Rheb Inhibits Protein Synthesis by Activating the PERK-eIF2α Signaling Cascade

Tyagi, Richa; Shahani, Neelam; Gorgen, Lindsay; Ferretti, Max B; Pryor, William M.; Chen, Po‐Yu; Swarnkar, Supriya; Worley, Paul F.; Karbstein, Katrin; Snyder, Solomon H.; Subramaniam, Srinivasa

doi:10.1016/j.celrep.2015.01.014

Cited by 48 publications

(32 citation statements)

References 56 publications

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“…Our work demonstrates that AKT inactivation represents a major mechanism that induces the PERK-eIF2aS51P arm in TSC-deficient cells by ER stress. Nevertheless, additional mechanisms cannot be excluded as for example the ability of Rheb GTPase to physically interact with and activate PERK (50). We also demonstrate that an important property of mTORC2 inactivation is the activation of PERK and induction of eIF2aS51P, which represents a prosurvival mechanism used by TSC-deficient cells to counteract the deleterious effects of ER stress (Fig.…”

Section: Discussionmentioning

confidence: 84%

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: Discussionmentioning

confidence: 84%

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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“…viral infection, nutrient and heme-deprivation, [23]. In addition to these other mechanisms it has recently been reported that RHEB GTPase which stimulates mTOR activity also phosphorylates eIF2α attenuating protein translation [24]. Thus, when mTOR is shut down either by FF + 2-DG or rapamycin, RHEB may be playing a role in the increased phosphorylation we detect in eIF2α which may not necessarily reflect increased ER stress.…”

Section: Discussionmentioning

confidence: 87%

Combining 2-deoxy-D-glucose with fenofibrate leads to tumor cell death mediated by simultaneous induction of energy and ER stress

et al. 2016

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Unregulated growth and replication as well as an abnormal microenvironment, leads to elevated levels of stress which is a common trait of cancer. By inducing both energy and endoplasmic reticulum (ER) stress, 2-Deoxy-glucose (2-DG) is particularly well-suited to take advantage of the therapeutic window that heightened stress in tumors provides. Under hypoxia, blocking glycolysis with 2-DG leads to significant lowering of ATP resulting in energy stress and cell death in numerous carcinoma cell types. In contrast, under normoxia, 2-DG at a low-concentration is not toxic in most carcinomas tested, but induces growth inhibition, which is primarily due to ER stress. Here we find a synergistic toxic effect in several tumor cell lines in vitro combining 2-DG with fenofibrate (FF), a drug that has been safely used for over 40 years to lower cholesterol in patients. This combination induces much greater energy stress than either agent alone, as measured by ATP reduction, increased p-AMPK and downregulation of mTOR. Inhibition of mTOR results in blockage of GRP78 a critical component of the unfolded protein response which we speculate leads to greater ER stress as observed by increased p-eIF2α. Moreover, to avoid an insulin response and adsorption by the liver, 2-DG is delivered by slow-release pump yielding significant anti-tumor control when combined with FF. Our results provide promise for developing this combination clinically and others that combine 2-DG with agents that act synergistically to selectively increase energy and ER stress to a level that is toxic to numerous tumor cell types.

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“…Rheb-PERK signaling is activated under ER stress leading to inhibition of protein synthesis, indicating that Rheb may function as a molecular switch between stimulation and inhibition of protein synthesis under physiological as well as pathological conditions (Tyagi et al, 2015).…”

Section: Response To Other Stressesmentioning

confidence: 99%

“…Although in general, Rheb-mTORC1 signaling promotes protein synthesis, recently, it was reported that Rheb inhibits protein synthesis by mediating phosphorylation of eukaryotic initiation factor 2α (eiF2α) via PERK independent of mTORC1 signaling (Tyagi et al, 2015). Rheb-PERK signaling is activated under ER stress leading to inhibition of protein synthesis, indicating that Rheb may function as a molecular switch between stimulation and inhibition of protein synthesis under physiological as well as pathological conditions (Tyagi et al, 2015).…”

Section: Response To Other Stressesmentioning

confidence: 99%

“…The noncanonical mediators of Rheb signaling are as follows: B-Raf kinase (Im et al, 2002;Karbowniczek et al, 2004); FKBP38 (Ma et al, 2010); NIX, and LC3 (Melser et al, 2013); RASSF1A (Nelson and Clark, 2016); carbamoylphosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD) (Sato et al, 2015); β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) ; protein kinase-like endoplasmic reticulum kinase (PERK) (Tyagi et al, 2015); and syntenin (Sugiura et al, 2015). Taken together, Rheb can regulate multiple cellular events both dependent and independent of mTORC1 and hence have roles in development, maintenance and degenerative processes.…”

Section: Non-canonical Rheb Pathwaymentioning

confidence: 99%

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Rheb in neuronal degeneration, regeneration, and connectivity

Potheraveedu

Schöpel

Stoll

et al. 2017

Biological Chemistry

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Abstract:The small GTPase Rheb was originally detected as an immediate early response protein whose expression was induced by NMDA-dependent synaptic activity in the brain. Rheb's activity is highly regulated by its GTPase activating protein (GAP), the tuberous sclerosis complex protein, which stimulates the conversion from the active, GTP-loaded into the inactive, GDP-loaded conformation. Rheb has been established as an evolutionarily conserved molecular switch protein regulating cellular growth, cell volume, cell cycle, autophagy, and amino acid uptake. The subcellular localization of Rheb and its interacting proteins critically regulate its activity and function. In stem cells, constitutive activation of Rheb enhances differentiation at the expense of self-renewal partially explaining the adverse effects of deregulated Rheb in the mammalian brain. In the context of various cellular stress conditions such as oxidative stress, ER-stress, death factor signaling, and cellular aging, Rheb activation surprisingly enhances rather than prevents cellular degeneration. This review addresses cell type-and cell state-specific function(s) of Rheb and mainly focuses on neurons and their surrounding glial cells. Mechanisms will be discussed in the context of therapy that interferes with Rheb's activity using the antibiotic rapamycin or low molecular weight compounds.

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Rheb Inhibits Protein Synthesis by Activating the PERK-eIF2α Signaling Cascade

Cited by 48 publications

References 56 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

Combining 2-deoxy-D-glucose with fenofibrate leads to tumor cell death mediated by simultaneous induction of energy and ER stress

Rheb in neuronal degeneration, regeneration, and connectivity

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