IndraLab

Statements


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sparser
"Hamartin and tuberin associate in viva and patients with alterations in either gene show identi- cal symptoms [50’,51]."

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"XREF_BIBR Accumulation of the TSC1 and TSC2 complex is achieved through competitive inhibition of complex formations between 14-3-3 and TSC2 by DNA-damage-inducible transcript 4 (DDIT4 or REDD1)."

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"TSC2 and TSC1 can form a dimer and inhibit the GTPase activity of Rheb, a critical activator of mTOR signaling XREF_BIBR."

"In turn, Akt phosphorylates the tuberous scleorisis complex, TSC1/TSC2 (hamartin/tuberin) that serves as a GTPase activating protein (GAP) for the small G protein, Ras homolog enriched in brain (Rheb)."

sparser
"Interestingly, crosstalk between PI3K/Akt/mTOR pathways and MAPK pathways has been investigated that elevated ERK negatively affects mTOR phosphorylation through TSC1-TSC2 complex and Rheb [ xref ]."

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"However, mTORC2 activation requires PI3K and the TSC1 and TSC2 complex, but is independent of Rheb and is largely insensitive to either nutrients or energy conditions [XREF_BIBR]."

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"We find that mTORC2 isolated from a variety of cells lacking a functional TSC1 and TSC2 complex is impaired in its kinase activity toward Akt."

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"TSC1 and TSC2 form a heterodimeric complex that can regulate protein synthesis by controlling mTORC1 activity."

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"These results suggest that FIP200 interaction with the TSC1 and TSC2 complex might not be required for FIP200 regulation of cell cycle progression."

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"Akt and PKB both regulates and is regulated by the TSC1 and TSC2 complex."

"In the context of Tsc1/2 loss, Ozcan et al. (2008) recently showed that mTORC1 hyperactivation leads to aberrant protein synthesis rate and activation of the unfolded protein response."

sparser
"In normal cells, hamartin and tuberin form a molecular complex involved in intracellular signaling pathways controlling cell growth and proliferation, including the mammalian target of rapamycin (mTOR) cascade."

sparser
"However, we did not observe either a decrease in TSC2 association with 14-3-3 proteins or an increase in association of TSC2 with TSC1 in response to increased REDD1 abundance, suggesting that REDD1 may work through additional mechanisms to regulate TSC2 function."

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"These findings support a model in which phosphorylation of hamartin regulates the function of the hamartin and tuberin complex during the G2/M phase of the cell cycle."

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"Neurons which have lost expression of the TSC1 and TSC2 complex are prone to apoptosis [XREF_BIBR]."

sparser
"Using a similar cross-species screening approach, we performed genome-wide screens to identify SS/L interactions with the TSC1 and TSC2 genes."

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"Recently, it has been shown that TSC1 and TSC2 form a complex that inactivates mTOR and so inhibits the activity of S6K [68]."

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"Finally, ROS inhibits the Tsc1 and Tsc2 complex, thereby relieving Tor from upstream inhibition (Yoshida etal., 2011)."

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"Due to sustained mTORC1 signaling, cells lacking the TSC1 and TSC2 complex can proliferate in the absence of growth factors."

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"In addition to the PTEN-AKT-FOXO3 signaling pathway [XREF_BIBR], suppression of mTORC1 activity by the TSC1 and TSC2 complex in oocytes has been shown to be a prerequisite for maintaining the dormancy of primordial follicles based on extensive studies using mice with oocyte specific deletion of TSC1 and TSC2 genes [XREF_BIBR], [XREF_BIBR]."

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"It has also been shown that hamartin can bind to tuberin to prevent tuberin ubiquitination and degradation."

sparser
"Finally, we observed that inhibition of basal Erk activity could promote the interaction of endogenous TSC1-TSC2, whereas MAPK activation upon PMA treatment led to disruption of the endogenous complex[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"These mice express a dominant and negative TSC2 that binds to TSC1, but has a deletion and substitution mutation in its GAP-domain, resulting in inactivation of the complex."

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"The TSC1 and TSC2 complex known to inhibit mTORC1 activity is required for proper activation of mTORC2."

sparser
"TSC1 and TSC2 normally form a heterodimer TSC1/2 that inhibits the TORC1 complex."

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"AMPK phosphorylates and activates the TSC1 and TSC2 complex [XREF_BIBR]."

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"Recent studies of Drosophila and mammalian cells demonstrate that the TSC1 and TSC2 complex functions as GTPase activating protein against Rheb - a Ras like small GTPase, which in turn regulates TOR signaling in nutrient stimulated cell growth."

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"XREF_BIBR One key upstream regulator of mTORC1 is TSC1 and TSC2 complex (XREF_FIG)."

sparser
"It has been demonstrated that tuberin and hamartin interact directly with each other, forming a cytoplasmic protein complex [ xref ]."

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"Loss-of-function mosaic mutations in negative regulators of mTOR kinase, as TSC1 and TSC2, induce mTOR hyperactivation by disturbing the function of the TSC1 and TSC2 complex."

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"Our studies demonstrate that TSC patient derived missense mutations on TSC2 can differentially affect the ability of the TSC1 and TSC2 complex to inhibit mTORC1 and activate mTORC2."

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"The effects of amino acid changes to TSC1 or TSC2 on TSC1 and TSC2 complex formation, on the activation of rheb GTPase activity by the complex, and on the phosphorylation status of S6K and S6 can be determined [XREF_BIBR, XREF_BIBR, XREF_BIBR]."

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"Many groups have demonstrated several mechanisms by which TSC1 and TSC2 complex can block mTORC1 activity."

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"7 The complex hamartin and tuberin is an important inhibitor of tumor growth."

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"mTORC1 (referred to as mTOR) integrates information from many extracellular and intracellular signals (e.g. Ras-ERK and PI3K-Akt) that converge on the immediate upstream mTOR regulators : TSC1 and TSC2 complex and Ras-homolog enriched in brain (Rheb)."

sparser
"It was also reported that activated AMPK reduced the activity of mTOR by phosphorylating TSC2, resulting to inhibit the mTOR by activation of TSC1-TSC2 complex."

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"The in vivo and in vitro association of TBC7 and the TSC1 and TSC2 complex was confirmed by the co-immunoprecipitation and pull-down analysis, respectively, and TBC7 was revealed to bind to the C-terminal half region of TSC1, which is distinct from the binding site with TSC2."

sparser
"In this study, an attempt has been made to assess the impact of each novel missense variant based on their TSC1-TSC2 hydrophobic interactions and its effect on protein function."

sparser
"This is consistent with the recent finding that tuberin and hamartin interact and with the clinical similarity between TSC1- and TSC2-linked disease."

