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TSC2 inhibits MTOR. 631 / 669
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"TSC2 usually inhibits mTOR via Rheb (Ras homolog enriched in brain), a GTP binding protein."
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"All these observations are consistent with our model that TSC2 acts downstream of AMPK to inhibit mTOR."
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"TSC2 negatively regulates Notch1 signaling in an mTOR dependent and -independent fashion."
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"This TSC2 phosphorylation inhibits mTOR activity ( Levine et al., 2006 )."
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"Other downstream targets of AMPK include TSC2, which inhibits mammalian target of rapamycin complex 1 (mTORC1) and protein synthesis; xref HMG-CoA reductase, which leads to the inhibition of cholesterol synthesis; xref peroxisome proliferator-activated receptor-gamma coactivator (PPARα) 1α, which stimulates mitochondrial biogenesis, xref , xref and many others."
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"AMPK phosphorylates Raptor or TSC2 and thus inhibits the mTOR pathway to induce autophagy71 72."
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"Hamartin and tuberin, the products of TSC1 and TSC2, respectively, form heterodimers and inhibit the mammalian target of rapamycin."
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"The phosphorylation of TSC2 leads to the activation of mammalian target of rapamycin (mTOR), a multi-function protein thought to mediate nutrient sensing and multiple metabolic outcomes in mammalian t[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Our data demonstrate that TSC1 and TSC2 differentially regulate actin stress fiber formation and cell migration, and that only TSC2 loss promotes mTOR- and mTORC2 dependent pro migratory cell phenotype."
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"When active, AMPK phosphorylates TSC2 as well as Raptor to block the activity of mTOR and the complex mTORC1 during energy stress."
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"Hypoxia induces REDD1 expression via HIF, and as REDD1 binds to and sequesters 14-3-3 from complexes with TSC2, TSC2 can inactivate mTOR [57–59] ."
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"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling."
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"On one hand, AMPK can phosphorylate TSC2 and Raptor to inhibit mTOR (Inoki et al., 2003; Gwinn et al., 2008); on the other hand, AMPK can directly phosphorylate ULK1 at Ser317 and Ser777 to activate the ULK1 complex and initiate autophagy (Kim et al., 2011)."
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"Loss of TSC2 leads to activation of mTOR (mammalian target of rapamycin), which, in addition to activating protein synthesis and cell growth, also potently inhibits autophagy [XREF_BIBR]."
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"TSC2 can directly inactivate mTOR once its activity is enhanced by AMPK mediated phosphorylation [ xref , xref ]."
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"TSC2 can inhibit mTOR signaling, which can be reversed by AKT phosphorylation."
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"MTOR is negatively regulated by TSC1 and TSC2; thus, mTOR is inactivated by AMPK, and autophagy is induced (Ding et al. 2007)."
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"Loss or inactivation of TSC2 activates cellular mTOR."
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"Deletion of Tsc2 in mouse oocytes caused increased mTOR activity followed by accelerated recruitment of the OR starting by P23 and follicle depletion by 4 months."
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"This is caused by inactivation of TSC1 and TSC2, thus inhibiting PI3K and mTOR signaling downstream of AKT1."
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"However, the HCMV UL38 protein, which is expressed with early kinetics, is thought to subvert this response by binding to and inhibiting TSC2, which with TSC1 indirectly represses mTOR, thereby promoting mTOR function [87,88]."
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"Our data support that RTP801 and RTP801L work downstream of AKT and upstream of TSC2 to inhibit mTOR functions."
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"FIS also activates the mTOR repressor TSC2 by inhibiting Akt and activating AMPK [114]."
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"Similarly, mTOR activation by TSC2 knockdown in WM35 activated both Akt and SGK1, but only the latter was inhibited by rapamycin."
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"AMPK has been shown to dephosphorylate TSC2, which inhibits mTOR activity and stimulates autophagy ( Tanwar et al., 2012; Wu et al., 2015; Xu et al., 2014 )."
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"Mutations in PTEN, TSC1/TSC2, and AKT1-3 often disrupt the mTOR pathway, complicating the genetic landscape of PanNETs."
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"Since hamartin and tuberin negatively regulate mTOR activity, which in turn phosphorylates and thereby activates important translation factors such as p70 S6 kinase 1 (S6K1) and eukaryote initiation factor 4E binding protein (eIF4E-BP), a major role of the TSC-mTOR signaling pathway has been suggested for tumorigenesis, and both genes were initially recognized as tumor suppressors [XREF_BIBR]."
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"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling."
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"TSC2 is able to form a complex with TSC1 and inhibits mTOR activity, which is usually assessed in terms of the phosphorylation status of the downstream substrate 4E-BP1 XREF_BIBR, XREF_BIBR."
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"TSC2 negatively regulates the activity of the GTPase Rheb and thereby inhibits mammalian target of rapamycin complex 1 (mTORC1) signaling."
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"The activation of AMPK triggers its downstream target, the tuberous sclerosis complex 2 (TSC2), which inhibits the mTOR signaling pathway, and hampers the activation of ribosomal protein S6 kinase beta-1 (p70S6K/pS6), necessary for cancer cell growth [9]."
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"In the majority of cells under stress conditions, activation of AMPK phosphorylates TSC2 leading to TSC1 and TSC2 dependent suppression of mTOR to inhibit cell proliferation [XREF_BIBR, XREF_BIBR]."
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"Rheb potently activates mTOR when in a GTP-bound state and TSC1–TSC2 inhibits mTOR indirectly by reverting Rheb to an inactive GDP-bound form [9] ."
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"The serine/threonine kinase mTOR is a well‐characterized substrate of Akt and it is known that Akt‐mediated activation of mTOR occurs through phosphorylation and inactivation of tuberous sclerosis complex 2 (TSC2), which normally inhibits mTOR (Hay 2005)."
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"Activated AMPK directly phosphorylates tuberous sclerosis complex 2 (TSC2), inhibiting the mammalian target of rapamycin complex 1 (mTORC1) [ 173 ]."
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"TSC2 directly interacts with PC-1 to inhibit mTOR signaling, and the loss of PC-1 in ADPKD is thought to be attributed to inappropriate mTOR activity (Brook-Carter et al., 1994; Shillingford et al., 2006)."
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"[34] Their products, “hamartin” and “tuberin,” inhibit the mammalian target of rapamycin (mTOR), which is an immunosuppressive agent."
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"The TSC2 inhibited mTOR and other substrates, including S6K, 4EBP-1 and EIF2, which resulted in reduced cell size and growth rates."
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"The protein TSC2 negatively regulates the mTOR pathway by binding and blocking the GTPase activity of Rheb, a positive regulator of mTORC1 activity [XREF_BIBR]."
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"The TSC2 and TSC1 gene products negatively regulate the mTOR complex 1 preventing constitutive activation of the mTOR pathway (8)."
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"GSK-3beta phosphorylates and activates TSC2, which in turn inhibits mTOR 11, where GSK-3beta is required for mTOR regulation by energy starvation 11."
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"For example, Ozcan et al. reported that the loss of TSC1 or TSC2 (the inhibitor of mTOR) and the subsequent activation of mTORC1 led to ERS, thereby making the cells more susceptible to apoptosis and death [35]."
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"MTOR is inhibited, in part, by two tumor-suppressor proteins, TSC2 and PTEN."
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"Signaling through mTOR is also controlled by upstream members of the pathway such as the Ras homolog enriched in brain (Rheb), a GTPase that activates mTOR, and tuberin (also known as TSC2), a GTPase activating protein, which, with its binding partner hamartin (also known as TSC1), acts to repress mTOR."
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"The loss of function of tuberous sclerosis complex 2 (Tsc2), which is an upstream inhibitor of mTOR, was found to disrupt neuroepithelial growth [119]."
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"In the case of insulin signaling, tuberin serves as a substrate of Akt and inhibits mTOR function through its GAP activity on Rheb (reviewed in Ref."
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"Loss of TSC2 results in constitutive activation of RHEB and its target mTOR."
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"Interestingly, loss of either TSC1 or TSC2, which leads to hyperactive mTOR, also triggers ER stress and the UPR - indicating that hyperactive mTOR leads to the activation of PERK and generates the PA to support increased mTOR activity."
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"Furthermore, our results also found that DEX upregulated TSC2 expression and then decreased the phosphorylation mTOR."
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"This leads to upregulation of p53 target genes, among which TSC2 inhibits the mTOR protein that stimulates protein synthesis and inhibits autophagy, a process that leads to digestion of cellular compo[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"SIRT1 interacts with tuberous sclerosis protein 2 (TSC2),which is an upstream inhibitor of TORC1, and negatively regulates mTOR signaling in a TSC2 dependent manner( Ghosh et al., 2010 )."
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"The hamartin–tuberin complex normally inhibits mammalian target of rapamycin complex 1 (mTORC1) in a cell."
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"The TSC1/TSC2 complex is the main upstream regulator of mTOR, and hyperactivated mTOR, caused by the loss of TSC1 or TSC2, leads to uncontrolled cell proliferation and tumor growth [31]."
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"The phosphorylation of ERK leads to the dissociation of TSC1/TSC2, which in turn impairs the ability of TSC2 to inhibit the mTOR signaling."
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"p53 has two target genes, Sestrin1 and Sestrin2, which activate the AMP-responsive protein kinase as well as induce it to phosphorylate TSC2 and stimulate its GTPase activating protein activity, thereby inhibiting the mammalian target of rapamycin [45]."
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"Starvation induces GADD34 to form a stable complex with Tuberous sclerosis complex 1 (TSC1) and Tuberous sclerosis complex 2 (TSC2), which suppresses the mTOR signaling pathway and induces autophagy [187]."
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"Akt can directly phosphorylate and activate mTOR, as well as indirectly activating it by phosphorylating and inactivate tuberous sclerosis complex 2 (TSC2), also called tuberin, which normally inhibits mTOR through the GTP binding protein Ras homolog enriched in brain (Rheb) [XREF_BIBR]."
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"Under normal conditions, their protein products, hamartin and tuberin, inhibit mTOR function."
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"AMPK activates TSC2, which in turn inhibits mTOR [ xref ]."
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"Under basal conditions, TSC2 negatively regulates mTOR, so that Akt mediated TSC2 phosphorylation activates mTOR, which in turns activates p70S6K and 4E-BP1, promoting translation of mRNAs important to cancer cell growth [XREF_BIBR, XREF_BIBR]."
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"The PI3K/Akt axis also regulates cell growth via the phosphorylation and inhibition of hamartin and tuberin (TSC1 and TSC2) ( Potter et al., 2002 ), which effectively activates the mTOR pathway result[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Normally, polycystin-1 and the TSC1/TSC2 tumor suppressor genes work together to antagonize mTOR activity, which helps control cell growth by preventing the G1-replication phase of the cell cycle, ultimately leading to apoptosis [25]."
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"AMPK activates TSC2 phosphorylation to catalyze the conversion of Rheb-GTP to Rheb-GDP and thus inhibits mTOR XREF_BIBR."
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"First, AMPK activates TSC2, which inhibits mTOR, thus reducing activity of ribosomal S6 kinase and eukaryotic initiation factor-4 (eIF4)."
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"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling."
25699578
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"XREF_BIBR, XREF_BIBR The products of two p53 target genes, Sestrin 1 and 2 activate AMPK, which phosphorylates TSC2 and stimulates its GAP activity enabling mTOR inhibition."
20054236
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"Adiponectin upon binding with its receptors (AdipoRs) activates AMPK, which subsequently phosphorylates and activates a tumor suppressor TSC2 to inhibit mTOR."
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"MTOR, on the other hand, is activated indirectly by Akt through phosphorylation of TSC2 in the TSC1 and TSC2 (hamartin and tuberin) heterodimer that inhibits mTOR signaling."
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"Dimerized TSC-1/TSC-2 inhibits the GTPase Ras-homolog enriched in brain (Rheb), which is required for mTOR activation; therefore, TSC-1/TSC-2 normally inhibits mTOR."
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"This mechanism of p53-induced autophagy involves activation of 5′ AMP-activated protein kinase (AMPK) as well as the tuberus sclerosis complex kinases, TSC1 and TSC2, which finally inhibit mTOR kinase."
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"However, activated AMPK induces the inactivation of mTOR either by phosphorylation of Raptor or by direct phosphorylation of TSC2 (tuberous sclerosis complex 2), an mTOR negative regulator, which trig[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"In normal and adult kidney, PC1 functions by inducing the formation of PC1, tuberin, and mTOR complex thereby inhibiting mTOR activity XREF_BIBR, yet in human ADPKD patients and mouse models, null of PC1 leads to the inability to assemble this inhibitory complex thereby causing mTOR pathway inappropriately activated XREF_BIBR, XREF_BIBR."
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"In more detail, ATM activates TSC2 via AMPK, and TSC2 inhibits mTOR inducing autophagy."
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"It is known that TSC2 complex inhibits mTOR activation to promote autophagy through its GTPase protein (GAP) activity toward small GTPase Rheb [XREF_BIBR, XREF_BIBR]."
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"29 Increased AMP enhances AMPK activity, leading to TSC2 inhibition of mTOR in response to energy expenditure and reduced protein synthesis."
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"In a parallel pathway, 5′AMP-activated protein kinase (AMPK) phosphorylates and activates TSC2, thereby inhibiting mTOR activation in response to changes in the intracellular ATP/AMP ratio [ 4 ]."
16359855
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"AMPK also activates tuberous sclerosis complex 2 (TSC2) to inhibit mammalian target of rapamycin (mTOR), and promotes cell survival under energy starvation conditions [15,16] ."
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"TSC is caused by heterozygous pathogenic variants in TSC1 or TSC2, which inhibit mTOR complex 1 (mTORC1)."
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"TSC2 negatively regulates mTOR by acting as a GTPase-activating protein (GAP) for the small GTPase Rheb, which binds and activates mTOR [18,19] ."
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"We can not exclude that Tsc2 might have additional unidentified functions that compensate Tsc1-mutant phenotypes; however, since the loss of either Tsc1 or Tsc2 abolishes the Rheb-GTPase-activating activity, resulting in constitutively activated mTOR, it is unlikely that Tsc2 alone can suppress mTOR activation in the absence of Tsc1."
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"Both increased TSC2 phosphorylation and enhanced formation of the TSC1.TSC2 heterodimer can negatively regulate mTOR activity."
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"S6K and hamartin expression were equivalent in all samples, but tuberin expression was greatly reduced in the angiomyolipoma samples, consistent with the two-hit mechanism.Since phosphorylation activa[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"AMPK phosphorylates TSC2 at Ser1387 and raptor at Ser792 to indirectly inhibit mTOR kinase activity [XREF_BIBR]."
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"It is caused by mutations in the TSC1 or TSC2 tumor suppressor genes, resulting in hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway and subsequent cell cycle dysregulation."
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"Growth factor signals and energy status are transmitted to mTOR C1 via TSC a complex of TSC1 and TSC2 proteins, which bind to Rheb and inhibit mTOR C1 activation."
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"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling."
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"AMPK promotes autophagy by at least the following ways : phosphorylating the tuberous sclerosis (TSC) complex proteins TSC1 and TSC2, which in turn downregulate mTOR activity and induce autophagy 59, phosphorylating FOXO3, phosphorylating ULK1, and dissociating Beclin1 and Bcl-2 by stimulating JNK1-Bcl-2 signaling XREF_BIBR - XREF_BIBR."
