TY - JOUR
T1 - Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation
AU - Yang, Weiwei
AU - Xia, Yan
AU - Ji, Haitao
AU - Zheng, Yanhua
AU - Liang, Ji
AU - Huang, Wenhua
AU - Gao, Xiang
AU - Aldape, Kenneth
AU - Lu, Zhimin
N1 - Funding Information:
Acknowledgements We thank T. Hunter (The Salk Institute for Biological Studies) for Abl and Src knockout cells, H. Clevers (Netherlands Institute for Developmental Biology) for the pTOP-FLASH and the pFOP-FLASH, and Y. Li (Baylor College of Medicine) for a WNT1 lenti-vector. This work was supported by National Cancer Institute grants 5R01CA109035 (Z.L.), 5 P50 CA127001-03 and CA16672 (Cancer Center Support Grant); a research grant (RP110252; Z.L.) from the Cancer Prevention and Research Institute of Texas (CPRIT), an American Cancer Society Research Scholar Award RSG-09-277-01-CSM (Z.L.), and a Sister Institution Network Fund from The University of Texas MD Anderson Cancer Center (Z.L.).
PY - 2011/12/1
Y1 - 2011/12/1
N2 - 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 effect, 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/Wingless and highlight the essential non-metabolic functions of PKM2 in EGFR-promoted β-catenin transactivation, cell proliferation and tumorigenesis.
AB - 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 effect, 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/Wingless and highlight the essential non-metabolic functions of PKM2 in EGFR-promoted β-catenin transactivation, cell proliferation and tumorigenesis.
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U2 - 10.1038/nature10598
DO - 10.1038/nature10598
M3 - Article
C2 - 22056988
AN - SCOPUS:82555170271
SN - 0028-0836
VL - 480
SP - 118
EP - 122
JO - Nature
JF - Nature
IS - 7375
ER -