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MTOR — TSC2
Pathways - manually collected, often from reviews:
Text-mined interactions from Literome
Lu et al., Blood 2013 (Multiple Myeloma) :
We identify
TSC2 , a negative
regulator of
mTOR-C1 , as a novel Pim2 substrate and show that Pim2 directly phosphorylates TSC2 on Ser-1798 and relieves the suppression of TSC2 on mTOR-C1
Balgi et al., PloS one 2009 :
TSC2 , a negative regulator of mTORC1, was
required for inhibition of
mTORC1 signaling by rottlerin but not for mTORC1 inhibition by perhexiline, niclosamide and amiodarone ... Transient exposure of immortalized mouse embryo fibroblasts to these drugs was not toxic in nutrient-rich conditions but led to rapid cell death by apoptosis in starvation conditions, by a mechanism determined in large part by the tuberous sclerosis complex protein
TSC2 , an upstream
regulator of
mTORC1
Weichhart et al., Immunity 2008 (Inflammation...) :
Conversely, deletion of
TSC2 , the key negative
regulator of
mTOR , diminished NF-kappaB but enhanced STAT3 activity and reversed this proinflammatory cytokine shift
Kaur et al., J Biol Chem 2007 :
Interestingly, the induction of expression of ISG15 and CXCL10 proteins by IFNs was also strongly enhanced in cells lacking expression of the tuberin ( TSC2 ( -/- ) ) or hamartin ( TSC1 ( -/- ) ) genes, consistent with the known negative regulatory
effect of the
TSC1-TSC2 complex on
mTOR activation
Tee et al., Semin Cell Dev Biol 2005 (Disease...) :
Recent studies reveal that the tuberous sclerosis complex
(TSC)-1/2 , PTEN, and LKB1 tumor suppressor proteins tightly
control mTOR
Wang et al., Biochim Biophys Acta 2013 (Genetic Diseases, X-Linked...) :
By promoting
TSC2 degradation, CUL4B could positively
regulate mTOR activity in neocortical neurons of frontal cortex ... Consistent with this hypothesis, CUL4B knockdown induced upregulation of
TSC2 in neocortical neurons
resulted in a decreased protein level of active
phospho-mTOR ( Ser2448 ) and a reduced expression of active phospho-p70S6K ( Thr389 ) and phospho-4E-BP1 ( Thr37/46 ), two main substrates of mTOR mediated phosphorylation
Vary et al., J Nutr 2006 :
Likewise, the extent of phosphorylation of
TSC2 , a potential upstream
regulator of
mTOR , was not significantly altered during meal feeding
O'Brien et al., Arch Immunol Ther Exp (Warsz) 2012 (MAP Kinase Signaling System) :
Furthermore, we highlight the importance of tight control of mTOR signaling by
tuberous sclerosis complex 1 for T-cell homeostasis, and the
regulation of
mTOR signaling by diacylglycerol kinases and the RasGRP1-Ras-Erk1/2 pathway in the context of TCR signaling
Wang et al., Autophagy 2012 (Brain Ischemia...) :
Overexpression or knockdown of Nampt
regulated the phosphorylation of
mTOR and S6K1 signaling pathway upon OGD stress through enhancing phosphorylation of
TSC2 at Ser1387 but not Thr1462 site
Lee et al., EMBO J 2007 (Hamartoma...) :
Thus, loss of TSC1 or
TSC2 , the negative
regulators of
mTOR , results in dramatic accumulation of p53 and apoptosis in response to stress conditions
Sarkar et al., Mol Cell 2011 (Huntington Disease) :
Additionally, NO inhibits IKKß and reduces AMPK phosphorylation, leading to
mTORC1 activation via
TSC2
Hwang et al., BMB Rep 2011 (Ischemia) :
The loss of
TSC2 , which is upstream of mTOR, activates S6K1, promotes cell growth and survival,
activates mTOR kinase activities, inhibits mTORC1 and mTORC2 via mTOR inhibitors, and suppresses S6K1 and Akt ... The loss of
