Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation

Weiwei Yang, Yan Xia, Haitao Ji, Yanhua Zheng, Ji Liang, Wenhua Huang, Xiang Gao, Kenneth Aldape and Zhimin Lu ()
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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

Nature, 2011, vol. 480, issue 7375, 118-122

Abstract: 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.

Date: 2011
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DOI: 10.1038/nature10598

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