Cited by 1,397Immune cells in cancerCancer, Hypoxia, and MetabolismImmune Response and Inflammation

The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index; none of the 26 sources its claims cite is checked for support yet.

Pyruvate Kinase M2 Regulates Hif-1α Activity and IL-1β Induction and Is a Critical Determinant of the Warburg Effect in LPS-Activated Macrophages

Open access

Palsson-McDermott, Eva M., Curtis, Anne M., Goel, Gautam, Lauterbach, Mario A.R., Sheedy, Frederick J., Gleeson, Laura E., van den Bosch, Mirjam W.M., Quinn, Susan R., Domingo-Fernandez, Raquel, Johnston, Daniel G.W., Jiang, Jian-kang, Israelsen, William J., Keane, Joseph, Thomas, Craig, Clish, Clary, Vander Heiden, Matthew, Xavier, Ramnik J., O’Neill, Luke A.J.·2015·Cell Metabolism

DOI 10.1016/j.cmet.2014.12.005PMC PMC5198835

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Abstract

Macrophages activated by the TLR4 agonist LPS undergo dramatic changes in their metabolic activity. We here show that LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2). Activation of PKM2 using two well-characterized small molecules, DASA-58 and TEPP-46, inhibited LPS-induced Hif-1α and IL-1β, as well as the expression of a range of other Hif-1α-dependent genes. Activation of PKM2 attenuated an LPS-induced proinflammatory M1 macrophage phenotype while promoting traits typical of an M2 macrophage. We show that LPS-induced PKM2 enters into a complex with Hif-1α, which can directly bind to the IL-1β promoter, an event that is inhibited by activation of PKM2. Both compounds inhibited LPS-induced glycolytic reprogramming and succinate production. Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS and Salmonella typhimurium-induced IL-1β production, while boosting production of IL-10. PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response.

AI snapshot

Written from the paper’s full text.

TL;DR

LPS induces PKM2 in macrophages, where dimeric/monomeric PKM2 complexes with Hif-1α and binds the IL-1β promoter to promote Warburg-like glycolysis and pro-inflammatory activation. Forcing PKM2 into tetramers with DASA-58 or TEPP-46 inhibits Hif-1α activity, IL-1β induction, glycolytic reprogramming, and succinate accumulation, while shifting macrophages toward an M2-like/IL-10-high phenotype and impairing bacterial killing in vivo.

Key findings

LPS induced PKM2 expression and tyrosine 105 phosphorylation in BMDMs; Pkm2 mRNA increased approximately 2.8-fold after 24 hours, and phospho-PKM2 showed a 10.3-fold increase in relative band intensity, consistent with inactive monomer/dimer formation.
PKM2 activators DASA-58 and TEPP-46 promoted tetramerization, inhibited LPS-induced nuclear translocation of PKM2, and blocked LPS-induced Hif-1α protein, pro-IL-1β, Il1b mRNA, and the Hif-1α target Ldha, without affecting IL-6 or TNF.
LPS increased PKM2–Hif-1α association and binding of both to the IL-1β promoter; TEPP-46/DASA-58 inhibited this binding. PKM2 deletion reduced LPS-induced Hif-1α, Il1β, and Ldha, and reduced glycolysis, while increasing oxidative phosphorylation.
DASA-58 blocked LPS-induced succinate and glycolytic intermediates; LPS caused up to a ten-fold increase in glycolysis that was markedly inhibited by TEPP-46 and DASA-58. In vivo, TEPP-46 reduced LPS- and Salmonella typhimurium-induced IL-1β, boosted IL-10, and increased bacterial dissemination.

Methods

Primary BMDMs and peritoneal cells from C57BL/6 mice, RAW 264.7 macrophages, and conditional PKM2fl/fl BMDMs were treated with LPS, TEPP-46, DASA-58, tamoxifen, Mtb, or S. typhimurium.
Main assays included Western blotting, DSS crosslinking, size-exclusion chromatography, nuclear/cytosolic fractionation, ELISA, qPCR, co-immunoprecipitation, oligonucleotide pulldown, sequential ChIP, Seahorse extracellular flux analysis, microarray profiling, and LC-MS metabolomics.
In vivo models used LPS-induced sepsis and S. typhimurium infection in mice treated with TEPP-46 or vehicle, measuring serum cytokines, peritoneal cell IL-1β, and bacterial CFU in liver/spleen.

