Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive

Jacinto, Estela; Loewith, Robbie; Schmidt, Anja; Lin, Shuo; Rüegg, Markus A.; Hall, Alan; Hall, Michael N.

doi:10.1038/ncb1183

Cited by 1,838 publications

(1,426 citation statements)

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“…In contrast, TORC2 has different substrates and is responsible for phosphorylation of the hydrophobic sites in both AKT and PKC (9, 13). Interestingly, TORC1 but not TORC2 is inhibited by rapamycin (6,8,9). These observations clearly demonstrate that the two TOR complexes have different physiological functions in vivo.…”

mentioning

confidence: 59%

Bnip3 Mediates the Hypoxia-induced Inhibition on Mammalian Target of Rapamycin by Interacting with Rheb

Wang²,

Kim

et al. 2007

Journal of Biological Chemistry

230

193

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The mammalian target of rapamycin (mTOR) is a central controller of cell growth, and it regulates translation, cell size, cell viability, and cell morphology. mTOR integrates a wide range of extracellular and intracellular signals, including growth factors, nutrients, energy levels, and stress conditions. Rheb, a Ras-related small GTPase, is a key upstream activator of mTOR. In this study, we found that Bnip3, a hypoxia-inducible Bcl-2 homology 3 domain-containing protein, directly binds Rheb and inhibits the mTOR pathway. Bnip3 decreases Rheb GTP levels in a manner depending on the binding to Rheb and the presence of the N-terminal domain. Both knockdown and overexpression experiments show that Bnip3 plays an important role in mTOR inactivation in response to hypoxia. Moreover, Bnip3 inhibits cell growth in vivo by suppressing the mTOR pathway. These observations demonstrate that Bnip3 mediates the inhibition of the mTOR pathway in response to hypoxia.Target of rapamycin (TOR), 2 is an evolutionarily conserved serine/threonine kinase that plays a central role in cell growth (1-3). TOR regulates many processes, including protein translation, ribosome biogenesis, autophagy, and metabolism. TOR functions to integrate a wide range of extracellular and intracellular signals to produce a concerted cellular response, such as to stimulate cell growth. For example, mammalian target of rapamycin (mTOR) is activated by growth factor and nutrient availability. In contrast, mTOR is inhibited by cellular energy starvation and various stress conditions, including osmotic stress and hypoxia. These observations established a fundamental importance of mTOR in signal integration in regulation of cell growth.Recent studies have demonstrated that TOR exists in two functionally distinct protein complexes, termed TOR complex 1 (TORC1) and TOR complex 2 (TORC2) (3, 4). The two TOR complexes were initially identified in yeast and subsequently were also characterized in Drosophila and mammalian cells. TORC1 contains mTOR, mLST8, PRAS40, and Raptor, whereas TORC2 contains mTOR, mLST8, Rictor, and Sin1 (5-12). TORC1 is responsible for phosphorylation of Thr 389 of S6K1 (ribosomal protein S6 kinase) and 4EBP1 (eukaryote initiation factor 4E-binding protein), two important regulators in protein synthesis (1). In contrast, TORC2 has different substrates and is responsible for phosphorylation of the hydrophobic sites in both AKT and PKC (9, 13). Interestingly, TORC1 but not TORC2 is inhibited by rapamycin (6,8,9). These observations clearly demonstrate that the two TOR complexes have different physiological functions in vivo.Much progress has been made regarding the mechanisms of TORC1 regulation. Tuberous sclerosis complex (TSC) is a genetic disease characterized by benign hamartomas in various tissues (14). Mutations in either the TSC1 or TSC2 tumor suppressor gene are responsible for TSC development. TORC1 is highly activated in TSC tumors or cells with mutation of either TSC1 or TSC2. Both genetic and biochemical data have demonstrated th...

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mentioning

confidence: 59%

Bnip3 Mediates the Hypoxia-induced Inhibition on Mammalian Target of Rapamycin by Interacting with Rheb

Wang²,

Kim

et al. 2007

Journal of Biological Chemistry

230

193

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“…TSC2 was known to regulate actin cytoskeleton through TORC2, which is critical for NMJ growth and function (Eaton et al, 2002;Luo 2002;Loewith et al, 2002;Coyle et al, 2004;Jacinto et al, 2004;Natarajan et al, 2013). Detailed studies on synaptic growth and enlargement were not yet reported in mice and more investigations in mammals into the role of Rheb and mTORC2 (Yang et al, 2006) would help to understand the regulation of brain connectivity.…”

