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MTOR MTOR (1 - 20 of 20)
PMID: 18070882
Rapid turnover of the mTOR complex 1 (mTORC1) repressor REDD1 and activation of mTORC1 signaling following inhibition of protein synthesis.
... the mTOR complex 1 (mTORC1) repressor ... and activation of mTORC1 signaling ...   (details)

MTOR MTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC1   (MLST8   RPTOR   MTOR )

PMID: 18070882

Rapid turnover of the mTOR complex 1 (mTORC1) repressor REDD1 and activation of mTORC1 signaling following inhibition of protein synthesis.
Source

The Journal of biological chemistry (2/8/2008)

Abstract

Rapid turnover of the mTOR complex 1 (mTORC1) repressor REDD1 and activation of mTORC1 signaling following inhibition of protein synthesis. mTORC1 is a complex of proteins that includes the mammalian target of rapamycin (mTOR) and several regulatory proteins. It is activated by a variety of hormones (e.g. insulin) and nutrients (e.g. amino acids) that act to stimulate cell growth and proliferation and repressed by hormones (e.g. glucocorticoids) that act to reduce cell growth. Curiously, mTORC1 signaling is reported to be rapidly (e.g. within 1-2 h) activated by inhibitors of protein synthesis that act on either mRNA translation elongation or gene transcription. However, the basis for the mTORC1 activation has not been satisfactorily delineated. In the present study, mTORC1 signaling was found to be activated in response to inhibition of either the initiation or elongation phases of mRNA translation. Changes in mTORC1 signaling were inversely proportional to alterations in the expression of the mTORC1 repressor, REDD1, but not the expression of TRB3 or TSC2. Moreover the cycloheximide-induced increase in mTORC1 signaling was significantly attenuated in cells lacking REDD1, showing that REDD1 plays an integral role in the response. Finally, the half-life of REDD1 was estimated to be 5 min or less. Overall, the results are consistent with a model in which inhibition of protein synthesis leads to a loss of REDD1 protein because of its rapid degradation, and in part reduced REDD1 expression subsequently leads to de-repression of mTORC1 activity.

PMID: 18776922
Regulation of androgen receptor transcriptional activity by rapamycin in prostate cancer cell proliferation and survival.
... and mTORC2 by ... activity resulted from ... of mTORC1, ...   (details)

MTOR MTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

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

PMID: 18776922

Regulation of androgen receptor transcriptional activity by rapamycin in prostate cancer cell proliferation and survival.
Source

Oncogene (11/27/2008)

Abstract

Regulation of androgen receptor transcriptional activity by rapamycin in prostate cancer cell proliferation and survival. The mTOR (mammalian target of rapamycin) inhibitor rapamycin caused growth arrest in both androgen-dependent and androgen-independent prostate cancer cells; however, long-term treatment induced resistance to the drug. The aim of this study was to investigate methods that can overcome this resistance. Here, we show that rapamycin treatment stimulated androgen receptor (AR) transcriptional activity, whereas suppression of AR activity with the antiandrogen bicalutamide sensitized androgen-dependent, as well as AR-sensitive androgen-independent prostate cancer cells, to growth inhibition by rapamycin. Further, the combination of rapamycin and bicalutamide, but not the individual drugs, induced significant levels of apoptosis in prostate cancer cells. The net effect of rapamycin is determined by its individual effects on the mTOR complexes mTORC1 (mTOR/raptor/GbetaL) and mTORC2 (mTOR/rictor/sin1/GbetaL). Inhibition of both mTORC1 and mTORC2 by rapamycin-induced apoptosis, whereas rapamycin-stimulation of AR transcriptional activity resulted from the inhibition of mTORC1, but not mTORC2. The effect of rapamycin on AR transcriptional activity was mediated by the phosphorylation of the serine/threonine kinase Akt, which also partially mediated apoptosis induced by rapamycin and bicalutamide. These results indicate the presence of two parallel cell-survival pathways in prostate cancer cells: a strong Akt-independent, but rapamycin-sensitive pathway downstream of mTORC1, and an AR-dependent pathway downstream of mTORC2 and Akt, that is stimulated by mTORC1 inhibition. Thus, the combination of rapamycin and bicalutamide induce apoptosis in prostate cancer cells by simultaneously inhibiting both pathways and hence would be of therapeutic value in prostate cancer treatment.