Limitations

The paper does not include a dedicated limitations section.
Limitations evident from the text: most mechanistic work uses mouse BMDMs/PECs and RAW cells; in vivo infection experiments use TEPP-46 only because DASA-58 is not pharmacokinetically validated in vivo; some data are not shown; and the mechanism by which PKM2 promotes IL-10 production is stated to require further analysis.
The Mtb ELISA results are described as means ± SEMs for one representative experiment with n=2, limiting statistical robustness.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.cmet.2014.12.005

Cites

38 of 38 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 26 cited sources checked · 0 supported · 0 flagged

A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Disuccinimidyl suberate (DSS) crosslinking of lysates from LPS treated BMDMs suggest that LPS induced PKM2 is primarily of a monomeric configuration (Figure 1B).”
- Also stated in: § Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs) · boosted
  “This is further supported by results from the cross-linking experiments shown in Figure 1B, where DSS cross-linked lysates from LPS treated BMDMs failed to reveal any high molecular weight PKM2 complexes.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
Load-bearingStrength:boosted· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, there is an increased binding of both PKM2 and Hif-1α to this promoter site in response to LPS (compare lane 2 to lane 1).”
- Also stated in: § LPS promotes binding of PKM2 and Hif-1α to the IL-1β promoter · plain
  “As seen in Figure 3C, LPS causes increased binding of endogenous Hif-1α to the IL-1β promoter (left panel), and interestingly after this sample was put through a second round of ChIP specific for PKM2 (right panel) we also see an increased binding of endogenous PKM2 to the same copy of DNA in response to LPS.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > LPS promotes binding of PKM2 and Hif-1α to the IL-1β promoter
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes

Show all 74 claims

It may state two separate claims as one. 51
Probably not a substantial claim. 9
The quote only partly states this claim. 1

