Phosphorylation of Bad at Thr-201 by JNK1 Promotes Glycolysis through Activation of Phosphofructokinase-1

Deng, Hongbin; Yu, Fei; Chen, Jian-Qun; Zhao, Yingming; Xiang, Jialing; Lin, Anning

doi:10.1074/jbc.m800024200

Cited by 58 publications

(49 citation statements)

References 57 publications

(45 reference statements)

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“…PFK-1 activity was measured as previously described (12). Briefly, whole kidneys or renal outer medullary tissues were homogenized in cold sucrose buffer [0.32 M sucrose and 10 mM Tris·HCl (pH 7.4), Sigma].…”

Section: Methodsmentioning

confidence: 99%

TIGAR regulates glycolysis in ischemic kidney proximal tubules

Kim

Devalaraja-Narashimha

Padanilam

2015

American Journal of Physiology-Renal Physiology

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Tp53-induced glycolysis and apoptosis regulator (TIGAR) activation blocks glycolytic ATP synthesis by inhibiting phosphofructokinase-1 activity. Our data indicate that TIGAR is selectively induced and activated in renal outermedullary proximal straight tubules (PSTs) after ischemia-reperfusion injury in a p53-dependent manner. Under severe ischemic conditions, TIGAR expression persisted through 48 h postinjury and induced loss of renal function and histological damage. Furthermore, TIGAR upregulation inhibited phosphofructokinase-1 activity, glucose 6-phosphate dehydrogenase (G6PD) activity, and induced ATP depletion, oxidative stress, autophagy, and apoptosis. Small interfering RNA-mediated TIGAR inhibition prevented the aforementioned malevolent effects and protected the kidneys from functional and histological damage. After mild ischemia, but not severe ischemia, G6PD activity and NADPH levels were restored, suggesting that TIGAR activation may redirect the glycolytic pathway into gluconeogenesis or the pentose phosphate pathway to produce NADPH. The increased level of NADPH maintained the level of GSH to scavenge ROS, resulting in a lower sensitivity of PST cells to injury. Under severe ischemia, G6PD activity and NADPH levels were reduced during reperfusion; however, blockade of TIGAR enhanced their levels and reduced oxidative stress and apoptosis. Collectively, these results demonstrate that inhibition of TIGAR may protect PST cells from energy depletion and apoptotic cell death in the setting of severe ischemia-reperfusion injury. However, under low ischemic burden, TIGAR activation induces the pentose phosphate pathway and autophagy as a protective mechanism.

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Section: Methodsmentioning

confidence: 99%

TIGAR regulates glycolysis in ischemic kidney proximal tubules

Kim

Devalaraja-Narashimha

Padanilam

2015

American Journal of Physiology-Renal Physiology

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“…Although this association does not depend on BAD's phosphorylation status, stimulation of PFK-1 depends on the phosphorylation of BAD on Thr201, a target of JNK-1 downstream of the IL-3 signaling pathway. Importantly, glycolytic rates are blunted in cells expressing a phosphorylation-defective mutant of BAD at this position (Deng et al, 2008). Concomitant with a stimulatory effect on glycolysis, Thr201 phosphorylation inhibits BAD's apoptotic activity by interfering with its association with BCL-X L .…”

Section: Bad and Glucose Metabolismmentioning

confidence: 98%

BAD: undertaker by night, candyman by day

2008

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The BH3-only pro-apoptotic proteins are upstream sensors of cellular damage that selectively respond to specific, proximal death and survival signals. Genetic models and biochemical studies indicate that these molecules are latent killers until activated through transcriptional or post-translational mechanisms in a tissue-restricted and signal-specific manner. The large number of BH3-only proteins, their unique subcellular localization, protein-interaction network and diverse modes of activation suggest specialization of their damage-sensing function, ensuring that the core apoptotic machinery is poised to receive input from a wide range of cellular stress signals. The apoptotic response initiated by the activation of BH3-only proteins ultimately culminates in allosteric activation of pro-apoptotic BAX and BAK, the gateway proteins to the mitochondrial pathway of apoptosis. From activation of BH3-only proteins to oligomerization of BAX and BAK and mitochondrial outer membrane permeabilization, an intricate network of interactions between the pro-and anti-apoptotic members of the BCL-2 family orchestrates the decision to undergo apoptosis. Beyond regulation of apoptosis, multiple BCL-2 proteins have recently emerged as active components of select homeostatic pathways carrying other cellular functions. This review focuses on BAD, which was the first BH3-only protein linked to proximal survival signals through phosphorylation by survival kinases. In addition to findings that delineated the physiological role of BAD in apoptosis and its dynamic regulation by phosphorylation, studies pointing to new roles for this protein in other physiological pathways, such as glucose metabolism, are highlighted. By executing its 'day' and 'night' jobs in metabolism and apoptosis, respectively, BAD helps coordinate mitochondrial fuel metabolism and the apoptotic machinery.