TSC2 , which is upstream of mTOR, activates S6K1, promotes cell growth and survival, activates mTOR kinase activities,
inhibits mTORC1 and
mTORC2 via mTOR inhibitors, and suppresses S6K1 and Akt ... The loss of
TSC2 , which is upstream of mTOR, activates S6K1, promotes cell growth and survival, activates mTOR kinase activities,
inhibits mTORC1 and mTORC2 via mTOR inhibitors, and suppresses S6K1 and Akt
Buller et al., Am J Physiol Cell Physiol 2008 :
Since GSK-3 can inhibit mammalian target of rapamycin (mTOR) signaling via phosphorylation of the tuberous sclerosis complex subunit 2 ( TSC2 ) tumor suppressor, we investigated whether chronic GSK-3 effects on glucose uptake and GLUT1 expression depended on
TSC2 phosphorylation and TSC
inhibition of
mTOR
Huang et al., Mol Cell Biol 2008 :
The
TSC1-TSC2 complex is
required for proper activation of
mTOR complex 2 ... However, how
mTORC2 is regulated and whether the
TSC1-TSC2 complex is
involved are unknown ... Our data also suggest that the
TSC1-TSC2 complex positively
regulates mTORC2 in a manner independent of its GTPase activating protein activity toward Rheb ... These data demonstrate that the
TSC1-TSC2 complex inhibits
mTORC1 and activates mTORC2, which through different mechanisms promotes Akt activation ... These data demonstrate that the
TSC1-TSC2 complex inhibits mTORC1 and
activates mTORC2 , which through different mechanisms promotes Akt activation
Ru et al., J Mol Neurosci 2012 :
A
role of the
mammalian target of rapamycin (mTOR) in glutamate induced down-regulation of tuberous sclerosis complex proteins 2 (
TSC2 ) ... Interestingly, the
mTOR-specific inhibitor rapamycin
blocks the glutamate induced
TSC2 down-regulation ... This finding suggests that NMDAR activation evokes an
mTOR mediated negative regulation of
TSC2
Vega-Rubin-de-Celis et al., Biochemistry 2010 :
REDD1
induced-mTORC1 inhibition
requires the
TSC1/TSC2 complex , and REDD1 has been proposed to act by directly binding to and sequestering 14-3-3 proteins away from TSC2 leading to TSC2 dependent inhibition of mTORC1 ... REDD1 induced-mTORC1 inhibition requires the TSC1/TSC2 complex, and REDD1 has been proposed to act by directly binding to and sequestering 14-3-3 proteins away from TSC2 leading to
TSC2 dependent inhibition of
mTORC1
Nie et al., Nat Neurosci 2010 :
Furthermore,
Tsc2 deficiency and hyperactive Rheb constitutively
activated mTOR and inhibited ephrin induced growth cone collapse
Alexander et al., Cell cycle (Georgetown, Tex.) 2010 :
We found that
TSC2 activation
results in
mTORC1 repression and subsequent induction of autophagy
Tanwar et al., PLoS Genet 2012 (Adenoma...) :
Deletion of the genes for Tuberous Sclerosis 1 (Tsc1) or
Tsc2 ,
regulators of
mTORC1 that are downstream of LKB1 signaling, in the oviductal and uterine stroma phenocopies some of the defects observed in Lkb1 mutant mice, confirming that dysregulated mTORC1 activation in the Lkb1 deleted stroma contributes to the phenotype
Yu et al., Mol Cancer Ther 2008 :
Overexpression of constitutively activated Akt or disruption of
TSC1-TSC2 complex by small interfering RNA or gene knockout only partially
restored curcumin mediated inhibition of
mTOR and downstream signaling, indicating that they are not the primary effectors of curcumin mediated inhibition of Akt/mTOR signaling
Habib et al., Genes & cancer 2011 :
These novel data provide evidence that loss of