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"As such, loss of either TSC1 or TSC2 leads to mTOR activation."
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"Contrary to these observations, it was shown that constitutive activation of mTOR by TSC2 deficiency inhibited pro-inflammatory IL-12 production and increased IL-10 in macrophages upon LPS stimulation[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling."
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"11 AMPK also indirectly activates ULK1 by phosphorylating TSC2 and RPTOR to inactivate MTOR."
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"These data indicate that Tsc2 is required for proper downregulation of Hif-1alpha levels following prolonged exposure to hypoxia.In the absence of growth factors, TSC2 inhibits mTOR leading to the acc[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Upon Akt activation, growth factors (PDGF, VEGF and IGF-1) and insulin block the TSC2 (tuberous sclerosis complex 2) complex, which in turn inhibits the mTOR protein (mammalian target of rapamycin)."
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"AKT activation leads to cell growth by activating mTOR through TSC1/2 phosphorylation, while increased levels of TSC1 and TSC2 inhibit the mTOR pathway; mTOR positively regulates 4E-BP1 and p70S6k, which are activated in a variety of cancers."
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"Since TSC2 inhibits mTOR by inactivating the small GTPase Rheb (Inoki etal, 2003), increased levels of AMPK activated TSC2 at the lysosomal surface may explain diminished basal mTOR activity in KO cells."
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"These data are consistent with a model whereby loss of TSC2 results in activation of mTOR, which in turn upregulates HIF-1alpha."
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"Once activated, AMPK can phosphorylate several downstream targets: the phosphorylation of acetyl coenzyme A (CoA) carboxylase inhibits fatty acid synthesis; the phosphorylation of hamartin (also known as TSC1) and TSC2 inhibits protein synthesis and anabolic metabolism (via effects on mTOR); and the phosphorylation of p53 promotes mitochondrial respiration and causes cell cycle arrest and apoptosis."
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"Loss of TSC1 or TSC2 leads to unchecked activation of mTOR, which leads to unregulated protein synthesis, increased cell growth and proliferation, increased angiogenesis, and changes in cell orientati[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"AMPK activation phosphorylates tuberous sclerosis complex 2 (TSC2), which inhibits mTOR and induces autophagy [XREF_BIBR]."
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"Because loss of TSC2 upregulates mTOR activity, we examined whether TSC2 dependent stress fiber remodeling and migration is mediated by mTOR."
25360538
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"In sestrin over expressing cells, siRNA knockdown of TSC2 restores the activation of mTOR by upstream signals, suggesting the TSC complex is necessary for sestrin 's inhibitory activity."
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"Their studies all suggest that the onset of epilepsy is related to the time point of PTEN depletion.Some study found that the encoded products of TSC2 and TSC1 inhibit mTOR-mediated signaling of ribos[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"TSC2 inhibits the activity of mTOR, which is downstream of IGF-1/PI3K/AKT signaling [ 179 ]."
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"We investigated the effect of the signaling molecule tuberin, which modulates the mammalian target of rapamycin pathway, on renal hypertrophy and fibronectin expression."
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"The source of this discrepancy is currently unknown.The phosphorylation of TSC2 by Akt is believed to inhibit the tumor suppressive function of the TSC complex, thus potentiating mTOR signaling."
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"We show by biotin switch assay that TSC2, which in the activated state acts to suppress mTOR activation, by forming a Rheb inactivating complex with TSC1, is constitutively nitrosylated in melanoma cells."
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"For suppressing mTOR activity, AMPK phosphorylates and activates TSC2, an mTOR upstream regulator, while phosphorylating and inactivating RAPTOR, a subunit of mTORC1 [13]."
| PMC
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"In fact, Myc inhibits mTOR repressor TSC2, thus increasing mTOR activity to facilitate cap dependent translation through S6K and 4E-BP phosphorylation [XREF_BIBR]."
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"We found that silencing of TSC2 could cause mTOR activation, as showed by elevated phosphorylation level of S6 (Figure 6B)."
32420585
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"Once the AMPK pathway activated, AMPK phosphorylates tuberous sclerosis 2 (TSC2), which then inhibits mTOR and eventually promotes autophagy."
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"Indeed, mTOR function is physiologically suppressed by neurofibromin and tuberin, encoded by NF1 and TSC1/2."
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"In the absence of growth factors, TSC2 inhibits mTOR leading to the accumulation of unphosphorylated S6."
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"Under metabolic stress, AMPK activates ULK1, the human homologue of yeast ATG1, and phosphorylates tuberous sclerosis protein 2 (TSC2) to inhibit mTOR and activate autophagy [XREF_BIBR, XREF_BIBR]."
| PMC
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"Decreased insulin leads to decreased signaling through the phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) pathway, subsequently allowing tuberous sclerosis complex 2 (TSC2) to inhibit mTOR [ xref ]."
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"TSC1 and TSC2 negatively regulate the activity of the mammalian target of rapamycin complex 1 (mTORC1), and deletion of Tsc1 or Tsc2 from mouse oocytes in primordial and further developed follicles has been shown to cause overactivation of the entire ovarian pool and subsequent POF in early adulthood [69,70]."
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"We then looked for TSC2 and various tubular markers in kidney tissues to determine if TSC2 can be scaffolded to TSC1 and TBC1D7 to maintain the stability of the TSC complex and inhibit mTOR signaling ."
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"In turn, elevated AKT activity increased phosphorylation and degradation of the downstream target TSC2, activating mTOR signaling, a key integrator coordinating proliferative and metabolic signals required for cell growth and survival (XREF_FIG)."
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"Phosphorylated co-signaling molecules are attached to mTOR, while phosphorylation of TSC2 directly inhibits the activity of mTOR."
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"Thomas Weichhart from the Medical University of Vienna presented a mouse model in which deletion of the tuberous sclerosis 2 (TSC2) gene in myeloid cells induces constitutive mTOR activation, followed by spontaneous multiorgan granuloma formation that appears to be more chronic than many prior murine granuloma models."
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"Mechanistically, elevated expression of GRP78 activates AMP-activated protein kinase (AMPK) and tuberous sclerosis 2 (TSC2), both of which inhibit mechanistic target of rapamycin (mTOR), resulting in initiation of autophagy ( xref , xref )."
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"Activated AMPK can phosphorylate and activate tuberous sclerosis complex 2(TSC2), which negatively regulates mammalian target of rapamycin (mTOR) activity ( Inoki et al., 2003 )."
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"TSC2 is an essential component in the formation of a functional heterodimer to suppress MTORC1 activity, and loss of TSC2 leads to the constitutive MTOR activation and impaired autophagy.32 The effects of MBCD disruption on the autophagic flux were similar in both Tsc2C/C and tsc2!"
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"The PTEN and TSC2 tumor suppressors function to antagonize mTOR (mammalian target of rapamycin) activation by Akt; hence, compound heterozygous inactivation of Pten and Tsc2 in the mouse may in principle exacerbate the tumor phenotypes observed in the single mutants in a reciprocal manner."
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"In its inactive form , Rheb is unable to stimulate the mammalian target of rapamycin ( mTOR ) ; hence , Tuberin indirectly prevents mTOR activity under poor growth conditions ."
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"To downregulate protein synthesis, AMPK phosphorylates TSC2, which in turn inhibits mTOR pathway, leading to dephosphorylation of ribosomal subunit component RPS6 (S6) and sequestration of translation initiation factor 4E (eIF4E)."
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"Akt phosphorylates several substrates, including TSC2 (tuberous sclerosis complex, tuberin), which finally activates the mammalian target of rapamycin (mTOR) and provides a direct link between insulin signaling and nutrient sensing."
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"When upstream signals are activated, TSC1 and TSC2 is inhibited by AKT, allowing mTOR activation."
26458815
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"Apigenin mediated activation of calcium/calmodulin protein kinase beta promotes the activation AMPK which in turn phosphorylates the TSC2 and thus inhibits the mTOR activity [XREF_BIBR]."
| PMC
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"GADD34 induced by viral infection forms a stable complex with TSC1/2 and PP1 (Protein phosphatase 1), dephosphorylates TSC2 at Thr1462, and inhibits the mTOR signaling, resulting in the suppression of[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"14-3-3 mediates mTOR signaling by regulating the product of tuberous sclerosis complex (TSC) 2 tumor suppressor gene, tuberin that inhibits the downstream target of mTOR, p70 ribosomal S6 kinase [96] [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"AMPK indirectly inhibits the mTOR pathway by phosphorylating – and thereby activating – tuberous sclerosis complex 2 (TSC2), which is part of the TSC1-TSC2 complex that inhibits mTOR1."
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"Polycystin-1 and the TSC1 and TSC2 tumor suppressor complex both act to suppress the activity of mTOR."
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"For example, low levels of intracellular ATP, under starvation conditions, activate the adenosine monophosphate-activated protein kinase (AMPK), which in turn phosphorylates tuberous sclerosis complex[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"AKT inhibits TSC2 mediated inhibition of the mammalian target of rapamycin, or mTOR, functionality."
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"TSC2 is phosphorylated by AKT, resulting in the loss of TSC2′s ability to inhibit mTORC1 and activate mTOR."
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"Furthermore, p53 activates genes such as AMP activated protein kinase beta, tuberin and PTEN to suppress the mTOR (nutrient sensor) signaling pathway, which participates in aerobic glycolysis and oxidative phosphorylation."
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"This leads to upregulation of p53 target genes, among which TSC2 inhibits the mTOR protein that stimulates protein synthesis and inhibits autophagy, a process that leads to digestion of cellular compo[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"The tumor suppressor TSC2 (tuberous sclerosis 2) is phosphorylated by Akt, which activates the mTOR kinase [XREF_BIBR]."
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"AMPK is able to phosphorylate tuberous sclerosis 2 (TSC2) and regulatory-associated protein of mTOR (RAPTOR) which inactivates mTOR, an inhibitor of ULK1."
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"Moreover, recent studies have suggested that Redd1 plays an important role in the TSC1/TSC2-mediated inhibition of the mammalian target of rapamycin (mTOR) ( Brugarolas et al., 2004 )."
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"TSC1/TSC2 negatively regulate mTOR in response to cellular energy deficit."
26169313
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"We have previously demonstrated that ERK1/2 inactivates TSC2 through a direct phosphorylation event, which leads to TSC2 dissociation from TSC1 and impairment of TSC2 inhibition of mTOR signalling."
22359342
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"The inactivation of TSC2 leads to proteasomal degradation of the TSC1 and TSC2 protein complex which in turn activates the mammalian target of rapamycin (mTOR) activation."
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"Given that TSC2 inhibits MTOR at the lysosomes in response to nutrient shortage [43], one can hypothesize that increased TSC2 leads to overactivation of autophagy potentially affecting neuronal development in EZH2-deficient cells.Methylation of H3K9 is another repressive histone mark associated with silenced autophagy-related gene expression [44–46]."
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"Silencing of TSC2 enhanced mTOR activity in stimulated T cells cultured alone and completely restored mTOR activity in T cells co-cultured with MDSC."
27007050
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"Phosphorylation of TSC2 and Raptor by AMPK inhibits mTOR anabolic activity XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR."
28180061
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"Phosphorylation of TSC2 by Erk promotes dissociation of the tuberous sclerosis complex and attenuates TSC2-mediated inhibition of mTOR in cells."
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"TSC2 protein complexes with TSC1 and blocks the ability of the Rheb (Ras homolog enriched in brain) GTPase to activate mTOR (mammalian target of rapamycin), a crucial signal transducer which regulates protein synthesis and cell growth."
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"Collectively, these data demonstrate that TSC2 deficiency promotes increases in YAP/TAZ abundance, mTOR activity, and PAVSMC proliferation through ECM remodeling."
36473049
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"Loss of Tsc1 and Tsc2 activates mTOR and disruptsPI3K-Akt signaling through downregulation of PDGFR.J Clin Invest 2003; 112:1223-33; PMID :14561707; http://dx.doi.org/10.1172/JCI200317222[17] Inoki K, Corradetti MN, Guan KL."
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"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling."
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"Loss of Tsc1 and Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR."
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"Silencing of TSC2 restored mTOR activity in T cells cultured with MDSC, but it also led to T cell apoptosis, suggesting the key role of this inhibition in the survival of T cells to MDSC."
27007050
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"TSC2 isoform A does not inhibit mTOR activation."
24318044
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"Full-length TSC2 protein interacts with TSC1 to inhibit the activation of mTOR by Rheb."
24318044
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"In more detail, ATM activates TSC2 via AMPK, and TSC2 inhibits mTOR inducing autophagy."
32987354
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"Moreover AMPK can also phosphorylate TSC2 and raptor when activated upon metabolic stress by a low ATP/AMP ratio, thereby inhibiting mTOR."
19362111
reach
"On the contrary, the anti-oncogene phosphatase and tensin homology deleted on chromosome 10 (PTEN), TSC complex subunit 1 (TSC1), and TSC complex subunit 2 (TSC2) can inhibit the progress of the mTOR pathway."
29556324
reach
"At the molecular level, TSC is caused by either the loss or malfunction of either hamartin (TSC1) or tuberin (TSC2), which interact in a heterodimer known as the TSC1 and TSC2 complex, to negatively regulate mammalian target of rapamycin complex 1 (mTORC1)."
22198573
reach
"As TSC2 is a suppressor of mTOR, the inhibition of the mTOR pathway would be expected when PI3K is also inhibited [33]."
39062762
sparser
"Rapid advances in our knowledge of TSC were catalyzed by the discovery that hamartin-tuberin normally inhibits the mechanistic target of rapamycin (mTOR; previously known as mammalian target of rapamycin) serine/threonine kinase ( xref )."
23580196
sparser
"Activated AMPK phosphorylates TSC2 [ xref ], which in turn inhibits mTOR."
35813430
reach
"The Tsc2 product, tuberin, negatively regulates the mTOR pathway."
25088526
reach
"AMPK can suppress the action of mTOR complex 1 (mTORC1) either by direct phosphorylating the Raptor, a regulatory component of mTORC1, or by the phosphorylation of tuberous sclerosis protein 2 (TSC2), which consequently inhibits the mTOR activity [141,142]."
37886966
trips
"TSC2 negatively regulates the activity of the GTPase Rheb and thereby inhibits mammalian target of rapamycin complex 1 (mTORC1) signaling."
20818424
reach
"XREF_BIBR, XREF_BIBR It is known that 3 induced activation of AMPK leads to TSC2 phosphorylation mediated mTOR inhibition."
25122135
reach
"AMPK activates TSC2, which in turn inhibits mTOR [49]."
35562967
reach
"We found that loss of Tsc2 potentiated store operated Ca 2+ entry (SOCE) in an mTOR complex 1 (mTORC1)-dependent way."
23108404
reach
"Both TSC1 and TSC2 inhibit the mammalian target of rapamycin (mTOR) complexes pathway, which is crucial for cell proliferation, growth, and differentiation, and is stimulated by various energy sources and hormonal signaling pathways."
39334956
reach
"It is caused by mutations in the genes encoding hamartin (TSC1) and tuberin (TSC2) that are involved in the regulation of cell proliferation and differentiation and inhibit the mTOR pathway [XREF_BIBR]."
