mTOR Signaling in Growth Control and Disease

Cell, Journal Year: 2012, Volume and Issue: 149(2), P. 274 - 293

Published: April 1, 2012

Language: Английский

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mTOR Signaling in Growth, Metabolism, and Disease

Cell, Journal Year: 2017, Volume and Issue: 168(6), P. 960 - 976

Published: March 1, 2017

Language: Английский

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mTOR: from growth signal integration to cancer, diabetes and ageing

Nature Reviews Molecular Cell Biology, Journal Year: 2010, Volume and Issue: 12(1), P. 21 - 35

Published: Dec. 15, 2010

Language: Английский

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Defining the Role of mTOR in Cancer

Cancer Cell, Journal Year: 2007, Volume and Issue: 12(1), P. 9 - 22

Published: July 1, 2007

Language: Английский

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Molecular mechanisms of mTOR-mediated translational control

Nature Reviews Molecular Cell Biology, Journal Year: 2009, Volume and Issue: 10(5), P. 307 - 318

Published: April 2, 2009

Language: Английский

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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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mTOR signaling at a glance

Journal of Cell Science, Journal Year: 2009, Volume and Issue: 122(20), P. 3589 - 3594

Published: Oct. 7, 2009

The mammalian target of rapamycin (mTOR) signaling pathway integrates both intracellular and extracellular signals serves as a central regulator cell metabolism, growth, proliferation survival. Discoveries that have been made over the last decade show mTOR is activated during various cellular processes (e.g. tumor formation angiogenesis, insulin resistance, adipogenesis T-lymphocyte activation) deregulated in human diseases such cancer type 2 diabetes. These observations attracted broad scientific clinical interest mTOR. This highlighted by growing use inhibitors [rapamycin its analogues (rapalogues)] pathological settings, including treatment solid tumors, organ transplantation, coronary restenosis rheumatoid arthritis. Here, we highlight summarize current understanding how nucleates distinct multi-protein complexes, intra- are processed affect survival.The protein 289-kDa serine-threonine kinase belongs to phospho-inositide 3-kinase (PI3K)-related family conserved throughout evolution. poster depicts an overview structural domains. at least two complex 1 (mTORC1) (mTORC2) (reviewed Guertin Sabatini, 2007).mTORC1 has five components: mTOR, which catalytic subunit complex; regulatory-associated (Raptor); lethal with Sec13 8 (mLST8, also known GβL); proline-rich AKT substrate 40 kDa (PRAS40); DEP-domain-containing mTOR-interacting (Deptor) (Peterson et al., 2009). exact function most proteins mTORC1 still remains elusive. It proposed Raptor might activity regulating assembly recruiting substrates for (Hara 2002; Kim 2002). role mLST8 unclear, deletion this does not vivo (Guertin 2006). PRAS40 Deptor characterized negative regulators 2009; Sancak 2007; Vander Haar 2007). When reduced, recruited complex, where they promote inhibition mTORC1. was regulates functioning direct inhibitor binding (Wang Upon activation, directly phosphorylates Deptor, reduces their physical interaction further activates Wang 2007).mTORC2 comprises six different proteins, several common mTORC2: mTOR; rapamycin-insensitive companion (Rictor); stress-activated interacting (mSIN1); observed Rictor-1 (Protor-1); mLST8; Deptor. There some evidence Rictor mSIN1 stabilize each other, establishing foundation mTORC2 (Frias 2006; Jacinto interacts Protor-1, but physiological clear (Thedieck Woo Similar mTORC1, negatively 2009); so far, only endogenous mTORC2. Finally, essential function, knockout severely stability 2006).Now many identified, additional biochemical studies will be needed clarify functions these potential implications health disease. Below, discuss mTORC2.mTORC1 positively growth promoting anabolic processes, biosynthesis lipids organelles, limiting catabolic autophagy. Much knowledge about comes from bacterial macrolide rapamycin. entering cell, binds FK506-binding 12 (FKBP12) FKBP12-rapamycin domain (FRB) thus inhibiting