TSC-2 , PTEN, and p53 as well as
activation of PI 3-K and
mTOR is associated with kidney cancer in the Eker rat, while sustained expression of TSC-2, PTEN, and p53 may prevent progression of kidney cancer in TSC patients
Arvisais et al., J Biol Chem 2006 :
AKT independent phosphorylation of
TSC2 and
activation of
mTOR and ribosomal protein S6 kinase signaling by prostaglandin F2alpha
Liu et al., J Biol Chem 2011 (Colonic Neoplasms) :
In contrast, stable knockdown of
TSC2 , a negative
regulator of
mTOR activity, increases PHLPP expression
Kato et al., PloS one 2013 :
Knockdown of
TSC2 , a negative
regulator of
mTORC1 , caused activation of mTORC1 and enhanced Cd induction of the IRE1-JNK pathway and apoptosis without affecting other UPR branches
Weichhart et al., Blood 2011 :
Interestingly, long-term activation of monocytes with lipopolysaccharide
enhanced the expression of
TSC2 , the principle negative regulator of mTOR, whereas dexamethasone blocked TSC2 expression and reestablished
mTOR activation
Koyanagi et al., PloS one 2011 :
Activation of
mTORC1 by
TSC2 ablation increases mitochondrial biogenesis and enhances insulin secretion from pancreatic beta cells
Zhang et al., Breast Cancer Res Treat 2012 (Breast Neoplasms) :
Although NDGA stimulated AMP activated protein kinase (AMPK)/tuberous sclerosis complex 2 (TSC2) signaling, which negatively regulates mTORC1, AMPK and
TSC2 deletion could not
diminish the inhibition of
mTORC1 by NDGA
Gan et al., J Biol Chem 2006 :
Together, these results suggest that FAK might regulate S6K activation and cell size through its interaction with and phosphorylation of TSC2 and also provide a previously unappreciated
role of
TSC2 in the regulation of
mTOR signaling by cell adhesion
Sun et al., Proc Natl Acad Sci U S A 2011 (Neoplasms) :
PKM2 level was augmented in mouse kidney tumors due to deficiency of
tuberous sclerosis complex 2 and consequent
mTOR activation , and was reduced in human cancer cells by mTOR suppression
Melnik et al., Exp Dermatol 2013 :
Antiandrogens may attenuate mTORC1 by suppressing
mTORC2 mediated
Akt/TSC2 signalling
DeYoung et al., Genes Dev 2008 (Breast Neoplasms) :
REDD1 mutants that fail to bind 14-3-3 are defective in eliciting
TSC2/14-3-3 dissociation and
mTORC1 inhibition , while TSC2 mutants that do not bind 14-3-3 are inactive in hypoxia signaling to mTORC1
Brugarolas et al., Genes Dev 2004 (Anoxia) :
Here we show that
mTOR inhibition by hypoxia
requires the
TSC1/TSC2 tumor suppressor complex and the hypoxia-inducible gene REDD1/RTP801
Pollizzi et al., Molecular cancer 2009 (Disease Models, Animal...) :
Loss of either TSC1 or
TSC2 in TSC hamartomas
leads to activation of
mTORC1 and suppression of AKT
Hayashi et al., Am J Physiol Endocrinol Metab 2007 :
Consistent with this, GH increased the phosphorylation of
TSC2 , an upstream
regulator of
mTORC1 , at sites that are targets for Akt/PKB
Korotchkina et al., Aging 2010 :
Here we showed that shRNA mediated knockdown of
TSC2 , a negative
regulator of
mTOR , partially converted quiescence into senescence in these nutlin arrested cells
Paturi et al., J Appl Physiol 2010 (Cumulative Trauma Disorders...) :
The amount of
Tuberin/TSC2 phosphorylation, an
inhibitor of
mTOR , was unchanged in the LZ soleus after overload while it was increased ( 68.3 %, P < 0.05 ) in OZ animals
Das et al., J Biol Chem 2012 (Tuberous Sclerosis) :
TSC2 deficiency
induces constitutive activation of
