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MTOR RPTOR (1 - 10 of 10)
PMID: 19117990
Distinct roles for mammalian target of rapamycin complexes in the fibroblast response to transforming growth factor-beta.
mTORC2 promotes ... is required for ... not mTORC1 activation ...   (details)

MTOR RPTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC2   (MAPKAP1   MLST8   RICTOR   MTOR )
Theme:  mTORC1   (MLST8   RPTOR   MTOR )

PMID: 19117990

Distinct roles for mammalian target of rapamycin complexes in the fibroblast response to transforming growth factor-beta.
Source

Cancer research (1/1/2009)

Abstract

Distinct roles for mammalian target of rapamycin complexes in the fibroblast response to transforming growth factor-beta. Transforming growth factor-beta (TGF-beta) promotes a multitude of diverse biological processes, including growth arrest of epithelial cells and proliferation of fibroblasts. Although the TGF-beta signaling pathways that promote inhibition of epithelial cell growth are well characterized, less is known about the mechanisms mediating the positive response to this growth factor. Given that TGF-beta has been shown to promote fibrotic diseases and desmoplasia, identifying the fibroblast-specific TGF-beta signaling pathways is critical. Here, we investigate the role of mammalian target of rapamycin (mTOR), a known effector of phosphatidylinositol 3-kinase (PI3K) and promoter of cell growth, in the fibroblast response to TGF-beta. We show that TGF-beta activates mTOR complex 1 (mTORC1) in fibroblasts but not epithelial cells via a PI3K-Akt-TSC2-dependent pathway. Rapamycin, the pharmacologic inhibitor of mTOR, prevents TGF-beta-mediated anchorage-independent growth without affecting TGF-beta transcriptional responses or extracellular matrix protein induction. In addition to mTORC1, we also examined the role of mTORC2 in TGF-beta action. mTORC2 promotes TGF-beta-induced morphologic transformation and is required for TGF-beta-induced Akt S473 phosphorylation but not mTORC1 activation. Interestingly, both mTOR complexes are necessary for TGF-beta-mediated growth in soft agar. These results define distinct and overlapping roles for mTORC1 and mTORC2 in the fibroblast response to TGF-beta and suggest that inhibitors of mTOR signaling may be useful in treating fibrotic processes, such as desmoplasia.

PMID: 19346248
Mammalian target of rapamycin complex 1 (mTORC1) activity is associated with phosphorylation of raptor by mTOR.
... that mTOR-mediated raptor phosphorylation ...   (details)

MTOR RPTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

PMID: 19346248

Mammalian target of rapamycin complex 1 (mTORC1) activity is associated with phosphorylation of raptor by mTOR.
Source

The Journal of biological chemistry (5/29/2009)

Abstract

Mammalian target of rapamycin complex 1 (mTORC1) activity is associated with phosphorylation of raptor by mTOR. mTORC1 contains multiple proteins and plays a central role in cell growth and metabolism. Raptor (regulatory-associated protein of mammalian target of rapamycin (mTOR)), a constitutively binding protein of mTORC1, is essential for mTORC1 activity and critical for the regulation of mTORC1 activity in response to insulin signaling and nutrient and energy sufficiency. Herein we demonstrate that mTOR phosphorylates raptor in vitro and in vivo. The phosphorylated residues were identified by using phosphopeptide mapping and mutagenesis. The phosphorylation of raptor is stimulated by insulin and inhibited by rapamycin. Importantly, the site-directed mutation of raptor at one phosphorylation site, Ser (863), reduced mTORC1 activity both in vitro and in vivo. Moreover, the Ser (863) mutant prevented small GTP-binding protein Rheb from enhancing the phosphorylation of S6 kinase (S6K) in cells. Therefore, our findings indicate that mTOR-mediated raptor phosphorylation plays an important role on activation of mTORC1.

PMID: 19487463
Site-specific mTOR phosphorylation promotes mTORC1-mediated signaling and cell growth.
... -stimulated mTOR S1261 phosphorylation promotes mTORC1 autokinase ...   (details)

MTOR RPTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  mTORC1   (MLST8   RPTOR   MTOR )

PMID: 19487463

Site-specific mTOR phosphorylation promotes mTORC1-mediated signaling and cell growth.
Source

Molecular and cellular biology (August 2009)