PMID: 18794129
Enhancing mammalian target of rapamycin (mTOR)-targeted cancer therapy by preventing mTOR/raptor inhibition-initiated, mTOR/rictor-independent Akt activation.
... the role of mTOR/rictor in mTOR inhibitor ...   (details)

MTOR MTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTOR-RICTOR   (MLST8   RICTOR   MTOR )

PMID: 18794129

Enhancing mammalian target of rapamycin (mTOR)-targeted cancer therapy by preventing mTOR/raptor inhibition-initiated, mTOR/rictor-independent Akt activation.
Source

Cancer research (9/15/2008)

Abstract

Enhancing mammalian target of rapamycin (mTOR) -targeted cancer therapy by preventing mTOR/raptor inhibition-initiated, mTOR/rictor-independent Akt activation. It has been shown that mammalian target of rapamycin (mTOR) inhibitors activate Akt while inhibiting mTOR signaling. However, the underlying mechanisms and the effect of the Akt activation on mTOR-targeted cancer therapy are unclear. The present work focused on addressing the role of mTOR/rictor in mTOR inhibitor-induced Akt activation and the effect of sustained Akt activation on mTOR-targeted cancer therapy. Thus, we have shown that mTOR inhibitors increase Akt phosphorylation through a mechanism independent of mTOR/rictor because the assembly of mTOR/rictor was inhibited by mTOR inhibitors and the silencing of rictor did not abrogate mTOR inhibitor-induced Akt activation. Moreover, Akt activation during mTOR inhibition is tightly associated with development of cell resistance to mTOR inhibitors. Accordingly, cotargeting mTOR and phosphatidylinositol 3-kinase/Akt signaling prevents mTOR inhibition-initiated Akt activation and enhances antitumor effects both in cell cultures and in animal xenograft models, suggesting an effective cancer therapeutic strategy. Collectively, we conclude that inhibition of the mTOR/raptor complex initiates Akt activation independent of mTOR/rictor. Consequently, the sustained Akt activation during mTOR inhibition will counteract the anticancer efficacy of the mTOR inhibitors.

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 MTOR

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

MTOR MTOR

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

MTOR MTOR

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: 21357504
Rapamycin treatment augments both protein ubiquitination and Akt activation in pressure-overloaded rat myocardium.
... mTORC1 that ... to enhance protein ... and mTORC2 that ...   (details)

MTOR MTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

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

PMID: 21357504

Rapamycin treatment augments both protein ubiquitination and Akt activation in pressure-overloaded rat myocardium.
Source

American journal of physiology. Heart and circulatory physiology (May 2011)

Abstract

Rapamycin treatment augments both protein ubiquitination and Akt activation in pressure-overloaded rat myocardium. Ubiquitin-mediated protein degradation is necessary for both increased ventricular mass and survival signaling for compensated hypertrophy in pressure-overloaded (PO) myocardium. Another molecular keystone involved in the hypertrophic growth process is the mammalian target of rapamycin (mTOR), which forms two distinct functional complexes: mTORC1 that activates p70S6 kinase-1 to enhance protein synthesis and mTORC2 that activates Akt to promote cell survival. Independent studies in animal models show that rapamycin treatment that alters mTOR complexes also reduces hypertrophic growth and increases lifespan by an unknown mechanism. We tested whether the ubiquitin-mediated regulation of growth and survival in hypertrophic myocardium is linked to the mTOR pathway. For in vivo studies, right ventricle PO in rats was conducted by pulmonary artery banding; the normally loaded left ventricle served as an internal control. Rapamycin (0.75 mg/kg per day) or vehicle alone was administered intraperitoneally for 3 days or 2 wk. Immunoblot and immunofluorescence imaging showed that the level of ubiquitylated proteins in cardiomyocytes that increased following 48 h of PO was enhanced by rapamycin. Rapamycin pretreatment also significantly increased PO-induced Akt phosphorylation at S473, a finding confirmed in cardiomyocytes in vitro to be downstream of mTORC2. Analysis of prosurvival signaling in vivo showed that rapamycin increased PO-induced degradation of phosphorylated inhibitor of ?B, enhanced expression of cellular inhibitor of apoptosis protein 1, and decreased active caspase-3. Long-term rapamycin treatment in 2-wk PO myocardium blunted hypertrophy, improved contractile function, and reduced caspase-3 and calpain activation. These data indicate potential cardioprotective benefits of rapamycin in PO hypertrophy.