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"Our study takes advantage of signaling defects triggered by loss of the TSC1 and TSC2 complex to determine the contributions of specific branches downstream of these proteins."

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"When a non phosphorylatable form of TSC2 (S939A) was overexpressed, phosphorylation dependent binding of the scaffold protein 14-3-3 to TSC2 was diminished and no re-distribution of the TSC1 and TSC2 complex was observed following IGF-1 stimulation."

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"Hamartin and tuberin interact directly with each other and it has been reported that tuberin may act as a chaperone, preventing hamartin self aggregation and maintaining the tuberin and hamartin complex in a soluble form."

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"The TSC1 and TSC2 complex is the most prominent upstream inhibitor of mTOR signaling, integrating several upstream signals such as growth factor, energy, stress and possibly amino acids."

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"LKB1 phosphorylates AMPK, which subsequently targets the TSC1 and TSC2 complex that then inhibits mTOR."

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"TSC2 missense mutations inhibit tuberin phosphorylation and prevent formation of the tuberin and hamartin complex."

sparser
"These two proteins together, along with TBC1D7 (Tre2-Bub2-Cdc16-1 domain family member 7) ( xref ), form the hamartin-tuberin complex, also called the TSC1/TSC2 complex or TSC complex."

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"Assembly of the TSC1 and TSC2 complex is promoted by phosphorylation of TSC2 [XREF_BIBR]."

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"This finding is consistent with current models where AMPK serves to activate the Tsc1 and Tsc2 complex, thus limiting Tor activation under conditions of energy depletion."

sparser
"Phosphorylation of TSC2 on S664 disrupts the TSC1-TSC2 complex promoting mTORC1 activation ( xref )."

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"To distinguish between pathogenic mutations and harmless polymorphisms, we have analysed the effects of different amino acid changes on the activity of the TSC1 and TSC2 complex."

sparser
"Tuberin must be associated to hamartin, the TSC1 gene product (see below), to achieve full activation; this complex favors a GTP-to-GDP conversion of Rheb, which results in the inactivation of Rheb and the inhibition of mTORC1."

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"As the hamartin and tuberin complex normally inhibits the mTOR pathway, mutation of either TSC1 or TSC2 leads to abnormal disinhibition of the mTOR pathway."

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"We review the fundamental roles of TSC1 and TSC2 in cell signalling and propose that because the hamartin and tuberin complex (hereafter referred to as TSC1-2) acts as a global regulator and integrator of a range of physiological processes (' GRIPP ') the neurocognitive manifestations of TSC result directly from cell signalling abnormalities."

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"Our results suggest that the Tsc1 and Tsc2 complex mediated suppression of mTORC1 activity is indispensable for maintenance of the dormancy of primordial follicles, thus preserving the follicular pool, and that mTORC1 activity in oocytes promotes follicular activation."

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"In contrast to nutrients, growth factors such as IGF-I stimulate mTOR via an IGF-IR, PI3K, Akt pathway that disrupts the TSC1 and TSC2 complex."

sparser
"R611W) mutation suggests a generally more severe phenotype, consistent with in vitro observations that this mutation causes severe impairment of TSC1TSC2 binding and function ( Nellist et al., 2005[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"In this connection, in cultured mouse hepatocytes under nutrient restriction, changes in PC composition of cellular membranes lead to the formation of Them2/PC-TP complex that directly suppresses mTORC1 signaling by interacting with tuberous sclerosis complex 2 (TSC2) to stabilize the TSC1-TSC2 complex ( xref )."

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"Upon activation by various stimuli, PI3K and AKT or similar effectors can relieve the inhibitory effect of the TSC1 and TSC2 complex through their phosphorylation to favor mTOR and S6K activation in the downstream."

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"In the regulation of general protein synthesis, ERK can either directly phosphorylate TSC2 and suppress TSC1 and TSC2 complex formation to activate mTOR [33] or directly phosphorylate the ribosomal S6[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"NO treatment decreased the binding of TSC1 to TSC2, whereas L-NIL enhanced binding."

sparser
"TSC1 and TSC2 form a complex that inhibits Rheb-directed mTOR activation through a GTPase-activating protein (GAP) domain in the TSC2 C terminus ( xref )."

sparser
"Why mutations in InR do not appear to strongly affect branch complexity remains a question for future study, but may reflect that Sima/Hifα exerts a negative feedback on TOR activity – Hifα-target gene, Scylla , activates TSC1-TSC2 ( xref ) – and additionally, that loss of InR does not impact endoreplication."

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"This imbalance in the TSC1 and TSC2 complex may have reduced inhibition of mTOR in the IPDR and PNDR groups."

sparser
"Tuberous Sclerosis Complex (TSC) is a multi-system disorder caused by mutations in TSC1 or TSC2 ( xref ) that is highly associated with epilepsy, autism, and intellectual disability."

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"Combined with our previous study, our results here identify mTORC2 activation as a second distinct molecular function of the TSC1 and TSC2 complex."

sparser
"3) Hypoxia: Under hypoxic conditions, HIF-1α promotes the expression of REDD1 to inhibit mTORC1 by activating the TSC1-TSC2 complex (Brugarolas et al., 2004)."

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"In all the above cases we analysed the effect of the identified changes on the activity of the TSC1 and TSC2 complex in order to establish which of the changes were pathogenic mutations."

sparser
"In light of the relative abundance of clinical reports on BHD and TS co-incidence, our group revisited the idea that Tsc1-Tsc2 and FNIP1/2-FLCN are dedicated, exclusive complexes."

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"TSC1 physically prevents the ubiquitin mediated proteolytic degradation TSC2 and likely explains the greater Rheb GAP activity of the TSC1 and TSC2 complex when TSC1 is over expressed."

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"Similar inhibitory effects emerged upon inhibition of PI3K, blockade of the mTORC1 catalytic site by Torin 1, or overexpression of the inhibitory TSC1 and TSC2 complex, indicating that TACI augments NF-kappaB activation via PI3K-AKT-dependent TSC restrained signals from mTORC1."

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"In 2001, researchers working with drosophilia 5,6 reported that tuberin and hamartin, the TSC2 and TSC2 gene products, respectively, form a dimeric protein complex so called master switch, modulating [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"We found that 14-3-3beta does not interfere with TSC1-TSC2 binding and can form a ternary complex with these two proteins."

