Akt Determines Cell Fate Through Inhibition of the PERK-eIF2α Phosphorylation Pathway

Mounir, Zineb; Krishnamoorthy, Jothi Latha; Wang, Shuo; Papadopoulou, Barbara; Campbell, Shirley; Muller, William J.; Hatzoglou, Maria; Koromilas, Antonis E.

doi:10.1126/scisignal.2001630

Cited by 108 publications

(110 citation statements)

References 45 publications

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“…4A). Previous work by our group demonstrated a negative effect of AKT on PERK activity by phosphorylation at T799 (32). We noticed that ER stress increased PERK T799 phosphorylation in TSC-proficient compared with TSC-deficient cells, which was in line with the higher AKT activity in the former than latter cells (Fig.…”

Section: Disruption Of Mtorc2 Induces Eif2as51p As a Results Of Akt Insupporting

confidence: 77%

“…Analysis of cell death by flow cytometry was performed as previously described (32). Cells were analyzed on a BD FACScalibur using the FlowJo software (Tree Star Inc.).…”

Section: Flow-cytometry Analysismentioning

confidence: 99%

“…Protein extraction and immunoblot analyses were performed as described previously (32). The antibodies were obtained from Cell Signaling Technology unless otherwise indicated.…”

Section: Protein Extraction and Immunoblottingmentioning

confidence: 99%

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mTORC2 Balances AKT Activation and eIF2α Serine 51 Phosphorylation to Promote Survival under Stress

Tenkerian

Krishnamoorthy

Mounir³

et al. 2015

Molecular Cancer Research

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The mTOR nucleates two complexes, namely mTOR complex 1 and 2 (mTORC1 and mTORC2), which are implicated in cell growth, survival, metabolism, and cancer. Phosphorylation of the a-subunit of translation initiation factor eIF2 at serine 51 (eIF2aS51P) is a key event of mRNA translation initiation and a master regulator of cell fate during cellular stress. Recent studies have implicated mTOR signaling in the stress response, but its connection to eIF2aS51P has remained unclear. Herein, we report that genetic as well as catalytic inhibition of mTORC2 induces eIF2aS51P. On the other hand, the allosteric inhibitor rapamycin induces eIF2aS51P through pathways that are independent of mTORC1 inactivation. Increased eIF2aS51P by impaired mTORC2 depends on the inactivation of AKT, which primes the activation of the endoplasmic reticulum (ER)-resident kinase PERK/PEK. The biologic function of eIF2aS51P was characterized in tuberous sclerosis complex (TSC)-mutant cells, which are defective in mTORC2 and AKT activity. TSC-mutant cells exhibit increased PERK activity, which is downregulated by the reconstitution of the cells with an activated form of AKT1. Also, TSCmutant cells are increasingly susceptible to ER stress, which is reversed by AKT1 reconstitution. The susceptibility of TSC-mutant cells to ER stress is further enhanced by the pharmacologic inhibition of PERK or genetic inactivation of eIF2aS51P. Thus, the PERK/eIF2aS51P arm is an important compensatory prosurvival mechanism, which substitutes for the loss of AKT under ER stress.Implications: A novel mechanistic link between mTOR function and protein synthesis is identified in TSC-null tumor cells under stress and reveals potential for the development of antitumor treatments with stress-inducing chemotherapeutics.

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Section: Disruption Of Mtorc2 Induces Eif2as51p As a Results Of Akt Insupporting

confidence: 77%

“…Analysis of cell death by flow cytometry was performed as previously described (32). Cells were analyzed on a BD FACScalibur using the FlowJo software (Tree Star Inc.).…”

Section: Flow-cytometry Analysismentioning

confidence: 99%

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mTORC2 Balances AKT Activation and eIF2α Serine 51 Phosphorylation to Promote Survival under Stress

Tenkerian

Krishnamoorthy

Mounir³

et al. 2015

Molecular Cancer Research

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“…Increased AKT activity has been reported to lower PERK activity (Mounir et al 2011). We also noted that PERK mRNA levels were increased in cells with low AKT activity (Fig.…”

Section: Discussionsupporting

confidence: 56%

ER stress potentiates insulin resistance through PERK-mediated FOXO phosphorylation

et al. 2013

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Endoplasmic reticulum (ER) stress is emerging as a potential contributor to the onset of type 2 diabetes by making cells insulin-resistant. However, our understanding of the mechanisms by which ER stress affects insulin response remains fragmentary. Here we present evidence that the ER stress pathway acts via a conserved signaling mechanism involving the protein kinase PERK to modulate cellular insulin responsiveness. Insulin signaling via AKT reduces activity of FOXO transcription factors. In some cells, PERK can promote insulin responsiveness. However, we found that PERK also acts oppositely via phosphorylation of FOXO to promote FOXO activity. Inhibition of PERK improves cellular insulin responsiveness at the level of FOXO activity. We suggest that the protein kinase PERK may be a promising pharmacological target for ameliorating insulin resistance.

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“…Furthermore, the effects of PERK on FOXO protein increases the expression of insulin receptor, which increases the activity of AKT, and the activation of AKT, in turn, inhibits the activity of the PERK (31). Thus, the higher activation of AKT, the less PERK activity, comparably (32,33).…”

Section: Phosphorylation Of Foxo Proteinsmentioning

confidence: 99%

Post-translational modifications of FOXO family proteins

Wang

Huang

2016

Molecular Medicine Reports

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Abstract. The Forkhead box O (FOXO) protein family is predominantly involved in apoptosis, oxidative stress, DNA damage/repair, tumor angiogenesis, glycometabolism, regulating life span and other important biological processes. Its activity is affected by a variety of posttranslational modifications (PTMs), including phosphorylation, acetylation, ubiquitination, methylation and glycosylation. When cells are subjected to different environments, the corresponding PTMs act on the FOXO protein family, to change transcriptional activity or subcellular localization, and the expression of downstream target genes, will ultimately affect the biological behavior of the cells. In this review, we will discuss the biological characteristics of FOXO protein PTMs.

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Akt Determines Cell Fate Through Inhibition of the PERK-eIF2α Phosphorylation Pathway

Cited by 108 publications

References 45 publications

mTORC2 Balances AKT Activation and eIF2α Serine 51 Phosphorylation to Promote Survival under Stress

mTORC2 Balances AKT Activation and eIF2α Serine 51 Phosphorylation to Promote Survival under Stress

ER stress potentiates insulin resistance through PERK-mediated FOXO phosphorylation

Post-translational modifications of FOXO family proteins

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