In contrast effect on cannot physically interact or acutely inhibit (Jacinto 2004; Sarbassov 2004). On basis observations, respectively rapamycin-sensitive complexes. However, paradigm entirely accurate, chronic can, cases, blocking (Sarbassov addition, recent reports suggest important resistant (Choo 2008; Feldman Garcia-Martinez Thoreen 2009).mTORC1 controls synthesis, required through downstream effectors. promotes synthesis phosphorylating eukaryotic initiation factor 4E (eIF4E)-binding (4E-BP1) p70 ribosomal S6 (S6K1). phosphorylation 4E-BP1 prevents eIF4E, enabling eIF4E cap-dependent translation Richter Sonenberg, 2005). stimulation S6K1 leads increases mRNA biogenesis, elongation, regulation aly/REF-like (SKAR), programmed death 4 (PDCD4), elongation (eEF2K) Ma Blenis, activation shown ribosome biogenesis stimulating transcription RNA process involving phosphatase 2A (PP2A) IA (TIF-IA) (Mayer 2004).Autophagy – is, sequestration intra - components within autophagosomes degradation lysosomes organelle turnover. nutrient availability limited, organelles complexes autophagy provides biological material sustain energy production. Studies autophagy, whereas Codogno Meier, We unknown mechanism essentially insensitive (Thoreen recently three independent groups composed unc-51-like (ULK1), autophagy-related gene 13 (ATG13) focal adhesion family-interacting 200 (FIP200) (Ganley Hosokawa Jung revealed represses thereby repressing ULK1 ATG13.The lipid proliferation, beginning appreciated. demonstrated sterol regulatory element (SREBP1) (Porstmann 2008) peroxisome proliferator-activated receptor-γ (PPARγ) (Kim Chen, 2004), factors control expression genes encoding involved cholesterol homeostasis. Blocking transactivation PPARγ molecular SREBP1 unknown. Additionally, lipin-1 (Huffman 2002), phosphatidic acid (PA) glycerolipid coactivation linked PPARγ, PPARα PGC1-α. precise impact established.Mitochondrial metabolism regulated Inhibition lowers mitochondrial membrane potential, oxygen consumption ATP levels, profoundly alters phosphoproteome (Schieke Recently, it DNA copy number, well oxidative reduced increased mutations activate (Chen Cunningham conditional mouse skeletal muscle (Bentzinger 2008). colleagues discovered transcriptional coactivator (PGC1-α), nuclear cofactor plays key altering another factor, namely yin-yang (YY1) (Cunningham four major factors, status, amino acids regulate promotion growth. One sensors tuberous sclerosis (TSC), heterodimer TSC1 (also hamartin) TSC2 tuberin). TSC1/2 GTPase-activating (GAP) small Ras-related GTPase Rheb (Ras homolog enriched brain). active, GTP-bound form stimulate (Long 2005; determined. As Rheb-specific GAP, converting into inactive GDP-bound state (Inoki 2003; Tee 2003). Consistent inactivating loss heterozygosity give rise sclerosis, disease associated presence numerous benign tumors enlarged disorganized cells Crino 2006).Growth canonical Ras pathways. pathways B (PKB, AKT) Potter extracellular-signal-regulated 1/2 (ERK1/2) (Ma 2005), p90 (RSK1) (Roux inactivation can TSC1/2-independent manner dissociation (Sancak 2007).The cell-surface receptor tyrosine receptor, recruitment (IRS1), production phosphatidylinositol (3,4,5)-triphosphate [PtdIns(3,4,5)P3] PI3K, plasma membrane. types, strongly PI3K-AKT axis upstream PI3K. Activation IRS1 Harrington auto-regulatory pathway, S6K1-dependent feedback loop, profound metabolic tumorigenesis Manning, Other likely contribute retro-inhibition For example, suppresses platelet-derived (PDGFR) (Zhang How PDGFR determined.The status signaled AMP-activated (AMPK), master sensor Hardie, response depletion (low ATP:ADP ratio), AMPK TSC2, GAP towards reduce (Gwinn 2008).Oxygen levels multiple Wouters Koritzinsky, Under conditions mild hypoxia, reduction AMPK, inhibits described previous section (Arsham Liu Hypoxia damage (REDD1) (Brugarolas Reiling Hafen, REDD1 blocks releasing growth-factor-induced association 14-3-3 (DeYoung ability disrupting probably evolved limit energy-consuming when oxygen, scarce. promyelocytic leukemia (PML) suppressor BCL2/adenovirus E1B 19 protein-interacting 3 (BNIP3) hypoxia between positive (Bernardi Li 2007).Amino represent strong signal leucine, transported glutamine-dependent