Mechanistic target of rapamycin (MTOR) signaling during ovulation in mice

The mechanistic target of rapamycin (mTOR) forms two distinct intracellular multiprotein complexes that control a multitude of intracellular processes linked to metabolism, proliferation, actin cytoskeleton and survival. Recent studies have identified the importance of these complexes for transport regulation of ions and nutrients along the entire nephron. First reports could link altered activity of these complexes to certain disease entities i.e. diabetic nephropathy, AKI or hyperkalemia.

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Mechanistic target of rapamycin signaling in mouse models of accelerated aging

The Journals of Gerontology Series A ◽

10.1093/gerona/glz059 ◽

2019 ◽

Vol 75 (1) ◽

pp. 64-72 ◽

Cited By ~ 4

Author(s):

Jin Young Lee ◽

Brian K Kennedy ◽

Chen-Yu Liao

Keyword(s):

Mouse Models ◽

Accelerated Aging ◽

Nutrient Sensing ◽

Mtor Signaling ◽

Human Diseases ◽

Target Of Rapamycin ◽

Cellular Processes ◽

Positive Effects ◽

Mechanistic Target Of Rapamycin ◽

Age Related

Abstract The mechanistic target of rapamycin (mTOR) is an essential nutrient-sensing kinase that integrates and regulates a number of fundamental cellular processes required for cell growth, cell motility, translation, metabolism, and autophagy. mTOR signaling has been implicated in the progression of many human diseases, and its dysregulation has been reported in several pathological processes, especially in age-related human diseases and mouse models of accelerated aging. In addition, many studies have demonstrated that the regulation of mTOR activity has a beneficial effect on longevity in several mouse models of aging. However, not all mouse models of accelerated aging show positive effects on aging-associated phenotypes in response to targeting mTOR signaling. Here, we review the effects of interventions that modulate mTOR signaling on aging-related phenotypes in different mouse models of accelerated aging and discuss their implications with respect to aging and aging-related disorders.

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Review: Schistosoma mansoni phosphatidylinositol 3 kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway

Comparative Biochemistry and Physiology Part B Biochemistry and Molecular Biology ◽

10.1016/j.cbpb.2021.110632 ◽

2021 ◽

pp. 110632

Author(s):

Iman F. Abou-El-Naga

Keyword(s):

Schistosoma Mansoni ◽

Signaling Pathway ◽

Mtor Signaling ◽

Target Of Rapamycin ◽

Mtor Signaling Pathway ◽

Phosphatidylinositol 3 Kinase ◽

Mechanistic Target Of Rapamycin ◽

Phosphatidylinositol 3

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The Glucagon-Like Peptide 1 Receptor Agonist Liraglutide Stimulates Mechanistic Target of Rapamycin (mTOR) Signaling via PKA And Akt

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1044 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A510-A511

Author(s):

Thao D V Le ◽

Dianxin Liu ◽

Sheila Collins ◽

Julio E Ayala

Keyword(s):

Food Intake ◽

Cho Cells ◽

Mtor Signaling ◽

Target Of Rapamycin ◽

Mechanistic Target Of Rapamycin ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Pre Treatment ◽

