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


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.

Download full-text


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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Macrophages display a spectrum of functional activation phenotypes depending on the composition of the microenvironment they reside in, including type of tissue/organ and character of injurious challenge they are exposed to. Our understanding of how macrophage plasticity is regulated by the local microenvironment is still limited. Here we review and discuss the recent literature regarding the contribution of cellular metabolic pathways to the ability of the macrophage to sense the microenvironment and to alter its function. We propose that distinct alterations in the microenvironment induce a spectrum of inducible and reversible metabolic programs that might form the basis of the inducible and reversible spectrum of functional macrophage activation/polarization phenotypes. We highlight that metabolic pathways in the bidirectional communication between macrophages and stromals cells are an important component of chronic inflammatory conditions. Recent work demonstrates that inflammatory macrophage activation is tightly associated with metabolic reprogramming to aerobic glycolysis, an altered TCA cycle, and reduced mitochondrial respiration. We review cytosolic and mitochondrial mechanisms that promote initiation and maintenance of macrophage activation as they relate to increased aerobic glycolysis and highlight potential pathways through which anti-inflammatory IL-10 could promote macrophage deactivation. Finally, we propose that in addition to their role in energy generation and regulation of apoptosis, mitochondria reprogram their metabolism to also participate in regulating macrophage activation and plasticity.
    No preview · Article · Oct 2015 · Seminars in Immunology
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: SUMMARY We have come a long way in the 55 years since Edmond Fischer and the late Edwin Krebs discovered that the activity of glycogen phosphorylase is regulated by reversible protein phosphorylation. Many of the fundamental molecular mechanisms that operate in biological signaling have since been characterized and the vast web of interconnected pathways that make up the cellular signaling network has been mapped in considerable detail. Nonetheless, it is important to consider how fast this field is still moving and the issues at the current boundaries of our understanding. One must also appreciate what experimental strategies have allowed us to attain our present level of knowledge. We summarize here some key issues (both conceptual and methodological), raise unresolved questions, discuss potential pitfalls, and highlight areas in which our understanding is still rudimentary. We hope these wide-ranging ruminations will be useful to investigators who carry studies of signal transduction forward during the rest of the 21st century.
    Full-text · Article · Oct 2014 · Cold Spring Harbor perspectives in biology
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cutaneous melanoma is the most life-threatening neoplasm of the skin, accounting for most skin cancer deaths. Accumulating evidence suggests that targeting metabolism is an appealing strategy for melanoma therapy. Mitochondrial NAD(P)(+)-dependent malic enzyme (ME2), an oxidative decarboxylase, was evaluated for its biological significance in cutaneous melanoma progression. ME2 mRNA and protein expression significantly increased during melanoma progression, as evidenced by Gene Expression Omnibus (GEO) analysis and immunohistochemistry on clinically annotated tissue microarrays, respectively. In addition, ME2 knockdown attenuated melanoma cell proliferation in vitro. ME2 ablation resulted in reduced cellular ATP levels and elevated cellular ROS production, which activated the AMP-activated protein kinase (AMPK) pathway and inhibited acetyl-CoA carboxylase (ACC). Furthermore, ME2 expression was associated to cell migration and invasion. ME2 knockdown decreased anchorage-independent growth in vitro and tumor cell growth in vivo. These results suggested that ME2 might be an important factor in melanoma progression and a novel biomarker of invasion.Journal of Investigative Dermatology accepted article preview online, 09 September 2014. doi:10.1038/jid.2014.385.
    Full-text · Article · Sep 2014 · Journal of Investigative Dermatology
Show more