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      ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect

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          SUMMARY

          Pyruvate kinase M2 (PKM2) is upregulated in multiple cancer types and contributes to the Warburg effect by unclarified mechanisms. Here we demonstrate that EGFR-activated ERK2 binds directly to PKM2 I429/L431 via the ERK2 docking groove and phosphorylates PKM2 Ser37 but not PKM1. Phosphorylated PKM2 Ser37 recruits PIN1 for cis-trans isomerization of PKM2, which leads to PKM2 binding to importin α5 and nuclear translocation. Nuclear PKM2, acting as a coactivator of β-catenin, induces c-Myc expression, resulting in the upregulation of GLUT1, LDHA, and, in a positive feedback loop, PTB-dependent PKM2 expression. Replacement of wild type PKM2 with a nuclear translocation-deficient mutant (S37A) blocks the EGFR-promoted Warburg effect and brain tumor development. In addition, levels of PKM2 S37 phosphorylation correlate with EGFR and ERK1/2 activity in human glioblastoma specimens. Our findings highlight the importance of nuclear functions of PKM2 in the Warburg effect and tumorigenesis.

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          Most cited references29

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          Understanding the Warburg effect: the metabolic requirements of cell proliferation.

          In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed "the Warburg effect." Aerobic glycolysis is an inefficient way to generate adenosine 5'-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.
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            On the origin of cancer cells.

            O WARBURG (1956)
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              On the Origin of Cancer Cells

              O WARBURG (1956)
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                Author and article information

                Journal
                100890575
                21417
                Nat Cell Biol
                Nat. Cell Biol.
                Nature cell biology
                1465-7392
                1476-4679
                5 November 2012
                25 November 2012
                December 2012
                01 June 2013
                : 14
                : 12
                : 1295-1304
                Affiliations
                [1 ]Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
                [2 ]Department of Biochemistry and Molecular Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
                [3 ]Nanomedicine Center, Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai 201210, CHINA
                [4 ]Division of Signal Transduction, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
                [5 ]Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
                [6 ]Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
                [7 ]Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
                [8 ]The Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA
                Author notes
                [* ]Correspondence should be address to Z.L. ( zhiminlu@ 123456mdanderson.org )
                Article
                NIHMS417383
                10.1038/ncb2629
                3511602
                23178880
                7360d954-4f70-4106-9b8a-8a2bdb23b415

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                History
                Funding
                Funded by: National Cancer Institute : NCI
                Award ID: R01 CA109035 || CA
                Categories
                Article

                Cell biology
                Cell biology

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