Mtor Activity ◽

Stimulation Of

Abstract Glucagon-like peptide 1 receptor (GLP-1R) agonists enhance glucose-stimulated insulin secretion and act on several regions of the brain to reduce food intake and body weight, making the GLP-1R a major therapeutic target for the treatment of type 2 diabetes and obesity. Surprisingly, little is known about the signaling mechanisms mediating the food intake-lowering effects of GLP-1R agonists. We have previously shown that inhibiting the mechanistic Target of Rapamycin (mTOR) in the ventromedial hypothalamus blocks anorexia induced by GLP-1R activation in this brain nucleus (1). Therefore, the goal of the present studies is to elucidate the mechanisms by which GLP-1R activation stimulates mTOR signaling. To accomplish this, we treated Chinese Hamster Ovary cells stably expressing the human GLP-1R with the GLP-1R agonist liraglutide (Lira) in combination with inhibitors of various signaling molecules. Since PKA is a canonical target of GLP-1R signaling, and PKA phosphorylates mTOR and its regulating protein Raptor following β-adrenergic stimulation (2), we used the PKA inhibitors H89 and KT 5720 to examine whether PKA is required for the stimulation of mTOR activity by Lira. We expressed myc-tagged mTOR or Raptor in GLP-1R stably expressing CHO cells, treated them with Lira, immunoprecipitated myc-mTOR or myc-Raptor, and immunoblotted for the PKA substrate RRXS/T motif. We found that Lira significantly increased PKA-substrate motif phosphorylation of myc-Raptor but not myc-mTOR, and this was blocked by pre-treatment with H89. Lira also failed to stimulate phosphorylation of a Ser791Ala Raptor mutant that cannot be phosphorylated by PKA (2). To test whether Akt, a well-known regulator of mTOR activity, contributes to the activation of mTOR signaling by Lira, we pre-treated GLP-1R stably expressing CHO cells with either of the Akt inhibitors Akt-i 1/2 and MK-2206 followed by treatment with Lira or forskolin (Fsk), a cAMP inducer and PKA activator. Pre-treatment with either Akt-i 1/2 or MK-2206 blocked mTOR activation by both Lira and Fsk. This suggests that the contribution of Akt to Lira-induced mTOR activation is likely downstream of cAMP production. Taken together, our results suggest a novel two-pronged, PKA-dependent mechanism for the stimulation of mTOR signaling following GLP-1R activation – directly via phosphorylation of Raptor and indirectly via stimulation of Akt. Future studies will assess the respective contributions and temporal dynamics of each of these pathways. Reference: (1) Burmeister et al., Am J Physiol Endocrinol Metab. 2017 Aug;313: E651–E662. (2) Liu et al., J Clin Invest. 2016;126(5):1704-1716.

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mTOR Inhibition: From Aging to Autism and Beyond

Scientifica ◽

10.1155/2013/849186 ◽

2013 ◽

Vol 2013 ◽

pp. 1-17 ◽

Cited By ~ 14

Author(s):

Matt Kaeberlein

Keyword(s):

Mtor Inhibitors ◽

Cellular Level ◽

Mtor Signaling ◽

Target Of Rapamycin ◽

Mtor Inhibition ◽

Pharmacological Modulation ◽

Related Disease ◽

Mechanistic Target Of Rapamycin ◽

Age Related ◽

Growing Body

The mechanistic target of rapamycin (mTOR) is a highly conserved protein that regulates growth and proliferation in response to environmental and hormonal cues. Broadly speaking, organisms are constantly faced with the challenge of interpreting their environment and making a decision between “grow or do not grow.” mTOR is a major component of the network that makes this decision at the cellular level and, to some extent, the tissue and organismal level as well. Although overly simplistic, this framework can be useful when considering the myriad functions ascribed to mTOR and the pleiotropic phenotypes associated with genetic or pharmacological modulation of mTOR signaling. In this review, I will consider mTOR function in this context and attempt to summarize and interpret the growing body of literature demonstrating interesting and varied effects of mTOR inhibitors. These include robust effects on a multitude of age-related parameters and pathologies, as well as several other processes not obviously linked to aging or age-related disease.