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"The hamartin and tuberin complex is regulated by direct phosphorylation from a plethora of kinases, including AKT, ERK1/2, RSK1, MK2, AMPK, GSK3, IKKbeta, CDK1, and PLK1 XREF_BIBR, XREF_BIBR."

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"How does the TSC1 and TSC2 complex affect mTORC2 activity?"

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"Therefore, there is a correlation between the ability of the TSC1 and TSC2 complex to bind mTORC2 and the ability of growth factors to stimulate mTORC2 activity."

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"We found that association of FIP200 or its segments N1-859 and N1-638 with the TSC1 and TSC2 complex correlated with their ability to increase cell size, up-regulate S6K phosphorylation, and decrease TSC1 and TSC complex formation."

sparser
"Together, these results suggest that FIP200, through its N1-859 region association with the TSC1TSC2 complex, may negatively regulate TSC1TSC2 complex inhibition of the mTOR–S6K pathway, resulting in an increase in cell size."

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"The TSC1 and TSC2 protein complex is composed of the heterodimer TSC1 and TSC2, and is a direct target of Akt phosphorylation."

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"Oestrogen was shown to promote pulmonary metastases using the ELT3 (TSC2 -/-) uterine leiomyoma cells, although whether or not effects of oestrogen and the hamartin and tuberin complex are related remains unknown."

sparser
"Tuberin and hamartin form a complex in vivo [6,7] and function within the same pathway regulating cell growth [8–10] ."

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"Nevertheless, we can not rule out the possibility that Cot and tpl2-MKK 1/2-Erk 1/2 also inhibits the TSC1 and TSC2 complex and consequently increases mTORC1 activity by Erk1/2 direct phosphorylation of TSC2 on S664."

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"Tuberin can be inactivated by several mechanisms including changes in subcellular localization, dissociation from hamartin and other regulatory proteins, or degradation of the hamartin and tuberin complex [XREF_BIBR]."

sparser
"While the exact mechanism is not clear, CDK1 is known to phosphorylate S6K on S70 ( xref ), it is possible Hamartin releases the inhibitory CDK1 phosphorylation of p70 S6K. During mitosis, Hamartin is phosphorylated by Plk1 at S467 and S578, the phosphorylation of these residues destabilizes Hamartin and promotes the dissociation of the Tuberin-Hamartin complex. ( xref )."

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"Knowledge regarding the function of the tuberin and hamartin complex has led to therapeutic intervention trials."

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"Considering that TSC2 p.Val1547Ile is located in the GAP domain of TSC2, this variant is likely to affect the GAP activity of the TSC1 and TSC2 complex toward Rheb but not the formation of the TSC1 an[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

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"Taken together, these results suggest that SIGIRR modulates IL-1-induced mTOR activation through its impact on IRAK1 activation and consequent effect on IRAK1 mediated disruption of TSC1 and TSC2 complex."

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"Hamartin and tuberin form a complex and inhibit the mammalian target of the rapamycin pathway, which controls cell growth and proliferation [1]."

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"The TSC1 and TSC2 complex is inactivated in the eponymic syndrome, tuberous sclerosis complex (TSC), which is characterized by hamartomas in multiple organs."

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"Led by seminal studies in Drosophila, the TSC1 and TSC2 complex has been positioned in an ancestrally conserved signalling pathway that regulates cell growth."

sparser
"The heterodimer formed by the TSC1 product hamartin and the TSC2 product tuberin can suppress Rheb, an activator of mTORC1 ( Sato et al., 2012 )."

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"TSC2, as a GTPase activating (GAP) protein, binds with TSC1 to form a complex which negatively regulates a small GTPase, Ras homologue enriched in brain (Rheb) XREF_BIBR."

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"TSC2 is part of the TSC1 and TSC2 complex, which inhibits mTORC1 through its Rheb-GAP activity."

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"The endogenous interaction of TBC1D7 with the TSC1 and TSC2 complex was confirmed in reciprocal immunoprecipitations with a panel of six unique antibodies to TSC1 or TSC2, along with an antibody raised against TBC1D7 (XREF_FIG), the specificity of which was confirmed through siRNA mediated knockdown of TBC1D7 (XREF_SUPPLEMENTARY)."

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"Conversely, absence of a nitrogen source suppresses TORC1 in a manner dependent on GATOR1 as well as the Tsc1 and Tsc2 complex, whose mammalian equivalent functions as a growth-factor sensitive TORC1 inhibitor."

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"Hamartin and tuberin, the gene products of TSC1 and TSC2, respectively, form a complex that suppresses the signaling effector, mechanistic target of rapamycin (mTOR)."

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"Although it has been shown that hamartin and tuberin form a complex and mediate phosphoinositide 3-kinase/Akt-dependent phosphorylation of the ribosomal protein S6, it is not yet clear how inactivation of either protein leads to tuberous sclerosis."

sparser
"As mentioned above, phosphorylation of hamartin appears to be an important component of the control of hamartin-tuberin complex formation ( xref ; xref ), but it is still unclear whether the phosphorylation of hamartin is also involved in oxygen-sensing pathways."

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"p53 is able to inhibit the activity of mTOR through TSC1 and TSC2 complex (Feng et al., 2005)."

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"Third, unlike budding yeast, the structural and functional homologs of Rheb and the TSC1 and TSC2 complex are conserved as Rhb1 and the Tsc1 and Tsc2 complex, respectively."

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"Inhibition of mTORC1 is intricately regulated by the tuberous sclerosis Tsc-1 and Tsc-2 protein complex [XREF_BIBR]."

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"The TSC1 and TSC2 complex is activated by low cellular energy levels via AMP Kinase."

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"This is consistent with our previous conclusion that the TSC1 and TSC2 complex is a regulator of mTORC2 rather than a core component of the complex itself."

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"Overexpression of constitutively activated Akt or disruption of TSC1 and TSC2 complex by small interfering RNA or gene knockout only partially restored curcumin mediated inhibition of mTOR and downstream signaling, indicating that they are not the primary effectors of curcumin mediated inhibition of Akt and mTOR signaling."

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"ERK1/2, through the ERK1/2 substrate RSK, and phosphorylates and inhibits the TSC1 and TSC2 complex [XREF_BIBR, XREF_BIBR]."

sparser
"Tsc1 forms a complex with Tsc2, which regulates mTORC1 signalling, and this process is mediated by Akt."

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"In contrast to the previous studies that the TSC1 and TSC2 complex is a critical negative regulator of mTORC1 and that TSC1/2 deficient cells have reduced autophagy via mTORC1 dependent inhibition and phosphorylation of ULK1 at S757, we observed that TSC1 deficient macrophages had higher basal and infection induced autophagy compared to wild type controls."