PMID: 21415389
mTOR complex 2 activation by reconstituted high-density lipoprotein prevents senescence in circulating angiogenic cells.
... promoted mTOR phosphorylation ... and mTOR-rictor-dependent Akt activation, ...   (details)

MTOR MTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTOR-RICTOR   (MLST8   RICTOR   MTOR )

PMID: 21415389

mTOR complex 2 activation by reconstituted high-density lipoprotein prevents senescence in circulating angiogenic cells.
Source

Arteriosclerosis, thrombosis, and vascular biology (June 2011)

Abstract

mTOR complex 2 activation by reconstituted high-density lipoprotein prevents senescence in circulating angiogenic cells. [OBJECTIVE] Circulating angiogenic cells (CACs) participate in neovascularization and arterial repair. Although high-density lipoprotein (HDL) is known to enhance the functional activity of CACs, the mechanisms underlying this regulation are poorly understood. Here, we examined the mechanism (s) by which reconstituted HDL (rHDL) affects CAC senescence. [METHODS AND RESULTS] CACs isolated from human peripheral blood and treated with rHDL displayed reduced senescence, as measured by acidic ß-galactosidase staining. This protective effect was blocked by the mammalian target of rapamycin (mTOR) inhibitor (rapamycin). According to Western blot analysis and immunoprecipitation results, rHDL promoted mTOR phosphorylation, mTOR-rictor complex formation, and mTOR-rictor-dependent Akt activation, which were accompanied by increased nuclear translocation of human telomerase reverse transcriptase and enhanced nuclear telomerase activity. Suppression of rictor gene expression with a small interfering RNA blocked mTOR-rictor complex formation and Akt activation. The suppression also abolished the rHDL-induced inhibition of CAC senescence and promotion of nuclear telomerase activity. Treatment of aged mice with rHDL attenuated spleen-derived CAC senescence. In CACs isolated from rHDL-treated aged mice, the phosphorylated mTOR and Akt levels were significantly enhanced. [CONCLUSION] rHDL stimulates sustained mTOR phosphorylation and mTOR-rictor complex formation and inhibits senescence onset in CACs through mTOR complex 2 pathway activation.

PMID: 21490404
Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy.
... restrain mTORC1 activity ... constitutively activate mTOR in ...   (details)

MTOR MTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC1   (MLST8   RPTOR   MTOR )

PMID: 21490404

Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy.
Source

The Journal of clinical investigation (April 2011)

Abstract

Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. Mammalian target of rapamycin (mTOR) is a PI3K-related kinase that regulates cell growth, proliferation, and survival via mTOR complex 1 (mTORC1) and mTORC2. The mTOR pathway is often aberrantly activated in cancers. While hypoxia, nutrient deprivation, and DNA damage restrain mTORC1 activity, multiple genetic events constitutively activate mTOR in cancers. Here we provide a brief overview of the signaling pathways up- and downstream of mTORC1 and -2, and discuss the insights into therapeutic anticancer targets - both those that have been tried in the clinic with limited success and those currently under clinical development - that knowledge of these pathways gives us.