Abstract

Site-specific mTOR phosphorylation promotes mTORC1-mediated signaling and cell growth. The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) functions as a rapamycin-sensitive environmental sensor that promotes cellular biosynthetic processes in response to growth factors and nutrients. While diverse physiological stimuli modulate mTORC1 signaling, the direct biochemical mechanisms underlying mTORC1 regulation remain poorly defined. Indeed, while three mTOR phosphorylation sites have been reported, a functional role for site-specific mTOR phosphorylation has not been demonstrated. Here we identify a new site of mTOR phosphorylation (S1261) by tandem mass spectrometry and demonstrate that insulin-phosphatidylinositol 3-kinase signaling promotes mTOR S1261 phosphorylation in both mTORC1 and mTORC2. Here we focus on mTORC1 and show that TSC/Rheb signaling promotes mTOR S1261 phosphorylation in an amino acid-dependent, rapamycin-insensitive, and autophosphorylation-independent manner. Our data reveal a functional role for mTOR S1261 phosphorylation in mTORC1 action, as S1261 phosphorylation promotes mTORC1-mediated substrate phosphorylation (e.g., p70 ribosomal protein S6 kinase 1 [S6K1] and eukaryotic initiation factor 4E binding protein 1) and cell growth to increased cell size. Moreover, Rheb-driven mTOR S2481 autophosphorylation and S6K1 phosphorylation require S1261 phosphorylation. These data provide the first evidence that site-specific mTOR phosphorylation regulates mTORC1 function and suggest a model whereby insulin-stimulated mTOR S1261 phosphorylation promotes mTORC1 autokinase activity, substrate phosphorylation, and cell growth.

PMID: 19864431
Regulation of mTOR complex 1 (mTORC1) by raptor Ser863 and multisite phosphorylation.
... that mTORC1 activation leads to raptor multisite ...   (details)

MTOR RPTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC1   (MLST8   RPTOR   MTOR )

PMID: 19864431

Regulation of mTOR complex 1 (mTORC1) by raptor Ser863 and multisite phosphorylation.
Source

The Journal of biological chemistry (1/1/2010)

Abstract

Regulation of mTOR complex 1 (mTORC1) by raptor Ser863 and multisite phosphorylation. The rapamycin-sensitive mTOR complex 1 (mTORC1) promotes protein synthesis, cell growth, and cell proliferation in response to growth factors and nutritional cues. To elucidate the poorly defined mechanisms underlying mTORC1 regulation, we have studied the phosphorylation of raptor, an mTOR-interacting partner. We have identified six raptor phosphorylation sites that lie in two centrally localized clusters (cluster 1, Ser (696) /Thr (706) and cluster 2, Ser (855) /Ser (859) /Ser (863) /Ser (877)) using tandem mass spectrometry and generated phosphospecific antibodies for each of these sites. Here we focus primarily although not exclusively on raptor Ser (863) phosphorylation. We report that insulin promotes mTORC1-associated phosphorylation of raptor Ser (863) via the canonical PI3K/TSC/Rheb pathway in a rapamycin-sensitive manner. mTORC1 activation by other stimuli (e.g. amino acids, epidermal growth factor/MAPK signaling, and cellular energy) also promote raptor Ser (863) phosphorylation. Rheb overexpression increases phosphorylation on raptor Ser (863) as well as on the five other identified sites (e.g. Ser (859), Ser (855), Ser (877), Ser (696), and Thr (706)). Strikingly, raptor Ser (863) phosphorylation is absolutely required for raptor Ser (859) and Ser (855) phosphorylation. These data suggest that mTORC1 activation leads to raptor multisite phosphorylation and that raptor Ser (863) phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation (e.g. on Ser (859) and Ser (855)). Importantly, mTORC1 containing phosphorylation site-defective raptor exhibits reduced in vitro kinase activity toward the substrate 4EBP1, with a multisite raptor 6A mutant more strongly defective that single-site raptor S863A. Taken together, these data suggest that complex raptor phosphorylation functions as a biochemical rheostat that modulates mTORC1 signaling in accordance with environmental cues.

PMID: 21307646
Mammalian target of rapamycin: hitting the bull's-eye for neurological disorders.
... of mTOR signaling is mediated primarily... mTORC1 and ...   (details)

MTOR RPTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC1   (MLST8   RPTOR   MTOR )
Theme:  mTOR-signaling   (RPTOR   MTOR )

PMID: 21307646

Mammalian target of rapamycin: hitting the bull's-eye for neurological disorders.
Source

Oxidative medicine and cellular longevity (0)