26097734
reach
"Constitutive mTOR activation by loss of TSC1 and TSC2 rapidly stimulates the targets of both PERK and IRE1, which UPR activation could not be observed in combined treatment of TSC1 and TSC2 depletion and rapamycin addition."
27992581
reach
"It is suggested to phosphorylate the mTOR inhibitor, tuberous sclerosis 2 (TSC2) and the mTOR interaction factor, raptor, which both lead to a reduction of mTOR kinase activity and an activation of th[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
33453674
reach
"Phosphorylation of TSC2 by ERK promoted dissociation of the tuberous sclerosis complex and attenuated TSC2 mediated inhibition of mTOR in cells."
19166931
sparser
"A great deal of ground breaking work has determined that the Tuberin and Hamartin Complex function as a negative regulator of protein synthesis and cell cycle progression through G1/S. This is largely attributed to the GTPase activity of Tuberin that indirectly inhibits the mammalian target of rapamycin (mTOR)."
30629673
reach
"Interestingly, while we previously showed activation of AMPKalpha and downstream tumor suppressor TSC2 which act to inhibit mTOR in both U251 and U87 parental cells [XREF_BIBR], U87TMZ appears to have lost the ability to act through this pathway which suggests direct inhibition of the Akt and mTOR axis."
24718901
reach
"Under periods of starvation, serum withdrawal, or other stresses, the GTPase activating protein TSC2 inhibiting Rheb and mTOR activity, and consequentially activating the serine/threonine kinase Atg1."
20118969
reach
"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling."
30044707
sparser
"TSC2 Is Not Required for mTOR Inhibition by Peroxide —TSC2 is necessary for acute hypoxic mTOR inhibition ( xref , xref )."
18768473
reach
"Furthermore, phosphorylation and activation of TSC2 by GSK3beta inhibits mTOR signaling."
22751699
reach
"Downstream targets of AKT are regulators of various cell survival pathways and include glycogen synthase kinase 3 beta (GSK3beta), TSC2 protein (downregulator of the kinase mTOR, which regulates S6 ki[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
20347887
reach
"In the setting of low concentrations of adenosine triphosphate (and high AMP), AMPK activates TSC2, which inhibits mTOR."
27865299
reach
"We next examined mTOR-related signaling, because AMPK phosphorylates the tumor suppressor tuberous sclerosis complex 2 (TSC2), thereby inhibiting mechanistic target of rapamycin (mTOR), which is involved in cell growth ."
35461323
reach
"In contrast, phosphorylation and activation of TSC2 by several kinases inhibits mTOR signaling."
22751699
reach
"Loss of TSC2 leads to activation of MTOR and downstream signaling elements, causes endoplasmic reticulum (ER) stress, activates the unfolded protein response, and results in tumor development [XREF_BIBR]."
25469175
reach
"Rheb potently activates mTOR when in a GTP-bound state and TSC1–TSC2 inhibits mTOR indirectly by reverting Rheb to an inactive GDP-bound form [9] ."
19166929
reach
"The activity of the complex depends predominantly on the phosphorylation status of TSC2, which normally inhibits mTOR through the inhibition of Ras homologue enriched in brain (Rheb), a small GTPase required for mTOR activation [40]."
22010859
reach
"The tumor suppressor tuberin, the TSC2 gene product, negatively regulates the mammalian target of rapamycin (mTOR) pathway, which is a key regulator of cell growth and proliferation and increasing evidence suggests that its deregulation is associated with human chronic diseases, including cancer [XREF_BIBR]."
25602702
reach
"AMPK impacts mTOR via phosphorylation and activation of the tumor suppressor protein tuberin, which negatively regulates mTOR activity."
38711049
sparser
"When present as a heterodimer the TSC1-TSC2 complex inhibits mTOR indirectly by converting the small GTPase Ras homolog enriched in brain (Rheb) to an inactive GDP bound form."
19795384
reach
"AMP activated protein kinase (AMPK), which is responsive to cellular energy depletion, can inhibit cell growth through TSC2 dependent suppression of mTOR signaling XREF_BIBR, XREF_BIBR."
21297943
sparser
"ERK-dependent phosphorylation of tuberin prevents its association with hamartin and the inhibition of Rheb and mTOR by the tuberin-hamartin complex."
20219622
reach
"TSC is an ASD caused by variants in the genes encoding TSC1 or TSC2, two proteins that normally inhibit the mTOR pathway."
31495451
reach
"Our findings showed that either TSC2 deletion or TSC2 mutant could lead to TSC2 loss-of-function and hyperactivation of mTOR signaling."
35143341
reach
"Tuberin is a suppressor of mTOR, and phosphorylated tuberin loses its suppressive effect against mTOR [XREF_BIBR]."
27338360
reach
"We set out to test the hypothesis that PPARgamma ligands activate tuberous sclerosis complex-2 (TSC2), a tumor suppressor gene that inhibits mTOR signaling."
17597835
reach
"In cardiomyocytes and fibroblasts, PDE5A inhibition also stimulates PKG1a phosphorylation of tuberin (TSC2 [tuberous sclerosis complex 2]), enhancing its inhibition of the mTOR (mechanistic target of rapamycin complex-1)."
39660453
reach
"Inhibition of TSC2 increases mTOR activity because Rheb positively regulates mTOR activation toward the regulation of a wide range of substrates, including S6K, 4EBP1 and ULK1 (Unc-51-Like Kinase 1) ([MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
37944568
reach
"Immunohistochemical analyses were used to examine the status of the lycopene sensitive mTOR pathway, which is negatively regulated by the Tsc2 complex."
25602702
reach
"These results may be generalizable and applicable to humans because TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling [XREF_BIBR]."
25602702
reach
"When upstream signals are activated, TSC1/TSC2 is inhibited by AKT, allowing mTOR activation."
34592229
reach
"LKB1 is linked to mTOR regulation through the sequential activation of AMP activated protein kinase (AMPK) and the tumor suppressor TSC2, a GTPase activating protein that negatively regulates mTOR through the small G protein Rheb."
18794113
reach
"TSC1 and TSC2 gene products typically act to inhibit mammalian target of rapamycin (mTOR) which is the basis of the current practice guidelines for malignant PEComa."
40330237
reach
"AMPK, when activated, phosphorylates tuberous sclerosis complex 2 (TSC2), thereby inhibiting mTOR activation [XREF_BIBR]."
16899133
reach
"Bourneville mutations cause tuberous sclerosis syndrome in the TSC protein TSC2, which suppresses mTOR action under hypoxic and energy-depleted circumstances [24,73]."
36428613
reach
"Fisetin functions as a dual mTORC1/C2 inhibitor, activating the mTOR repressor TSC2."
37565061
reach
"We found that PPARgamma ligands activate TSC2, which, in turn, inhibits mTOR signaling in NSCLC cells through PPARgamma independent pathways."
17597835
reach
"TSC2 inhibits mTOR via reduction of GTP-Rheb [28] ."
17616457
reach
"Silencing TSC2 restored the mTOR related signal and partially blocked the effect of rosiglitazone on cell growth inhibition."
17597835
reach
"The TSC1 / TSC2 protein complex inhibits the rapamycin target oapamycin (mTOR) and is involved in signaling pathways that control cell growth."
36447689
reach
"TSC1 and TSC2, which inhibit mTOR signaling, are known as important regulators of cell size and growth [XREF_BIBR, XREF_BIBR]."
24167408
reach
"Among the 4 patients who had PR or SD> 12 months, 1 patient with Hodgkin lymphoma had TSC2 loss, a molecular aberration that putatively activates the mTOR pathway."
27589687
reach
"Loss of tuberin results in a constitutively activated mTOR signalling leading to increased cell growth [XREF_BIBR]."
25699271
reach
"Loss of Tsc2 promotes mTOR activation and a hyperproliferative phenotype [22]."
32327294
reach
"On the other hand, AMPK indirectly activates cell autophagy by phosphorylating Raptor or TSC2 to inhibit the activity of mTOR."
34838647
reach
"Hamartin and tuberin, the protein products of TSC1 and TSC2, inhibit mammalian target of rapamycin (mTOR) (41)."
21289542
sparser
"TSC2 inhibits mTOR via reduction of GTP-Rheb [28] ."
17616457
reach
"Phosphorylation of the tumor suppressor TSC2 by Akt results in the inactivation of this Rheb GAP, thereby promoting the accumulation of (active) Rheb-GTP and the induction of mTOR activity."
16904612
reach
"The activation of AMPK by LKB1 leads to phosphorylation of tuberous sclerosis complex 2 (TSC-2), which in turn inhibits the mTOR protein (mammalian target of rapamycin), a key protein which regulates processes of cell growth and angiogenesis, and promotes cell division and protein synthesis."
23788884
reach
"TSC2 inactivation by Akt and PKB may also inhibit mTOR indirectly through inhibition of the small GTPase, Rheb [XREF_BIBR]."
16899133
reach
"Under energy depletion conditions, AMPK phosphorylates TSC2 and RAPTOR, two essential regulators of mTOR, to suppress mTOR resulting in autophagy induction [XREF_BIBR, XREF_BIBR]."
26111001
reach
"Surprisingly, rapamycin treatment also rescues lamination defects in tuberous sclerosis complex (TSC) 2 deficient mice, in which loss of TSC2 leads to activation of mTOR signaling and aberrant regulation of Reelin-Dab1 signaling."
27803648
reach
"Akt is known to directly phosphorylate Ser2448 for activation of mTOR and inhibit tuberous sclerosis complex 2 (TSC2) and AMP Kinase, which otherwise inhibits mTOR activity."
21302298
sparser
"Everolimus is believed to act via inhibition of the mTOR complex 1 (mTORC1) which is normally inhibited by the protein complex of TSC1 (hamartin), TSC2 (tuberin) and TBC1D7."
35233200
reach
"TSC1/2 form a protein complex that negatively regulates mTOR signaling, and loss of either TSC1 or TSC2 leads to constitutive activation of the mTOR pathway."
18988856
reach
"Upon activation, AMPK phosphorylates Raptor and TSC2, inhibiting the stability and activation of mTOR (12, 15, 16)."
37006245
reach
"TSC complex subunit 1 (TSC1) and TSC complex subunit 2 (TSC2) negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling."
36926197
reach
"It is now generally recognized that the primary function of the TSC1 and TSC2 protein complex is to inhibit mTOR signaling."
20412061
sparser
"43 For example patients with defective TSC2 gene, that inhibits mTOR, are prone to develop PNETs."
20705397
reach
"Additionally, Wnt signaling can inhibit GSK3 phosphorylation of TSC2 to stimulate mTOR signaling."
32854217
reach
"Under conditions of energy depletion, AMPK is activated and phosphorylates TSC2, leading to turn off the mTOR pathway [27,28,41] ."
25964188
eidos
"Once the AMPK pathway activated , AMPK phosphorylates tuberous sclerosis 2 ( TSC2 ) , which then inhibits mTOR and eventually promotes autophagy ."
33324654
reach
"Firstly, AMPK phosphorylates TSC2 and RAPTOR, two essential regulators of mTOR, to suppress mTOR."
26111001
reach
"Then, TSC2 in PKR gene silencing conditions can be blocked by sequestration with 14-3-3 proteins to prevent the inhibitory effect of TSC2 in the mTOR signalling pathway."
19602051
reach
"Activation of AMPK leads to suppression of mammalian target of rapamycin (mTOR) signaling, and the molecular mechanisms involve phosphorylation of tuberous sclerosis complex protein TSC2 at Thr 1227 and Ser 1345 that increases the activity of the TSC1 and TSC2 complex to inhibit mTOR [XREF_BIBR, XREF_BIBR]."
22353783
reach
"To investigate whether the suppressed AKT and mTOR pathway contributes to the reversibility of contact inhibition, they designed shRNA that silenced the expression of TSC2, an AKT substrate that inhibits mTOR activity by suppressing the mTOR activating small GTP binding protein Rheb."
25277173
eidos
"54 In addition , phosphorylated AKT ( p-Akt ) can inhibit TSC2 and TSC to activate mTOR ,55 and mTOR can induce mRNA translation by phosphorylating S6K and then p70S6K to increase the adhesion of ribosomes to the endoplasmic reticulum and thereby inhibit both the formation of autophagic membranes and autophagy activity.56 ,57 The corresponding results from our study showed that LACTB might inhibit the level of PIK3R3 to reduce the levels of PI3K , p-AKT and mTOR and thereby promote autophagy ."
32636680
reach
"Mutations in the TSC1 or TSC2 genes lead to disruption of the TSC1-TSC2 intracellular protein complex, causing overactivation of the mammalian target of rapamycin (mTOR) protein complex."
26067126
reach
"Although it is clear that growth factor induced activation of Akt blocks TSC1 and TSC2 inhibition of mTOR signaling [XREF_BIBR - XREF_BIBR], the molecular mechanism by which Akt inhibits the function of TSC1 and TSC2 protein complex as a cell growth suppressor is still undefined."
20412061
reach
"Activated Akt can phosphorylate and inactivate tuberous sclerosis complex 2 (TSC2), which negatively regulates mTOR."
21427355
sparser
"In other cell types, active AMPK was shown to phosphorylate TSC2, which in turn inhibits mTOR [13] and affects two families of characterized mTOR substrates through which mTOR stimulates translation: [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
18377870
reach
"Tuberous sclerosis is another AD “tumor syndrome,” caused by pathogenic variants in the TSC1 or TSC2 tumor suppressor genes, tuberin and hamartin, that inhibit the mammalian target of rapamycin (mTOR) pathway."
37644229
reach
"In HT29 colon tumoral cells XREF_BIBR, AMPK activation by synthetic molecules or polyphenolic compounds was shown to activate TSC2, which in turn inhibits TORC1 and mTOR and p70S6K."
24244361
reach
"Upon reduced levels of ATP, STK11 binds to and phosphorylates AMPK, which, in turn, can phosphorylate and inactivate the TSC2 complex to block mTOR and stop cell proliferation [37]."
37370686
reach
"However, treatment was not restricted to mTOR-addicted tumors as this may have led to more favorable outcomes through screening for patients with either tissue or liquid biopsy-proven β-catenin mutated HCC or tumors with loss of tuberous sclerosis complex 2 (TSC2), which both lead to increased mTOR signaling.54 55 Thus, subsets of patients with mTOR-addicted tumors may benefit from mTOR inhibitors in neoadjuvant or adjuvant settings."
39583094
reach
"TSC2 is an inhibitor of ras homologue enriched in brain (RHEB) and hence the loss of TSC2 leads to activation of mTOR and S6K."
24219910
reach
"It is caused by mutations in TSC1 or TSC2 genes causing hyperactivation of the mammalian target of rapamycin (mTOR) pathway."
31335226
reach
"Active PRKAA1 directly phosphorylates and enhances the ability of tuberin to inhibit mTOR signalling XREF_BIBR."
25330188
reach
"As it is central to multiple tumorigenic pathways, downregulation of mTOR pathway inhibitors such as PTEN and TSC2 was a highly significant finding (~ 85%) in a gene expression profiling of PNETs, even in the absence of a pathway specific mutation."
33537001
reach
"Specifically, AMPK phosphorylates key proteins such as Raptor at Ser722 and Ser792, a regulatory component of the mTORC1 complex (Gwinn et al., 2008), and TSC2 at Ser1387 and Thr1271, which inhibits the mTOR-activating factor Rheb."
