Faculty Opinions recommendation of Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1.

The mechanistic Target of Rapamycin complex 1 (mTORC1) senses intracellular amino acid levels through an intricate machinery, which includes the Rag GTPases, Ragulator and vacuolar ATPase (V-ATPase). The membrane-associated E3 ubiquitin ligase ZNRF2 is released into the cytosol upon its phosphorylation by Akt. In this study, we show that ZNRF2 interacts with mTOR on membranes, promoting the amino acid-stimulated translocation of mTORC1 to lysosomes and its activation in human cells. ZNRF2 also interacts with the V-ATPase and preserves lysosomal acidity. Moreover, knockdown of ZNRF2 decreases cell size and cell proliferation. Upon growth factor and amino acid stimulation, mTORC1 phosphorylates ZNRF2 on Ser145, and this phosphosite is dephosphorylated by protein phosphatase 6. Ser145 phosphorylation stimulates vesicle-to-cytosol translocation of ZNRF2 and forms a novel negative feedback on mTORC1. Our findings uncover ZNRF2 as a component of the amino acid sensing machinery that acts upstream of Rag-GTPases and the V-ATPase to activate mTORC1.

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Ragulator Is a GEF for the Rag GTPases that Signal Amino Acid Levels to mTORC1

Cell ◽

10.1016/j.cell.2012.07.032 ◽

2012 ◽

Vol 150 (6) ◽

pp. 1196-1208 ◽

Cited By ~ 529

Author(s):

Liron Bar-Peled ◽

Lawrence D. Schweitzer ◽

Roberto Zoncu ◽

David M. Sabatini

Keyword(s):

Amino Acid ◽

Rag Gtpases ◽

Amino Acid Levels

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Faculty Opinions recommendation of A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718014198.793478051 ◽

2013 ◽

Author(s):

Kun-Liang Guan

Keyword(s):

Amino Acid ◽

Tumor Suppressor ◽

Rag Gtpases

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Effects of amino acid levels during rearing on Cobb 500 slow-feathering broiler breeders: 1. Growth and development

Poultry Science ◽

10.1016/j.psj.2021.101327 ◽

2021 ◽

pp. 101327

Author(s):

Maria Camila Alfaro-Wisaquillo ◽

Edgar O. Oviedo-Rondón ◽

Hernan A. Cordova-Noboa ◽

Justina V. Caldas ◽

Gustavo A. Quintana-Ospina ◽

...

Keyword(s):

Amino Acid ◽

Growth And Development ◽

Broiler Breeders ◽

Amino Acid Levels

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88 Benefits of increasing amino acid intake in late gestation in prolific sows

Journal of Animal Science ◽

10.1093/jas/skaa054.136 ◽

2020 ◽

Vol 98 (Supplement_3) ◽

pp. 76-76

Author(s):

Ron Ball ◽

Crystal L Levesque ◽

D J Cadogan

Keyword(s):

Birth Weight ◽

Amino Acid ◽

Reproductive Performance ◽

Essential Amino Acid ◽

Control Diet ◽

Genetic Selection ◽

Late Gestation ◽

Negative Effects ◽

Amino Acid Levels ◽

The Many

Abstract Most sows are fed a constant energy and amino acid supply throughout gestation, in line with the recommendations of most authorities and swine genetic companies. These recommendations for sow feeding have seen little change in decades, despite the many ways that sows have changed dramatically in reproductive performance. Beginning in about the year 2000, sow litter size has steadily increased as a result of genetic selection. With this increase in litter number has been a steady decline in birth weight, and the resulting negative effects of lower birthweight on subsequent piglet performance. Many experiments using so-called ‘bump’ feeding, or increased energy intake in late gestation, have been conducted in attempts to arrest this decline in birthweight and piglet performance. Generally, these experiments have shown little to no improvement in birthweight and often have negative effects on sow feed intake during gestation. These experiments have ignored the fact that the energy:amino acid ratios (lysine, threonine, isoleucine, tryptophan) in late gestation are different than during early and mid-gestation. In recent research in Australia we hypothesised that rapidly increasing essential amino acid levels in late gestation would increase birth weight and potentially improve subsequent reproductive performance. Three hundred and thirty-four multiparous PIC sows (average parity 3.6, average LW 261 kg) were housed in a dynamic gestation pen after mating and randomly assigned to one of two diet regimes. Two 13.5 MJ/kg DE gestation diets were formulated and created by blending in an ESF. The Control diet contained 0.48 g SID lysine per MJ DE and SID threonine, methionine+ cysteine, isoleucine and tryptophan at 68%, 65%, 58% and18% of SID lysine and offered at 2.2kg/day from d 28 to d 110. Sow were then moved to the farrowing house and placed on a lactation diet at 3.5kg/d. The Treatment diet contained 0.55 g SID lysine/MJ DE and SID threonine, methionine+cysteine, isoleucine and tryptophan at 78%, 65%, 60% and 20% of SID lysine and offered at 2.1kg/d from d 28 to d 85 and then increased to 2.4 kg/d to d 110 d. Increasing essential amino acid levels in late gestation increased gestational weight gain (5.6 kg, P=0.004), increased total litter birth weight (1.25 kg, P=0.003), and increased the birthweight of liveborn pigs from 1.286 to 1.329 kg, (P=0.04). There was no significant effect on the total number born or born alive. Piglet performance is not available because this commercial farm practices cross-fostering. Effects of continuation of this feeding regime in the same sows during subsequent parities is currently being evaluated.