A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We here show that LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2).”
- Also stated in: § Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs) · plain
  “LPS induced high levels of PKM2 in BMDMs up to 48 hours (Figure 1A).”
- Also stated in: § Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs) · boosted
  “LPS strongly induced Pkm2 mRNA expression (Figure 1C), with expression levels increasing approximately 2.8 fold after 24 hours of LPS.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > Abstract
Load-bearingStrength:boosted· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“LPS- induced expression of PKM2 causes concurrent phosphorylation of Tyrosine 105 to an extent comparable or greater to the increased expression levels.”
- Also stated in: § Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs) · plain
  “This phosphorylation is evident after just one hour, with the strongest induction after 48 hours (Figure 1A middle panel, 10.3 fold increase in relative band intensity).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“however as expected Pkm1 expression was compensatorily increased (Figure 5B).”
- Also stated in: § Isoform-specific deletion of PKM2 inhibits LPS-mediated activation of Hif-1α and expression of Hif-1α target genes in macrophages · plain
  “whereas PKM1 protein was upregulated following Tamoxifen and LPS-treatment compared to control (Figure 5C second panel).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Isoform-specific deletion of PKM2 inhibits LPS-mediated activation of Hif-1α and expression of Hif-1α target genes in macrophages
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
In the paper
“However, although as expected LPS causes a reduction on OCR in PKM2+/+ cells (Tannahill et al., 2013), the same inhibitory effect was still observed in BMDMs derived from PKM2−/− cells (data not shown).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Isoform-specific deletion of PKM2 inhibits LPS-mediated activation of Hif-1α and expression of Hif-1α target genes in macrophages
What the sources say
- Not checked yetcites Tannahill et al., 2013 source
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
In the paper
“We confirmed that LPS stimulation leads to accumulation of upstream glycolytic intermediates, such as G6P, FBP, DHAP and 2-PG, and TCA cycle intermediates including succinate (Tannahill et al., 2013).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
What the sources say
- Not checked yetcites Tannahill et al., 2013 source
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“This impairs the ability of the PKM2 and Hif-1α complex to bind to the Hif-1α motif in the promoter of the known Hif-1α target gene IL-1β (Peyssonnaux et al., 2007; Zhang et al., 2006), thereby inhibiting the transcriptional activity of Hif-1α and induction of IL-1β”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
What the sources say
- Not checked yetcites Peyssonnaux et al., 2007 source
- Not checked yetcites Zhang et al., 2006 source
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“In order to examine the functional relevance of PKM2 for LPS action we next examined the effect of two highly specific small-molecule PKM2 activators, TEPP-46 and DASA-58.”
- Also stated in: § Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs) · plain
  “They promote the formation of active PKM2 tetramers thereby boosting PKM2 enzymatic activity and limiting tumor growth in vivo (Anastasiou et al., 2012).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
What the sources say
- Not checked yetcites Anastasiou et al., 2012 source
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“Phosphorylation of PKM2 on Tyrosine 105 is indicative of monomer/dimer formation, as it prevents PKM2 tetramer configuration, further promoting the Warburg effect (Hitosugi et al., 2009).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
What the sources say
- Not checked yetcites Hitosugi et al., 2009 source
Load-bearingStrength:hedged· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“PKM2 has been shown to interact with Hif-1α and stimulate Hif-1α transactivation domain function and recruitment of p300 to the Hif Response Element (HRE) of Hif-1α target genes (Luo et al., 2011).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > LPS promotes binding of PKM2 and Hif-1α to the IL-1β promoter
What the sources say
- Not checked yetcites Luo et al., 2011 source
Load-bearingStrength:boosted· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response.”
- Also stated in: § INTRODUCTION · boosted
  “This event is required for macrophage activation by LPS and we identify PKM2 as a critical modulator of IL-1β production, macrophage polarization, glycolytic reprogramming and Warburg metabolism in LPS-activated macrophages.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > Abstract
Load-bearingStrength:boosted· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Current data indicates that PKM2, when highly expressed, exists in an equilibrium of enzymatically inactive pyruvate kinase dimers (or monomers) which can translocate into the nucleus(Christofk et al., 2008; Hitosugi et al., 2009), and enzymatically active tetramers which are retained in the cytosol(Mazurek et al., 2005).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
What the sources say
- Not checked yetcites Christofk et al., 2008 source
- Not checked yetcites Hitosugi et al., 2009 source
- Not checked yetcites Mazurek et al., 2005 source
Load-bearingStrength:hedged· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The pyruvate kinase activity of the tetramers can be regulated by the concentration of the naturally occurring upstream glycolytic intermediate FBP (Ashizawa et al., 1991; Jurica et al., 1998), serine (Chaneton et al., 2012), as well as by a multitude of post-translational modifications (Wu and Le, 2013) including tyrosine phosphorylation.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
What the sources say
- Not checked yetcites Ashizawa et al., 1991 source
- Not checked yetcites Jurica et al., 1998 source
- Not checked yetcites Chaneton et al., 2012 source
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
Probably not a substantial claim. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“As the main causative agent of tuberculosis, Mtb signals mainly through TLR 2, 6 and 9 (Bafica et al., 2005; Means et al., 1999).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Activation of PKM2 using TEPP-46 modulates the anti-Mycobacterium tuberculosis response of macrophages
What the sources say
- Not checked yetcites Bafica et al., 2005 source
- Not checked yetcites Means et al., 1999 source
Strength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“TEPP-46, but not DASA-58, is pharmacokinetically validated in vivo (Anastasiou et al., 2012).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Activation of PKM2 results in increased bacterial dissemination in a Salmonella typhimurium model of infection
What the sources say
- Not checked yetcites Anastasiou et al., 2012 source
Load-bearingStrength:plain· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“This event has been shown to be important for the Warburg effect in hypoxia and cancer(Hitosugi et al., 2009).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
What the sources say
- Not checked yetcites Hitosugi et al., 2009 source
Strength:boosted· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passes
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Activation of PKM2 also limits this response and this will lead to Hif-1α destabilization.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
- Rests on an assumption: Hif-1α is stabilized by succinate inhibiting PHDs.
In the paper
“These well-characterized and highly specific compounds bind PKM2, which then forms a tight tetramer with PKM1-like kinetic properties, an event that is resistant to inhibition by tyrosine phosphorylation.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
What the sources say
- Not checked yetcites Anastasiou et al., 2012 source
Load-bearingStrength:boosted· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one.
In the paper
“This could explain the increase in IL-10 production, which in the case of M2 macrophage activity may require mitochondrial oxidative metabolism (Krawczyk et al., 2010).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
What the sources say
- Not checked yetcites Krawczyk et al., 2010 source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Secondly, the decrease in succinate will further limit Hif-1α through stabilization and degradation.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
Load-bearingStrength:plain· not yet calibratedCausal:direct· not yet calibrated
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
It may state two separate claims as one. The quote only partly states this claim.
- Rests on an assumption: Hif-1α is stabilized by succinate inhibiting PHDs.