39702310
reach
"In this case, previous studies have demonstrated that TSC2 inhibits small G protein Rheb by its own GAP activity and inhibits the activation of downstream mTOR , and thus inhibits the downstream targe[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
32652105
reach
"Activation of AMPK, a target of several glucose lowering agents used in diabetes treatment, including metformin and the thiazolidenediones, stimulates insulin action in peripheral tissues, acting to phosphorylate and stimulate the TSC1 : TSC2 complex, which subsequently inactivates mammalian target of rapamycin and regulatory associated protein of mTOR (mTOR and Raptor)."
20354156
reach
"Two of these genes, TSC1 and TSC2, are downstream of AMPK and negatively regulate mTOR in response to cellular energy deficits."
24612911
reach
"Phosphorylation of tuberin by AMPK enhances tuberin repression of mTOR signaling, and tuberin is essential for altered cell growth in response to energy deprivation."
18701472
reach
"Loss of TSC1 or TSC2 leads to hyperactive mTOR signaling, which is the main cause of tumor growth in TSC patients, and the decreased AKT1 activity due to the negative feedback regulation of mTOR may account for the benign nature of TSC tumors."
23108404
reach
"When active, AMPK can phosphorylate TSC2 on serine 1387 to ultimately inhibit the activity of mTOR and the mTORC1 complex [XREF_BIBR]."
25219658
sparser
"In a previous study, Chen et al. found that active TSC2 inhibits mTOR through RHEB by detecting differential phosphorylation of short TSC2 or long TSC2 splicing variants and its effect on mTOR signaling pathway, leading to continuous stimulation of carcinogenic autophagy in ESCC cells ( xref )."
38617776
reach
"TSC1 and TSC2 inhibit mTOR signaling via direct inhibition of the Ras homolog enriched in brain, Rheb."
29709573
reach
"Tuberous sclerosis is a genetic condition resulting from mutations in the TSC1 or TSC2 gene, which negatively regulate mTOR activity."
26403076
reach
"It is generally believed that activation of PI3K and Akt stimulates the mTOR pathway by phosphorylating and inactivating the tumor suppressor protein tuberous sclerosis complex 2 (TSC2), which negatively regulates mTOR activity."
21427355
reach
"Furthermore, recent data show that TSC2, which can inhibit mTOR signalling, is inactivated by Akt [5], providing an additional input from PI-3K and Akt into regulation of mTOR and its downstream effec[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
12753910
sparser
"Stimulation of REDD2 disrupted the 14-3-3 and TSC2 complex competitively and allowed TSC2-dependent inhibition of mTOR [36] ."
24412152
reach
"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling."
29940807
reach
"Phosphorylation of TSC2 by GSK-3 enhances the suppression of mTOR signaling in cultured cells and GSK-3 suppresses mTOR signaling in hippocampal tissue."
23295207
reach
"Finally, AMPK stimulates tuberous sclerosis complex (TSC) 1-TSC2 complex activity, which inhibits mTOR."
31915514
sparser
"Additionally, phosphorylated AMPK activates tumour-suppressing TSC-2 that inhibits mTOR, which not only promotes translation and proliferation but also disrupts autophagosome assembly [ xref ]."
33921022
sparser
"Hamartin and tuberin inhibit the mechanistic target of rapamycin (mTOR), a kinase that regulates protein and lipid synthesis."
36615165
reach
"TSC is characterized primarily by non-malignant tumors in multiple organ systems as a result of mutations in TSC1 (hamartin) or TSC2 (tuberin), which normally combine to downregulate mTOR signaling related cell growth and proliferation [3, 4]."
35587487
reach
"It has been suggested that Erk1/2 activation, contrary to AMPK stimulation, may cause TSC1–TSC2 dissociation and impair TSC2 capability of blocking mTOR signaling [30] ."
19723512
sparser
"AMPK can phosphorylate and activate TSC-2, which subsequently inactivates mTOR."
34136478
reach
"Recent studies demonstrate that activation of AMPK phosphorylate and activates TSC2 that negatively regulates mTOR XREF_BIBR."
20637208
reach
"GSK-3beta activates TSC2 and consequently further suppresses mTOR, whereas Akt inhibits TSC2 thus decreasing TSC2 suppression of mTOR."
22227453
sparser
"P53 is linked to autophagy via inhibition of mTOR by AMPK, TSC1, and TSC2, and plays a important role in the transcriptional regulation of autophagy-related target genes ( xref )."
29430945
reach
"Phosphorylation of the tumor suppressor TSC2 by Akt results in its inactivation, thereby promoting the accumulation of (active) Rheb-GTP and the induction of mTOR activity."
20213674
reach
"These data identify a unique mechanism for modulation of TSC2 repression of mTOR signaling via membrane retention of this tumor suppressor, and identify PC-1 as a regulator of this downstream component of the PI3K signaling cascade."
20169078
reach
"Akt induced phosphorylation of the tumour suppressor TSC2 (also known as tuberin) causes the dissociation of TSC2 and TSC1 (also known as hamartin), relieving their inhibition of mTOR kinase."
17319972
reach
"This membrane retention of TSC2 enhances TSC2 repression of mTOR signaling in human cells."
20169078
reach
"Incubation of RMCs with 1,25 (OH) 2 D 3 for 48 h increased VDR expression (p < 0.05), restored the expression of TSC1 and TSC2 and 4E-BP1, and blocked the aberrant upregulation of Rheb, mTOR and p70S6K."
29416624
reach
"Akt phosphorylates tuberous sclerosis complex 2 (TSC2) and disrupts the TSC1/TSC2 complex, leading to activation of mTOR [26] ."
25148938
reach
"FST also activated the mTOR repressor TSC2 (tuberous sclerosis 2), commonly associated with inhibition of Akt and activation of AMPK [XREF_BIBR]."
25654230
reach
"Hamartin and tuberin act as a complex upstream of mTOR and inhibit the mTOR pathway via inhibition of Rheb (Ras homolog enriched in brain) (XREF_FIG)."
22544534
reach
"As the tuberous sclerosis genes, TSC1 and TSC2, normally inhibit mTOR, the mTOR pathway is hyperactivated in TSC, promoting tumor growth and epileptogenesis, and mTOR inhibitors are a proven treatment for tumors and epilepsy in TSC."
31605778
sparser
"Metformin activates AMPK indirectly via a suppressor protein, liver kinase B1 (LKB1), and via the activation of tuberous sclerosis complex 2 (TSC-2) which inhibits the mammalian target of rapamycin (mTOR) protein, one of the key proteins in regulating cell division, protein synthesis, growth and angiogenic processes [ xref , xref ]."
24308813
reach
"Identification of mutations in the tuberous sclerosis 1 (TSC1) and TSC2 genes producing constitutive activation of the mammalian target of rapamycin (mTOR) pathway presents an opportunity for targeted therapy."
27793946
reach
"Supporting an increased protein degradation relative to synthesis due to food deprivation, starved trout muscle contained high levels of the transcript for tuberous sclerosis component 2 (TSC2) which has been shown, in mammals, to inhibit mTOR a positive regulator of cell growth and proliferation [XREF_BIBR], and of the transcript encoding the translational repressor 4E-BP1, which presumably reinforces the inhibition of cap dependent translation resulting from inactivation of Akt and mTOR [XREF_BIBR]."
18045468
reach
"In this study, we found that OGD-induced ER stress caused increases in REDD1 levels and TSC2 phosphorylation, increases that reduced mTOR activity and led to subsequent autophagic changes in cytotroph[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
29208245
reach
"Furthermore, mTOR signaling could be further repressed by CP1 under conditions in which AMPK was activated and mTOR was repressed by TSC2."
20169078
reach
"Akt is a serine/threonine kinase that lies upstream of mTOR in the pathway because Akt phosphorylates TSC2, which de-represses Rheb to interact with FKBP38 and allow mTOR activation [XREF_BIBR]."
19216841
reach
"However, mTOR is negatively regulated by complex of tuberin and hamartin [XREF_BIBR]."
21513566
reach
"Besides directly phosphorylating and activating Ulk1, AMPK also phosphorylates TSC2 and Raptor, key regulators of mTOR, thereby inhibiting the suppressive effect of mTOR ( Egan et al., 2011; Kim et al[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
26549445
reach
"HERC1 is a ubiquitin ligase that destabilizes TSC2 24, and TSC2 in complex with TSC1 inhibits FRAP1 function XREF_BIBR, XREF_BIBR."
21946537
reach
"It has to be pointed out that pAkt is an upstream positive regulator of mTOR through TSC2 inhibition expected to increase mTOR signaling."
29632324
reach
"The relevance of the mTOR pathway in the pathophysiology of TSC was first suggested in simplified biological systems, such as drosophila and yeast, in which hamartin and tuberin were shown to inhibit mTOR signaling."
23644232
reach
"Higher level or activation of Tuberin, which is a product of the tumor suppressor gene TSC-2 and inhibits Rheb, can inhibit activation of the mTOR signaling pathway [XREF_BIBR - XREF_BIBR]."
28638431
reach
"However, Akt can phosphorylate TSC-2 and inhibit the formation of the TSC-1/TSC-2 complex, thereby releasing the inhibitory effect on Rheb and activating mTOR[17]."
39493568
reach
"Local cap dependent mRNA translation is also controlled by mammalian target of rapamycin (mTOR), which in turn is negatively regulated by the tuberous sclerosis complex proteins TSC1 and TSC2."
27669991
reach
"AKT can activate mTOR indirectly promoting the dissociation of the tuberous sclerosis complex 2 (TSC2), which sequesters mTOR."
30006194
reach
"Additionally, AMPK-induced phosphorylation of tuberous sclerosis complex 2 (TSC2) inhibits mammalian target of rapamycin (mTOR), promoting cell survival under energy starvation [ 15 , 16 ]."
29432731
reach
"AMPK phosphorylates and activates TSC-2 upstream of mTOR, promoting TSC-1/TSC-2 complex formation, decreasing mTOR activity, and thus, leading to ICC apoptosis[26]."
39493568
reach
"In evaluating the mechanism of increased mTOR activity documented in gliomas, we asked whether decreased expression levels of hamartin and tuberin may relieve the inhibitory control of mTOR and lead to elevated mTOR activity."
18759130
reach
"This proliferation of smooth muscle like cells is reported to be due to the activation of mammalian target of rapamycin (mTOR) caused by mutations in the tuberous sclerosis complex 1 (TSC1) or TSC2 genes."
29021448
reach
"Thus, as shown in XREF_FIG, membrane tethered CP1 enhanced TSC2 retention at the membrane and protected this tumor suppressor from AKT phosphorylation to enhance TSC2 repression of mTOR."
20169078
reach
"We have demonstrated that the short intracellular C-terminal tail of polycystin-1 (CP1) when membrane bound, enhances TSC2 mediated repression of mTOR signaling in human cells."
20169078
reach
"To validate whether Rheb was involved in PRL-3-mediated TSC2 suppression and activation of mTOR, we used a Rheb activation assay to directly study the levels of active Rheb (Rheb-GTP) in PRL-3-overexpressing cells."
26597054
reach
"In such cases loss of TSC1 and TSC2 would be required to activate mTOR."
18759130
reach
"Arginine supplementation was recently shown to alleviate TSC2-mediated inhibition of mTOR, autophagic block, and muscle loss in GAA-KO mice [ 35 ], and may augment MPS in catabolic conditions [ 42 ]."
35718712
reach
"The inactive mutation of TSC1 or TSC2 is found in patients with LAM to activate the crucial mammalian target of rapamycin (mTOR) signaling pathway and result in enhanced cell proliferation and migration."
33072782
reach
"The RAP-GAP domain of tuberin promotes this reaction and inhibits the RHEB–GTP-dependent stimulation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) [40,41]."
36232477
reach
"AMPK mediates its effect on cell growth through inhibition of mTOR, via phosphorylation of the tuberous sclerosiscomplex (TSC2), a subunit of the larger TSC1/TSC2 (hamartin/tuberin) complex that negat[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
21168492
reach
"Stimulation of REDD2 disrupted the 14-3-3 and TSC2 complex competitively and allowed TSC2-dependent inhibition of mTOR [36] ."
24412152
reach
"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling."
23226094
reach
"AKT phosphorylates TSC2 at different sites, thus suppressing its control of RHEB and mTOR [33]."
37628917
reach
"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 and S6K1 cooperates with IFNbeta in inhibiting human LAM and TSC2-null ELT3 cell proliferation."
18094073
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"For example, low levels of intracellular ATP, under starvation conditions, activate the adenosine monophosphate-activated protein kinase (AMPK), which in turn phosphorylates tuberous sclerosis complex[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
35500868
reach
"AMPK also activates tuberous sclerosis complex 2 (TSC2) to inhibit mammalian target of rapamycin (mTOR), and promotes cell survival under energy starvation [17,18] ."
25229685
reach
"TSC is caused by heterozygous loss of function mutations in the tumor suppressor genes TSC1 (OMIM # 605284) and TSC2 (OMIM # 191092), causing hyperactivation of the mechanistic Target Of Rapamycin (mT[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
29432982
reach
"Under normal conditions, the TSC2 complex ubiquitinates and consequently degrades mTOR."
39000254
sparser
"The common mechanism of insulin-induced mTOR-signaling relies on phosphorylation of TSC2 protein by PKB/Akt and resulting release of the TSC2 inhibition of mTOR."
17537394
reach
"Additionally, PC-1/C-domain enhances the interaction of TSC2 with its partner TSC1 which further suppresses the mTOR cascade [74]."
36422197
reach
"Hamartin and tuberin, the TSC1 and TSC2 protein products respectively, normally inhibit mTOR signaling through an indirect pathway."
38783199
sparser
"The serine/threonine kinase mTOR is a well‐characterized substrate of Akt and it is known that Akt‐mediated activation of mTOR occurs through phosphorylation and inactivation of tuberous sclerosis complex 2 (TSC2), which normally inhibits mTOR (Hay xref )."
30318853
reach
"AMPK can phosphorylate TSC2 to inhibit mTOR signaling."
36936290
reach
"AMPK has been reported to repress the synthesis of mTOR complex 1 (mTORC1) through phosphorylating the TSC1-TSC2 complex, thereby reducing the activity of mTOR and alleviating the inhibition of mTOR on autophagy [43, 44]."
37466835
reach
"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling."
30317878
reach
"TSC1 and TSC2 encode the protein hamartin and tuberin, which together suppress the activity of the mammalian target of rapamycin (mTOR) pathway (4)."
36505768
reach
"TSC2 is a well-known inhibitor of mTOR (Inoki et al., 2003), which can induce fatty acid biosynthesis via the activation of SREBP transcription factors (Eberle et al., 2004; Porstmann et al., 2008)."
37292722
reach
"Stabilisation and increased abundance of TSC2 suppress the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signalling pathway and thereby promote autophagy, thus possibly reducing cell prolife[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
22405572
reach
"Mutations in either of the two tumor-suppressor genes, TSC1 on chromosome 9q34 and TSC2 on chromosome 16p13.3, which encode proteins hamartin and tuberin respectively, disrupt mTOR regulated cellular [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
30279084
reach
"HIF-1α is activated by the mechanistic target of rapamycin (mTOR) and, typically, in response to food intake, the body will indirectly activate mTOR due to chain signaling from Insulin Receptor Substrate (IRS) to Phosphoinositide 3-kinase (PI3K) and then Protein Kinase B (Akt), resulting in the inactivation of Tuberous Sclerosis Complex 2 (TSC2) (which is a suppressor of mTOR), and thus activation of HIF-1α and glucose uptake."