Abstract

Mammalian target of rapamycin: hitting the bull's-eye for neurological disorders. The mammalian target of rapamycin (mTOR) and its associated cell signaling pathways have garnered significant attention for their roles in cell biology and oncology. Interestingly, the explosion of information in this field has linked mTOR to neurological diseases with promising initial studies. mTOR, a 289 kDa serine/threonine protein kinase, plays an important role in cell growth and proliferation and is activated through phosphorylation in response to growth factors, mitogens, and hormones. Growth factors, amino acids, cellular nutrients, and oxygen deficiency can down-regulate mTOR activity. The function of mTOR signaling is mediated primarily through two mTOR complexes: mTORC1 and mTORC2. mTORC1 initiates cap-dependent protein translation, a rate-limiting step of protein synthesis, through the phosphorylation of the targets eukaryotic initiation factor 4E-binding protein 1 (4EBP1) and p70 ribosomal S6 kinase (p70S6K). In contrast, mTORC2 regulates development of the cytoskeleton and also controls cell survival. Although closely tied to tumorigenesis, mTOR and the downstream signaling pathways are significantly involved in the central nervous system (CNS) with synaptic plasticity, memory retention, neuroendocrine regulation associated with food intake and puberty, and modulation of neuronal repair following injury. The signaling pathways of mTOR also are believed to be a significant component in a number of neurological diseases, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, tuberous sclerosis, neurofibromatosis, fragile X syndrome, epilepsy, traumatic brain injury, and ischemic stroke. Here we describe the role of mTOR in the CNS and illustrate the potential for new strategies directed against neurological disorders.

PMID: 21576368
mTOR kinase domain phosphorylation promotes mTORC1 signaling, cell growth, and cell cycle progression.
mTOR kinase ... phosphorylation promotes mTORC1 signaling ...   (details)

MTOR RPTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  mTORC1   (MLST8   RPTOR   MTOR )

PMID: 21576368

mTOR kinase domain phosphorylation promotes mTORC1 signaling, cell growth, and cell cycle progression.
Source

Molecular and cellular biology (July 2011)

Abstract

mTOR kinase domain phosphorylation promotes mTORC1 signaling, cell growth, and cell cycle progression. 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.

PMID: 21763421
cAMP inhibits mammalian target of rapamycin complex-1 and -2 (mTORC1 and 2) by promoting complex dissociation and inhibiting mTOR kinase activity.
... of mTORC1/2 is caused by ... in mTOR catalytic ...   (details)

MTOR RPTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  mTORC1   (MLST8   RPTOR   MTOR )

PMID: 21763421

cAMP inhibits mammalian target of rapamycin complex-1 and -2 (mTORC1 and 2) by promoting complex dissociation and inhibiting mTOR kinase activity.
Source

Cellular signalling (December 2011)

Abstract

cAMP inhibits mammalian target of rapamycin complex-1 and -2 (mTORC1 and 2) by promoting complex dissociation and inhibiting mTOR kinase activity. cAMP and mTOR signalling pathways control a number of critical cellular processes including metabolism, protein synthesis, proliferation and cell survival and therefore understanding the signalling events which integrate these two signalling pathways is of particular interest. In this study, we show that the pharmacological elevation of [cAMP] (i) in mouse embryonic fibroblasts (MEFs) and human embryonic kidney 293 (HEK293) cells inhibits mTORC1 activation via a PKA-dependent mechanism. Although the inhibitory effect of cAMP on mTOR could be mediated by impinging on signalling cascades (i.e. PKB, MAPK and AMPK) that inhibit TSC1/2, an upstream negative regulator of mTORC1, we show that cAMP inhibits mTORC1 in TSC2 knockout (TSC2 (-/-)) MEFs. We also show that cAMP inhibits insulin and amino acid-stimulated mTORC1 activation independently of Rheb, Rag GTPases, TSC2, PKB, MAPK and AMPK, indicating that cAMP may act independently of known regulatory inputs into mTOR. Moreover, we show that the prolonged elevation in [cAMP] (i) can also inhibit mTORC2. We provide evidence that this cAMP-dependent inhibition of mTORC1/2 is caused by the dissociation of mTORC1 and 2 and a reduction in mTOR catalytic activity, as determined by its auto-phosphorylation on Ser2481. Taken together, these results provide an important insight into how cAMP signals to mTOR and down-regulates its activity, which may lead to the identification of novel drug targets to inhibit mTOR that could be used for the treatment and prevention of human diseases such as cancer.