57 of 57

The paper relies on this without support.
There is only limited information on the precise molecular determinants of the profound metabolic change in LPS-activated macrophages.
“There is only limited information on the precise molecular determinants of this profound change in metabolism.”
The paper relies on this without support.
LPS-activated macrophages have a high demand for biosynthetic precursors and increased energy demand, and these events are required for the cells to respond to infection or tissue injury during inflammation.
“In macrophages activated with the TLR4 agonist LPS there is a high demand for biosynthetic precursors including proteins, lipids, and nucleic acids as well as increased energy demand. These events are required for the cells to respond to infection or tissue injury during inflammation.”
The paper relies on this without support.
PKM2 enters the nucleus as a dimer.
“Since previous reports have established that PKM2 enters the nucleus as a dimer, we then carried out further DSS cross-linking studies in order to support a model for nuclear exclusion of PKM2 following treatment with our small molecule activators.”
The paper relies on this without support.
Hif-1α is stabilized by succinate inhibiting PHDs.
“Hif-1α will also be stabilized by succinate inhibiting PHDs, providing further regulation of Hif-1α.”
The paper relies on this without support.
Mycobacterium tuberculosis utilizes TLR2, TLR6 and TLR9.
“This extended our observation beyond TLR4 and LPS to a bacterial pathogen that utilizes TLR2, TLR6 and TLR9.”

5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

Chromatography treatment is named TEPP-58 instead of TEPP-46
Minor
The methods name TEPP-58 for the size-exclusion experiment, while the results identify TEPP-46 as the treatment in that experiment.