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Novel roles of mechanistic target of rapamycin signaling in regulating fetal growth†

Biology of Reproduction ◽

10.1093/biolre/ioy249 ◽

2018 ◽

Vol 100 (4) ◽

pp. 872-884 ◽

Cited By ~ 8

Author(s):

Madhulika B Gupta ◽

Thomas Jansson

Keyword(s):

Growth Factors ◽

Fetal Growth ◽

Mtor Signaling ◽

Target Of Rapamycin ◽

Fetal Life ◽

Maternal Circulation ◽

Growth And Survival ◽

Mechanistic Target Of Rapamycin ◽

Igf I ◽

Stress Signals

Abstract Mechanistic target of rapamycin (mTOR) signaling functions as a central regulator of cellular metabolism, growth, and survival in response to hormones, growth factors, nutrients, energy, and stress signals. Mechanistic TOR is therefore critical for the growth of most fetal organs, and global mTOR deletion is embryonic lethal. This review discusses emerging evidence suggesting that mTOR signaling also has a role as a critical hub in the overall homeostatic control of fetal growth, adjusting the fetal growth trajectory according to the ability of the maternal supply line to support fetal growth. In the fetus, liver mTOR governs the secretion and phosphorylation of insulin-like growth factor binding protein 1 (IGFBP-1) thereby controlling the bioavailability of insulin-like growth factors (IGF-I and IGF-II), which function as important growth hormones during fetal life. In the placenta, mTOR responds to a large number of growth-related signals, including amino acids, glucose, oxygen, folate, and growth factors, to regulate trophoblast mitochondrial respiration, nutrient transport, and protein synthesis, thereby influencing fetal growth. In the maternal compartment, mTOR is an integral part of a decidual nutrient sensor which links oxygen and nutrient availability to the phosphorylation of IGFBP-1 with preferential effects on the bioavailability of IGF-I in the maternal–fetal interface and in the maternal circulation. These new roles of mTOR signaling in the regulation fetal growth will help us better understand the molecular underpinnings of abnormal fetal growth, such as intrauterine growth restriction and fetal overgrowth, and may represent novel avenues for diagnostics and intervention in important pregnancy complications.

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Profiling of the fetal and adult rat liver transcriptome and translatome reveals discordant regulation by the mechanistic target of rapamycin (mTOR)

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00114.2015 ◽

2015 ◽

Vol 309 (1) ◽

pp. R22-R35 ◽

Cited By ~ 17

Author(s):

Joan M. Boylan ◽

Jennifer A. Sanders ◽

Nicola Neretti ◽

Philip A. Gruppuso

Keyword(s):

Liver Regeneration ◽

Ribosomal Proteins ◽

Mtor Signaling ◽

Late Gestation ◽

Target Of Rapamycin ◽

Growth Factor Signaling ◽

Translation Control ◽

Adult Rats ◽

Mechanistic Target Of Rapamycin

The mechanistic target of rapamycin (mTOR) integrates growth factor signaling, nutrient abundance, cell growth, and proliferation. On the basis of our interest in somatic growth in the late gestation fetus, we characterized the role of mTOR in the regulation of hepatic gene expression and translation initiation in fetal and adult rats. Our strategy was to manipulate mTOR signaling in vivo and then characterize the transcriptome and translating mRNA in liver tissue. In adult rats, we used the nonproliferative growth model of refeeding after a period of fasting and the proliferative model of liver regeneration following partial hepatectomy. We also studied livers from preterm fetal rats (embryonic day 19) in which fetal hepatocytes are asynchronously proliferating. All three models employed rapamycin to inhibit mTOR signaling. Analysis of the transcriptome in fasted-refed animals showed rapamycin-mediated induction of genes associated with oxidative phosphorylation. Genes associated with RNA processing were downregulated. In liver regeneration, rapamycin induced genes associated with lysosomal metabolism, steroid metabolism, and the acute phase response. In fetal animals, rapamycin inhibited expression of genes in several functional categories that were unrelated to effects in the adult animals. Translation control showed marked fetal-adult differences. In both adult models, rapamycin inhibited the translation of genes with complex 5′ untranslated regions, including those encoding ribosomal proteins. Fetal translation was resistant to the effects of rapamycin. We conclude that the mTOR pathway in liver serves distinct physiological roles in the adult and fetus, with the latter representing a condition of rapamycin resistance.

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