36662841
sparser
"TSC2 inhibits mammalian target of rapamycin complex 1 (mTORC1), a protein complex essential for protein translation and cell growth."
25309720
reach
"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling."
29508625
reach
"Deficiencies or dysfunction of either hamartin or tuberin activate the mammalian target of rapamycin (mTOR) and other downstream proteins, resulting in increased protein translation and inappropriate [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
24998373
reach
"Loss or impaired function of either Tsc1 or Tsc2, which together act to negatively regulate mTOR signaling, leads to strong and sustained mTOR signaling activation 13.Notably, the Ras/Mek/Erk pathway is also highly activated in 50-100% of HCCs and correlated with a poor prognosis 14."
36451866
reach
"One of the major downstream substrates of Akt is TSC2, which is phosphorylated to activate the mammalian target of Rapamycin (mTOR), another important tumorigenesis promoting kinase."
27196761
reach
"Another nutrient-sensing regulatory kinase, AMPK, plays roles in autophagy induction by phosphorylating TSC2 and Raptor to inactivate mTOR or by directly interacting with ULK1 during glucose starvation (4, 6)."
34287052
reach
"Activated AMPK promotes GAP activity of the TSC1/2 complex by directly phosphorylating TSC2 at T1227 and S1345, thus inactivating RHEB and mTOR and activating autophagy [89,90,91]."
39766224
reach
"Loss of either Tsc1 or Tsc2 decreases the inhibition of mTOR, leading to its activation 27."
36451866
reach
"Nevertheless, the ability of the Rheb-GAP, TSC1 and TSC2, to inhibit mTOR signaling in vivo is consistent with the inference that Rheb-GDP provides a less effective stimulus than Rheb-GTP."
15854902
reach
"Besides controlling carbohydrate and lipid metabolism, AMPK phosphorylates major mTOR signaling regulators like TSC2, thus functioning to suppress mTOR signaling that governs anabolic responses, such as protein synthesis."
23050966
reach
"Activated AMPK phosphorylates Unc-51-like kinase (ULK1) and the tuberous sclerosis TSC1/TSC2 complex, thereby inhibiting mTOR complex 1 (mTORC1) activation to induce autophagy (Gwinn et al., 2008; Egan et al., 2011)."
36408240
reach
"In prior work, Linke and colleagues demonstrated that constitutive activation of mechanistic target of rapamycin complex 1 (mTORC1) by the deletion of Tsc2 in mice enhanced macrophage proliferation, inhibited apoptosis, and led to spontaneous granuloma formation in vivo (3)."
38690977
reach
"Both proteins TSC1 and TSC2 downregulate mTOR, which eventually lead to the promotion of autophagy [XREF_BIBR - XREF_BIBR]."
26934368
reach
"Moreover, AMPK can inhibit the activity of the mTOR complex 1 (mTORC1), either phosphorylating the regulatory Raptor component or activating TSC2 which subsequently inhibit mTOR activity [XREF_BIBR]."
22411934
reach
"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling."
23668243
reach
"Therefore, homozygous loss of TSC1 or TSC2 leads to high constitutive activation of mTOR signaling, as detected in mouse embryonic fibroblasts, in the tumors of rodent models of TSC, and in human TSC cells and tumors."
15533996
reach
"It has conventionally been believed that the effect of AMPK on cell growth is mediated through inhibition of mTOR via phosphorylation of the tuberous sclerosis complex (TSC2), a subunit of the larger TSC1 and TSC2 (hamartin and tuberin) complex that negatively regulates mTOR signaling."
22835064
sparser
"The tumor suppressor genes, such as PTEN, tuberous sclerosis complex 1 (TSC1), and tuberous sclerosis complex 2 (TSC2) can inhibit the upstream signal of mTOR and stimulate autophagy, while PI3K/Akt inhibits autophagy by activating mTOR signaling pathway. xref In this review, we focus on autophagy induced by resveratrol through the regulation of mTOR and p62 signaling pathway."
31802896
reach
"AMPK can induce autophagy by phosphorylating TSC2 and RPTOR to inactivate mTOR, and AMPK can directly activate autophagy by phosphorylating ULK1 during nutrient deprivation [XREF_BIBR]."
27456933
reach
"15 ATM is exported to the cytoplasm in response to high concentration of ROS and reactive nitrogen species (RNS) like nitric oxide (NO), and deactivates mTOR through a series of phosphorylation dependent activation processes involving liver kinase B1 (LKB1), AMPK and the tumor suppressor tuberous sclerosis 2 (TSC2)."
26938301
reach
"Other downstream targets of AMPK include TSC2, which inhibits mammalian target of rapamycin complex 1 (mTORC1) and protein synthesis; XREF_BIBR HMG-CoA reductase, which leads to the inhibition of cholesterol synthesis; XREF_BIBR peroxisome proliferator activated receptor-gamma coactivator (PPARalpha) 1alpha, which stimulates mitochondrial biogenesis, XREF_BIBR, XREF_BIBR and many others."
25018645
reach
"AMPK, in physiological states, is responsible for Tuberous Complex 2 (TSC2) activation that negatively regulates m-TOR activation, while p-AKT, which lies upstream of m-TOR [24,25], inhibits the TSC2 complex resulting in mTOR activation [26]."
36145334
reach
"Hypoxia induces REDD1 expression via HIF, and as REDD1 binds to and sequesters 14-3-3 from complexes with TSC2, TSC2 can inactivate mTOR [57–59] ."
22800641
reach
"TSC2 is a well-known inhibitor of mTOR (62), which can induce fatty acid biosynthesis via the activation of SREBP transcription factors (63, 64)."
38117060
reach
"Here we review recent findings demonstrating that the TSC1 and TSC2 inhibitory complex normally acts on Rheb to mediate mTOR and S6K1 signalling."
15562827
reach
"The Tsc1 and Tsc2 complex interacts with PI3K and Akt signaling such that inhibition of TSC1 and TSC2 activates mTOR and disrupts PI3K-Akt signaling."
26010875
reach
"Notably, this increase in mTOR activity induced by TSC2 inhibition completely rescued Bmpr1a -/- apoptotic cell elimination during cell competition."
29720666
reach
"Binding of UL38 acts to “silence” the TSC2 inhibition of mTOR activity (Fig. 3), resulting in an increase in mTOR substrate phosphorylation.82, 83 This action phenocopies Akt activation, as Akt will directly phosphorylate and inhibit TSC2."
22340720
reach
"Further, the UL38 inactivation of TSC2 also blocks the ability of the metabolic sensor AMPK to modulate mTOR activity by activating TSC2."
22340720
reach
"Metformin also activates AMPK; subsequently, TSC2, followed by p53 activation, inhibits mTOR, consequently inhibiting translation and biogenesis in ribosomes."
33564559
reach
"Loss of TSC2 causes excess mTOR signaling that inhibits autophagy."
39082334
reach
"RSK1 phosphorylation and inactivation of the tumor suppressor Tuberin at Ser 1798 led to activation of mTOR and enhanced proliferation [XREF_BIBR]."
20045011
reach
"The tuberous sclerosis 1 (TSC1) and TSC2 complex negatively regulates the activity of an mTOR containing multiprotein complex called mTOR complex 1."
24818661
reach
"Tuberous sclerosis complex is caused by mutations to the TSC1 or TSC2 gene, either of which disrupts the mechanistic target of rapamycin (mTOR) pathway."
39309045
reach
"The mTOR pathway is negatively regulated by tumor suppressor genes TSC1 and TSC2, as well as by their upstream regulators including phosphatase and tensin homolog (PTEN), the STE20 related kinase adaptor alpha (STRADalpha and neurofibromin 1 (NF1) (XREF_FIG)."
22578218
reach
"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling."
16019436
reach
"These data suggest that PC1 functions by inducing the formation of a complex with tuberin and the Ser/Thr kinase mTOR thereby inhibiting mTOR activity."
17102641
reach
"Activation of AMPK suppresses mammalian target of rapamycin (mTOR) signaling and the molecular mechanism involves phosphorylation of tuberous sclerosis complex protein TSC2 at Thr1227 and Ser1345 that increases the activity of TSC1 and TSC2 complex to inhibit mTOR."
19483724
reach
"As low-energy states activate AMPK, TSC2 is phosphorylated, repressing mTOR, which leads to a cross-regulation between AMPK and mTOR activity [24,25]."
36671400
sparser
"These data imply that TSC2 can inhibit mTOR while simultaneously induce Akt and NF-κB in the EEF cells."
26374334
reach
"The TSC1 and TSC2 proteins negatively regulate mTOR Complex 1 (mTORC1) by inhibiting Rheb activity [XREF_BIBR]."
22018000
reach
"Activated AKT inhibits the tuberous sclerosis complex 2 (TSC2), which normally inhibits mTOR."
39640863
reach
"It is possible that they express negative mTOR regulators such as TSC2, which limits mTOR signalling in Drosophila intestinal stem cells but not progenitors, or that stem cells are more adept than progenitors at using low levels of nutrients for proliferation, perhaps because of their slower cycling."
24449845
reach
"AMPK, a cellular energy sensor, directly phosphorylates TSC2 to inhibit mTOR."
19356717
reach
"On the other hand, tuberous sclerosis complex 2 (TSC2), which is a tumor suppressor, can be phosphorylated by GSK3β to inhibit the mTOR pathway [17] ."
26454215
reach
"An important mTOR regulatory pathway is the low-energy activated AMP kinase, which phosphorylates TSC2, which then complexes with TSC1, inhibiting mTOR [19,20,29]."
29685622
reach
"TSC2-depleted tumor cells had disrupted mTOR regulation following CTL attack, which was associated with enhanced cell death."
36715448
reach
"To confirm whether USP5 was regulated by mTOR signaling, we activated mTOR signaling by the knockdown TSC2, and subsequently blocked the activation by Rapa."
37060095
reach
"Furthermore, because glucose restriction in skeletal muscle cells has been shown to increase activity of AMPK [XREF_BIBR] and can suppress growth related signalling of P70S6K via TSC2 inhibition of mTOR [XREF_BIBR], we also investigated AMPK signalling at the same time points."
29189984
reach
"MTOR activity is negatively regulated by the heterodimer TSC1 (hamartin) and TSC2 (tuberin)."
21765994
reach
"TSC2 knockdown activates mTOR, converting macrophages to an angiogenic-promoting M2-like phenotype and increasing the release of IL-10 (90)."
37564659
reach
"Genetically, all types of AML are characterized by the inactivation of the TSC1 or TSC2, which impairs the regulation of the mTOR signaling pathway and leads to increased cell proliferation [53]."
36699622
reach
"In mouse oocytes, disruption of the negative mTOR regulators Tsc1 (Adhikari et al. 2010) and Tsc2 (Adhikari et al. 2009) led to overactivation of primordial follicles and subsequent infertility, though interestingly, mTOR itself may not be necessary for primordial follicle activation due to compensatory potential of the PI3K/Akt pathway."
35928672
reach
"In physiological conditions, AMPK is in charge of tuberous sclerosis complex 2 (TSC2) activation which in turn negatively regulates mTOR activation [33] ."
30414938
reach
"LKB1 is a serine/threonine kinase that phosphorylates AMPK (AMP activated protein kinase), which in turn phosphorylates and activates TSC2 to negatively regulate the mTOR signaling pathway."
23297823
reach
"These abnormalities include upregulation of the PI3K and Akt pathway, directly or by loss of the tumor suppressor phosphatase PTEN, as well as mTOR upregulation by TSC2 loss."
14667501
reach
"The inactivation of TSC2 results in TSC1-TSC2 dissociation and markedly impairs the ability of TSC2 to inhibit mTOR signals, leading to cell proliferation and disease progression."
30867766
trips
"Activation of MK2, a downstream kinase of p38α, enhances mTOR complex 1 (mTORC1) activity by preventing TSC2 from inhibiting mTOR activation."
21757713
reach
"Inactivation of Tuberin allows GTP bound-Rheb to accumulate and activate the mammalian target of rapamycin (mTOR)/Raptor (TORC1) complex, which ultimately regulates protein synthesis and cell growth [XREF_BIBR]."
22114931
reach
"Therefore, in both assays, the TSC2 I820del and L1511H variants were unable to inhibit mTOR, indicating that both these variants are pathogenic, while the TSC2 R1772C and T993M variants were just as active as wild-type TSC2 and are therefore not pathogenic amino acid substitutions."
18302728
reach
"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling."
25307277
eidos
"AMPK activation is believed to activate the downstream target tuberous sclerosis complex 2 ( TSC2 ) , which in turn inhibits the mammalian target of rapamycin ( mTOR ) signaling pathway ( Plews , et al. 2015 ) ."
31307011
reach
"In neonatal rat cardiomyocytes, loss of TSC2 abolished HDAC dependent inhibition of mTOR activity, and increased expression of TSC2 was sufficient to reduce hypertrophy in response to phenylephrine."
27048565
reach
"Nuclear p53 transactivates TSC2 (tuberous sclerosis) and AMPK (AMP activated protein kinase), both of which downregulate mTOR activity, thus indirectly promoting autophagy (XREF_FIG) [XREF_BIBR, XREF_BIBR]."
27941671
sparser
"The activation of EPH receptor leads to inhibition of MAPK1, in turn, allowing TSC2 to inhibit RHEB and MTOR."
36239373
reach
"Indeed, genetically reducing TSC2 causes mTOR hyperactivity in people and rodents."
23425014
sparser
"First, AMPK activates TSC2, which inhibits mTOR, thus reducing activity of ribosomal S6 kinase and eukaryotic initiation factor-4 (eIF4)."
23456821
reach
"AMPK phosphorylates tuberous sclerosis 2 (TSC2), and inhibits RHEB (mTOR activator protein) activation, resulting in mTORC1 inactivation [20,21] ."
23499993
reach
"In contrast, Akt enhances the phosphorylation and inhibition of TSC2, thereby relieving the TSC2-dependent inhibition of RHEB toward mTOR [20,21] ."
23499993
eidos
"MTOR can be activated by TSC2 inhibition ( 101 ) ."
33732237
eidos
"Under metabolic stress , AMPK activates ULK1 , the human homologue of yeast ATG1 , and phosphorylates tuberous sclerosis protein 2 ( TSC2 ) to inhibit mTOR and activate autophagy [ 40,41 ] ."
| PMC
reach
"In the PI3K and Akt signaling pathway, activated Akt phosphorylates and decreases the ability of tuberous sclerosis complex 2 (TSC2) to inhibit the mammalian target of rapamycin (mTOR), resulting in the activation of mTOR [XREF_BIBR]."
21898543
reach
"In a second phase, we postulate that calpain activation, through PTEN, hamartin and tuberin degradation relieves mTOR inhibition and stimulates protein synthesis, which might be critical for providing long-term consolidation of modified spine structures."
23467348
reach
"These results suggest that Wnt signaling inhibits the GSK-3-dependent phosphorylation of TSC2, thereby activating mTOR signaling to increase protein synthesis and promote cell growth."