mTOR , leading to a state of insulin resistance due to a negative feedback regulation, resulting in reduced Akt phosphorylation
Zhang et al., PloS one 2009 :
Loss of function of the
TSC1-TSC2 complex results in constitutive
mTORC1 signaling and, through mTORC1 dependent feedback mechanisms and loss of mTORC2 activity, leads to a concomitant block of Akt signaling to its other downstream targets ... In examining the requirements for different Akt mediated phosphorylation sites on TSC2, we find that only
TSC2 mutants lacking all five previously identified Akt sites fully
block insulin stimulated
mTORC1 signaling in reconstituted Tsc2 null cells, and this mutant also inhibits adipogenesis
Goncharova et al., Mol Pharmacol 2008 (Leiomyoma...) :
Our study demonstrates that IFNbeta dependent activation of STATs and p38 MAPK is not sufficient to fully inhibit proliferation of cells with TSC2 dysfunction and that
TSC2 dependent inhibition of
mTOR/S6K1 cooperates with IFNbeta in inhibiting human LAM and TSC2-null ELT3 cell proliferation
Wolff et al., Mol Cell Biol 2011 (Anoxia) :
We previously reported that
mTORC1 regulation by hypoxia
involves Redd1 and the
Tsc1/Tsc2 complex
Mills et al., Proc Natl Acad Sci U S A 2008 (Lymphoma) :
Here, we demonstrate that loss of
TSC2 in the E mu-myc murine lymphoma model
leads to
mTORC1 activation and accelerated oncogenesis caused by a defective apoptotic program despite compromised AKT phosphorylation
Linehan et al., Nat Rev Urol 2010 (Carcinoma, Renal Cell...) :
TSC1-TSC2 is downstream of AMPK and negatively
regulates mTOR in response to cellular energy deficit
Huang et al., Cancer Res 2009 (Angiomyolipoma...) :
We also show that the
TSC1-TSC2 complex can directly
stimulate the in vitro kinase activity of
mTORC2
Jozwiak et al., J Neurooncol 2006 (Brain Neoplasms...) :
The importance of these proteins is confirmed by their ubiquitous character and by the fact that
TSC1/TSC2 complex is
involved in the regulation of the activity of
mTOR , a master controller of protein translation
Lu et al., Clin Cancer Res 2008 (Endometrial Neoplasms...) :
Loss of
tuberous sclerosis complex-2 function and
activation of
mammalian target of rapamycin signaling in endometrial carcinoma ... In tumors that retained TSC2 expression, phosphorylation of tuberin at S939 was observed with a high frequency, indicating that
mTOR repression by
TSC2 had been relieved via AKT phosphorylation of this tumor suppressor
Sofer et al., Mol Cell Biol 2005 :
REDD1 likely acts on the TSC1/2 complex, as regulation of
mTOR substrate phosphorylation by REDD1
requires TSC2 and is blocked by overexpression of the TSC1/2 downstream target Rheb but is not blocked by inhibition of AMPK
Smith et al., J Biol Chem 2005 :
The tuberous sclerosis protein
TSC2 is not
required for the regulation of the
mammalian target of rapamycin by amino acids and certain cellular stresses ... Some studies have suggested that
TSC2 also
mediates the control of
mTOR by amino acids ... Although
TSC2 is not
required for amino acid control of
mTOR , amino acid withdrawal does decrease the proportion of Rheb in the active GTP bound state
Coevoets et al., Eur J Hum Genet 2009 (Tuberous Sclerosis) :
We have developed a straightforward, semiautomated in-cell western ( ICW ) assay to investigate the effects of amino acid changes on the
TSC1-TSC2 dependent inhibition of
mTOR activity
Inoki et al., Genes Dev 2003 :