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"The activated Akt then inactivates the TSC1 and TSC2 heterodimer to activate mTORC1 and phosphorylate downstream targets, including p70S6K1 XREF_BIBR."

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"XREF_BIBR, XREF_BIBR Moreover, ERK1/2 has been reported to phosphorylate TSC2, leading to the dissociation of the TSC1 and TSC2 complex and the activation of the mTOR signaling pathway."

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"To determine if the TSC1 and TSC2 complex can directly stimulate mTORC2, we tested whether purified TSC1 and TSC2 complex could increase the in vitro kinase activity of mTORC2 isolated from Tsc2 -/- MEFs."

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"We suggest that individual missense mutations in TSC1 would unlikely eliminate the binding of TSC1 to TSC2."

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"Phospho-AKT inhibits the formation of the hamartin and tuberin complex and promotes the phosphorylation of p70S6K and 4E-BP1."

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"Disruption of the TSC1 and TSC2 complex through the loss of either Tsc1 or Tsc2, results in constitutive activation of mTORC1."

sparser
"PI3KC1 activates the downstream target AKT, leading to activation of mammalian target of rapamycin (mTOR) by inhibiting the tuberous sclerosis complex 1/2 (TSC1TSC2), which results in inhibition of autophagy."

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"Whether the physical association between the TSC1 and TSC2 complex and mTORC2 plays some regulatory role for one or both complexes is not currently known."

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"Rheb becomes activated, i.e., GTP loaded, when the TSC1 and TSC2 complex is repressed through an array of upstream kinases within mitogenic and hormone stimulated pathways (depicted in XREF_FIG)."

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"mTORC2 does not seem to be regulated by the hamartin and tuberin complex or by Rheb."

sparser
"How the binding of TSC1 and TSC2 might result in an activity that neither alone contains is unclear."

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"In response to IGF-1 treatment, there was a relative re-distribution of the TSC1 and TSC2 complex, composed of TSC1 and phosphorylated TSC2, from the membrane to the cytosol."

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"In contrast, loss of the Tsc1 and Tsc2 complex seems to have little impact on TORC1 activity under the same conditions."

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"mTORC1 is under tonic inhibition by the Tsc1 and Tsc2 complex, and Tsc1 deletion results in constitutively increased mTORC1 signaling."

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"Under hypoxia conditions, mTORC1 activity is down-modulated through different mechanisms [activation of AMP activated protein kinase (AMPK) and of mTOR suppressing TSC1 and TSC2 complex through some H[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"Tuberin and hamartin form a complex that inhibits signaling by the mammalian target of rapamycin (mTOR), a critical nutrient sensor and regulator of cell growth and proliferation."

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"The heterodimeric TSC2 and TSC1 complex has a highly specific GAP (GTPase activating protein) activity towards Rheb (Ras homolog enriched in brain), a major regulator of mTORC1 (mammalian target of rapamycin complex 1) XREF_BIBR."

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"To this end, we inhibited the activity of Tor genetically, by over-expressing the Tor inhibitor complex TSC1 and TSC2, and pharmacologically, by feeding flies the Tor inhibitor rapamycin."

sparser
"A possible function of the interaction between 14-3-3 proteins and phosphorylated tuberin is to inhibit the formation of tuberin-hamartin complex, in order to decrease the stability of tuberin and release of the activated mTOR [ xref ]."

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"These findings may have therapeutic implications for the treatment of TSC derived tumors.The TSC1 and TSC2 complex has recently been implicated in the cell survival response."

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"Characterization of the cytosolic tuberin and hamartin complex."

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"In the proposed model, PC-1 is a constitutive partner of the tuberin and hamartin complex that is required for its GTPase activity towards Rheb."

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"mTORC1 independent downstream pathways of the hamartin and tuberin complex."

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"Next, we addressed whether the dAkt feedback signaling is routed from dAkt to the Tsc1 and Tsc2 complex by evaluating the P-dAkt immunoreactivity in akt q, tsc1 Q87X double mutant clones."

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"Moreover, using the in utero CRISPR-Cas9 somatic genome editing system, we clearly demonstrated that a focal cortical disruption of the TSC1 and TSC2 complex, encoded by Tsc1 and Tsc2, was sufficient [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"However, Akt-mediated phosphorylation inhibits the formation of the TSC1-TSC2 complex causing the accumulation of GTP-bound Rheb."

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"These findings reveal that the Tuberin and Hamartin heterodimer and Rheb respectively inhibit and activate the nutrient signaling input to mTOR."

sparser
"Alternatively, the binding of TSC1 and TSC2 might alter their conformations, and allow for the interactions of downstream players."

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"By contrast, TSC1 and TSC2 complex positively regulates mTORC2 through association with rapamycin-insensitive companion of mTOR."

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"Lkb1 also regulates mTOR via the TSC1 and TSC2 complex as Lkb1 normally phosphorylates AMPK XREF_BIBR, for which TSC2 is a substrate XREF_BIBR."

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"Extracellular signal regulated kinases (ERKs), protein p90 ribosomal S6 kinase 1 (RSK1), and glycogen synthase kinase -3 beta (GSK-3beta) also can modulate the activity TSC1 and TSC2 complex."

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"Inhibition of mTOR is mediated by pathways that involve DDIT4 and REDD1, AKT1, the TSC1 and TSC2 complex, and the GTPase RHEB [XREF_BIBR, XREF_BIBR]."

sparser
"Additionally, tuberin is phosphorylated at serine and tyrosine residues in response to growth factors, which affects the interaction between hamartin and tuberin [ xref ]."

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"Clinical trials of sirolimus treatment for patients with LAM were initiated based on reports that the protein products of the TSC1 and TSC2 complex are negative regulators of mTOR [XREF_BIBR]."

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"Neurodevelopmental delays along with cognitive impairments are thought to stem from synaptic structure and function aberrations that are characteristic of ASDs and monogenic IDs such as FXS, RTT, tuberous sclerosis (TSC caused by mutations in the TSC1/TSC2 complex)."

sparser
"Pharmacological inhibition of PLK1 by the small-molecule inhibitor BI-2536 significantly decreased the viability and clonogenic survival of hamartin and tuberin deficient cells, which was associated with increased apoptosis."

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"This disorder is caused by mutations in TSC1 or TSC2 that encode tumour suppressor proteins which form the complex TSC1 and TSC2 that regulate protein synthesis in a wide range of mammalian cell types, including neurons 67."