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THE EFFECT OF GROWTH AND ADRENOCORTICOTROPIC HORMONES ON THE AMINO ACID LEVELS IN THE PLASMA

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)57061-7 ◽

1949 ◽

Vol 177 (1) ◽

pp. 91-95 ◽

Cited By ~ 7

Author(s):

Choh.Hao. Li ◽

I. Geschwind ◽

Herbert M. Evans

Keyword(s):

Amino Acid ◽

Amino Acid Levels

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Fetal sex modulates placental microRNA expression, potential microRNA-mRNA interactions, and levels of amino acid transporter expression and substrates: INFAT study subpopulation analysis of n-3 LCPUFA intervention during pregnancy and associations with offspring body composition

BMC Molecular and Cell Biology ◽

10.1186/s12860-021-00345-x ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Eva-Maria Sedlmeier ◽

Dorothy M. Meyer ◽

Lynne Stecher ◽

Manuela Sailer ◽

Hannelore Daniel ◽

...

Keyword(s):

Body Composition ◽

Amino Acid ◽

Amino Acid Transporter ◽

Microrna Expression ◽

Sexually Dimorphic ◽

Mrna Levels ◽

Control Male ◽

Cord Plasma ◽

Amino Acid Levels ◽

Acid Transporter

Abstract Background Previously, we revealed sexually dimorphic mRNA expression and responsiveness to maternal dietary supplementation with n-3 long-chain polyunsaturated fatty acids (LCPUFA) in placentas from a defined INFAT study subpopulation. Here, we extended these analyses and explored the respective placental microRNA expression, putative microRNA-mRNA interactions, and downstream target processes as well as their associations with INFAT offspring body composition. Results We performed explorative placental microRNA profiling, predicted microRNA-mRNA interactions by bioinformatics, validated placental target microRNAs and their putative targets by RT-qPCR and western blotting, and measured amino acid levels in maternal and offspring cord blood plasma and placenta. microRNA, mRNA, protein, and amino acid levels were associated with each other and with offspring body composition from birth to 5 years of age. Forty-six differentially regulated microRNAs were found. Validations identified differential expression for microRNA-99a (miR-99a) and its predicted target genes mTOR, SLC7A5, encoding L-type amino acid transporter 1 (LAT1), and SLC6A6, encoding taurine transporter (TauT), and their prevailing significant sexually dimorphic regulation. Target mRNA levels were mostly higher in placentas from control male than from female offspring, whereas respective n-3 LCPUFA responsive target upregulation was predominantly found in female placentas, explaining the rather balanced expression levels between the sexes present only in the intervention group. LAT1 and TauT substrates tryptophan and taurine, respectively, were significantly altered in both maternal plasma at 32 weeks’ gestation and cord plasma following intervention, but not in the placenta. Several significant associations were observed for miR-99a, mTOR mRNA, SLC7A5 mRNA, and taurine and tryptophan in maternal and cord plasma with offspring body composition at birth, 1 year, 3 and 5 years of age. Conclusions Our data suggest that the analyzed targets may be part of a sexually dimorphic molecular regulatory network in the placenta, possibly modulating gene expression per se and/or counteracting n-3 LCPUFA responsive changes, and thereby stabilizing respective placental and fetal amino acid levels. Our data propose placental miR-99, SLC7A5 mRNA, and taurine and tryptophan levels in maternal and fetal plasma as potentially predictive biomarkers for offspring body composition.

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