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

MTOR MTOR

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 MTOR

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 MTOR

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: 22307628
Glycerolipid signals alter mTOR complex 2 (mTORC2) to diminish insulin signaling.
... pathway inhibits mTORC2 activity ... and mTOR, ...   (details)

MTOR MTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  mTORC2   (MAPKAP1   MLST8   RICTOR   MTOR )

PMID: 22307628

Glycerolipid signals alter mTOR complex 2 (mTORC2) to diminish insulin signaling.
Source

Proceedings of the National Academy of Sciences of the United States of America (1/31/2012)

Abstract

Glycerolipid signals alter mTOR complex 2 (mTORC2) to diminish insulin signaling. Increased flux through the glycerolipid synthesis pathway impairs the ability of insulin to inhibit hepatic gluconeogenesis, but the exact mechanism remains unknown. To determine the mechanism by which glycerolipids impair insulin signaling, we overexpressed glycerol-3-phosphate acyltransferase-1 (GPAT1) in primary mouse hepatocytes. GPAT1 overexpression impaired insulin-stimulated phosphorylation of Akt-S473 and -T308, diminished insulin-suppression of glucose production, significantly inhibited mTOR complex 2 (mTORC2) activity and decreased the association of mTOR and rictor. Conversely, in hepatocytes from Gpat1 (-/-) mice, mTOR-rictor association and mTORC2 activity were enhanced. However, this increase in mTORC2 activity in Gpat1 (-/-) hepatocytes was ablated when rictor was knocked down. To determine which lipid intermediate was responsible for inactivating mTORC2, we overexpressed GPAT1, AGPAT, or lipin to increase the cellular content of lysophosphatidic acid (LPA), phosphatidic acid (PA), or diacylglycerol (DAG), respectively. The inhibition of mTOR/rictor binding and mTORC2 activity coincided with the levels of PA and DAG species that contained 16: 0, the preferred substrate of GPAT1. Furthermore, di-16: 0-PA strongly inhibited mTORC2 activity and disassociated mTOR/rictor in vitro. Taken together, these data reveal a signaling pathway by which phosphatidic acid synthesized via the glycerol-3-phosphate pathway inhibits mTORC2 activity by decreasing the association of rictor and mTOR, thereby down-regulating insulin action. These data demonstrate a critical link between nutrient excess, TAG synthesis, and hepatic insulin resistance.

PMID: 22362401
Reactive hyperemia is not responsible for stimulating muscle protein synthesis following blood flow restriction exercise.
... exercise increased the ... of mTOR, ... in mTORC1 signaling ...   (details)

MTOR MTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC1   (MLST8   RPTOR   MTOR )

PMID: 22362401

Reactive hyperemia is not responsible for stimulating muscle protein synthesis following blood flow restriction exercise.
Source

Journal of applied physiology (Bethesda, Md. : 1985; May 2012)

Abstract

Reactive hyperemia is not responsible for stimulating muscle protein synthesis following blood flow restriction exercise. Blood flow restriction (BFR) to contracting skeletal muscle during low-intensity resistance exercise training increases muscle strength and size in humans. However, the mechanism (s) underlying these effects are largely unknown. We have previously shown that mammalian target of rapamycin complex 1 (mTORC1) signaling and muscle protein synthesis (MPS) are stimulated following an acute bout of BFR exercise. The purpose of this study was to test the hypothesis that reactive hyperemia is the mechanism responsible for stimulating mTORC1 signaling and MPS following BFR exercise. Six young men (24 ± 2 yr) were used in a randomized crossover study consisting of two exercise trials: low-intensity resistance exercise with BFR (BFR trial) and low-intensity resistance exercise with sodium nitroprusside (SNP), a pharmacological vasodilator infusion into the femoral artery immediately after exercise to simulate the reactive hyperemia response after BFR exercise (SNP trial). Postexercise mixed-muscle fractional synthetic rate from the vastus lateralis increased by 49% in the BFR trial (P < 0.05) with no change in the SNP trial (P > 0.05). BFR exercise increased the phosphorylation of mTOR, S6 kinase 1, ribosomal protein S6, ERK1/2, and Mnk1-interacting kinase 1 (P < 0.05) with no changes in mTORC1 signaling in the SNP trial (P > 0.05). We conclude that reactive hyperemia is not a primary mechanism for BFR exercise-induced mTORC1 signaling and MPS. Further research is necessary to elucidate the cellular mechanism (s) responsible for the increase in mTOR signaling, MPS, and hypertrophy following acute and chronic BFR exercise.

