Article

Pyruvate Kinase M2 Regulates Gene Transcription by Acting as a Protein Kinase

Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
Molecular cell (Impact Factor: 14.02). 02/2012; 45(5):598-609. DOI: 10.1016/j.molcel.2012.01.001
Source: PubMed

ABSTRACT

Pyruvate kinase isoform M2 (PKM2) is a glycolysis enzyme catalyzing conversion of phosphoenolpyruvate (PEP) to pyruvate by transferring a phosphate from PEP to ADP. We report here that PKM2 localizes to the cell nucleus. The levels of nuclear PKM2 correlate with cell proliferation. PKM2 activates transcription of MEK5 by phosphorylating stat3 at Y705. In vitro phosphorylation assays show that PKM2 is a protein kinase using PEP as a phosphate donor. ADP competes with the protein substrate binding, indicating that the substrate may bind to the ADP site of PKM2. Our experiments suggest that PKM2 dimer is an active protein kinase, while the tetramer is an active pyruvate kinase. Expression of a PKM2 mutant that exists as a dimer promotes cell proliferation, indicating that protein kinase activity of PKM2 plays a role in promoting cell proliferation. Our study reveals an important link between metabolism alteration and gene expression during tumor transformation and progression.

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Available from: Xueliang Gao, Feb 03, 2015
    • "This is consistent with Hif1 being a known STAT3 target gene [11], and also demonstrates that STAT3 is sufficient to induce metabolic reprogramming in macrophages. Considering that un-phosphorylated STAT3 is continuously shuttling between the cytoplasm generating a nuclear reservoir of STAT3 available for activation [79], PKM2 mediated STAT3 activation could contribute to macrophage activation upon metabolic reprogramming [76] [80]. Because IL-6 is an external signal that induces phosphorylation of STAT3 [81], increased tissue IL-6 levels, as observed in chronic inflammatory conditions, and certain forms of fibrosis, and vascular remodeling associated with pulmonary hypertension [11] [82] [83] may be sufficient to promote metabolic reprogramming in tissue macrophages and thus initiate and maintain macrophage activation [11]. "
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    • "phosphorylated in response to growth factors, PKM2 may undergo a switch in both oligomerization state (from a tetramer to a dimer) and catalytic function (from its glycolytic role to a protein kinase), and affect transcription by phosphorylating both histones (e.g., T11 on histone H3, which promotes acetylation at K9, a modification that stimulates transcription) (Yang et al. 2012) and transcription factors (e.g., Y705 in STAT3, which promotes its dimerization and transactivator function) (Gao et al. 2012). "
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    • "For instance, the M2 isoform of pyruvate kinase (PKM2), which forms a tetramer in the cytosol, is the final key enzyme in aerobic glycolysis. However , PKM2 can translocate into the nucleus to act as a protein kinase in its dimeric form and phosphorylate signal transducer and activator of transcription 3 (Gao et al., 2012) or to directly interact with HIF1-a to promote downstream target transactivation (Luo et al., 2011). The possibilities of different subcellular localizations, conformations, and nonenzymatic functions of ME are worthy of further investigation. "
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