fashion (Nicklin Glutamine, imported SLC1A5 [solute carrier (neutral transporter) member 5], exchanged import leucine via heterodimeric system SLC7A5 [antiport solute 7 (cationic transporter, y+ system, 5] SLC3A2 (activators dibasic neutral transport) 2]. then remained obscure years. TSC1/2, because sensitive deprivation lack (Nobukuni Some implicated vacuolar protein-sorting-associated 34 (VPS34) sensing 2005); however, VPS34 established (Juhasz 2008).Recently, teams, ours, Rag related GTPases, acid-sensitive necessary acids, bind relocalization discrete locations cytoplasm perinuclear region contains activator explain why activators Rheb, absence acids.In addition above, other signals, genotoxic stress, inflammation, Wnt ligand PA, all signaling. Genotoxic stress mechanisms. instance, p53 rapidly process, turn (Feng increasing tensin deleted chromosome 10 (PTEN) Stambolic 2001). Inflammatory mediators complex. Pro-inflammatory cytokines, TNFα, IκB kinase-β (IKKβ), inactivates TSC1, leading (Lee relationship inflammation thought angiogenesis 2007) development resistance TSC1/2. Stimulation glycogen synthase (GSK3), PA identified Many exogenous overexpression PA-producing enzymes phospholipase D1 (PLD1) PLD2 significantly Foster, A study suggests affects facilitating stabilizing (Toschi 2009).In defined (see above), relatively little biology. early lethality caused mice, inhibitors, complicated Nonetheless, discoveries few Using genetic approaches, roles survival, cytoskeleton organization. discussed more detail below.Cell highly dependent AKT, effectors Manning Cantley, Full requires sites: Ser308, phosphoinositide-dependent (PDK1), Ser473, unidentified years, our group 2005 subsequently ablation specifically Ser473 some, all, following of, therefore activates, forkhead box O1 (FoxO1) FoxO3a cell-cycle arrest apoptosis Calnan Brunet, By contrast, GSK3 affected inactivation. serum- glucocorticoid-induced (SGK1), shares homology (Garcia-Martinez Alessi, retains basal inhibited, SGK1 totally abrogated under conditions. Because phosphorylate FoxO1 sites, possible mTORC2-deficient responsible FoxO3a.mTORC2 cytoskeletal knocking down actin polymerization perturbs morphology suggested Cα (PKCα) phosphorylation, paxillin adhesions, GTP loading RhoA Rac1. lead characterized. increase considered plausible With growth-factor stimulation, phosphorylated PtdIns(3,4,5)P3 pleckstrin (PH) domain. conditions, PDK1 PH Ser308 Lawlor Interestingly, component possesses C-terminus, suggesting translocation Ser473. Additional work support model identify play mTORC2.Over decade, greatly progressed, researchers better understand Despite advances, network far complete questions remain answered. control? integrated other? What adult tissues organs what dysfunction dysregulation disease? Are there processes? Finding answers advance biology, help therapeutic avenues treat diseases.

Language: Английский

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mTOR regulation of autophagy

FEBS Letters, Journal Year: 2010, Volume and Issue: 584(7), P. 1287 - 1295

Published: Jan. 18, 2010

Nutrient starvation induces autophagy in eukaryotic cells through inhibition of TOR (target rapamycin), an evolutionarily‐conserved protein kinase. TOR, as a central regulator cell growth, plays key role at the interface pathways that coordinately regulate balance between growth and response to nutritional status, factor stress signals. Although has been known for more than decade, underlying regulatory mechanisms have not clearly understood. This review discusses recent advances understanding mechanism by which regulates with focus on mammalian (mTOR) its regulation machinery.

Language: Английский

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Activation of a Metabolic Gene Regulatory Network Downstream of mTOR Complex 1

Molecular Cell, Journal Year: 2010, Volume and Issue: 39(2), P. 171 - 183

Published: July 1, 2010

Language: Английский

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FoxO3 Controls Autophagy in Skeletal Muscle In Vivo

Cell Metabolism, Journal Year: 2007, Volume and Issue: 6(6), P. 458 - 471

Published: Dec. 1, 2007

Language: Английский

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