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

By Xueliang Gao, Haizhen Wang, Jenny J. Yang, Xiaowei Liu, Zhiren Liu. Molecules and Cells, 2012

751 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7cd0cacd1a3b01a02b9907773dcff983422661ca

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Citations in the corpus

SIRT5-Mediated Lysine Desuccinylation Impacts Diverse Metabolic Pathways (2013, background): “Recent studies identified additional functional roles in the nucleus as a protein kinase regulating histone H3 and STAT3 phosphorylation (Gao et al., 2012; Yang et al., 2012).”
Metabolic control of cell death (2014, background): “P A A uthor M anuscript approach identified MCL-1 as a target for the chemotherapy-enhancing effects of the TORC1 inhibitor rapamycin (47) As glucose uptake by plasma membrane transporters relies on growth factor receptor signaling, the withdrawal of growth factors also promotes apoptosis (48).”
Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages (2015, positive): “Other nuclear functions of dimeric PKM2 includes the ability to act as a protein kinase, activating transcription of mek5 through phosphorylation of STAT3(Gao et al., 2012) as well as promoting β-catenin translocation, leading to expression of cyclinD1 and c-myc(Yang et al., 2011).”
Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013, background): “Of particular interest to immunologists is that PKM2 can phosphorylate signal transducer and activator of transcription 3 (STAT3) at Tyr(705), promoting increased STAT3-dependent transcription (63).”
Structure and dynamics of molecular networks: A novel paradigm of drug discovery: A comprehensive review (2012, background): “…of cancer-specific metabolism, such as the PKM2 isoenzyme of pyruvate kinase playing a predominant role in the Warburg-effect (Warburg, 1956; Steták et al., 2007; Christofk et al., 2008; Kung et al., 2012), were also shown to play a direct role in cancer-specific signaling (Gao et al., 2012).”
HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations. (2013, positive): “Finally, PKM2 functions as a protein kinase that phosphorylates STAT3, thereby increasing its transcriptional activity (76).”
Signal transduction in cancer. (2015, neutral): “PKM2 can also enter the nucleus and play a role in gene expression (Luo et al. 2011; Gao et al. 2012).”
PKM2 Phosphorylates Histone H3 and Promotes Gene Transcription and Tumorigenesis (2012, positive): “Given that PKM2 phosphorylates Stat3 at Y705 (to activate transcription of MEK5) (Gao et al., 2012) and histone H3 at T11, EGFR activation results in nuclear translocation of PKM2 that binds to gene promoter regions, where PKM2 phosphorylates H3-T11, leading to HDAC3 disassociation from the promoter”
Cancer Cell Metabolism: One Hallmark, Many Faces (2012, background): “protein kinase that catalyzes phosphorylation of the STAT3 transcription factor, subsequently leading to the elevated expression of cancer-relevant genes such as MEK5 (144).”