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 MTOR

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: 22461615
Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity.
... second mTOR complex ... that mTORC2 was required for ...   (details)

MTOR MTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  mTORC2   (MAPKAP1   MLST8   RICTOR   MTOR )

PMID: 22461615

Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity.
Source

Science (New York, N.Y.; 3/30/2012)

Abstract

Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Rapamycin, an inhibitor of mechanistic target of rapamycin complex 1 (mTORC1), extends the life spans of yeast, flies, and mice. Calorie restriction, which increases life span and insulin sensitivity, is proposed to function by inhibition of mTORC1, yet paradoxically, chronic administration of rapamycin substantially impairs glucose tolerance and insulin action. We demonstrate that rapamycin disrupted a second mTOR complex, mTORC2, in vivo and that mTORC2 was required for the insulin-mediated suppression of hepatic gluconeogenesis. Further, decreased mTORC1 signaling was sufficient to extend life span independently from changes in glucose homeostasis, as female mice heterozygous for both mTOR and mLST8 exhibited decreased mTORC1 activity and extended life span but had normal glucose tolerance and insulin sensitivity. Thus, mTORC2 disruption is an important mediator of the effects of rapamycin in vivo.

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

MTOR MTOR

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.

PMID: 23030823
Akt is efficiently activated by PIF-pocket- and PtdIns(3,4,5)P3-dependent mechanisms leading to resistance to PDK1 inhibitors.
   (details)

MTOR MTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC2   (MLST8   RICTOR   MTOR )

PMID: 23030823

Akt is efficiently activated by PIF-pocket- and PtdIns(3,4,5)P3-dependent mechanisms leading to resistance to PDK1 inhibitors.
Source

The Biochemical journal (12/1/2012)

Abstract

Akt is efficiently activated by PIF-pocket- and PtdIns (3,4,5) P3-dependent mechanisms leading to resistance to PDK1 inhibitors. Mutations leading to inappropriate activation of Akt isoforms contribute to proliferation and survival of a significant proportion of human cancers. Akt is activated by phosphorylation of its T-loop residue (Thr) by PDK1 (3-phosphoinositide-dependent kinase-1) and its C-terminal hydrophobic motif (Ser473) by mTORC2 [mTOR (mammalian target of rapamycin) complex 2]. Potent PDK1 inhibitors such as GSK2334470 have recently been elaborated as potential anti-cancer agents. However, these compounds were surprisingly ineffective at suppressing Akt activation. In the present study we demonstrate that resistance to PDK1 inhibitors results from Akt being efficiently recruited to PDK1 via two alternative mechanisms. The first involves ability of Akt and PDK1 to mutually interact with the PI3K (phosphoinositide 3-kinase) second messenger PtdIns (3,4,5) P3. The second entails recruitment of PDK1 to Akt after its phosphorylation at Ser473 by mTORC2, via a substrate-docking motif termed the PIF-pocket. We find that disruption of either the PtdIns (3,4,5) P3 or the Ser473 phosphorylation/PIF-pocket mechanism only moderately impacts on Akt activation, but induces marked sensitization to PDK1 inhibitors. These findings suggest that suppression of Ser473 phosphorylation by using mTOR inhibitors would disrupt the PIF-pocket mechanism and thereby sensitize Akt to PDK1 inhibitors. Consistent with this, we find combing PDK1 and mTOR inhibitors reduced Akt activation to below basal levels and markedly inhibited proliferation of all of the cell lines tested. Our results suggest further work is warranted to explore the utility of combining PDK1 and mTOR inhibitors as a therapeutic strategy for treatment of cancers that harbour mutations elevating Akt activity.