1 of 1

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Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation
Yang, W., Xia, Y., Ji, H., Zheng, Y., Liang, J., Huang, W., Gao, X., Aldape, K., & Lu, Z. (2011) · Nature · doi:10.1038/nature10598 · Cited by 1,051 · cited 2×
“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).”
ERK1/2-dependent phosphorylation and nuclear translocation of PKM2 promotes the Warburg effect
Yang, W., Zheng, Y., Xia, Y., Ji, H., Chen, X., Guo, F., Lyssiotis, C. A., Aldape, K., Cantley, L. C., & Lu, Z. (2012) · Nature Cell Biology · doi:10.1038/ncb2629 · Cited by 926
Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis
Anastasiou, D., Yu, Y., Israelsen, W. J., Jiang, J.-K., Boxer, M. B., Hong, B. S., Tempel, W., Dimov, S., Shen, M., Jha, A., et al. (2012) · Nature Chemical Biology · doi:10.1038/nchembio.1060 · Cited by 816 · cited 12×
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript active PKM2 tetramers thereby boosting PKM2 enzymatic activity and limiting tumor growth in vivo (Anastasiou et al., 2012).”
InfluentialSelf-citation
Pyruvate kinase type M2 and its role in tumor growth and spreading
Mazurek, S., Boschek, C. B., Hugo, F., & Eigenbrodt, E. (2005) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2005.04.009 · Cited by 812 · cited 2×
“Numerous studies have reported a key role for PKM2 in aerobic glycolysis of tumors (Christofk et al., 2008; Mazurek et al., 2005; Tamada et al., 2012).”
Human Toll-Like Receptors Mediate Cellular Activation by Mycobacterium tuberculosis
Means, T. K., Wang, S., Lien, E., Yoshimura, A., Golenbock, D. T., & Fenton, M. J. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.163.7.3920 · Cited by 804 · cited 1×
“As the main causative agent of tuberculosis, Mtb signals mainly through TLR 2, 6 and 9 (Bafica et al., 2005; Means et al., 1999).”
Tyrosine Phosphorylation Inhibits PKM2 to Promote the Warburg Effect and Tumor Growth
Hitosugi, T., Kang, S., Vander Heiden, M. G., Chung, T.-W., Elf, S., Lythgoe, K., Dong, S., Lonial, S., Wang, X., Chen, G. Z., et al. (2009) · Science Signaling · doi:10.1126/scisignal.2000431 · Cited by 784 · cited 6×
“Current data indicates that PKM2, when highly expressed, exists in an equilibrium of enzymatically inactive pyruvate kinase dimers (or monomers) which can translocate into the nucleus(Christofk et al., 2008; Hitosugi et al., 2009), and enzymatically active tetramers Cell Metab.”
Influential
Pyruvate Kinase M2 Regulates Gene Transcription by Acting as a Protein Kinase
Gao, X., Wang, H., Yang, J. J., Liu, X., & Liu, Z.-R. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.01.001 · Cited by 772 · cited 2×
“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).”
Genes of glycolysis are ubiquitously overexpressed in 24 cancer classes
Altenberg, B., & Greulich, K. O. (2004) · Genomics · doi:10.1016/j.ygeno.2004.08.010 · Cited by 662 · cited 2×
“PKM2 on the other hand is upregulated in tumors (Altenberg and Greulich, 2004) and exists primarily as an enzymatically inactive monomer or dimer.”
Serine is a natural ligand and allosteric activator of pyruvate kinase M2
Chaneton, B., Hillmann, P., Zheng, L., Martin, A. C. L., Maddocks, O. D. K., Chokkathukalam, A., Coyle, J. E., Jankevics, A., Holding, F. P., Vousden, K. H., et al. (2012) · Nature · doi:10.1038/nature11540 · Cited by 661 · cited 6×
“, 1998), serine (Chaneton et al., 2012), as well as by a multitude of post-translational modifications (Wu and Le, 2013) including tyrosine phosphorylation.”
Influential
TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis
Bafica, A., Scanga, C. A., Feng, C. G., Leifer, C., Cheever, A., & Sher, A. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20051782 · Cited by 601 · cited 1×
“As the main causative agent of tuberculosis, Mtb signals mainly through TLR 2, 6 and 9 (Bafica et al., 2005; Means et al., 1999).”
PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells