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"These data indicate that activity of the TSC1 and TSC2 complex is dynamically regulated in cells undergoing ER stress and may mediate the modulation of mTOR activity in response to ER stress."

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"MMP-2 activity was increased in both Tsc2 -/- and Tsc1 -/- MEFs, and this induction was unaffected by either Rapamycin treatment or Rheb knockdown, suggesting this regulation is a Rheb independent function of the TSC1 and TSC2 complex."

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"To identify the critical subunit of mTORC2 that mediates the interaction with the TSC1 and TSC2 complex, we co-overexpressed the core components of mTORC2 and examined the ability of these proteins to coimmunoprecipitate with the TSC1 and TSC2 complex, using FLAG-TSC1 as a handle."

sparser
"SEGAs have been shown to have either TSC1 or TSC2 biallelic inactivation in about 80% of cases, following the classic Knudson two hit model, leading to complete loss of function of the tuberin-hamartin protein complex and mTORC1 (mechanistic Target Of Rapamycin Complex 1) hyperactivation [ xref , xref , xref ]."

sparser
"Tuberin and Hamartin form a tumor suppressor heterodimer that inhibits the mammalian target of rapamycin (mTOR) nutrient signaling input, but how this occurs is unclear."

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"VPS34 regulates TSC1 and TSC2 heterodimer to mediate RheB and mTORC1 and S6K1 activation and cellular transformation."

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"We also find that purified TSC1 and TSC2 complex can stimulate the in vitro kinase activity of mTORC2 and that the interaction between the two complexes is mediated primarily through TSC2 and Rictor."

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"Interestingly, most of the signals that regulate Rheb and mTORC1 impinge on the TSC1 and TSC2 complex, such that poor growth conditions activate the complex while growth promoting conditions inhibit the complex to, respectively, inhibit or activate Rheb and mTORC1."

sparser
"TSC1 and TSC2 form a protein complex, referred to as the TSC complex, which is a critical negative regulator of mTORC1 ( Dibble and Manning, 2013 )."

sparser
"Pathological mutations in these genes disrupt the interaction between hamartin and tuberin and affect cell function via the improper regulation of the mechanistic/mammalian target of rapamycin (mTOR) signalling cascade and multiple downstream effectors responsible for the modulation of key cellular processes, including protein synthesis, autophagy, cell growth, and proliferation [ xref ]."
| PMC

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"TSC1 acts to stabilize TSC2, preventing its degradation and both function together as the TSC1 and TSC2 heterodimer [XREF_BIBR, XREF_BIBR]."

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"mTOR is stimulated by signals that activate AKT, which inactivates TSC1 and TSC2 complex [XREF_BIBR, XREF_BIBR - XREF_BIBR]."

sparser
"Hamartin and tuberin form a heterodimer that negatively regulates the mTORC1 (mammalian target of rapamycin complex 1) signaling cascade by inactivating the small G protein Rheb ( xref )."

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"The elution profiles of TOR, AKT, FMRP and 14-3-3zeta were consistent with previous findings and therefore it is unlikely that the apparent large size estimates for the TSC1 and TSC2 complex in the cytosolic and 100 mM NaCl extracts were artefacts of the lysis and fractionation procedure."

sparser
"Hypoxia has been reported to inhibit mTOR (Arsham et al., xref ) via induction of the hypoxia-responsive gene DDIT4 (Dig2/RTP801/REDD1) and subsequent formation of a complex consisting of the tuberous sclerosis tumor suppressor proteins TSC1 (hamartin) and TSC2 (tuberin) (Brugarolas et al., xref )."

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"Therefore, when the TSC1 and TSC2 complex is active, it stimulates the intrinsic GTPase activity of Rheb, effectively converting Rheb to its GDP bound state and shutting down mTORC1 activity."

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"This inhibitory effect is particularly evident in cells lacking the TSC1 and TSC2 complex, where elevated mTORC1-S6K1 signaling leads to a strong attenuation of PI3K activation downstream of insulin and the insulin receptor substrate proteins, IRS1 and IRS2 [XREF_BIBR, XREF_BIBR]."

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"Despite these uncertainties surrounding the pathway 's details, mTOR signaling during ischemia and hypoxia is known to depend on hamartin and tuberin complex formation."

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"TSC2 contains the active site of the TSC1 and TSC2 complex and therefore has a clearly defined functional role."

sparser
"However, TSC1-TSC2 can also activate mTORC2 independently of this activity [ xref ]."
| PMC

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"As the TSC molecules are not conserved in S. cerevisiae, S. pombe is an adequate model organism to gain insight into the regulation of amino acid incorporation and the amino acid transporters by the Tsc1 and Tsc2 complex."

sparser
"AMPK phosphorylation of TSC1 activates the TSC1-TSC2 complex, in turn inhibiting mTORC1 through its Rheb-GAP activity [ xref , xref ]."
| PMC

reach
"29 Finally, loss-of-heterozygosity of TSC1 (9q34), a 23-exon gene that encodes one of the subunits of the TSC1 and TSC2 heterodimer, has been reported in approximately 50% of cases, in addition to num[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"AKT regulates the dissociation, while CDK1 regulates the formation, of the hamartin-tuberin complex – either indirectly, or directly through phosphorylation of hamartin ( xref ; xref ), as was also mentioned above."

sparser
"Activated Erk1/2 directly phosphorylates TSC2 at sites different from the Akt target sites, thereby causing functional inactivation of the TSC1-TSC2 complex and ultimately mTORC1 activation [Ma et al., 2005] ."

reach
"We found that IL-1-mediated disruption of TSC1 and TSC2 complex was greatly reduced in IRAK1 deficient cells derived from 293-IL-1R cells, indicating that IL-1-induced IRAK1 dependent mTOR activation is also through the disruption of TSC1 and TSC2 complex."

reach
"TSC1 and TSC2 complex is upstream inhibitor of mTORC1, and thus in the absence of either TSC1 or TSC2, mTORC1 signaling is chronically increased [XREF_BIBR]."

reach
"TSC2 forms a complex with TSC1 to promote GTP hydrolysis by the small GTPase Rheb."

reach
"mTORC1 activation occurs only when RHEB is bound to GTP [XREF_BIBR]; therefore, mutation or knockdown of PC1 reduces TSC1 and TSC2 complex formation, which causes mTORC1 hyperactivation [XREF_BIBR]."

sparser
"The hamartin and tuberin proteins together form a cytoplasmic complex that acts as a tumor suppressor, and also regulates signal transduction critical for multiple downstream cellular development and [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"In the current article, the authors propose that cortical tubers result from somatic mutations in patients with heterozygous germline mutations resulting in complete loss of function of TSC1 and TSC2 complex and hyperactivation of mTORC1 in a subset of cortical progenitor cells."

