Class III PI-3-kinase activates phospholipase D in an amino acid–sensing mTORC1 pathway

Yoon, Mee Sup; Du, Guangwei; Backer, Jonathan M.; Frohman, Michael A.; Chen, Jiawen

doi:10.1083/jcb.201107033

Cited by 140 publications

(176 citation statements)

References 60 publications

(124 reference statements)

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“…During times of amino acid sufficiency, a second complex, GATOR2, inhibits GATOR1 activity and is required for amino acid-dependent activation of mTORC1 but, unlike the RAGulator, is not involved in localizing Rag proteins to lysosomal membranes (Bar-Peled et al 2013). Interestingly, PLD1 has been found to also translocate to lysosomal membranes in the presence of amino acids (Yoon et al 2011a). Therefore, a model can be suggested in which sufficient amino acid levels lead to translocation of mTORC1 to lysosomal membranes, where associated RHEB induces PC hydrolysis yielding PA that can activate mTORC1 (Fig.…”

Section: General Mechanisms Of Activationmentioning

confidence: 99%

A recollection of mTOR signaling in learning and memory

2013

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Mechanistic target of rapamcyin (mTOR) is a central player in cell growth throughout the organism. However, mTOR takes on an additional, more specialized role in the developed neuron, where it regulates the protein synthesis-dependent, plastic changes underlying learning and memory. mTOR is sequestered in two multiprotein complexes (mTORC1 and mTORC2) that have different substrate specificities, thus allowing for distinct functions at synapses. We will examine how learning activates the mTOR complexes, survey the critical effectors of this pathway in the context of synaptic plasticity, and assess whether mTOR plays an instructive or permissive role in generating molecular memory traces.

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Section: General Mechanisms Of Activationmentioning

confidence: 99%

A recollection of mTOR signaling in learning and memory

2013

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“…Much has been learned in the last several years on the mechanistic basis for the sensing of amino acids by mTOR at the lysosomal membrane via Rag GTPases (27,41). The activation of mTOR in response to amino acids also requires PLD (19,20,42). However, very little is known about the dependence of mTOR on glucose, another critical nutrient sensed by mTOR.…”

Section: Pa As a Broader Indicator Of Nutrient Sufficiencymentioning

confidence: 99%

“…However, growth factors (6) and nutrients (19,20) also stimulate PA production through the action of phospholipases that breakdown membrane phospholipids, potentially leading to high PA concentrations at specific locations and times. This can be accomplished by PLD, or a combination of phospholipase C (PLC), which generates DG, and the subsequent conversion to PA by DGK.…”

Section: Phosphatidic Acid (Pa)mentioning

confidence: 99%

Phospholipase D and the Maintenance of Phosphatidic Acid Levels for Regulation of Mammalian Target of Rapamycin (mTOR)

Foster

Salloum

Menon

et al. 2014

Journal of Biological Chemistry

105

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Phosphatidic acid (PA) is a critical metabolite at the heart of membrane phospholipid biosynthesis. However, PA also serves as a critical lipid second messenger that regulates several proteins implicated in the control of cell cycle progression and cell growth. Three major metabolic pathways generate PA: phospholipase D (PLD), diacylglycerol kinase (DGK), and lysophosphatidic acid acyltransferase (LPAAT). The LPAAT pathway is integral to de novo membrane phospholipid biosynthesis, whereas the PLD and DGK pathways are activated in response to growth factors and stress. The PLD pathway is also responsive to nutrients. A key target for the lipid second messenger function of PA is mTOR, the mammalian/mechanistic target of rapamycin, which integrates both nutrient and growth factor signals to control cell growth and proliferation. Although PLD has been widely implicated in the generation of PA needed for mTOR activation, it is becoming clear that PA generated via the LPAAT and DGK pathways is also involved in the regulation of mTOR. In this minireview, we highlight the coordinated maintenance of intracellular PA levels that regulate mTOR signals stimulated by growth factors and nutrients, including amino acids, lipids, glucose, and Gln. Emerging evidence indicates compensatory increases in one source of PA when another source is compromised, highlighting the importance of being able to adapt to stressful conditions that interfere with PA production. The regulation of PA levels has important implications for cancer cells that depend on PA and mTOR activity for survival.

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“…Activation of mTORC1 has been linked to a myriad of energetic and hormonal signals (e.g. growth factors, amino acids and mechanical stimuli) that converge on the lysosome to augment protein synthesis by enhancing its interaction with two direct activators, a small GTPase called Rheb (Inoki et al, 2003a,b) and the glycerophospholipid phosphatidic acid (PA) (Sun et al, 2008;Yoon et al, 2011;You et al, 2014).…”

Section: Cellular Regulation Of Exercise Training Adaptation: a Primermentioning

confidence: 99%

Effects of skeletal muscle energy availability on protein turnover responses to exercise

Smiles

Hawley

Camera

2016

Journal of Experimental Biology

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Skeletal muscle adaptation to exercise training is a consequence of repeated contraction-induced increases in gene expression that lead to the accumulation of functional proteins whose role is to blunt the homeostatic perturbations generated by escalations in energetic demand and substrate turnover. The development of a specific 'exercise phenotype' is the result of new, augmented steady-state mRNA and protein levels that stem from the training stimulus (i.e. endurance or resistance based). Maintaining appropriate skeletal muscle integrity to meet the demands of training (i.e. increases in myofibrillar and/or mitochondrial protein) is regulated by cyclic phases of synthesis and breakdown, the rate and turnover largely determined by the protein's half-life. Cross-talk among several intracellular systems regulating protein synthesis, breakdown and folding is required to ensure protein equilibrium is maintained. These pathways include both proteasomal and lysosomal degradation systems (ubiquitin-mediated and autophagy, respectively) and the protein translational and folding machinery. The activities of these cellular pathways are bioenergetically expensive and are modified by intracellular energy availability (i.e. macronutrient intake) and the 'training impulse' (i.e. summation of the volume, intensity and frequency). As such, exercisenutrient interactions can modulate signal transduction cascades that converge on these protein regulatory systems, especially in the early post-exercise recovery period. This review focuses on the regulation of muscle protein synthetic response-adaptation processes to divergent exercise stimuli and how intracellular energy availability interacts with contractile activity to impact on muscle remodelling.

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Class III PI-3-kinase activates phospholipase D in an amino acid–sensing mTORC1 pathway

Abstract: In response to amino acid availability, the class III PI-3-kinase hVps34 activates the phospholipase PLD and mTORC1 signaling to regulate mammalian cell size.

Cited by 140 publications

References 60 publications

A recollection of mTOR signaling in learning and memory

A recollection of mTOR signaling in learning and memory

Phospholipase D and the Maintenance of Phosphatidic Acid Levels for Regulation of Mammalian Target of Rapamycin (mTOR)

Effects of skeletal muscle energy availability on protein turnover responses to exercise

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