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“…The activities of each of the 11 enzymes were individually measured according to previously reported methods (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23).…”

Section: Measurement Of Enzyme Activity At Saturating Substrate Concementioning

confidence: 99%

Evidence That Does Not Support Pyruvate Kinase M2 (PKM2)-catalyzed Reaction as a Rate-limiting Step in Cancer Cell Glycolysis

Xie

Dai²,

Hu³

2016

Journal of Biological Chemistry

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It has been recognized that the rate-limiting function of pyruvate kinase M2 (PKM2) in glycolysis plays an important role in distributing glycolytic intermediates for anabolic and catabolic purposes in cancer cells. However, after analysis of the catalytic capacity of PKM2 relative to other glycolytic enzymes, the regulation range of PKM2 activity, metabolic flux control, and thermodynamics, we suggest that the PKM2-catalyzed reaction is not a rate-limiting step in cancer cell glycolysis. Hexokinase and phosphofructokinase 1 (PFK1), the first and third enzyme along the pathway, are rate-limiting enzymes that limit the overall glycolytic rate, whereas PKM2 and lactate dehydrogenase, the last two enzymes in the pathway, are for the fast removal of upstream intermediates to prevent the obstruction of the pathway. The argument is in accordance with the catalytic capacity of glycolytic enzymes, regulation range of enzyme activities, metabolic flux control, and thermodynamics.During tumorigenesis, pyruvate kinase (PK) isotype in cells switches from pyruvate kinase M1 (PKM1) or pyruvate kinase L (PKL) to PKM2 (1, 2), suggesting that PKM2 plays a part in tumor initiation and development. PK catalyzes the last step of glycolysis and is commonly regarded as a rate-limiting enzyme. In cancer cells, PKM2 is considered as a rate-limiting enzyme, because its enzyme activity is sensitive to allosteric regulation (3, 4) and it catalyzes a thermodynamically favorable reaction. It is proposed that when it is allosterically inhibited, its catalytic rate is lower than the upstream glycolytic rate; hence, phosphoenolpyruvate (PEP) 4 and upstream glycolytic intermediate may accumulate and flow to anabolic pathways; when it is allosterically activated, its activity is higher than the upstream glycolytic rate, and the upstream glycolytic intermediate would flow to pyruvate, which is then converted to lactate or enters mitochondria for complete oxidation. There are several lines of evidence that support this hypothesis (1, 4 -11).However, the evidence to support PKM2 as a rate-limiting enzyme is not sufficient. If PKM2 is a rate-limiting enzyme, the following lines of evidence are required: (a) PKM2 catalyzes an irreversible reaction; (b) its enzyme activity relative to other glycolytic enzymes is low; (c) its activity is sensitive to regulation; and (d) when its activity is allosterically activated, its catalytic rate should be higher than the upstream glycolytic rate and when its activity is allosterically inhibited, its catalytic rate should be lower than upstream glycolytic rate. So far, there is evidence of points a and c but no b and d.

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Phosphorylation of Bad at Thr-201 by JNK1 Promotes Glycolysis through Activation of Phosphofructokinase-1

Cited by 58 publications

References 57 publications

TIGAR regulates glycolysis in ischemic kidney proximal tubules

TIGAR regulates glycolysis in ischemic kidney proximal tubules

BAD: undertaker by night, candyman by day

Evidence That Does Not Support Pyruvate Kinase M2 (PKM2)-catalyzed Reaction as a Rate-limiting Step in Cancer Cell Glycolysis

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