reach
"Since the inhibition of mTORC1 markedly increased PDGFRalpha expression and then led to activation of AKT, we next evaluated whether the combination of rapamycin with AG1295 (a specific PDGFR inhibitor) could achieve a better inhibitory effect on the growth of cells lacking TSC1 and TSC2 complex."

reach
"It has been suggested that a putative transmembrane domain in the N-terminal region of TSC1 (amino acids 127-144) may be important for the correct localisation of the TSC1 and TSC2 complex [12]."

reach
"AKT inhibits the TSC2 and TSC1 complex, leading to activation of mTORC1 XREF_BIBR."

reach
"Since TSC1 stabilizes TSC2 by preventing the association between TSC2 and HERC1 ubiquitin ligase, enhances TSC2 GAP function, and further inhibits mTOR activity (Chong-Kopera et al., 2006), we investi[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"In TSC, mutation of TSC1 or TSC2 leads to a loss or decrease in function of the hamartin and tuberin complex, resulting in disinhibition or hyperactivation of the mTOR pathway, particularly mTORC1 (XREF_FIG)."

reach
"Besides, other recent studies have shown that REDD1 is an upstream regulator of TSC1 and TSC2 complex activity, which acts to repress signaling through the mammalian target of rapamycin complex 1 (mTORC1) in mammalian cells."

sparser
"Functionally, TSC1 is necessary to maintain the stability, activity, and the correct intracellular localization of the TSC1-TSC2 complex ( xref )."

reach
"Other genetic manipulations causing more severe Tsc2 deficiency, or dysfunction of the TSC1 and TSC2 complex, lead to abnormal social behaviors in mice [XREF_BIBR, XREF_BIBR]."

sparser
"The effects that the missense changes in the GAP-related domain have on GAP activity toward rap1 and rab5 are now under investigation, as is the effect that the single-residue deletion ΔI365 has on th[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"TSC mutations are particularly disruptive in the phosphoinositide 3 kinase (PI3K)/Protein kinase B (PKB or AKT)/mTOR pathway, as the mTOR pathway is inhibited by the complex of two proteins Hamartin (TSC1) and Tuberin (TSC2)."

reach
"The proteins hamartin and tuberin, respectively, encoded by the TSC1 and TSC2 genes, form a complex that downregulates the mTOR pathway."

reach
"The hamartin-tuberin complex plays diverse roles in cell cycle regulation, chiefly through inhibition of the mammalian target of rapamycin (mTOR) cascade [1–3]."

sparser
"In addition, genetic polymorphisms in immune-related gene loci, including MET (met proto-oncogene) receptor tyrosine kinase gene, threonine kinase C gene PRKCB1, CD99 molecule-like 2 region (CD99L2) [ xref ], Jumanji AT rich interactive domain 2 (JARID2) [ xref ] gene, the thyroid peroxidase gene (TPO) [ xref ], tuberous sclerosis proteins 1 and 2 (TSC1-TSC2) genes [ xref ], and phosphatase and tensin homolog (PTEN) [ xref ], have been associated with ASD."

reach
"Because constitutive activation of mTORC1 is the primary molecular defect caused by loss of function of the TSC1 and TSC2 complex, we determined whether aberrant mTORC1 signaling was responsible for HCC development in the LTsc1KO model."

reach
"Therefore, as seen above with the glioblastoma cell line, tuberin is aberrantly phosphorylated in the absence of growth stimuli when PTEN is mutated, and this is dependent on PI3K activity.Recent frui[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"In contrast, activation of mTORC1 by IL-1beta-IRAK1/4 signaling, which degrades TSC1 and TSC2 complex, promotes Th17 differentiation, and malfunction of mTORC1 by deletion of Rheb and Raptor, encoding central components of mTORC1, impairs Th17 differentiation."

reach
"Based on our findings, it is possible that mutations leading to aberrant activation of the PI3K-Akt pathway, such as PTEN mutations, could inhibit the function of the tuberin and hamartin complex by c[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Both diseases are caused by mutations of TSC1 or TSC2 (TSC is tuberous sclerosis complex) that impair GAP (GTPase activating protein) activity of the TSC1 and TSC2 complex for Rheb, leading to inappropriate activity of signalling downstream of mTORC1 (mTOR complex 1)."

reach
"An active TSC1 and TSC2 complex shifts this ratio in favor of GDP-Rheb, which can not activate mTORC1 [XREF_BIBR]."

reach
"A second coiled-coil domain is encoded by exons 17 to 23 which stabilizes the tuberin and hamartin complex [XREF_BIBR]."

sparser
"Notably, TSC2 has already been shown to interact with 143-3 proteins when phosphorylated, and that this interaction disrupts the function of the TSC1-TSC2 complex ( xref ; xref )."

reach
"Therefore, the TSC1 and TSC2 complex may provide a platform for the stimulation of the TORC1 activity by TR3."

reach
"mTORC1 signaling in neuronal translation has been established as a regulator of long lasting synaptic plasticity and memory as it integrates signals from many neuronal surface receptors and channels via ERK- and PI3K and Akt mediated phosphorylation of the TSC1 and TSC2 complex."

reach
"In addition, Akt is vital in maintaining the activity of mTOR through the control of the TSC1 and TSC2 complex (Maiese et al., 2013c)."

reach
"The TSC1 and TSC2 complex converts active GTP bound Ras-homolog-enhanced-in-the-brain (Rheb) into its inactive GDP bound form [XREF_BIBR], [XREF_BIBR] (XREF_FIG)."

reach
"In C2C12 myotubes, however, we found no effect of IGF-1 stimulation on the functional interaction between TSC1 and TSC2, even though the phosphorylation level of TSC2 was altered."