Israelsen, W. J., Dayton, T. L., Davidson, S. M., Fiske, B. P., Hosios, A. M., Bellinger, G., Li, J., Yu, Y., Sasaki, M., Horner, J. W., et al. (2013) · Cell · doi:10.1016/j.cell.2013.09.025 · Cited by 549 · cited 3×
“BMDMs from mice carrying a PKM2fl/fl allele were previously described (Israelsen et al., 2013).”
Influential
Inhibition of Hypoxia-inducible Factor (HIF) Hydroxylases by Citric Acid Cycle Intermediates
Koivunen, P., Hirsilä, M., Remes, A. M., Hassinen, I. E., Kivirikko, K. I., & Myllyharju, J. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610415200 · Cited by 521 · cited 2×
“…of the TCA cycle intermediate succinate as a consequence of this metabolic switch in highly glycolytic activated ‘M1’ macrophages has revealed that succinate facilitates the signal leading to stabilization of Hypoxia Inducible Factor-1α (Hif-1α) (Koivunen et al., 2007; Tannahill et al., 2013).”
PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis
Yang, L., Xie, M., Yang, M., Yu, Y., Zhu, S., Hou, W., Kang, R., Lotze, M. T., Billiar, T. R., Wang, H., et al. (2014) · Nature Communications · doi:10.1038/ncomms5436 · Cited by 509 · cited 1×
“Our results are in agreement with the study of Yang et al who demonstrated that inhibition of PKM2 with shikonin prevented lethality in a model of septic shock, although the mechanism of shikonin is not fully understood (Yang et al., 2014).”
Cutting Edge: Essential Role of Hypoxia Inducible Factor-1α in Development of Lipopolysaccharide-Induced Sepsis
Peyssonnaux, C., Cejudo-Martin, P., Doedens, A., Zinkernagel, A. S., Johnson, R. S., & Nizet, V. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.12.7516 · Cited by 480 · cited 2×
“This impairs the ability of the PKM2 and Hif-1a complex to bind to the Hif-1amotif in the promoter of the known Hif-1a target gene IL-1b (Peyssonnaux et al., 2007; Zhang et al., 2006), thereby inhibiting the transcriptional activity of Hif-1a and induction of IL-1b and conceivably other Hif-1a-dependent genes in respo…”
The allosteric regulation of pyruvate kinase by fructose-1,6-bisphosphate
Jurica, M. S., Mesecar, A., Heath, P. J., Shi, W., Nowak, T., & Stoddard, B. L. (1998) · Structure · doi:10.1016/s0969-2126(98)00021-5 · Cited by 426 · cited 14×
“Tyrosine phosphorylation of PKM2 at residue 105 will inhibit the formation of a tetramer by dislodging the binding of FBP.”
Influential
JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1α–mediated glucose metabolism
Wang, H., Hsieh, Y., Cheng, W.-C., Lin, C.-P., Lin, Y.-S., Yang, S.-F., Chen, C.-C., Izumiya, Y., Yu, J., Kung, H.-J., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1311249111 · Cited by 306 · cited 4×
“[PubMed: 23535595] Wang HJ, Hsieh YJ, Cheng WC, Lin CP, Lin YS, Yang SF, Chen CC, Izumiya Y, Yu JS, Kung HJ, et al. JMJD5 regulates PKM2 nuclear translocation and reprograms HIF-1alpha-mediated glucose metabolism.”
Influential
Pyruvate Kinase M2: Multiple Faces for Conferring Benefits on Cancer Cells
Tamada, M., Suematsu, M., & Saya, H. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-0859 · Cited by 238 · cited 1×
“Numerous studies have reported a key role for PKM2 in aerobic glycolysis of tumors (Christofk et al., 2008; Mazurek et al., 2005; Tamada et al., 2012).”
IL-10 Blocks Phagosome Maturation in Mycobacterium tuberculosis– Infected Human Macrophages
O'Leary, S., O'Sullivan, M. P., & Keane, J. (2011) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2010-0319oc · Cited by 229 · cited 1×
“These data are consistent with IL-10 promoting pathogen persistence by contributing to Mtb- phagosome maturation (O’Leary et al., 2011).”
Self-citation
SAICAR stimulates pyruvate kinase isoform M2 and promotes cancer cell survival in glucose-limited conditions
Keller, K. E., Tan, I. S., & Lee, Y.-S. (2012) · Science · doi:10.1126/science.1224409 · Cited by 228 · cited 4×
“SAICAR stimulates pyruvate kinase isoform M2 and promotes cancer cell survival in glucose-limited conditions.”
Influential
Nuclear PKM2 regulates the Warburg effect