22017973
reach
"MTOR is inhibited upon withdrawal of growth factors, such as insulin or insulin like growth factors, by a cascade of phosphorylation reactions involving Class I PI3K, Akt, TSC1 and TSC2, and Rheb."
22661635
reach
"Cheng Y et al. (80) found that knockdown of the TSC1/TSC2 gene was able to activate mTOR of phosphatase and tensin homology deleted on chromosome 10 (PTEN)/tuberous sclerosis complex 1 (TSC1)/tuberous sclerosis complex 2 (TSC2) in germ cells leading to primordial follicle recruitment, POI and infertility (81)."
37600717
sparser
"TSC is caused by heterozygous pathogenic variants in TSC1 or TSC2 , which inhibit mTOR complex 1 (mTORC1)."
37494191
reach
"Everolimus is believed to act via inhibition of the mTOR complex 1 (mTORC1) which is normally inhibited by the protein complex of TSC1 (hamartin), TSC2 (tuberin) and TBC1D7."
35233200
reach
"[XREF_BIBR] Finally, phosphorylation of TSC2 by AMPK suppresses mTOR and promotes energy producing autophagy."
30276337
sparser
"Furthermore, because glucose restriction in skeletal muscle cells has been shown to increase activity of AMPK [ xref ] and can suppress growth-related signalling of P70S6K via TSC2 inhibition of mTOR [ xref ], we also investigated AMPK signalling at the same time points."
29189984
reach
"TSC derives from inactivating mutations of either the TSC1 or TSC2 tumor suppressor gene, and the resulting inactivation of the TSC1 and TSC2 protein complex causes hyperactivation of the mammalian target of rapamycin (mTOR), leading to uncontrolled cell growth and proliferation."
19539245
reach
"Activated AKT phosphorylates the TSC1-TSC2 complex, which will inhibit the mTOR complex downstream through Rheb [28]."
36833359
reach
"The AMPK pathway also signals to mTORC1 via TSC2, and recent studies indicate that at least two mechanisms operate: TSC2 phosphorylation at sites different from those targeted by Akt, and raptor phosp[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
18614042
reach
"We next determined whether TSC2 was required for the ability of apicidin to inhibit the mTOR pathway."
27048565
reach
"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling."
28537457
reach
"Once activated, AMP kinase phosphorylates TSC2 which then suppresses mTOR."
18703865
eidos
"Moreover , Class I HDAC inhibition blocked mTOR activity by increasing expression of TSC2 , a negative regulator of mTOR ."
33915138
sparser
"AMPK plays multiple roles in the metabolic control of proliferating cells including the regulation of protein translation through stimulation of TSC1-TSC2 complex-mediated inhibition of mTOR ( Inoki e[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
17723208
reach
"Importantly, TSC2 overexpression suppressed mTOR signaling and then activated the autophagy."
31783925
sparser
"AMPK activation phosphorylates tuberous sclerosis complex 2 (TSC2), which inhibits mTOR and induces autophagy [ xref ]."
23894332
reach
"Evidence suggests that tuberous sclerosis 2 (TSC2) suppresses mTOR signaling and thus induces autophagy [13, 14]."
31783925
reach
"Interestingly, we noticed sodium Danshensu dose-dependently increased TSC2 protein expression and significantly reduced p-mTOR protein expression and p-mTOR/mTOR ratio in astrocytes compared with the OGD/R group."
36388798
reach
"Akt activates mTOR through (i) phosphorylation and inhibition of tuberous sclerosis complex 2 (TSC2), which inactivates the mTOR activating GTP binding protein Rheb, and/or (ii) phosphorylation of PRAS40 a member of mTORC1, one of the two functional complexes of mTOR, which includes mLST8 and Gbl and the scaffold protein Raptor."
23632475
reach
"25 Phosphorylation of tuberous sclerosis complex 2 (TSC2) by AMPK after ATP depletion results in activation of the TSC1:TSC2 complex, which negatively regulates the activity of mTOR complex 1 (mTORC1)."
36239337
reach
"This results in TSC2 mediated mTOR inhibition."
32948744
reach
"Evidence suggests that TSC2 suppresses mTOR signaling and thus induces autophagy [13, 14]."
31783925
sparser
"Specifically AMPK phosphorylates the Tuberous Sclerosis 2 (TSC2) protein that inhibits mTOR and activates autophagy in an analogous mechanism to that seen during starvation[ xref , xref - xref ]."
29358854
reach
"Mutations in either TSC1 or TSC2, which encode hamartin and tuberin, respectively, cause the abnormal activation of mammalian target of rapamycin (mTOR)."
25574245
reach
"TSC2 constitutively functions to downregulate mTOR activation, thus regulating p70S6K activation in response to IGF-I."
19729319
reach
"AMPK is known to phosphorylate and enhance TSC2, which inhibits the mTOR pathway, promoting autophagy [XREF_BIBR, XREF_BIBR]."
26121129
reach
"TSC is caused by mutations in the TSC1 or TSC2 gene resulting in activation of the mechanistic target of rapamycin (mTOR) signaling pathway."
30976976
reach
"The heterodimer of TSC2 (tuberin) and TSC1 (hamartin) represses mTOR activity by acting as the GTPase-activator protein for the small G protein Rheb (Ras homolog enriched in brain), a potent activator of mTORC1 when present in a GTP bound state."
20388847
reach
"AMPK activation leads to inhibition of mTOR complex 1 (mTORC1), by activation of the negative mTORC1 regulator TSC2 and by inhibition of the mTORC1 subunit RAPTOR [36]."
31781355
reach
"Thus, these results confirmed that TSC2 suppressed mTOR signaling and thus induced autophagy."
31783925
reach
"Phosphomimicking of mutations in Tsc2 induces mTOR activity, whereas a phosphorylation-deficient mutation in the same transgene inhibits mTOR activity and the growth of developing Drosophila ."
18177819
reach
"First, in the nucleus, p53 has been reported to promote autophagy by transactivating genes encoding : DRAM1, which is induced by DNA damage and localized to lysosomes with autophagosome accumulation; and sestrin 1 and 2, AMPK beta1 and beta2, and TSC2, which act on the AMPK pathway to inhibit the autophagy suppressor mTOR, thus activating autophagy [XREF_BIBR, XREF_BIBR]."
26780878
sparser
"The TSC2 inhibited mTOR and other substrates, including S6K, 4EBP-1 and EIF2, which resulted in reduced cell size and growth rates."
25866088
reach
"PGC-1 is regulated by the upstream NAD+/AMPK signal, which provides cardiac protection by phosphorylating TSC2 to inhibit mTOR [9]."
35474295
reach
"Indeed, hypoxia- and glucocorticoid-induced REDD1 is known to play an important role in the TSC1/TSC2-mediated inhibition of mTOR, a central regulator of protein translation [6] , resulting in inhibit[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
26296313
reach
"However, it has also been reported that TSC1 and TSC2 may function to inhibit S6K independent of mTOR (Jaeschke et al., 2002; Radimerski et al., 2002)."
14651849
reach
"Mutations in the TSC1 and TSC2 genes inhibit the mTOR complex, resulting in the activation of mTORC1 and the subsequent dysregulation of downstream cellular pathways involved in the proliferation and growth of cells."
38892169
reach
"As a result, the mTOR is inhibited by the TSC2 (Tuberous Sclerosis Complex 2)."
38927242
reach
"Activated AMPK could phosphorylate tumor suppressor tuberous sclerosis complex 2 (TSC2) to inhibit mTOR activity, which plays a critical role in cancer progression [XREF_BIBR]."
28271076
reach
"When HDAC activity is suppressed, either pharmacologically or through genetic ablation, TSC2 abundance increases, thereby inhibiting mTOR activity."
27048565
reach
"In support of our findings, miR21-3p is already known to modulate the mTOR pathway via TSC2 mRNA downregulation [15], and P53-dependent mTOR inhibition is mediated by TSC2 [24]."
33923420
reach
"TSC2 protein complexes with TSC1 and blocks the ability of the Rheb (Ras homolog enriched in brain) GTPase to activate mTOR signaling and thus induces autophagy [13, 14]."
31783925
reach
"Here, we provide the evidence of an additional layer of regulation of p53-mTOR crosstalk through the rapid elimination of miR-21-3p and consequent stabilization of p53 and enhancement of TSC2 repressor activity of mTOR."
33923420
reach
"Specifically AMPK phosphorylates the Tuberous Sclerosis 2 (TSC2) protein that inhibits mTOR and activates autophagy in an analogous mechanism to that seen during starvation [XREF_BIBR, XREF_BIBR - XREF_BIBR]."
29358854
reach
"Physiologically, TSC2 down-regulates mammalian target of rapamycin (mTOR), which is a key player controlling cell proliferation, by modulating Ras homolog enriched in brain (RHEB) activity."
36481196
reach
"AMPK regulates autophagy by inhibition of mTOR by phosphorylation of TSC2 and Raptor."
22661635
reach
"TSC2 functions in complex with TSC1, and negatively regulates the Rheb and mTOR pathway and cell growth [XREF_BIBR]."
23022476
reach
"TSC2 functions as a heterodimer with TSC1, and together functions to indirectly inhibit mTOR through inhibition of the GTPase RAS homolog enriched in the brain (RHEB)."
35573694
sparser
"Upon Akt activation, growth factors (PDGF, VEGF and IGF-1) and insulin block the TSC2 (tuberous sclerosis complex 2) complex, which in turn inhibits the mTOR protein (mammalian target of rapamycin)."
25520571
reach
"Our results showed that TSC2 overexpression effectively rescued the MALAT1 overexpression-mediated inhibition of autophagy and activation of mTOR signaling, indicating that MALAT1 suppressed autophagy via inhibiting TSC2-mTOR signaling."
31783925
reach
"AMPK is able to activate autophagy either through inhibition of mTOR by phosphorylation of TSC2 ( Inoki et al., 2003 ) or raptor ( Gwinn et al., 2008 ), or by direct phosphorylation of ULK1 ( Egan et [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
25443289
reach
"In this study, we provided first evidence that MALAT1 epigenetically repress TSC2 transcription via recruiting EZH2 to TSC2 promoter regions to induce H3K27me3, and thereby induce mTOR activation and subsequent autophagy inhibition.Autophagy can be activated as a stress response shortly after AMI; however, sustained ischemia impaired cardiomyocyte autophagy flux, which exacerbated the post-infarct adverse cardiac modeling [27]."
31783925
reach
"We proposed that phosphorylation of TSC2 by GSK3 after the AMPK priming phosphorylation enhances the ability of TSC2 to inhibit mTOR signaling."
16959574
reach
"These results suggest that phosphorylation of TSC2 by GSK3 increases the ability of TSC2 to inhibit mTOR signaling.Previously, we found that mTOR activity contributed to cell apoptosis under glucose s[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
16959574
reach
"TSC1 and TSC2 are downstream of AMPK and negatively regulate mTOR in response to cellular energy deficit."
20448661
reach
"These results were inconsistent when considering that mTOR was negatively regulated by TSC2."
29725001
reach
"Another important kinase sensor of the extracellular environment growth conditions is AMPK, which phosphorylates and activates TSC2 suppression of mTOR, and one clinically available AMPK inhibitor metformin has been repurposed for cancer treatments [XREF_BIBR]."
33668092
reach
"AMPK activates TSC2 by phosphorylation [29], whereas activation of TSC2 suppresses mTOR signalling [30], and activation of AMPK down-regulates mTOR activity [31], supporting a positive role of AMPK in regulating autophagy."
29508625
reach
"Surprisingly, F-box proteins beta-TrCP and Fbw5 were reported as substrate receptors for CRL4 beta-TrCP [XREF_BIBR] and CRL4 Fbw5 [XREF_BIBR] targeting inhibitors of mTOR signalling REDD1 (regulated in development and DNA damage response 1) and TSC2 (tuberous sclerosis protein 2) respectively."
25886174
reach
"In response to energy deficit in the cell, AMPK phosphorylates TSC2 which then complexes with TSC1 and negatively regulates the mTOR pathway."
20448661
reach
"AMPK regulates numerous metabolic pathways including mTOR, which is inhibited by the phosphorylation of TSC2 and raptor."
30006197
reach
"For instance, lncRNA MALAT1 can recruit EZH2 to induce H3K27me3 modification in the TSC2 promoter region, thus repressing its transcription, while TSC2 overexpression inhibits mTOR signaling and activates autophagy."
33335796
reach
"Previously we found that AMPK phosphorylation of TSC2 is required to inhibit mTOR pathway (Inoki et al., 2003)."
16959574
reach
"ERK dependent phosphorylation of TSC2, particularly at Ser664, leads to TSC1-TSC2 dissociation and markedly impairs the ability of TSC2 to inhibit mTOR signaling."
19694499
reach
"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling."
19448707
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"Hamartin and tuberin, the TSC1 and TSC2 protein products respectively, normally inhibit mTOR signaling through an indirect pathway."
38168450
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"[17, 18] Indeed, CDK4/6i have been shown to restore sensitivity to anti-HER2 therapy by suppressing Rb and TSC2 phosphorylation, thus attenuating mTOR complex 1 (mTORC1) activity."
39375745
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"They also showed that down-regulation of S6K, an mTOR target, phophorylation by Redd1 requires Tsc2 and Redd1 probably acts up-stream of the Tsc1 and Tsc2 complex to down-regulate mTOR function in response to hypoxia."
33718332
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"The activated p53 can activate AMPK to phosphorylate TSC2, inhibit mTOR, trigger autophagy, and cause cell cycle arrest and apoptosis."
35344810
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"However, activating mTOR only, by genetic deletion of TSC2, led to less axon regeneration (Park et al. 2008), indicating that additional effectors, such as GSK3, might mediate the regeneration induced by PTEN inhibition."
34518340
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"Specifically, GSK3 has been shown to phosphorylate key components of the mTOR pathway, including tuberous sclerosis complex 2 (TSC2), which inhibits mTOR activity."
40158191
reach
"Under the condition of starvation, AMPK phosphorylates tuberous sclerosis 2 (TSC2), which inhibits mTOR and S6K1 pathway [XREF_BIBR] : phosphorylation of TSC2 by AMPK is critical in the process of mRNA translation and cell size regulation during energy deficiency (XREF_FIG)."
20814441
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"XREF_BIBR Both sestrins can trigger the AMPK and target it to phosphorylate and activate TSC1 and TSC2 complex, thereby inhibiting the signaling of mTOR, a critical autophagy inhibitor of cells, XREF_BIBR, XREF_BIBR and so CX-5461-induced autophagy through AMPK and mTOR signaling pathway in U2-OS cells might arise from the upregulation of Sesn1/2 by p53."
27729807
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"The active TSC2 inhibited mTOR via RHEB, leading to continually stimulated oncogenic autophagy of ESCC cells."
32308763
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"Consistent with DACH1 impacting TSC2 and Rictor, Ingenuity Pathway Analysis (IPA) showed DACH1 inhibits mTOR signaling (23 genes) p = 1.1 × 10 (Supplementary Fig. S11)."
37095257
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"Upon stimuli, AMPK ca activate autophagy by directly phosphorylating and activating ULK1 or indirectly activating ULK1 with TSC2 mediated mTOR inhibition."
