What controls TOR?

Jacinto, Estela

doi:10.1002/iub.56

Cited by 36 publications

(43 citation statements)

References 144 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The mTORC1 signaling pathway is a complex regulatory mechanism that can sense and respond to the availability of nutrients, energy, stress, and mitogens to modulate protein synthesis (21,22,27). Upon its activation, mTORC1 catalyzes the phosphorylation of S6K1 at its Thr-389 residue leading to its activation, which in turn phosphorylates rpS6.…”

Section: Resultsmentioning

confidence: 99%

“…The mammalian target of rapamycin (mTOR), a key Ser-Thr kinase highly conserved from yeast to mammals, exists intracellularly in two functionally distinct complexes, mTORC1 and mTORC2 (21)(22)(23). mTORC1 consists of the mTOR catalytic subunit and associated proteins raptor, PRAS40, and mLST8/ G␤L.…”

mentioning

confidence: 99%

“…This complex is involved in the regulation of protein synthesis, cell growth, proliferation, and autophagy in a nutrientand energy-responsive manner. It has been shown that activation of mTORC1 leads to the rapamycin-sensitive phosphorylation of S6K1, which in turn phosphorylates ribosomal S6 protein (rpS6) (21)(22)(23)(24)(25). The mTORC2 is activated by growth factors via a mechanism involving mTOR, rictor, mLST8/G␤L, mSin1, and protor.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Mammalian Target of Rapamycin Complex 1 (mTORC1) Plays a Role in Pasteurella multocida Toxin (PMT)-induced Protein Synthesis and Proliferation in Swiss 3T3 Cells

Oubrahim

Wong

Wilson

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Pasteurella multocida toxin (PMT) is a highly mitogenic bacterial protein whose detailed mechanism is not well understood. Results: PMT deamidates and activates G␣ q/11 leading to mTORC1 activation. Conclusion: G␣ q/11 /PLC␤/PKC-mediated mTORC1 activation is at least partially responsible for PMT-induced cell growth, migration, and proliferation in Swiss 3T3 cells. Significance: Understanding PMT-induced mTORC1 activation could help elucidate mechanisms of oncogene regulation.

show abstract

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Mammalian Target of Rapamycin Complex 1 (mTORC1) Plays a Role in Pasteurella multocida Toxin (PMT)-induced Protein Synthesis and Proliferation in Swiss 3T3 Cells

Oubrahim

Wong

Wilson

et al. 2013

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…These findings suggested that inhibition of mTOR intrinsic catalytic activity cannot explain the mechanism of action of rapamycin or amino acid withdrawal on mTOR-mediated signaling (45). Thus, alternate mechanisms have been postulated (46). Rapamycin binding could theoretically hinder reception of upstream activating signals or impair access of docked substrates to the mTOR catalytic domain without affecting mTOR intrinsic catalytic activity; alternatively, rapamycin binding could lead to activation of a phosphatase that dephosphorylates mTORC1 substrates (47).…”

mentioning

confidence: 99%

mTOR Ser-2481 Autophosphorylation Monitors mTORC-specific Catalytic Activity and Clarifies Rapamycin Mechanism of Action

