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

Yang, Weiwei; Zheng, Yanhua; Xia, Yan; Ji, Haitao; Chen, Xiaomin; Guo, Fang; Lyssiotis, Costas A.; Aldape, Kenneth; Cantley, Lewis C.; Lu, Zhimin

doi:10.1038/ncb2629

Cited by 738 publications

(797 citation statements)

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“…The physical association of JMJD5 with PKM2 seems to be a dominant factor. In support of this notion, Yang et al (18) showed that the intersubunit segment of PKM2 was phosphorylated by Erk2, facilitating its translocation into the nucleus. These results together suggest a mechanism whereby PKM2 can be regulated by JMJD5 binding-induced nuclear translocation.…”

Section: Discussionmentioning

confidence: 93%

“…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. Thus, disruption of the tetrameric form is likely to be the key to translocate PKM2 into the nucleus.…”

Section: Jmjd5 Knockdown Reduces Cell Growth and Glycolytic Genes Inmentioning

confidence: 99%

“…Thus, both cytosolic and nuclear PKM2 contribute to altered metabolism and proliferation in cancer. The mechanisms associated with PKM2 translocation are multiple, including phosphorylation by ERK1 at S37 (18) and hydroxylation by PHD3 at P403 and P408 (14). The latter allows PKM2 to bind HIF-1α and hypoxia response elements (HREs) to regulate metabolic gene transcription and promote tumorigenesis under hypoxic conditions.…”

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confidence: 99%

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

Wang

Hsieh

Cheng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

255

220

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JMJD5, a Jumonji C domain-containing dioxygenase, is important for embryonic development and cancer growth. Here, we show that JMJD5 is up-regulated by hypoxia and is crucial for hypoxiainduced cell proliferation. JMJD5 interacts directly with pyruvate kinase muscle isozyme (PKM)2 to modulate metabolic flux in cancer cells. The JMJD5-PKM2 interaction resides at the intersubunit interface region of PKM2, which hinders PKM2 tetramerization and blocks pyruvate kinase activity. This interaction also influences translocation of PKM2 into the nucleus and promotes hypoxiainducible factor (HIF)-1α-mediated transactivation. JMJD5 knockdown inhibits the transcription of the PKM2-HIF-1α target genes involved in glucose metabolism, resulting in a reduction of glucose uptake and lactate secretion in cancer cells. JMJD5, along with PKM2 and HIF-1α, is recruited to the hypoxia response element site in the lactate dehydrogenase A and PKM2 loci and mediates the recruitment of the latter two proteins. Our data uncover a mechanism whereby PKM2 can be regulated by factor-bindinginduced homo/heterooligomeric restructuring, paving the way to cell metabolic reprogram.Warburg effect | aerobic glycolysis | breast cancer | cancer metabolism J MJD5 is a Jumonji C domain-containing dioxygenase shown to be involved in lysine demethylation (1-3) and hydroxylation functions (4). Although the exact cellular substrates and functions of JMJD5 remain unclear, JMJD5 was shown to positively regulate cyclin A1 but negatively regulate p53 and p21 (1-3). Knockdown of JMJD5 in Michigan Cancer Foundation (MCF)-7 cells inhibits cell proliferation (1), and JMJD5 −/− embryos showed severe growth retardation, resulting in embryonic lethality at the midgestation stage (3). These data, together with its general overexpression in tumor tissues, implicate a role of JMJD5 in carcinogenesis. In this paper, we define a role of JMJD5 in regulating tumor metabolism under normoxic and hypoxic conditions through its interaction with pyruvate kinase muscle isozyme (PKM)2.One of the hallmarks of cancer cells is their altered metabolism, referred to as aerobic glycolysis, or the Warburg effect (5). This generally involves an increased uptake of glucose, use of intracellular glucose to pyruvate via glycolysis, and the conversion into lactate in the presence of sufficient oxygen. Along this metabolic flux, PKM1 or its spliced variant, PKM2, which dephosphorylates phosphoenolpyruvate (PEP) into pyruvate, the last step of glycolysis, is an important signal integrator whose activities determine the cytosolic level of pyruvate, thereby affecting subsequent metabolic flow to lactate, tricarboxylic acid cycle or biosynthetic pathway (6). Enzymatically, PKM2, an embryonic isoform found abundantly in tumor cells, is less active than PKM1, which allows the accumulation of glycolytic intermediates and diversion into biosynthetic pathways, demanded by rapid-proliferating cells.As a pivotal regulator of tumor metabolism, PKM2's activity is further modulated by allosteric regulation vi...