PMID: 22140653
mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling.
mTOR kinase inhibitors block mTORC1 and ...   (details)

MTOR RPTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  mTORC1   (MLST8   RPTOR   MTOR )

PMID: 22140653

mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling.
Source

Cancer discovery (August 2011)

Abstract

mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. mTOR kinase inhibitors block mTORC1 and mTORC2 and thus do not cause the mTORC2 activation of AKT observed with rapamycin. We now show, however, that these drugs have a biphasic effect on AKT. Inhibition of mTORC2 leads to AKT serine 473 (S473) dephosphorylation and a rapid but transient inhibition of AKT T308 phosphorylation and AKT signaling. However, inhibition of mTOR kinase also relieves feedback inhibition of receptor tyrosine kinases (RTK), leading to subsequent phosphoinositide 3-kinase activation and rephosphorylation of AKT T308 sufficient to reactivate AKT activity and signaling. Thus, catalytic inhibition of mTOR kinase leads to a new steady state characterized by profound suppression of mTORC1 and accumulation of activated AKT phosphorylated on T308, but not S473. Combined inhibition of mTOR kinase and the induced RTKs fully abolishes AKT signaling and results in substantial cell death and tumor regression in vivo. These findings reveal the adaptive capabilities of oncogenic signaling networks and the limitations of monotherapy for inhibiting feedback-regulated pathways. SIGNIFICANCE: The results of this study show the adaptive capabilities of oncogenic signaling networks, as AKT signaling becomes reactivated through a feedback-induced AKT species phosphorylated on T308 but lacking S473. The addition of RTK inhibitors can prevent this reactivation of AKT signaling and cause profound cell death and tumor regression in vivo, highlighting the possible need for combinatorial approaches to block feedback-regulated pathways.

PMID: 22425248
Transcription factor Foxo1 represses T-bet-mediated effector functions and promotes memory CD8(+) T cell differentiation.
... of mTORC1 abrogated mTORC2-mediated Akt ...   (details)

MTOR RPTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC2   (MAPKAP1   MLST8   RICTOR   MTOR )
Theme:  mTORC1   (MLST8   RPTOR   MTOR )

PMID: 22425248

Transcription factor Foxo1 represses T-bet-mediated effector functions and promotes memory CD8(+) T cell differentiation.
Source

Immunity (3/23/2012)

Abstract

Transcription factor Foxo1 represses T-bet-mediated effector functions and promotes memory CD8 (+) T cell differentiation. The evolutionary conserved Foxo transcription factors are important regulators of quiescence and longevity. Although, Foxo1 is known to be important in regulating CD8 (+) T cell trafficking and homeostasis, its role in functional differentiation of antigen-stimulated CD8 (+) T cells is unclear. Herein, we demonstrate that inactivation of Foxo1 was essential for instructing T-bet transcription factor-mediated effector differentiation of CD8 (+) T cells. The Foxo1 inactivation was dependent on mTORC1 kinase, given that blockade of mTORC1 abrogated mTORC2-mediated Akt (Ser473) kinase phosphorylation, resulting in Foxo1-dependent switch from T-bet to Eomesodermin transcription factor activation and increase in memory precursors. Silencing Foxo1 ablated interleukin-12- and rapamycin-enhanced CD8 (+) T cell memory responses and restored T-bet-mediated effector functions. These results demonstrate an essential role of Foxo1 in actively repressing effector or terminal differentiation processes to promote memory CD8 (+) T cell development and identify the functionally diverse mechanisms utilized by Foxo1 to promote quiescence and longevity.

PMID: 22980037
Shedding new light on neurodegenerative diseases through the mammalian target of rapamycin.
mTOR signaling is dependent upon ... and mTORC2 complexes ...   (details)

MTOR RPTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC2   (MAPKAP1   MLST8   RICTOR   MTOR )
Theme:  mTOR-signaling   (MLST8   RPTOR   MTOR )

PMID: 22980037

Shedding new light on neurodegenerative diseases through the mammalian target of rapamycin.
Source

Progress in neurobiology (November 2012)

Abstract

Shedding new light on neurodegenerative diseases through the mammalian target of rapamycin. Neurodegenerative disorders affect a significant portion of the world's population leading to either disability or death for almost 30 million individuals worldwide. One novel therapeutic target that may offer promise for multiple disease entities that involve Alzheimer's disease, Parkinson's disease, epilepsy, trauma, stroke, and tumors of the nervous system is the mammalian target of rapamycin (mTOR). mTOR signaling is dependent upon the mTORC1 and mTORC2 complexes that are composed of mTOR and several regulatory proteins including the tuberous sclerosis complex (TSC1, hamartin/TSC2, tuberin). Through a number of integrated cell signaling pathways that involve those of mTORC1 and mTORC2 as well as more novel signaling tied to cytokines, Wnt, and forkhead, mTOR can foster stem cellular proliferation, tissue repair and longevity, and synaptic growth by modulating mechanisms that foster both apoptosis and autophagy. Yet, mTOR through its proliferative capacity may sometimes be detrimental to central nervous system recovery and even promote tumorigenesis. Further knowledge of mTOR and the critical pathways governed by this serine/threonine protein kinase can bring new light for neurodegeneration and other related diseases that currently require new and robust treatments.