Yang, W., & Lu, Z. (2013) · Cell Cycle · doi:10.4161/cc.26182 · Cited by 218 · cited 1×
“Current evidence indicates that nuclear PKM2 thereby drives the Warburg effect in tumors (Yang and Lu, 2013).”
In vivo regulation of monomer-tetramer conversion of pyruvate kinase subtype M2 by glucose is mediated via fructose 1,6-bisphosphate
Ashizawa, K., Willingham, M. C., Liang, C. M., & Cheng, S. Y. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)55378-3 · Cited by 172 · cited 11×
“Tyrosine phosphorylation of PKM2 at residue 105 will inhibit the formation of a tetramer by dislodging the binding of FBP.”
Influential
Evaluation of Substituted N,N′-Diarylsulfonamides as Activators of the Tumor Cell Specific M2 Isoform of Pyruvate Kinase
Boxer, M. B., Jiang, J., Heiden, M. G. V., Shen, M., Skoumbourdis, A. P., Southall, N. T., Veith, H., Leister, W., Austin, C. P., Park, H. W., et al. (2009) · Journal of Medicinal Chemistry · doi:10.1021/jm901577g · Cited by 163 · cited 2×
“EXPERIMENTAL PROCEDURES Reagents TEPP-46 and DASA-58 synthesized in accordance with published methods (Boxer et al., 2010; Jiang et al., 2010).”
Self-citation
Concentration-dependent control of pyruvate kinase M mutually exclusive splicing by hnRNP proteins
Chen, M., David, C. J., & Manley, J. L. (2012) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2219 · Cited by 133 · cited 1×
“These are generated by exclusive alternative splicing of the Pkm pre- mRNA (Chen et al., 2012; Takenaka et al., 1991).”
Evaluation of thieno[3,2-b]pyrrole[3,2-d]pyridazinones as activators of the tumor cell specific M2 isoform of pyruvate kinase
Jiang, J., Boxer, M. B., Heiden, M. G. V., Shen, M., Skoumbourdis, A. P., Southall, N. T., Veith, H., Leister, W., Austin, C. P., Park, H. W., et al. (2010) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2010.04.015 · Cited by 129 · cited 2×
“EXPERIMENTAL PROCEDURES Reagents TEPP-46 and DASA-58 synthesized in accordance with published methods (Boxer et al., 2010; Jiang et al., 2010).”
Self-citation
Evidence that hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation of interleukin-1β (IL-1β) in astrocyte cultures
Zhang, W., Petrovic, J.-M., Callaghan, D., Jones, A., Cui, H., Howlett, C., & Stanimirovic, D. (2006) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2006.01.014 · Cited by 125 · cited 2×
“…the ability of the PKM2 and Hif-1α complex to bind to the Hif-1α motif in the promoter of the known Hif-1α target gene IL-1β (Peyssonnaux et al., 2007; Zhang et al., 2006), thereby inhibiting the transcriptional activity of Hif-1α and induction of IL-1β and conceivably other Hif-1α-dependent…”
The Role of Ets2 Transcription Factor in the Induction of MicroRNA-155 (miR-155) by Lipopolysaccharide and Its Targeting by Interleukin-10
Quinn, S. R., Mangan, N. E., Caffrey, B. E., Gantier, M. P., Williams, B. R. G., Hertzog, P. J., McCoy, C. E., & O'Neill, L. A. J. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.522730 · Cited by 100 · cited 5×
“ChIP was performed as previously described (Quinn et al., 2014; Tannahill et al., 2013).”
InfluentialSelf-citation
Isolation and characterization of the human pyruvate kinase M gene
TAKENAKA, M., Noguchi, T., Sadahiro, S., Hirai, H., Yamada, K., Matsuda, T., Imai, E., & Tanaka, T. (1991) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1991.tb15991.x · Cited by 98 · cited 1×
“These are generated by exclusive alternative splicing of the Pkm pre- mRNA (Chen et al., 2012; Takenaka et al., 1991).”
Dual roles of PKM2 in cancer metabolism
Wu, S., & Le, H. (2012) · Acta Biochimica et Biophysica Sinica · doi:10.1093/abbs/gms106 · Cited by 89 · cited 2×
“…can be regulated by the concentration of the naturally occurring upstream glycolytic intermediate FBP (Ashizawa et al., 1991; Jurica et al., 1998), serine (Chaneton et al., 2012), as well as by a multitude of post-translational modifications (Wu and Le, 2013) including tyrosine phosphorylation.”
Metabolism of Tumours
Dickens, F. (1940) · Nature · doi:10.1038/145512b0 · Cited by 84