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Section: Discussionmentioning

confidence: 93%

Section: Jmjd5 Knockdown Reduces Cell Growth and Glycolytic Genes Inmentioning

confidence: 99%

mentioning

confidence: 99%

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

Wang

Hsieh

Cheng

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

255

220

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“…Intriguingly, the dimeric form of PKM2 which predominantly exists in cancer cells is also be reported to bias the protein kinase function toward stat3 (6). Moreover, recent studies showed that PKM2 can function as a coactivator of hypoxia-inducible factor-1␣ (HIF-1␣) and ␤-catenin under hypoxia or EGF treatment (10,11). These data indicate that PKM2 plays an important role in promoting tumor development through regulating gene transcriptions.…”

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confidence: 96%

A Novel Role for Pyruvate Kinase M2 as a Corepressor for P53 during the DNA Damage Response in Human Tumor Cells

Wang

et al. 2016

Journal of Biological Chemistry

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Edited by Patrick SungThe pyruvate kinase (PK) is a rate-limiting glycolytic enzyme catalyzing the dephosphorylation of phosphoenolpyruvate to pyruvate, yielding one molecule of ATP. The M2 isoform of PK (PKM2) is predominantly expressed in normal proliferating cells and tumors, and both metabolic and non-metabolic activities for the enzyme in promoting tumor cell proliferation have been identified. However, the exact roles of PKM2 in tumor initiation, growth and maintenance are not yet fully understood. Using immunoprecipitation-coupled LC-MS/MS in MCF7 cells exposed to DNA-damaging agent, we report that the nuclear PKM2 interacts directly with P53 protein, a critical safeguard for genome stability. Specifically, PKM2 inhibits P53-dependent transactivation of the P21 gene by preventing P53 binding to the P21 promoter, leading to a nonstop G 1 phase. As a result, PKM2 expression provides a growth advantage for tumor cells in the presence of a DNA damage stimulus. In addition, PKM2 interferes with phosphorylation of P53 at serine 15, known to stimulate P53 activity by the ATM serine/threonine kinase. These findings reveal a new role for PKM2 in modulating the DNA damage response and illustrate a novel mechanism of PKM2 participating in tumorigenesis.Pyruvate kinase (PK), 4 a rate-limiting enzyme of glycolysis, catalyzes the transfer of phosphate from phosphoenolpyruvate (PEP) to ADP, yielding one molecule of ATP and pyruvate. The PK consists of four isoforms, the PKLR gene-encoded PKL and PKR isoforms and the PKM gene-encoded M1 (PKM1) and M2 (PKM2) isoforms, which express in different types of mammalian cells and tissues. PKM1 constitutively forms stable tetramers (the active form of PK) and is expressed in normal adult tissues that require high levels of energy, such as the heart, brain, and skeletal muscle. In contrast, PKM2 exists in either tetramers or dimers with less activity and metabolic intermediate fructose-1,6-bisphosphate (FBP) can allosterically activate PKM2 by promoting the formation of tetramer from dimer (1, 2). PKM2 is selectively expressed in normal proliferating cells as well as tumor cells, indicating an indispensable role in cancer development.There are two known mechanisms by which PKM2 favors tumor cell growth, one dependent on and one independent of glycolysis. As a glycolytic enzyme, PKM2 in tumor cells shifts glucose metabolism from oxidative phosphorylation to glycolysis under normoxic conditions, a phenomenon termed the Warburg effect or aerobic glycolysis (3). On the other hand, non-metabolic function of PKM2, which is mainly associated with the nuclear PKM2, has been identified as a major contributor during tumorigenesis. For example, nuclear PKM2 displays kinase activity in phosphorylating a number of protein substrates, including histone H3 (4, 5), signal transducer and activator of transcription 3 (stat3) (6, 7), Bub3 (8), and myosin light chain 2 (MLC2) (9), for which PKM2 uses the high-energy phosphate from PEP but not ATP as a phosphate donor. The PKM2-induced phosphorylation...

