ERK2 Mediates Metabolic Stress Response to Regulate Cell Fate

Shin, Sang Yong; Buel, Gwen R.; Wolgamott, Laura; Plas, David R.; Asara, John M.; Blenis, John; Yoon, Sang-Oh

doi:10.1016/j.molcel.2015.06.020

Cited by 88 publications

(95 citation statements)

References 43 publications

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“…As noted previously, we initially confirmed that the GCN2 pathway responded to glucose starvation252627, as well as to conventional amino acid depletion. We then demonstrated that this pathway contributed to ATF4 protein production and to the transcription of ATF4-dependent genes (Supplementary Fig.…”

Section: Discussionsupporting

confidence: 83%

“…Indeed, GCN2 is a well-described sensor for amino acid availability and recent reports have also described that it can be activated in response to glucose starvation252627. We found that GCN2 silencing in HBEC 3KT-RL cells moderated Glc shortage-induced ATF4 upregulation (Fig.…”

Section: Resultssupporting

confidence: 60%

“…S4a–c). A recent functional study conducted by Shin et al reported the sequential activation of PERK and GCN2 during glucose limitation27. Indeed, they revealed that PERK activation was an early event (within 18 hours), whereas GCN2 activation occurred at a later stage (54 hours), and triggered cell death27.…”

Section: Discussionmentioning

confidence: 99%

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Nutrient shortage triggers the hexosamine biosynthetic pathway via the GCN2-ATF4 signalling pathway

Chaveroux

Sarcinelli

Barbet

et al. 2016

Sci Rep

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The hexosamine biosynthetic pathway (HBP) is a nutrient-sensing metabolic pathway that produces the activated amino sugar UDP-N-acetylglucosamine, a critical substrate for protein glycosylation. Despite its biological significance, little is known about the regulation of HBP flux during nutrient limitation. Here, we report that amino acid or glucose shortage increase GFAT1 production, the first and rate-limiting enzyme of the HBP. GFAT1 is a transcriptional target of the activating transcription factor 4 (ATF4) induced by the GCN2-eIF2α signalling pathway. The increased production of GFAT1 stimulates HBP flux and results in an increase in O-linked β-N-acetylglucosamine protein modifications. Taken together, these findings demonstrate that ATF4 provides a link between nutritional stress and the HBP for the regulation of the O-GlcNAcylation-dependent cellular signalling.The regulation of metabolic fluxes is a key process in the cellular response to changes in nutrient availability, and dysregulation of this process may contribute to the development of various diseases 1,2 . The hexosamine biosynthetic pathway (HBP) plays a central role in sensing the nutritional status of the cell, since it integrates molecules coming from carbohydrates, fatty acids, amino acids and nucleotides metabolism 3 . The HBP converts fructose-6-phosphate, a glucose derivative, into UDP-N-acetylglucosamine (UDP-GlcNAc), a central nucleotide sugar acting as a donor substrate for the glycosylation of proteins and lipids. In addition, UDP-GlcNAc is used for the O-GlcNAcylation of proteins, i.e. the addition of N-acetylglucosamine to their serine and threonine residues. Similarly to phosphorylation, O-GlcNAcylation regulates cellular activities, such as signalling and transcription 4 . It has been proposed that O-GlcNAcylated proteins modulate cellular responses to nutrient deprivation and stress, and that their dysregulation is implicated in a wide range of pathologies 5 . Despite these wide-ranging biological effects, the mechanisms underlying the adaptation of the HBP flux to nutrient availability remains poorly understood.The first and rate-limiting enzyme of the HBP, namely glutamine:fructose-6-phosphate aminotransferase 1 (GFAT1), which drives the HBP flux, is involved in various physiopathological processes 6-9 . GFAT1 activity is inhibited by UDP-GlcNAc, the end product of the HBP 10 , and the AMP-activated protein kinase-mediated phosphorylation 11 . In contrary, GFAT1 is stimulated upon phosphorylation by protein kinase A and calcium/ calmodulin-dependent protein kinase II 12 . More recently, it was shown that GFAT1 production is upregulated by a transcription factor of the unfolded protein response (UPR), namely the spliced form of X-box binding protein 1 (XBP1s), resulting in the stimulation of the HBP flux and protein O-GlcNAcylation 13 . These authors unveiled in this way an intrinsic link between the HBP and disruption of the endoplasmic reticulum (ER) homeostasis, i.e. ER stress, which activates the UPR.UPR signalling is mediat...