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A guide to immunometabolism for immunologists
O'Neill, L. A. J., Kishton, R. J., & Rathmell, J. (2016) · Nature Reviews Immunology · doi:10.1038/nri.2016.70 · Cited by 3,315
Self-citation
The metabolic signature of macrophage responses
Viola, A., Munari, F., Sánchez-Rodríguez, R., Scolaro, T., & Castegna, A. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01462 · Cited by 2,021
“M1 macrophages express predominantly the PFKFB3 isoform (53) which, if compared to the other isoforms, less efficiently catalyzes the conversion of fructose-2,6-bisphosphate in fructose 6phosphate, enhancing the glycolytic flux.”
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Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation
Cruzat, V., Macedo Rogero, M., Noel Keane, K., Curi, R., & Newsholme, P. (2018) · Nutrients · doi:10.3390/nu10111564 · Cited by 1,261
Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation
Cruzat, V., Macedo Rogero, M., Noel Keane, K., Curi, R., & Newsholme, P. (2018) · doi:10.20944/preprints201809.0459.v1 · Cited by 1,261
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den Bossche, J. V., O'Neill, L. A. J., & Menon, D. (2017) · Trends in Immunology · doi:10.1016/j.it.2017.03.001 · Cited by 1,187
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Authors: Palsson-McDermott, E. M., Curtis, A. M., Goel, G., Lauterbach, M. A. R., Sheedy, F. J., Gleeson, L. E., van den Bosch, M. W. M., Quinn, S. R., Domingo-Fernandez, R., Johnston, D. G. W., Jiang, J.-K., Israelsen, W. J., Keane, J., Thomas, C., Clish, C., Vander Heiden, M., Xavier, R. J., & O’Neill, L. A. J.
Affiliations: Broad Institute (US)
Trinity College Dublin (IE)
National Institutes of Health (US)
Koch Institute for Integrative Cancer Research At MIT (US)
ORCID: Goel, Gautam
Lauterbach, Mario A.R.
Sheedy, Frederick J.
Gleeson, Laura E.
Quinn, Susan R.
Johnston, Daniel G.W.
Jiang, Jian-kang
Israelsen, William J.
Keane, Joseph
Thomas, Craig
Clish, Clary
Xavier, Ramnik J.
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2015-01
Volume: 21
Issue: 1
Pages: 65-80
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2014.12.005
PMC: PMC5198835
OpenAlex: W2153586956
Cited by: 1,397
References: 38
Citations by year: 2026: 154 · 2025: 177 · 2024: 186 · 2023: 133 · 2022: 132 · 2021: 161 · 2020: 140 · 2019: 81 · 2018: 85 · 2017: 77 · 2016: 51 · 2015: 19
FWCI: 38.04
Type: journal article
Language: en
Update notices: erratum (2015-02-03)
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 370 d)
Locations: Cell Metabolism (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
Funders: Health Research Board
Seventh Framework Programme (FP7-2007-2013, HEALTH-14-2011-281608)
National Institutes of Health
European Research Council
Science Foundation Ireland
Wellcome Trust
Topics: Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords: PKM2, HIF-1α, IL-1β, Warburg effect, macrophage polarization, M1/M2 macrophages, lipopolysaccharide stimulation, TLR4, glycolytic reprogramming, succinic acid, TEPP-46, IL-10, Salmonella typhimurium, inflammation, macrophage metabolism
MeSH terms: Animals, Bone Marrow Cells, Cells, Cultured, Glycolysis, Lipopolysaccharides, Macrophage Activation, Macrophages, Mice, Inbred C57BL, Promoter Regions, Genetic, Protein Binding, Pyruvate Kinase, RNA, Messenger, Salmonella typhimurium, Gene Expression, Enzyme Activators, Toll-Like Receptor 4, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Interleukin-1beta

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Pyruvate Kinase M2 Regulates Hif-1α Activity and IL-1β Induction and Is a Critical Determinant of the Warburg Effect in LPS-Activated Macrophages

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