Soliman

Acosta-Jaquez

Dunlop

et al. 2010

Journal of Biological Chemistry

196

159

View full text Add to dashboard Cite

The mammalian target of rapamycin (mTOR) Ser/Thr kinase signals in at least two multiprotein complexes distinguished by their different partners and sensitivities to rapamycin. Acute rapamycin inhibits signaling by mTOR complex 1 (mTORC1) but not mTOR complex 2 (mTORC2), which both promote cell growth, proliferation, and survival. Although mTORC2 regulation remains poorly defined, diverse cellular mitogens activate mTORC1 signaling in a manner that requires sufficient levels of amino acids and cellular energy. Before the identification of distinct mTOR complexes, mTOR was reported to autophosphorylate on Ser-2481 in vivo in a rapamycin-and amino acid-insensitive manner. These results suggested that modulation of mTOR intrinsic catalytic activity does not universally underlie mTOR regulation. Here we re-examine the regulation of mTOR Ser-2481 autophosphorylation (Ser(P)-2481) in vivo by studying mTORC-specific Ser(P)-2481 in mTORC1 and mTORC2, with a primary focus on mTORC1. In contrast to previous work, we find that acute rapamycin and amino acid withdrawal markedly attenuate mTORC1-associated mTOR Ser(P)-2481 in cycling cells. Although insulin stimulates both mTORC1-and mTORC2-associated mTOR Ser(P)-2481 in a phosphatidylinositol 3-kinase-dependent manner, rapamycin acutely inhibits insulin-stimulated mTOR Ser(P)-2481 in mTORC1 but not mTORC2. By interrogating diverse mTORC1 regulatory input, we find that without exception mTORC1-activating signals promote, whereas mTORC1-inhibitory signals decrease mTORC1-associated mTOR Ser(P)-2481. These data suggest that mTORC1-and likely mTORC2-associated mTOR Ser-2481 autophosphorylation directly monitors intrinsic mTORC-specific catalytic activity and reveal that rapamycin inhibits mTORC1 signaling in vivo by reducing mTORC1 catalytic activity.

show abstract

“…Cellular mTOR regulation remains incompletely defined, however (13,24,31). mTOR senses and integrates signals from diverse environmental cues such as growth factors and hormones (i.e., insulin, insulin-like growth factor [IGF], and epidermal growth factor [EGF]), nutrients (i.e., amino acids and glucose), and cellular stresses (15,22,34,53,72). mTOR interacts with different partner proteins to form at least two functionally distinct signaling complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) (2,4).…”

mentioning

confidence: 99%

mTOR Kinase Domain Phosphorylation Promotes mTORC1 Signaling, Cell Growth, and Cell Cycle Progression

Ekim

Magnuson

Acosta-Jaquez

et al. 2011

Molecular and Cellular Biology

109

View full text Add to dashboard Cite

The mammalian target of rapamycin complex 1 (mTORC1) functions as an environmental sensor to promote critical cellular processes such as protein synthesis, cell growth, and cell proliferation in response to growth factors and nutrients. While diverse stimuli regulate mTORC1 signaling, the direct molecular mechanisms by which mTORC1 senses and responds to these signals remain poorly defined. Here we investigated the role of mTOR phosphorylation in mTORC1 function. By employing mass spectrometry and phospho-specific antibodies, we demonstrated novel phosphorylation on S2159 and T2164 within the mTOR kinase domain. Mutational analysis of these phosphorylation sites indicates that dual S2159/T2164 phosphorylation cooperatively promotes mTORC1 signaling to S6K1 and 4EBP1. Mechanistically, S2159/T2164 phosphorylation modulates the mTOR-raptor and raptor-PRAS40 interactions and augments mTORC1-associated mTOR S2481 autophosphorylation. Moreover, mTOR S2159/T2164 phosphorylation promotes cell growth and cell cycle progression. We propose a model whereby mTOR kinase domain phosphorylation modulates the interaction of mTOR with regulatory partner proteins and augments intrinsic mTORC1 kinase activity to promote biochemical signaling, cell growth, and cell cycle progression.

show abstract

What controls TOR?

Cited by 36 publications

References 144 publications

Mammalian Target of Rapamycin Complex 1 (mTORC1) Plays a Role in Pasteurella multocida Toxin (PMT)-induced Protein Synthesis and Proliferation in Swiss 3T3 Cells

Mammalian Target of Rapamycin Complex 1 (mTORC1) Plays a Role in Pasteurella multocida Toxin (PMT)-induced Protein Synthesis and Proliferation in Swiss 3T3 Cells

mTOR Ser-2481 Autophosphorylation Monitors mTORC-specific Catalytic Activity and Clarifies Rapamycin Mechanism of Action

mTOR Kinase Domain Phosphorylation Promotes mTORC1 Signaling, Cell Growth, and Cell Cycle Progression

Contact Info

Product

Resources

About