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“…For example, the mammalian pyruvate kinase PKM2 is translocated to the nucleus when the EGF receptor is activated, where it phosphorylates histone H3 instead of its usual metabolic substrate (12). A second example is the yeast homocitrate synthase, encoded by the genes LYS20 and LYS21.…”

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confidence: 99%

Functions for diverse metabolic activities in heterochromatin

Xue

Pillus

2016

Proc. Natl. Acad. Sci. U.S.A.

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Growing evidence demonstrates that metabolism and chromatin dynamics are not separate processes but that they functionally intersect in many ways. For example, the lysine biosynthetic enzyme homocitrate synthase was recently shown to have unexpected functions in DNA damage repair, raising the question of whether other amino acid metabolic enzymes participate in chromatin regulation. Using an in silico screen combined with reporter assays, we discovered that a diverse range of metabolic enzymes function in heterochromatin regulation. Extended analysis of the glutamate dehydrogenase 1 (Gdh1) revealed that it regulates silent information regulator complex recruitment to telomeres and ribosomal DNA. Enhanced N-terminal histone H3 proteolysis is observed in GDH1 mutants, consistent with telomeric silencing defects. A conserved catalytic Asp residue is required for Gdh1's functions in telomeric silencing and H3 clipping. Genetic modulation of α-ketoglutarate levels demonstrates a key regulatory role for this metabolite in telomeric silencing. The metabolic activity of glutamate dehydrogenase thus has important and previously unsuspected roles in regulating chromatin-related processes.I n eukaryotic nuclei, DNA is wrapped around histones to form nucleosomes, the basic subunits of chromatin (1). The physical and chemical properties of chromatin are regulated by at least two types of enzymatic activities: chromatin remodeling and posttranslational modifications of histones and chromatin-associated proteins (2, 3). These enzymatic activities directly determine the accessibility of DNA for transcription, replication, and repair.In Saccharomyces cerevisiae, three genomic regions are known to contain loci repressed by chromatin-related activities. These include the HM silent mating-type loci (HMR and HML), regions within the ribosomal DNA (rDNA), and some telomeres. Transcriptional silencing at these loci is established and maintained by a number of factors, including the Sirtuin class III deacetylase activity of silent information protein 2 (Sir2). Notably, Sir2 uses NAD + as a cofactor to deacetylate histones H3 and H4 in newly deposited nucleosomes. Other than Sir2, the composition of the silencing complexes and the mechanisms of silencing are different for the three silenced regions, with the telomeres and the HM loci more similar to each other and the rDNA locus having distinct features (reviewed in ref. 4). Silencing at telomeres and the HM loci was long considered to follow a sequential model: initial deacetylation by Sir2 creates binding sites for Sir3 and Sir4, which in turn regulate the spreading of Sir2 across these regions (5). More recent high-resolution studies report a less uniform landscape for silenced chromatin (6), although the central importance of the Sir proteins remains clear. They, together with transcription factors including Rap1 and Abf1, form a multisubunit silencing complex known as the silent information regulator (SIR) complex. Silencing at the rDNA locus does not involve the SIR complex but ra...

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

Cited by 738 publications

References 28 publications

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

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

A Novel Role for Pyruvate Kinase M2 as a Corepressor for P53 during the DNA Damage Response in Human Tumor Cells

Functions for diverse metabolic activities in heterochromatin

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