29670377
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"Together, our data suggest that loss of tuberin, which causes mTOR activation, leads to a novel cellular growth promoting pathway involving mitochondrial oxidant dependent p42/44 MAPK activation and mitogenic growth responses to PDGF."
16322235
reach
"The TSC1 and TSC2 proteins inhibit the activity of mammalian target of rapamycin (mTOR) in a complex manner in vivo."
36819539
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"Subsequently, we injected TSC2-shRNA intrathecally into CCI rats and found that after silencing TSC2 to overexpress mTOR, RIP3 was upregulated in the spinal dorsal horn (Fig. 5C–E)."
39893345
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"XREF_BIBR TSC1 or TSC2 depleted cells fail to attenuate downstream mTOR signaling in response to amino acid depletion, serum starvation or growth factor withdrawal."
20146692
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"TSC1/TSC2 negatively regulates ribosome translation via mechanistic target of rapamycin (mTOR) control (13), implying that increased translation enhances 6-TG’s inhibitory effect on N-glycosylation."
36921042
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"According to a model based on these data, in the absence of growth factors the TSC1 and TSC2 complex is hypophosphorylated and inhibits mTOR."
12935885
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"For example, hypoxia suppresses energy-costly mRNA translation and protein synthesis via AMPK and TSC2 mediated mTOR inhibition XREF_BIBR or other mechanisms XREF_BIBR, XREF_BIBR."
21283818
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"In addition we have seen that AKT, ERK and RSK can phosphorylate TSC2 on distinct sites to cooperate in the disruption of the TSC1/TSC2 complex and thus diminishing repression of mTOR to increase prot[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
17188374
reach
"Among many AMPK-substrates, phosphorylation of RPTOR (regulatory associated protein of MTOR, complex 1) and TSC2 (TSC complex subunit 2) inhibit MTOR signaling and regulate many processes including macroautophagy/autophagy.Posttranslational modification of proteins with ubiquitin orchestrates a vast number of biological processes, including targeted protein degradation by the ubiquitin-proteasome system (UPS), lysosomal/vacuolar protein degradation, endocytosis, intracellular trafficking, regulation of the secretory pathway and transcriptional regulation [3]."
31795790
reach
"The mutations of either TSC1 or TSC2 gene activate the mammalian target of rapamycin (mTOR) signaling pathway, resulting in cellular aberrant function and tumor growth [XREF_BIBR, XREF_BIBR]."
30107845
reach
"We previously identified a novel interaction between tuberous sclerosis-2 (TSC2) and death associated protein kinase-1 (DAPK), the consequence being that DAPK catalyses the inactivating phosphorylation of TSC2 to stimulate mammalian target of rapamycin complex 1 (mTORC1) activity."
21134130
sparser
"As a result, the mTOR is inhibited by the TSC2 (Tuberous Sclerosis Complex 2)."
38927242
sparser
"TSC2 (16p13.3) inhibits mTOR protein and regulates cell growth."
24649216
reach
"Although iron chelation may affect multiple signaling pathways related to cell survival, our data support the conclusion that REDD1 functions up-stream of tuberin to down-regulate the mTOR pathway in response to deferasirox."
19298223
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"At this time, GTP-bound Rheb is switched to GDP-bound Rheb by TSC2, which inhibits mTOR signaling and blocks protein synthesis [ 15–17 ]."
33059920
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"4,5 Loss of TSC1 or TSC2 leads to unchecked activation of mTOR, which leads to unregulated protein synthesis, increased cell growth and proliferation, increased angiogenesis, and changes in cell orien[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
26612197
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"We also analyzed REDD1 (RTP801), which has been shown to be strongly induced under hypoxic conditions in a HIF-1alpha dependent manner XREF_BIBR and recent studies also suggest that REDD1 plays a role in the TSC1 and TSC2 mediated inhibition of mTOR XREF_BIBR."
19587783
sparser
"The TSC1-TSC2 complex inhibits mTOR complex 1 (mTORC1), which functions to promote protein synthesis and cell growth."
24448243
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"The activated AMPK can phosphorylate and activate TSC2, and sequentially inhibit mTOR and activate autophagy XREF_BIBR."
22900043
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"49 In this process, activated AMPK directly phosphorylates TSC2 and RAPTOR to block mTor activation, inhibiting the mTor protein kinase complex, and thereby adjusting autophagy activity.50 Indeed, our research confirmed this point."
34876804
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"For example, Tsc2 knockout mouse embryonic fibroblasts demonstrate altered migration (Goncharova et al., 2014) and mTOR pathway hyperactivation caused by Tsc2 knockout in mice promotes activation of t[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
29481864
reach
"Phosphorylated TSC2 prevents Rheb activation, thereby inhibiting mTOR signaling."
39766864
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"Fisetin also activated the mTOR repressor TSC2 through inhibition of Akt and activation of AMPK."
20530556
reach
"Insulin also activates mammalian target of rapamycin (mTOR) through the PI3K–Akt pathway, which phosphorylates and inhibits the tuberous sclerosis complex 2 (TSC2), thus promoting GTPase activity of t[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
25445588
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"The canonical pathway for mTOR regulation is independent of erk1/2 and involves PI3K-PDK1-Akt-dependent inactivation of the mTOR suppressor TSC2, which then leads to mTOR-p70S6K dependent translation of mRNAs and de novo protein synthesis at active synapses (Hoeffer and Klann, 2010)."
20844138
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"Phosphorylation of TSC2 by upstream kinases inhibits the activity of this complex and reduces mTOR signaling [27], whereas dephosphorylation of TSC2 by various phosphatases inhibits mTOR and activates[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
21925170
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"10 The PI3K-AKT pathway phosphorylates and suppresses tuberous sclerosis 2, which inhibits mechanistic target of rapamycin complex 1, thereby activating S6K, resulting in phosphorylation of S6 and ac[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
28964793
reach
"In addition, SCs transfected with the miR-1764 agomir led to an improvement of proliferation capacity through down-regulating AMPKα2 level, which further decreased TSC2 expression and induced mTOR activation."
34481229
reach
"Hamartin and tuberin inhibit the mechanistic target of rapamycin (mTOR), a kinase that regulates protein and lipid synthesis."
36615165
reach
"The tumor suppressor gene Tuberous Sclerosis 1 (TSC1) forms a molecular complex with tuberin (TSC2) to inactivate the mTOR pathway (van Slegtenhorst et al., 1997)."
35726297
reach
"In the presence of growth factors such as insulin or insulin like growth factors, stimulated Akt and extracellular signal regulated protein kinases 1 and 2 (ERK1/2) can phosphorylate and disrupt the tuberous sclerosis complex 1/2 (TSC1 and TSC2), which activates mTOR inhibition and thus inhibiting autophagy [XREF_BIBR]."
28534010
reach
"GTP bound Ras homolog enriched in brain (Rheb) is a necessary mTOR activator that is inhibited by tuberous sclerosis complex 1 (TSC1) and tuberous sclerosis complex 2 (TSC2)."
29515798
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"Currently, sirolimus (rapamycin) is the only FDA approved drug for LAM (2), which inhibits the constitutively activated mTOR complex thus slowing disease progression (3,4)."
36798234
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"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."
21871173
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"TSC1 : TSC2 inhibits mTOR activity by stimulating the conversion of active Rheb-GTP to inactive Rheb-GDP [12,13]."
21890410
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"Our results revealed that ORFV promotes autophagy in OFTu cells by inhibiting the phosphorylation of PI3K and AKT, subsequently resulting in Akt-mediated phosphorylation of TSC2, thereby allowing TSC2 to inhibit mTOR."
36918891
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"Recently, Cai et al. used a human model system to elucidate the mechanism by which PC-1 regulates the mTOR pathway and found that PC-1 modulates phoshatidylinositol 3-kinase (PI3K)/AKT signaling to TS[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
21392577
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"These data identify a unique mechanism for modulation of TSC2 repression of mTOR signaling via membrane retention of this tumor suppressor, and identify PC-1 as a regulator of this downstream componen[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
21392577
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"In normal conditions, mTOR activity is inhibited by proteins hamartin and tuberin that are encoded by TISC1 and TISC2 genes."
20618393
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"First, AMPK phosphorylates and activates TSC2 function to suppress mTOR activity (XREF_FIG)."
25374355
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"Because mTOR can be alternatively downregulated by tuberous sclerosis complex 2 (TSC2) activation mediated by 5 ' adenosine monophosphate activated protein kinase (AMPK), we proposed that the activation of AMPK alpha1/2 by LKB1 and/or by calmodulin dependent protein kinase kinase (CaMKK) would also block the nuclear export of PTEN in a manner similar to that of inhibitors of PI3K, mTOR, and S6K."
21123367
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"AMPK then activates the downstream tuberous sclerosis complex 2 (TSC2), which represses mTOR activity and activates autophagy [44] ."
27666506
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"Moreover, since this phosphorylation is known to relieve TSC2 mediated inhibition of mTOR, the implication is that this is a mechanism by which KSHV ORF45 activated RSK regulates Akt/mTOR/S6K activity [XREF_BIBR]."
26133373
sparser
"One of the downstream targets of AMPK is the tumour-suppressor protein TSC2 that inhibits mTOR."
23322200
reach
"Morales et al demonstrated that inhibition of class I HDACs with apicidin induced the expression of the mTOR inhibitor tuberous sclerosis complex 2 (TSC2), which in turn attenuated cardiac hypertrophy by inhibiting mTOR."
35752619
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"TSC results from a loss of function of either TSC1 or TSC2, upstream inhibitors of the mTOR signaling (2)."
37903257
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"AMPK phosphorylates tuberous sclerosis complex-2 (TSC2 or tuberin) to inhibit mTOR signal and induce autophagy ( Hardie, 2011 )."
24028940
reach
"ERK dependent phosphorylation on serine 664 of TSC2 leads to the dissociation of TSC1-TSC2 and impairment of TSC2 to inhibit mTOR signaling."
22980037
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"AMPK also phosphorylates TSC2 (Ser1387) and RAPTOR (Ser792) to inhibit mTOR."
23686371
reach
"AMPK phosphorylates and activates tuberous sclerosis 1 protein (TSC1)/tuberous sclerosis 2 protein (TSC2), thereby inhibiting mTOR."
30864681
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"AMPK can inhibit mTOR activity through phosphorylation and activate tuberous sclerosis complex 2 (TSC2), which together with TSC1 can suppress mTOR activation [172]."
35682884
reach
"Phosphorylation of TSC2 by AMPK at Ser1345 suppresses mTOR activity to induce autophagy under energy starvation conditions."
24028940
sparser
"The tuberin-hamartin protein complex inhibits mTOR (a key protein in the regulation of cell cycle) through the so-called S6 ribosomal kinase plus eIf4EEI- and 4E-binding protein [ xref ] (suppressors of the initiation factor for protein synthesis)."
23401839
reach
"During energy depletion, AMPK phosphorylates TSC2 and enhances the ability of TSC1–2 to inhibit Rheb-dependent mTOR activation."
17632034
reach
"Recent studies also indicate that REDD1 (RTP801), induced under hypoxic conditions in a HIF-1alpha dependent manner XREF_BIBR, plays a role in the TSC1 (hamartin)/TSC2 (tuberin)-mediated inhibition of mTOR XREF_BIBR, these indicating a reciprocal regulatory control between HIF-1alpha and mTOR."
19587783
reach
"Dephosphorylation of TSC2 inhibits mTOR and activates autophagy."
25659802
reach
"Loss-of-function variations in either TSC1 or TSC2 cause hyperactivation of the mTOR pathway, resulting in excessive RNA translation and over-phosphorylation of RPS6 and EIF4E-binding proteins (4EBPs) (Betz and Hall, 2013)."
38804677
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"Here, we show that loss of Tsc2 in osteoblasts constitutively activates mTOR and destabilizes Irs1, causing osteoblasts to differentiate poorly and become resistant to insulin."
24591652
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"As described earlier, AMPK activation leads to inhibition of mTOR complex 1 (mTORC1), by activation TSC2, a negative regulator of mTORC1 and by inhibition of the mTORC1 subunit RAPTOR [ 103 , 104 ]."
32956662
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"The fragile X mental retardation protein (FMRP), an RNA binding protein, as well as hamartin (TSC1) and tuberin (TSC2) complex that inhibits the mammalian target of rapamycin (mTOR), regulate local protein synthesis at synapses."
30345165
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"In contrast, AMPK activation stimulates TSC by phosphorylating tuberin at different sites from Akt and thereby inhibits mTOR and slows growth."
21856125
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"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling."
30289335
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"Importantly, mutation of either p53 or the mTOR repressor Tsc2 is not only sufficient to rescue defective cell elimination but also makes cells into super-competitors that induce the elimination of ne[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
35803224
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"In addition, AKT directly blocks activation of TSC2 (an inhibitor of mTOR and inducer of autophagy) to provide further regulation of the autophagy process."
25762983
reach
"The stress-induced proteins REDD1 and REDD2 potently inhibit mTOR signaling, and REDD1 functions downstream of Akt and upstream of TSC2 ( Corradetti et al., 2005; Schwarzer et al., 2005 )."
16483933
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"These data imply that TSC2 can inhibit mTOR while simultaneously induce Akt and NF-kappaB in the EEF cells."
26374334
reach
"AMPK phosphorylates TSC2 as well as Raptor to block the activity of mTOR and the complex mTORC1 during energy stress [XREF_BIBR]."
26064426
reach
"Activation of AMPK modulates insulin signalling downstream of the insulin receptor [XREF_BIBR], most notably via differentially phosphorylating the tuberous sclerosis complex TSC1 and TSC2 to inactivate mTOR [XREF_BIBR, XREF_BIBR]."
22548055
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"FOXO transcription factors, which inhibit mammalian cell proliferation, are directly phosphorylated and inactivated by Akt ( Tran et al., 2003 ), whereas mTOR, which is associated with increased cell [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
16169463
eidos
"Moreover , Lithium inhibits Glycogen Synthase Kinase-3 Beta ( GSK-3beta ) signaling , which activates mTOR by inhibiting TSC2 ."
32443776
reach
"Recent studies have revealed that TSC2 plays an important role in the cell growth and proliferation pathway, in which TSC2 forms a functional complex with TSC1 and negatively regulates both growth factor and nutrient dependent activation of mTOR signalling to its downstream targets S6 kinase and 4EBP1 (Gao et al, 2002; Manning and Cantley, 2003; Saucedo et al, 2003; Stocker et al, 2003; Hay and Sonenberg, 2004)."
17622239
reach
"Upon stimuli, AMPK can activate autophagy by directly phosphorylating and activating ULK1 or indirectly activating ULK1 with TSC2-mediated mTOR inhibition [39]."
39091624
eidos
"Loss of Tsc2 promotes mTOR activation and a hyperproliferative phenotype [ 22 ] ."
32327294
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"The down-regulation of PRAS40, Rictor, Raptor, and GbetaL, which further led to loss of mTOR complex (mTORC) 1/2 formation, activation of mTOR repressor TSC2 by suppressing Akt and activating AMPK, suppression of Cap dependent translation, and hypophosphorylation of 4EBP1 as well as induction of autophagic programmed cell death, was reported after fisetin treatment (Suh etal.,2010)."
33473265
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"TSC1 or TSC2 deletion constitutively activates rapamycin-sensitive functions of mTOR independently of Akt."