These functions of
TSC1/TSC2 are likely
mediated by
mTOR
Mak et al., Cancer Invest 2004 (Tuberous Sclerosis) :
Tuberin , serving as a substrate of AKT and AMPK,
mediates mTOR activity by coordinating inputs from growth factors and energy availability in the control of cell growth, proliferation, and survival
Qi et al., Eur J Pharmacol 2013 :
Activation of
mTOR by insulin or inhibition of endogenous
TSC2 levels by siRNA obviously delayed PAB induced senescence
Sviripa et al., Bioorg Med Chem Lett 2013 :
AMPK also regulates lipid synthesis by inhibiting acetyl-CoA carboxylase (ACC) and
regulates mTOR signaling by activating
TSC2
Rolfe et al., Biochem J 2005 :
PE stimulation of cardiomyocytes induced the phosphorylation of
TSC2 ( tuberous sclerosis complex 2 ), a negative
regulator of
mTOR activity
Lacher et al., Oncogene 2010 (Cell Transformation, Neoplastic...) :
TSC2 negatively regulates the activity of the GTPase Rheb and thereby
inhibits mammalian target of rapamycin complex 1 ( mTORC1 ) signaling
Dey et al., PloS one 2012 (Hypertrophy) :
Tuberin and PRAS40, two other Akt substrates, and endogenous
inhibitors of
mTORC1 , regulate mesangial cell hypertrophy
Inoki et al., Nat Cell Biol 2002 (Tuberous Sclerosis) :
These functions of
TSC1-TSC2 are
mediated by inhibition of the
mammalian target of rapamycin (mTOR)
Henske , Pediatr Nephrol 2005 (Angiomyolipoma...) :
Recently, the
TSC1/TSC2 protein complex was shown to
inhibit the kinase
mTOR ( mammalian target of rapamycin )
Hong-Brown et al., Am J Physiol Cell Physiol 2012 :
Rag GTPases and
AMPK/TSC2/Rheb mediate the differential regulation of
mTORC1 signaling in response to alcohol and leucine
O'Brien et al., Eur J Immunol 2011 :
The
TSC1/TSC2 complex has been shown to
inhibit mTORC1 signaling in cell line models
Yoshida et al., Nat Med 2010 (Pulmonary Emphysema) :
Rtp801 ( also known as Redd1, and encoded by Ddit4 ), a stress related protein triggered by adverse environmental conditions,
inhibits mammalian target of rapamycin (mTOR) by stabilizing the
TSC1-TSC2 inhibitory complex and enhances oxidative stress dependent cell death
Hahn-Windgassen et al., J Biol Chem 2005 :
Our results demonstrate that Akt lies upstream of these two pathways and induces full inhibition of
TSC2 and
activation of
mTOR both through direct phosphorylation and by inhibition of AMPK mediated phosphorylation of TSC2
Guo et al., Mol Cancer Res 2013 :
Loss of either TSC1 or
TSC2 in TSC hamartomas
leads to activation of
mTORC1
Cook et al., Cancer Res 2012 :
Mechanistically, GRP78 integrated multiple cellular signaling pathways to inhibit apoptosis and stimulate prosurvival autophagy, which was dependent on
TSC2/AMPK mediated
mTOR inhibition but not on beclin-1
Shaw et al., Cancer Cell 2004 (Colonic Polyps...) :
Here, we report that LKB1 is required for repression of
mTOR under low ATP conditions in cultured cells in an AMPK- and
TSC2 dependent manner, and that Lkb1 null MEFs and the hamartomatous gastrointestinal polyps from Lkb1 mutant mice show elevated signaling downstream of mTOR
Tzatsos et al., J Biol Chem 2007 :
Energy depletion activates AMP activated protein kinase (AMPK) and inhibits cell growth via
TSC2 dependent suppression of
mTORC1 signaling
Mak et al., Am J Pathol 2005 (Angiomyolipoma...) :
Besides the negative regulatory
role of the
TSC1/TSC2 proteins on
mTOR , we have reported an effect on beta-catenin signaling at the level of the degradation complex in vitro