Section: Rheb In Synapse Size and Functionmentioning

confidence: 99%

“…TSC complex regulates the cytoskeleton via ERM (ezrin, radixin, and moesin) proteins, neurofilament light chain and activation of Rho family of proteins (Haddad et al, 2002). Whether this regulation also involves mTORC2 and its regulation of cytoskeleton (Jacinto et al, 2004) still needs to be investigated. TSC complex also regulate cofilin and induces alteration in the spine length (Haddad et al, 2002;Luo 2002;Tavazoie et al, 2005).…”

Section: Rheb In Spine Morphology and Functionmentioning

confidence: 99%

“…Recently, several signaling pathways of TSC complex and Rheb have been described that function independently of mTORC1 (Jacinto et al, 2004;Karbowniczek et al, 2006;Zhou et al, 2009;Neuman and Henske, 2011). Hence, the activation of these non-canonical pathways cause some of the clinical manifestations of TSC that are resistant to mTORC1 inhibition by rapamycin (Yasuda et al, 2014).…”

Section: Non-canonical Rheb Pathwaymentioning

confidence: 99%

“…mTORC2, in addition to mTOR and mLST8, contains the essential polypeptides: rapamycininsensitive companion of mTOR (rictor) and mammalian stress-activated map kinase-interacting protein 1 (mSin1) (Loewith et al, 2002;Sarbassov et al, 2004;Adami et al, 2007;Avruch and Long, 2009). mTORC2 may signal to the actin cytoskeleton through Rho and Rac (Jacinto et al, 2004;Sarbassov et al, 2004).…”

Section: Rheb Signaling Pathwaymentioning

confidence: 99%

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Rheb in neuronal degeneration, regeneration, and connectivity

Potheraveedu

Schöpel

Stoll

et al. 2017

Biological Chemistry

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Abstract:The small GTPase Rheb was originally detected as an immediate early response protein whose expression was induced by NMDA-dependent synaptic activity in the brain. Rheb's activity is highly regulated by its GTPase activating protein (GAP), the tuberous sclerosis complex protein, which stimulates the conversion from the active, GTP-loaded into the inactive, GDP-loaded conformation. Rheb has been established as an evolutionarily conserved molecular switch protein regulating cellular growth, cell volume, cell cycle, autophagy, and amino acid uptake. The subcellular localization of Rheb and its interacting proteins critically regulate its activity and function. In stem cells, constitutive activation of Rheb enhances differentiation at the expense of self-renewal partially explaining the adverse effects of deregulated Rheb in the mammalian brain. In the context of various cellular stress conditions such as oxidative stress, ER-stress, death factor signaling, and cellular aging, Rheb activation surprisingly enhances rather than prevents cellular degeneration. This review addresses cell type-and cell state-specific function(s) of Rheb and mainly focuses on neurons and their surrounding glial cells. Mechanisms will be discussed in the context of therapy that interferes with Rheb's activity using the antibiotic rapamycin or low molecular weight compounds.

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A historical perspective of macroautophagy regulation by biochemical and biomechanical stimuli

Dupont,

Claude‐Taupin,

Codogno

2023

FEBS Letters

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Macroautophagy is a lysosomal degradative pathway for intracellular macromolecules, protein aggregates and organelles. The formation of the autophagosome, a double membrane‐bound structure that sequesters cargoes before their delivery to the lysosome, is regulated by several stimuli in multicellular organisms. Pioneering studies in rat liver showed the importance of amino acids, insulin and glucagon in controlling macroautophagy. Thereafter, many studies have deciphered the signaling pathways downstream of these biochemical stimuli to control autophagosome formation. Two signaling hubs have emerged: the kinase mTOR, in a complex at the surface of lysosomes which is sensitive to nutrients and hormones; and AMPK, which is sensitive to the cellular energetic status. Besides nutritional, hormonal and energetic fluctuations, many organs have to respond to mechanical forces (compression, stretching and shear stress). Recent studies have shown the importance of mechanotransduction in controlling macroautophagy. This regulation engages cell surface sensors, such as the primary cilium, in order to translate mechanical stimuli into biological responses.

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Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive

Cited by 1,838 publications

References 27 publications

Bnip3 Mediates the Hypoxia-induced Inhibition on Mammalian Target of Rapamycin by Interacting with Rheb

Bnip3 Mediates the Hypoxia-induced Inhibition on Mammalian Target of Rapamycin by Interacting with Rheb

Rheb in neuronal degeneration, regeneration, and connectivity

A historical perspective of macroautophagy regulation by biochemical and biomechanical stimuli

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