"TSC2 is a GTPase-activating protein (GAP) toward Rheb, a Ras family GTPase"

reach
"Other pathways, such as extracellular signal regulated kinases (ERKs), protein p90 ribosomal S6 kinase 1 (RSK1), and glycogen synthase kinase -3 beta (GSK-3beta) also can modulate the activity TSC1 and TSC2 complex."

reach
"TSC2 contains a GTPase activating protein (GAP) domain, and the TSC1 and TSC2 complex has been shown to have GAP activity for a GTPase called ras homolog expressed in brain (RHEB)."

reach
"To better understand the molecular function of the TSC1 and TSC2 complex, we sought to identify proteins that interact with the complex at high stoichiometry."

sparser
"Interaction of hamartin with tuberin forms a heterodimer that inhibits signaling by the mammalian target of rapamycin to its downstream targets: eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1)."

reach
"The ICW is a rapid, reproducible assay, which can be applied to the characterisation of the effects of novel TSC2 variants on the activity of the TSC1 and TSC2 complex."

sparser
"Cytoplasmic Foxo1 promotes activation of mTORC1 in iNKT1 and iNKT2 cells through inhibiting TSC1-TSC2 interaction, whereas it is dispensable for mTORC1 activation in iNKT17 cells."

reach
"This multifunctional kinase is an upstream effector of the TSC1 and TSC2 complex that regulates mTOR signaling."

sparser
"Sirolimus is a typical mammalian target of rapamycin (mTOR) inhibitor, and tuberous sclerosis 1-tuberous sclerosis 2 complex (TSC1/TSC2) is an important negative effector in the mTOR pathway."

sparser
"Hamartin and tuberin bind together to form a complex, which inhibits mTOR."

reach
"In keeping with recent reports that the hamartin and tuberin complex may regulate Rheb and downstream S6K activation, we demonstrate that expression of either Rheb or S6K in primary astrocytes results in increased S6 pathway activation, and that inhibition of Rheb activity in Tsc1 deficient astrocytes using either pharmacologic or genetic strategies markedly reduces S6 activation."

reach
"Recent studies have established the TSC1 and TSC2 complex as a key regulator of cell size control, and rapid progress has been made in delineating the downstream biochemical pathways by which TSC regulates cell size as well as their roles in the regulation of other cellular functions."

reach
"Since p53 interacts with mTOR signaling at multiple levels via the Tsc1 and Tsc2 complex [XREF_BIBR, XREF_BIBR], we aimed to analyze whether hyperactivated mTOR signaling with a loss of p53 may specify ACC."

reach
"The PI3K-Akt signaling pathway is primarily responsible for this regulation, and the protein kinase Akt directly phosphorylates and inhibits TSC2, within the TSC1 and TSC2 complex [XREF_BIBR, XREF_BIBR]."

reach
"These, in a sense controversial data, reflect either the limitations of in vivo and in vitro experimental approaches, or reflect a differential interaction between hamartin and tuberin and the presenc[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"AKT also inactivates the complex formed by TSC1 and TSC2, tumor-suppressor proteins known to be mutated in tuberous sclerosis."

reach
"Interestingly, we have recently found a potentially novel function for FIP200 in the regulation of cell growth through its interaction with TSC1 and inhibition of TSC1 and TSC2 complex function."

reach
"Moreover, ablation of OPN by deficient TSC1 and TSC2 complex contributed to inactivation of AKT in TSC cells."

sparser
"Through control of mTORC activity, TSC1TSC2 promotes CD8 + T cell survival and controls the quiescent and memory states xref – xref ."

reach
"92 In accordance with a negative regulatory role for the TSC1 and TSC2 complex, robust mTORC1 activation was documented in all lymphocyte subsets of this patient."

reach
"ERK dependent TSC2 phosphorylation leads to dissociation of the TSC1 and TSC2 complex, which results in mTOR and S6K1 activation, increased cell proliferation and transformation."

reach
"TSC1 stabilises TSC2 and prevents TSC2 ubiquitination and proteosomal degradation XREF_BIBR, helps maintain the TSC1 and TSC2 complex in the correct intracellular localisation XREF_BIBR, XREF_BIBR and regulates TSC1-TSC2 activity through diverse signalling pathways XREF_BIBR."

sparser
"However, due to the limitations of this method, it does not allow us to conclude in which part of the GA, (i.e., cis-, medial-, or trans-) mTOR and TSC1-TSC2 complex exert their effects on cargo transport."

reach
"Furthermore, under oxidative stress mTORC1 activation is mediated via downregulation of the TSC1 and TSC2 complex 55."

reach
"AKT phosphorylates TSC2 on multiple sites, leading to the disruption of the TSC1 and TSC2 complex and promoting mTORC1 activation, thus inhibiting autophagosome formation."

reach
"Hamartin and tuberin complex maintains mTOR in a deactivated state through tuberin 's ability to stimulate GTP hydrolysis by Ras homologue expressed in brain (Rheb) [XREF_BIBR - XREF_BIBR]."

reach
"The TSC1 and TSC2 complex promotes mTORC2 activity."

sparser
"The gene products of TSC1 and TSC2 form a functional complex and inhibit the phosphorylation of S6K and 4EBP1, two key regulators of translation."

reach
"When the TSC1 and TSC2 complex is not functional, dis-regulated mTOR activity triggers cell cycle progression and tumor formation.AL is a group of genetically heterogeneous diseases with accumulation [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"According to a model based on these data, in the absence of growth factors the TSC1 and TSC2 complex is hypophosphorylated and inhibits mTOR."

sparser
"While elongation of the tuberin open reading frame by 17 amino acids did not interfere with tuberin-hamartin binding, a longer extension prevented this interaction."

reach
"Thus, as long as TSC1 and TSC2 complex is inhibited by AKT, RAP1 GTPase stimulates mTOR, mLST8, and raptor complex and cell growth [XREF_BIBR]."

reach
"The TSC1 and TSC2 complex serves as a critical node to coordinate multiple upstream signaling inputs including growth factor, energy and oxygen levels with mTORC1 activation [161]."

sparser
"Similar to studies with mammalian TSC proteins, we find that Tsc1 and Tsc2 bind in vitro."

reach
"For example, in response to energy stress, AMPK activates autophagy, a catabolic process that recycles intracellular nutrients to maintain cell survival under nutrient-deprived conditions, through phosphorylating autophagy regulators such as ULK1 (Egan et al., 2011; Kim et al., 2011), while inhibits mechanistic target of rapamycin complex 1 (mTORC1)-mediated protein synthesis by phosphorylating Raptor (an mTORC1 component) and the TSC1TSC2 complex (an upstream negative regulator of mTORC1) (Gwinn et al., 2008; Inoki et al., 2003)."

reach
"In contrast, amino acids stimulate mTORC1 signaling independent of TSC1 and TSC2 complex."

sparser
"Because the TSC signaling network is conserved between Drosophila and mammals and robust methods for Drosophila cell-based screens have been established ( xref ), we decided to perform combinatorial screens in Drosophila cells to identify synthetic interactions with TSC1 and TSC2 (also known as Gigas) and evaluate whether the identified candidates had conserved synthetic effects in mammals."

