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

Abstract

Summary Pyruvate kinase isoform M2 (PKM2) is a glycolysis enzyme catalyzing conversion of phosphoenolpyruvate (PEP) to pyruvate with 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 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 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.

JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α–mediated glucose metabolism

“…Additionally, size-exclusion chromatographic analysis of various combinations of purified recombinant proteins [PKM2/ R399E, a dimeric mutant (15); and/or JMJD5/ JMJD5ΔN80 (a binding-defective mutant)] clearly demonstrates that the tetrameric formation of PKM2 is hindered by JMJD5 but not JMJD5ΔN80, confirming that JMJD5 influences the PKM2 oligomerization via a direct binding (Fig. S6).…”

“…19). Gao et al recently showed that the nuclear PKM2 was mainly present as a dimer (15). Notably, Yang et al (18) found that PKM2 was phosphorylated at the segment involved in multimeric assembly by Erk2, implicating that the monomeric form is crucial for the phosphorylation of PKM2 and its nuclear translocation.…”

“…This was carried out principally by posttranslational modifications: Y105 phosphorylation by FGFR1 (9, 10), K305 acetylation in the presence of high-glucose concentrations (11), and C358 oxidation upon elevated reactive oxygen species levels (12). However, another way of modulating cytosolic PKM2 activity is its translocation into nucleus, where it serves as a transcriptional coactivator (13,14) or as a phosphotransferase (15) to modulate transcriptional program. Thus, PKM2 is found to function as a coactivator for Oct4, β-catenin, Stat3, and hypoxia-inducible factor (HIF)-1α (13)(14)(15)(16).…”

“…However, another way of modulating cytosolic PKM2 activity is its translocation into nucleus, where it serves as a transcriptional coactivator (13,14) or as a phosphotransferase (15) to modulate transcriptional program. Thus, PKM2 is found to function as a coactivator for Oct4, β-catenin, Stat3, and hypoxia-inducible factor (HIF)-1α (13)(14)(15)(16). PKM2 interacts with Oct4 to increase Oct4-mediated transactivation potential (16).…”

PKM2 Regulates Hepatocellular Carcinoma Cell Epithelial-mesenchymal Transition and Migration upon EGFR Activation

“…This reason may be that different dosages and treating time of have different effects on the proliferation of some cell lines, PKM2 is a key glycolytic enzyme that regulates the Warburg effect and is necessary for tumor growth (Wong et al, 2013). Recent studies indicated that nuclear PKM2 could activate gene transcription and cell proliferation in human glioblastoma, prostate cancer and breast cancer cells (Gao et al, 2012;Lee et al, 2008;Luo et al, 2011a;Luo et al, 2011b). Here we observed its role in EGFinduced EMT and cell motility in HCC cells.…”