PMID: 23111315
Coordinated time-dependent modulation of AMPK/Akt/mTOR signaling and autophagy controls osteogenic differentiation of human mesenchymal stem cells.
... early mTOR inhibition ... late activation of Akt/mTOR signaling, ...   (details)

MTOR MTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTOR-signaling   (RPTOR   MTOR )

PMID: 23111315

Coordinated time-dependent modulation of AMPK/Akt/mTOR signaling and autophagy controls osteogenic differentiation of human mesenchymal stem cells.
Source

Bone (January 2013)

Abstract

Coordinated time-dependent modulation of AMPK/Akt/mTOR signaling and autophagy controls osteogenic differentiation of human mesenchymal stem cells. We investigated the role of AMP-activated protein kinase (AMPK), Akt, mammalian target of rapamycin (mTOR), autophagy and their interplay in osteogenic differentiation of human dental pulp mesenchymal stem cells. The activation of various members of AMPK, Akt and mTOR signaling pathways and autophagy was analyzed by immunoblotting, while osteogenic differentiation was assessed by alkaline phosphatase staining and real-time RT-PCR/immunoblot quantification of osteocalcin, Runt-related transcription factor 2 and bone morphogenetic protein 2 mRNA and/or protein levels. Osteogenic differentiation of mesenchymal stem cells was associated with early (day 1) activation of AMPK and its target Raptor, coinciding with the inhibition of mTOR and its substrate p70S6 kinase. The early induction of autophagy was demonstrated by accumulation of autophagosome-bound LC3-II, upregulation of proautophagic beclin-1 and a decrease in the selective autophagic target p62. This was followed by the late activation of Akt/mTOR at days 3-7 of differentiation. The RNA interference-mediated silencing of AMPK, mTOR or autophagy-essential LC3ß, as well as the pharmacological inhibitors of AMPK (compound C), Akt (10-DEBC hydrochloride), mTOR (rapamycin) and autophagy (bafilomycin A1, chloroquine and ammonium chloride), each suppressed mesenchymal stem cell differentiation to osteoblasts. AMPK knockdown prevented early mTOR inhibition and autophagy induction, as well as late activation of Akt/mTOR signaling, while Akt inhibition suppressed mTOR activation without affecting AMPK phosphorylation. Our data indicate that AMPK controls osteogenic differentiation of human mesenchymal stem cells through both early mTOR inhibition-mediated autophagy and late activation of Akt/mTOR signaling axis.

PMID: 23300339
BSTA Promotes mTORC2-Mediated Phosphorylation of Akt1 to Suppress Expression of FoxC2 and Stimulate Adipocyte Differentiation.
   (details)

MTOR MTOR

Type:  positive regulation
Is this interaction correct?
Yes
No

Comments

Theme:  mTORC2   (MAPKAP1   MLST8   RICTOR   MTOR )

PMID: 23300339

BSTA Promotes mTORC2-Mediated Phosphorylation of Akt1 to Suppress Expression of FoxC2 and Stimulate Adipocyte Differentiation.
Source

Science signaling (2013)

Abstract

BSTA Promotes mTORC2-Mediated Phosphorylation of Akt1 to Suppress Expression of FoxC2 and Stimulate Adipocyte Differentiation. Phosphorylation and activation of Akt1 is a crucial signaling event that promotes adipogenesis. However, neither the complex multistep process that leads to activation of Akt1 through phosphorylation at Thr (308) and Ser (473) nor the mechanism by which Akt1 stimulates adipogenesis is fully understood. We found that the BSD domain-containing signal transducer and Akt interactor (BSTA) promoted phosphorylation of Akt1 at Ser (473) in various human and murine cells, and we uncovered a function for the BSD domain in BSTA-Akt1 complex formation. The mammalian target of rapamycin complex 2 (mTORC2) facilitated the phosphorylation of BSTA and its association with Akt1, and the BSTA-Akt1 interaction promoted the association of mTORC2 with Akt1 and phosphorylation of Akt1 at 473) in response to growth factor stimulation. Furthermore, analyses of bsta gene-trap murine embryonic stem cells revealed an essential function for BSTA and phosphorylation of Akt1 at Ser (473) in promoting adipocyte differentiation, which required suppression of the expression of the gene encoding the transcription factor FoxC2. These findings indicate that BSTA is a molecular switch that promotes phosphorylation of Akt1 at Ser (473) and reveal an mTORC2-BSTA-Akt1-FoxC2-mediated signaling mechanism that is critical for adipocyte differentiation.