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Section: Discussionsupporting

confidence: 83%

Section: Resultssupporting

confidence: 60%

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Nutrient shortage triggers the hexosamine biosynthetic pathway via the GCN2-ATF4 signalling pathway

Chaveroux

Sarcinelli

Barbet

et al. 2016

Sci Rep

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“…The expression of other mTORC2 targets such as PKCα and NDRG1 was also maintained in WT MEFs and became elevated upon prolonged glucose withdrawal in HeLa (Figure S5C–D). No Akt phosphorylation occurred in SIN1 −/− cells even upon glucose withdrawal and despite robust phosphorylation of ERK1/2 (Figure 4A), which was previously linked to glucose stress-induced Akt phosphorylation (Shin et al, 2015). Phosphorylation of the mTORC1 target S6K was slightly enhanced in WT MEFS but abolished during prolonged glucose starvation in HeLa.…”

Section: Resultsmentioning

confidence: 50%

mTORC2 Responds to Glutamine Catabolite Levels to Modulate the Hexosamine Biosynthesis Enzyme GFAT1

et al. 2016

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SUMMARY Highly proliferating cells are particularly dependent on glucose and glutamine for bioenergetics and macromolecule biosynthesis. The signals that respond to nutrient fluctuations to maintain metabolic homeostasis remain poorly understood. Here, we found that mTORC2 is activated by nutrient deprivation due to decreasing glutamine catabolites. We elucidate how mTORC2 modulates a glutamine-requiring biosynthetic pathway, the hexosamine biosynthesis pathway (HBP) via regulation of expression of GFAT1 (glutamine:fructose-6-phosphate amidotransferase 1), the rate-limiting enzyme of the HBP. GFAT1 expression is dependent on sufficient amounts of glutaminolysis catabolites particularly α-ketoglutarate, which are generated in an mTORC2-dependent manner. Additionally, mTORC2 is essential for proper expression and nuclear accumulation of the GFAT1 transcriptional regulator, Xbp1s. Thus, while mTORC1 senses amino acid abundance to promote anabolism, mTORC2 responds to declining glutamine catabolites in order to restore metabolic homeostasis. Our findings uncover the role of mTORC2 in metabolic reprogramming and have implications for understanding insulin resistance and tumorigenesis.

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“…Recent studies indicate that activation of Akt via phosphorylation at the mTORC2-targeted site is required for cell adaptation and survival during metabolic stress (Shin et al, 2015). Thus, defining the optimal dosage, time and/or route of administration would be crucial to prevent mTORC2/Akt inactivation and thus obtain beneficial effects of mTOR inhibition during ischemia.…”

Section: Discussionmentioning

confidence: 99%

Effects of rapamycin on cerebral oxygen supply and consumption during reperfusion after cerebral ischemia

Barsoum

Vega-Cotto

et al. 2016

Neuroscience

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Abstract—Activation of the mammalian target of rapamycin (mTOR) leads to cell growth and survival. We tested the hypothesis that inhibition of mTOR would increase infarct size and decrease microregional O2 supply/consumption balance after cerebral ischemia–reperfusion. This was tested in isoflurane-anesthetized rats with middle cerebral artery blockade for 1 h and reperfusion for 2 h with and without rapamycin (20 mg/kg once daily for two days prior to ischemia). Regional cerebral blood flow was determined using a C14-iodoantipyrine autoradiographic technique. Regional small-vessel arterial and venous oxygen saturations were determined microspectrophotometrically. The control ischemic-reperfused cortex had a similar blood flow and O2 consumption to the contralateral cortex. However, microregional O2 supply/consumption balance was significantly reduced in the ischemic-reperfused cortex. Rapamycin significantly increased cerebral O2 consumption and further reduced O2 supply/consumption balance in the reperfused area. This was associated with an increased cortical infarct size (13.5 ± 0.8% control vs. 21.5 ± 0.9% rapamycin). We also found that ischemia–reperfusion increased AKT and S6K1 phosphorylation, while rapamycin decreased this phosphorylation in both the control and ischemic-reperfused cortex. This suggests that mTOR is important for not only cell survival, but also for the control of oxygen balance after cerebral ischemia–reperfusion.

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ERK2 Mediates Metabolic Stress Response to Regulate Cell Fate

Cited by 88 publications

References 43 publications

Nutrient shortage triggers the hexosamine biosynthetic pathway via the GCN2-ATF4 signalling pathway

Nutrient shortage triggers the hexosamine biosynthetic pathway via the GCN2-ATF4 signalling pathway

mTORC2 Responds to Glutamine Catabolite Levels to Modulate the Hexosamine Biosynthesis Enzyme GFAT1

Effects of rapamycin on cerebral oxygen supply and consumption during reperfusion after cerebral ischemia

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