16169463
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"Recently, the TSC1 and TSC2 protein complex was shown to inhibit the kinase mTOR (mammalian target of rapamycin)."
15856327
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"1 A pathogenic variant in TSC1 or TSC2 2 , 3 , 4 disrupts mammalian target of rapamycin (mTOR) signaling, resulting in dysregulated cell growth and the development of hamartomas in multiple body systems."
39470995
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"DDIT4 has been previously found to inhibit mTOR by releasing the mTOR suppressor TSC2 from the 14-3-3 protein complex."
34373753
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"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling."
20919962
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"Taken together, these data indicate that 1) TSC2 inhibits mTOR activity and induces Akt activity through mTOR inhibition, and 2) TSC2 mediated induction of Akt enhances NF-kappaB activity."
26374334
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"TSC results from mutation in either TSC1 or TSC2, which together act to negatively regulate mTOR signaling (reviewed in Lipton and Sahin, 2014, and Tsai and Sahin, 2011)."
30304677
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"Expression of wt TSC2 effectively promoted hypoxic mTOR inhibition in serum-starved TSC2 −/− ERC15 cells, as indicated by rapid hypophosphorylation of p70 S6K or rpS6 ( Figure 5 B)."
16483933
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"Rapamycin and FKBP12 destabilizes the mTOR complex [XREF_BIBR] while p53 induces transcription of Sestrin 1 and 2 to activate AMPK and TSC2 inhibition of mTOR [XREF_BIBR]."
26158292
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"Loss of TSC1 or TSC2 function therefore causes activation of mTOR Complex 1 (mTORC1)."
26235615
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"AKT has additionally been observed to phosphorylate and subsequently repress tuberous sclerosis complex 2 (TSC2), which in turn suppresses mTOR signaling (112–114)."
36439412
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"Although loss of tuberin promotes cell growth and tumorigenesis, cells expressing tuberin must also be able to relieve tuberin repression of mammalian TOR (mTOR) signaling during conditions of mitogenic sufficiency."
16636147
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"For instance, uncontrolled mTOR pathway activity caused by the loss of the upstream regulator TSC2 leads to a significant increase in astrogliosis, which is a hallmark of the neurodevelopmental disorder, tuberous sclerosis ."
37034703
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"Upstream AKT kinase can repress the Tuberous Sclerosis complex (TSC) 1/2 by phosphorylating TSC2 to promote mTOR activity, which regulates cell proliferation, differentiation, apoptosis and metabolism, and inhibits autophagy (40)."
31572509
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"ERK dependent phosphorylation on serine 664 of TSC2 leads to TSC1-TSC2 dissociation and impairment of TSC2 ability to inhibit mTOR signaling, suggesting that the Ras and MAPK pathway upstream of the TSC complex and that ERK may modulate mTOR signaling pathway and contribute to disease progression through phosphorylation and inactivation of TSC2 [XREF_BIBR]."
21307646
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"Suppression of mTOR by tuberin takes place only when tuberin is tethered to the membrane."
25186187
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"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling."
22443084
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"Since tuberin is known to inhibit mTOR activity, we tested whether the activity of components of the mTOR pathway were downregulated upon Pam knockdown."
18308511
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"Therefore, MeHg-induced autophagy may also be due to the activation of AMPK/TSC2, which negatively regulates downstream mTOR and eventually causes the increase of neuronal autophagy level ( Pi et al.,[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
36403891
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"The AKT phosphorylation sites S939 and S981 are crucial residues that affect tuberin localization, with localization of tuberin to the membrane accounting for the ability of tuberin to inhibit mTOR signaling via its GAP activity for Rheb."
16636147
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"In line with cell size regulation and autophagy interplay induced by mechanical stress, we observed defaults in the mTORC1 pathway activation in FLCN knockdown cells, since phosphorylation of TSC2, known to inactivate the mTOR signaling sequence, was strongly diminished in siFLCN cells prone to shear stress (Supplemental Figure S4A and S4B)."
31225504
reach
"In the presence of a functional membrane bound PC1 C-terminal tail, phosphorylation of tuberin by PI3K and AKT is inhibited and TSC2 becomes tethered to the membrane, repressing mTOR signaling."
25186187
reach
"Interestingly, in 2001 and 2002, TSC1 and TSC2 were shown to canonically modulate the serine threonine kinase mechanistic target of rapamycin (mTOR), within the insulin growth factor (IGF) signaling pathway."
33052752
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"Abrogation of REDD1 mediated suppression of mTOR by TSC2 RNAi protected FASN inhibitor sensitive ovarian cancer cells (OVCA 420 cells) from orlistat induced death."
25151963
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"Interestingly, RTP801 is a negative regulator of mTOR, working downstream of Akt and upstream of TSC2 to inhibit mTOR activity [XREF_BIBR]."
21307646
reach
"Another negative regulator of mTOR, TSC2, was upregulated, affecting downstream mTOR signaling in PCCs (Figure 4D)."
35450293
sparser
"Under metabolic stresses, such as hypoxia and energy deprivation, LKB1-AMPK signaling can be activated, and subsequently phosphorylates and activates tuberous sclerosis complex 2 (TSC2), which next inhibits mTOR and mTORC1, leading to the activation of autophagy [ xref ]."
25244018
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"One study revealed that a coordinated phosphorylation of TSC2 by GSK-3beta and AMPK suppresses mTOR activity 53."
29445085
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"MTOR is inhibited, in part, by two tumor-suppressor proteins, TSC2 and PTEN."
23391115
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"We found that TSC2, but not TSC1, Rheb, or mTOR itself, associated with GST-ARD1 (XREF_FIG), suggesting that TSC2 may be involved in ARD1 mediated mTOR inhibition."
20145209
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"7-9 Tuberin is a crucial negative regulator of mTOR and substantially represses mTOR activity in normal kidney epithelial cells."
27550645
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"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling."
20021119
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"Tuberous sclerosis complex (TSC) is a genetic disorder affecting approximately 1 million patients worldwide. xref TSC is caused by inactivating mutations in TSC1 or TSC2 . xref , xref The proteins encoded by TSC1 and TSC2 inhibit the translation regulatory protein mTOR. xref , xref , xref , xref TSC patients have numerous types of growths called hamartomas and malformations including in the brain. xref Neurological manifestations in TSC are the greatest cause of morbidity in patients and includes seizures, intellectual disability, and a range of TSC associated neuropsychiatric disorders (TANDs) such as behavioral, psychiatric, neuropsychological, and autistic symptoms. xref , xref , xref , xref Malformations within the cerebral cortex called cortical tubers resemble focal cortical dysplasia (II) and are epileptogenic foci that are a leading cause of patient seizures. xref , xref , xref , xref , xref , xref , xref As one would expect, surgical resection of epileptogenic tubers reduces seizure burden. xref , xref , xref Tubers can be detected during late gestation and are therefore thought to be a byproduct of abnormal development."
38107199
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"Tsc2 negatively regulates mTOR through inhibition of Rheb, a small GTPase protein, by its GAP (GTPase activating protein) activity, so that the removal of Tsc2 activates mTORC1 by Rheb activation (XREF_FIG)."
20399730
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"In response to elevated ROS (both exogenous ROS such as H O or doxorubicin and endogenous ROS such as menadione or phenylethylisothiocyanate), cytoplasmic ATM acts as an ROS sensor and activates the tuberous sclerosis 2 (TSC2) tumor suppressor via the Liver kinase B1 (LKB1) / Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway to repress mammalian target of rapamycin complex 1 (mTORC1) and induce autophagy."
34421351
reach
"A loss of TSC2 function induces hyperactivation of mechanistic target of rapamycin (mTOR)."
36331254
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"According to a model based on these data, in the absence of growth factors the TSC1–TSC2 complex is hypophosphorylated and inhibits mTOR."
12935885
reach
"Furthermore, the activated Akt and Wnt ( Gui and Dai, 2020 ) inhibit GSK3 by phosphorylating TSC2 via AMPK-phosphorylate TSC2 manner ( Clarke and Simon, 2019 ) to inhibit mTOR."
34974186
eidos
"Cell stress and Akt-mTORC1 / - mTORC2 signaling The serine / threonine kinase mTOR is a well-characterized substrate of Akt and it is known that Akt-mediated activation of mTOR occurs through phosphorylation and inactivation of tuberous sclerosis complex 2 ( TSC2 ) , which normally inhibits mTOR ( Hay 2005 ) ."
30318853
reach
"In the absence of an upstream Wnt signal, GSK3 phosphorylates TSC2, which normally acts to inhibit cell growth by activating the GTPase activity of Rheb, causing inhibition of mTOR."
24212796
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"TSC2 usually inhibits mTOR via Rheb (Ras homolog enriched in brain), a GTP-binding protein."
22530122
sparser
"Muscle hypertrophy is also influenced by the availability of nutrients and the presence of endocrine and autocrine hormones such as IGF-I. A concerted anabolic signal is generated by leucine which facilitates the translocation of the kinase mTOR to the surface of the lysosome, where it is activated by Rheb, and by IGF-I which relieves the inherent inhibition of mTOR by TSC2."
22682632
eidos
"Their products , hamartin and tuberin , act as a complex to inhibit mTOR signaling ."
30657883
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"The TSC1/TSC2 protein complex inhibits mTOR and is involved in signaling pathways that regulate cell growth [162] ."
18187049
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"Several recent reports suggest that Redd1 plays a role in the TSC1/TSC2-mediated inhibition of mTOR under conditions of hypoxia and energy stress [8–11] ."
19059405
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"TSC2 phosphorylation on serine residues 1270 and 1388 enhances the activity of the TSC1/TSC2 complex, and thereby blocks the Ras homolog enriched in brain (RHEB)-dependent activation of mTOR [26,27] ."
25044308
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"In other cell types, active AMPK was shown to phosphorylate TSC2, which in turn inhibits mTOR [13] and affects two families of characterized mTOR substrates through which mTOR stimulates translation: [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
18377870
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"Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in TSC1 or TSC2 resulting in hyperactivity of the mammalian target of rapamycin and disabling brain lesions."
23349360
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"41 In normal conditions, AMPK is responsible for the activation of tuberous sclerosis complex 2 (TSC2) that negatively regulates mTOR activation."
37170684
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"During nutrient stress AMPK phosphorylates TSC2 on S and T to increase the GTPase activating protein (GAP) activity of TSC2 toward Rheb, thereby inhibiting mTOR activity XREF_BIBR."
22682632
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"An increase in Tsc2 expression could enhance the inhibitory regulation of the rapamycin (mTOR) pathway."
37771408
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"Our data corroborates the transgenic mouse data by showing that knockdown of TSC2 increases mTOR and NF-kappaB activity in PTEN null cells, suggesting that loss of TSC2 function coupled with loss of PTEN function activates mTOR and NF-kappaB which may promote tumorigenesis."
26374334
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"Thus, loss of either TSC1 or TSC2 leads to unchecked activation of mTOR."
34259631
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"TSC1 and TSC2 genes negatively regulated the activation of mTOR (24)."
36727048
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"Furthermore, excessive activation of mTOR induced by the knockdown of TSC2 inhibited insulin sensitivity in osteoblasts, leading to decreased osteogenic markers [60]."
37298150
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"Activated Akt phosphorylates TSC2 (tuberous sclerosis 2) at phosphorylation sites Ser-939 and Thr-1462 that leads to the inhibition of TSC2 thereby activating the mTOR (serine/threonine kinase) pathwa[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
25447154
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"TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling."
31597506
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"Moreover, ERK inhibitor increased TSC2 protein levels and attenuated mTOR activity in ANXA6 knockdown cells (Figure 6G)."
33135350
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"As unphosphorylated Tsc2 is known to inhibit mTOR [XREF_BIBR], our observed reduction in phosphorylated Tsc2 will result in increased inhibition of mTOR."
17892597
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"Additionally, metformin induced TSC-2 activation and inhibited mTOR activity in both bile duct cancer cell lines in this condition."
31205529
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"In addition, the activation of AMPK can phosphorylate TSC2 and the activated TSC2 can suppress mTOR complex 1 (mTORC1) to induce autophagy XREF_BIBR, XREF_BIBR."
30140075
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"In human peripheral monocytes stimulated by lipopolysaccharide, mTOR was inhibited by rapamycin or activated by RNA interference mediated knockdown of the mTOR repressor tuberous sclerosis complex 2 (TSC2)."
22287548
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"In adults, the supply of nutrients is periodic, so the activity of mTORC is also dynamic, which requires the participation of AMPK, TSC1, TSC2 (the upstream inhibitors of mTOR), etc.."
33815669
reach
"MTOR can be activated by TSC2 inhibition."
33732237
reach
"Indeed, Myc inhibits the mTOR repressor TSC2, thereby increasing mTOR activity to facilitate translation through S6K and 4E-BP phosphorylation [XREF_BIBR]."
27510264
reach
"Loss of Tsc1 and Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR."
14561707
reach
"Under metabolic stresses, such as hypoxia and energy deprivation, LKB1-AMPK signaling can be activated, and subsequently phosphorylates and activates tuberous sclerosis complex 2 (TSC2), which next inhibits mTOR and mTORC1, leading to the activation of autophagy [XREF_BIBR]."
25244018
reach
"The activated AMPK phosphorylates tuberous sclerosis complex protein 2 (TSC2) and inhibits mammalian target of rapamycin complex 1 (mTORC1)."
26879686
reach
"TSC2 (16p13.3) inhibits mTOR protein and regulates cell growth."
24649216
reach
"Tuberin (TSC2) functions as a GAP (GTPase-activating protein) for Rheb, and thus indirectly suppresses mTOR activity."
19570618
reach
"Ha et al. (2014) demonstrated that intracellular accumulation of TSC2 inhibits the activity of mTOR and increase autophagy [XREF_BIBR]."
33413124
reach
"The protein products of TSC1 and TSC2 form a complex to inhibit the mammalian target of rapamycin complex 1 (mTORC1), a key regulator of cellular energy status and cell growth (Inoki et al., 2003)."
35851298
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"Therefore, loss-of-function mutations or removal of PTEN, which leads to hyperactivation of Akt, or loss of TSC1 and TSC2, which leads to increased unbound RHEB, can cause an upregulation of mTOR signaling."
24672426
reach
"Loss of function in tuberous sclerosis complex 1 (TSC1) or 2 (TSC2) in systemic PEComas cause an activation of the mTOR pathway; however, primary cutaneous malignant PEComas are unrelated to tuberous sclerosis complex and show overactivation of the mTOR pathway by a different mechanism."
37360521
reach
"PTEN, TSC1 and TSC2 inhibit mTOR activity via PI3K/AKT inhibition [31]."
39200267
reach
"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."
18451215
reach
"In contrast, under ATP privation, the AMPK phosphorylates and potentiates tuberous sclerosis protein 2 (TSC2), which inhibits mTOR in combination with TSC1 (hamartin) [XREF_BIBR] (XREF_FIG)."
18400054
reach
"These results indicate less differentiation of SMCs in leiomyoma and establish a correlation between mTOR activation and SMC differentiation.The mTOR pathway can be activated by the loss of tuberin."
21145542
sparser
"In the setting of low concentrations of adenosine triphosphate (and high AMP), AMPK activates TSC2, which inhibits mTOR."
27865299