mTOR at the nexus of nutrition, growth, ageing and disease

Nature Reviews Molecular Cell Biology, Journal Year: 2020, Volume and Issue: 21(4), P. 183 - 203

Published: Jan. 14, 2020

Language: Английский

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The PI3K–AKT network at the interface of oncogenic signalling and cancer metabolism

Nature reviews. Cancer, Journal Year: 2019, Volume and Issue: 20(2), P. 74 - 88

Published: Nov. 4, 2019

Language: Английский

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Cancer Cells Tune the Signaling Pathways to Empower de Novo Synthesis of Nucleotides

Cancers, Journal Year: 2019, Volume and Issue: 11(5), P. 688 - 688

Published: May 17, 2019

Cancer cells exhibit a dynamic metabolic landscape and require sufficient supply of nucleotides other macromolecules to grow proliferate. To meet the requirements for cell growth, cancer must stimulate de novo nucleotide synthesis obtain adequate pools support nucleic acid protein along with energy preservation, signaling activity, glycosylation mechanisms, cytoskeletal function. Both oncogenes tumor suppressors have recently been identified as key molecular determinants that contribute maintenance homeostasis proliferation cells. Inactivation such TP53 LKB1 hyperactivation mTOR pathway MYC, RAS, AKT shown fuel in The mechanisms by which these hubs influence metabolism, especially pathways synthesis, continue emerge. Here, we focus on current understanding modulate and, based insights, discuss potential strategies target proliferation.

Language: Английский

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The mTOR–Autophagy Axis and the Control of Metabolism

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: July 1, 2021

The mechanistic target of rapamycin (mTOR), master regulator cellular metabolism, exists in two distinct complexes: mTOR complex 1 and 2 (mTORC1 2). MTORC1 is a switch for most energetically onerous processes the cell, driving cell growth building biomass instances nutrient sufficiency, conversely, allowing autophagic recycling components upon limitation. means by which kinase blocks autophagy include direct inhibition early steps process, control lysosomal degradative capacity inhibiting transactivation genes encoding structural, regulatory, catalytic factors. Upon mTOR, results reactivation mTORC1; thus, lies both downstream upstream mTOR. functional relationship between pathway involves regulatory loops that are significantly deciphered at level, but incompletely understood physiological level. Nevertheless, genetic evidence stemming from use engineered strains mice has provided significant insight into overlapping complementary metabolic effects activity exert during fasting overload.

Language: Английский

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Quantitative analysis of T cell proteomes and environmental sensors during T cell differentiation

Nature Immunology, Journal Year: 2019, Volume and Issue: 20(11), P. 1542 - 1554

Published: Oct. 7, 2019

Language: Английский

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Antigen receptor control of methionine metabolism in T cells

eLife, Journal Year: 2019, Volume and Issue: 8

Published: March 27, 2019

Immune activated T lymphocytes modulate the activity of key metabolic pathways to support transcriptional reprograming and reshaping cell proteomes that permits effector differentiation. The present study uses high resolution mass spectrometry labelling explore how murine cells control methionine cycle produce methyl donors for protein nucleotide methylations. We show antigen receptor engagement controls flux through RNA histone establish main rate limiting step synthesis is transporter expression. Only respond upregulate sustain transport are supplied with permit dynamic methylations epigenetic reprogramming drives These data highlight regulation licenses use multiple fundamental processes drive lymphocyte proliferation

Language: Английский

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Autophagy in aging and longevity

Human Genetics, Journal Year: 2019, Volume and Issue: 139(3), P. 277 - 290

Published: May 30, 2019

Language: Английский

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The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals

eLife, Journal Year: 2021, Volume and Issue: 10

Published: March 1, 2021

The mechanistic target of rapamycin complex 1 (mTORC1) stimulates a coordinated anabolic program in response to growth-promoting signals. Paradoxically, recent studies indicate that mTORC1 can activate the transcription factor ATF4 through mechanisms distinct from its canonical induction by integrated stress (ISR). However, broader roles as downstream are unknown. Therefore, we directly compared ATF4-dependent transcriptional changes induced upon insulin-stimulated signaling those activated ISR. In multiple mouse embryo fibroblast and human cancer cell lines, mTORC1-ATF4 pathway stimulated expression only subset genes ISR, including involved amino acid uptake, synthesis, tRNA charging. We demonstrate is metabolic effector both established role promoting protein synthesis previously unappreciated function for stimulating cellular cystine uptake glutathione synthesis.

Language: Английский

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Structural basis for the docking of mTORC1 on the lysosomal surface

Science, Journal Year: 2019, Volume and Issue: 366(6464), P. 468 - 475

Published: Oct. 10, 2019

The mTORC1 (mechanistic target of rapamycin complex 1) protein kinase regulates growth in response to nutrients and factors. Nutrients promote its translocation the lysosomal surface, where Raptor subunit interacts with Rag guanosine triphosphatase (GTPase)-Ragulator complex. switch heterodimeric GTPases among four different nucleotide-binding states, only one which (RagA/B•GTP-RagC/D•GDP) permits association. We used cryo-electron microscopy determine structure supercomplex Rag-Ragulator at a resolution 3.2 angstroms. Our findings indicate that α-solenoid directly detects nucleotide state RagA while "claw" threads between GTPase domains detect RagC. Mutations disrupted Rag-Raptor binding inhibited localization signaling. By comparison bound activator Rheb, we developed model active docked on lysosome.

Language: Английский

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What is cancer metabolism?

Cell, Journal Year: 2023, Volume and Issue: 186(8), P. 1670 - 1688

Published: Feb. 28, 2023

Language: Английский

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