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Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation

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  • Weiwei Yang

    (The University of Texas MD Anderson Cancer Center)

  • Yan Xia

    (The University of Texas MD Anderson Cancer Center)

  • Haitao Ji

    (The University of Texas MD Anderson Cancer Center)

  • Yanhua Zheng

    (The University of Texas MD Anderson Cancer Center)

  • Ji Liang

    (The University of Texas MD Anderson Cancer Center)

  • Wenhua Huang

    (Jiaxing Xinda Biotechnology Company, 1369 Cheng Nan Road, Science and Technology Building, STE 112)

  • Xiang Gao

    (Model Animal Research Center, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University)

  • Kenneth Aldape

    (The University of Texas MD Anderson Cancer Center)

  • Zhimin Lu

    (The University of Texas MD Anderson Cancer Center
    The University of Texas MD Anderson Cancer Center
    The University of Texas Graduate School of Biomedical Sciences at Houston)

Abstract

The embryonic pyruvate kinase M2 (PKM2) isoform is highly expressed in human cancer. In contrast to the established role of PKM2 in aerobic glycolysis or the Warburg effect1,2,3, its non-metabolic functions remain elusive. Here we demonstrate, in human cancer cells, that epidermal growth factor receptor (EGFR) activation induces translocation of PKM2, but not PKM1, into the nucleus, where K433 of PKM2 binds to c-Src-phosphorylated Y333 of β-catenin. This interaction is required for both proteins to be recruited to the CCND1 promoter, leading to HDAC3 removal from the promoter, histone H3 acetylation and cyclin D1 expression. PKM2-dependent β-catenin transactivation is instrumental in EGFR-promoted tumour cell proliferation and brain tumour development. In addition, positive correlations have been identified between c-Src activity, β-catenin Y333 phosphorylation and PKM2 nuclear accumulation in human glioblastoma specimens. Furthermore, levels of β-catenin phosphorylation and nuclear PKM2 have been correlated with grades of glioma malignancy and prognosis. These findings reveal that EGF induces β-catenin transactivation via a mechanism distinct from that induced by Wnt/Wingless4 and highlight the essential non-metabolic functions of PKM2 in EGFR-promoted β-catenin transactivation, cell proliferation and tumorigenesis.

Suggested Citation

  • Weiwei Yang & Yan Xia & Haitao Ji & Yanhua Zheng & Ji Liang & Wenhua Huang & Xiang Gao & Kenneth Aldape & Zhimin Lu, 2011. "Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation," Nature, Nature, vol. 480(7375), pages 118-122, December.
    • Handle: RePEc:nat:nature:v:480:y:2011:i:7375:d:10.1038_nature10598
    DOI: 10.1038/nature10598
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    Cited by:

    1. Jianxiong Chen & Shiyu Duan & Yulu Wang & Yuping Ling & Xiaotao Hou & Sijing Zhang & Xunhua Liu & Xiaoli Long & Jiawen Lan & Miao Zhou & Huimeng Xu & Haoxuan Zheng & Jun Zhou, 2024. "MYG1 drives glycolysis and colorectal cancer development through nuclear-mitochondrial collaboration," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Ting Dong & Guangan Hu & Zhongqi Fan & Huirui Wang & Yinghui Gao & Sisi Wang & Hao Xu & Michael B. Yaffe & Matthew G. Vander Heiden & Guoyue Lv & Jianzhu Chen, 2024. "Activation of GPR3-β-arrestin2-PKM2 pathway in Kupffer cells stimulates glycolysis and inhibits obesity and liver pathogenesis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    3. Fabiola Diniz & Nguyen Yen Nhi Ngo & Mariel Colon-Leyva & Francesca Edgington-Giordano & Sylvia Hilliard & Kevin Zwezdaryk & Jiao Liu & Samir S. El-Dahr & Giovane G. Tortelote, 2023. "Acetyl-CoA is a key molecule for nephron progenitor cell pool maintenance," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    4. Yi Zhang & Mingjie Wang & Ling Ye & Shengqi Shen & Yuxi Zhang & Xiaoyu Qian & Tong Zhang & Mengqiu Yuan & Zijian Ye & Jin Cai & Xiang Meng & Shiqiao Qiu & Shengzhi Liu & Rui Liu & Weidong Jia & Xianzh, 2024. "HKDC1 promotes tumor immune evasion in hepatocellular carcinoma by coupling cytoskeleton to STAT1 activation and PD-L1 expression," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Stergios Tsartsalis & Hannah Sleven & Nurun Fancy & Frank Wessely & Amy M. Smith & Nanet Willumsen & To Ka Dorcas Cheung & Michal J. Rokicki & Vicky Chau & Eseoghene Ifie & Combiz Khozoie & Olaf Ansor, 2024. "A single nuclear transcriptomic characterisation of mechanisms responsible for impaired angiogenesis and blood-brain barrier function in Alzheimer’s disease," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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