advanced Innovation Center for Genomics, Peking University, Beijing, 100871, China. hongwu@pku.edu.cn.
  • 7 Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, 90095, USA. hongwu@pku.edu.cn.
  • # Contributed equally.
PMID: 32312982 DOI: 10.1038/s41467-020-15819-3
Abstract

PI3K/Akt signaling is known to regulate Cancer metabolism, but whether metabolic feedback regulates the PI3K/Akt pathway is unclear. Here, we demonstrate the important reciprocal crosstalk between the PI3K/Akt signal and pentose phosphate pathway (PPP) branching metabolic pathways. PI3K/Akt activation stabilizes G6PD, the rate-limiting Enzyme of the PPP, by inhibiting the newly identified E3 Ligase TIRM21 and promotes the PPP. PPP metabolites, in turn, reinforce Akt activation and further promote Cancer metabolic reprogramming by blocking the expression of the Akt Inhibitor PHLDA3. Knockout of TRIM21 or PHLDA3 promotes crosstalk and cell proliferation. Importantly, PTEN null human Cancer cells and in vivo murine models are sensitive to anti-PPP treatments, suggesting the importance of the PPP in maintaining Akt activation even in the presence of a constitutively activated PI3K pathway. Our study suggests that blockade of this reciprocal crosstalk mechanism may have a therapeutic benefit for cancers with PTEN loss or PI3K/Akt activation.

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