reach
"Likewise, we find increased binding of TSC2, TSC1 and TBC1D7 to the Rag GTPases in response to various stresses (XREF_SUPPLEMENTARY), in agreement with relocalization of the entire TSC complex to lysosomes."

sparser
"Of particular relevance to TSC are genes that negatively interact with both TSC1 and TSC2 ."

reach
"The TSC1 and TSC2 complex can physically associate with mTORC2 to enhance the activity of mTORC2 using a mechanism that is independent of its GAP activity toward Rheb but which involves the N-terminal region of TSC2 and the C-terminal region of Rictor."

sparser
"Growth factors activate the PI3K-Akt pathway, which deactivates the heterodimer complex of TSC1 and TSC2, resulting in activation of mTORC1 through Ras-related small GTPase (Rheb)."

sparser
"TSC1 and TSC2 form a protein complex, referred to as the TSC complex, that is a critical negative regulator of mTORC1 ( xref )."

sparser
"Tsc2 forms a complex with hamartin (Tsc1), and disruption of Tsc2 in β-cells increases β-cell proliferation and mass in an mTORC1-dependent manner ( xref )."

reach
"Therefore, growth promoting conditions activate pathways that decrease TSC1 and TSC2 complex function, while poor growth conditions activate pathways that increase TSC1 and TSC2 complex function, thereby leading to the respective activation or inhibition of mTORC1."

sparser
"Disruption of the hamartin-tuberin complex, through the loss (inactivating mutations) of either the TSC1 or TSC2 gene, results in a constitutive activation of mTORC1."
| PMC

reach
"The TSC1 and TSC2 complex has inhibitory effect on GTPase Rheb, which activates mTORC1."

sparser
"Hamartin and tuberin form a heterodimer that inhibits the mammalian target of rapamycin complex 1 (mTORC1) kinase, a major cellular regulator of protein translation, cell growth and proliferation."

reach
"R2TP and PFDL is a major interactor of the TSC1 and TSC2 complex."

reach
"We next investigated the relationship between VPS34 and TSC1 and TSC2 heterodimer."

reach
"This TSC1 and TSC2 complex regulates activity of p70S6 kinase by inhibiting mTOR by way of the PI3K/Akt/mTOR pathway [XREF_BIBR]."

reach
"The mammalian target of rapamycin (mTOR), a serine threonine kinase belonging to the phosphatidylinositol kinase related kinase family, is a principal downstream target of TSC1 and TSC2 complex XREF_BIBR."

reach
"Phosphorylation of TSC2 at serine , serine , and threonine results in the binding of TSC2 to cytoplasmic protein 14-3-3, disengagement of the TSC1/TSC2 complex, and activation of Rheb and mTORC1 (54)."

reach
"Hamartin and tuberin, the products of the TSC1 and TSC2 genes, respectively, form a complex and inhibit signaling by the mammalian target of rapamycin."

sparser
"In this latter study, mTORC1 activity was increased by deleting TSC1, which forms a complex with TSC2 and negatively regulates the activity of the canonical mTORC1 activator, Rheb."

reach
"Down regulation of mTORC1 can occur under hypoxic and lower energy and ATP conditions through phosphorylation of the Tsc1 and Tsc2 complex, on residues distinct from those phosphorylated by Akt, by REDD1 (regulated in development and DNA damage response 1) and AMPK (AMP activated protein kinase), respectively [XREF_BIBR, XREF_BIBR]."

sparser
"Furthermore, the already mentioned TSC1 and TSC2 protein complexes are the signaling regulators for the expression of mTOR."

reach
"Either TSC1 or TSC2 gene mutation can lead to the structural or functional abnormalities of the hamartin and tuberin complex, causing the overactivation of mTOR signaling pathway and resulting in the [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Tuberin and hamartin form a heterodimer, suggesting they might affect the same processes."

reach
"It is also essential to determine the extent to which the TSC1 and TSC2 complex is required for mTORC2 signaling to substrates other than Akt-Ser473."

reach
"Tuberin and hamartin proteins bind tightly to form a heterodimer with tumor suppressor properties including regulation of cell growth by inhibiting mTOR via the Rheb (Ras homologue enriched in brain) protein [XREF_BIBR - XREF_BIBR]."

reach
"These findings implied that the function of the hamartin and tuberin complex was compromised."

reach
"Proteins encoded by TSC1 or TSC2 genes interact with each other to form the TSC1 and TSC2 complex."

sparser
"To investigate whether the TSC1 truncation proteins interacted directly with TSC2, we coexpressed TSC2 with the different TSC1 truncations and immunoprecipitated the truncation proteins from the Trito[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Loss of a functional TSC1 and TSC2 complex can lead to the loss of mTORC2 kinase activity in vitro [XREF_BIBR]."

reach
"For example, the TSC1 and TSC2 complex is the main regulator of mTORC1, and inactivation of TSC1 and TSC2 promotes mTORC1 activation [XREF_BIBR]."

reach
"The TSC1 and TSC2 complex, a negative regulator of mTORC1, is required for activation of mTORC2."

"TSC2 is also phosphorylated by Akt leading to its inactivation and consequently to increased mTOR activity."

sparser
"Hamartin (amino acids 302-430) and tuberin (amino acids 1-418) interacted strongly with one another."

reach
"These results indicate that the TSC1 and TSC2 complex modulates NF-kappaB activation under a variety of different conditions by regulating IKKalpha and beta activation."

reach
"Regulation of beta-catenin by hamartin and tuberin complex was also reported."

reach
"In addition, the Tsc1/Tsc2 complex inhibits mTORC1 activity, preventing C/EBPβ translocation ."

reach
"In general, signals impinging on mTORC1 regulation generally alter the GDP/GTP bound status of Rheb by regulating the TSC1 and TSC2 complex, which has GTPase activating protein (GAP) activity towards Rheb."

reach
"Tuberin is thus not functional and does not form heterodimers with hamartin, and TORC1/2 is constantly activated."

reach
"In cells, hamartin and tuberin form a complex which inhibits the mammalian target of rapamycin (mTOR), a central controller of cell growth and proliferation."

reach
"The TSC1 and TSC2 complex consolidates these diverse inputs and functions as an inhibitor of the mechanistic target of rapamycin (mTOR), an evolutionarily conserved serine threonine kinase [XREF_BIBR]."

reach
"Nevertheless, these results suggest that FIP200 functions in the nutrient input to the TSC1 and TSC2 complex rather than being a general component of the TSC1-TSC2 signaling pathway."

reach
"Phosphorylation of tuberin at this site affects its function through at least two mechanisms : first, phosphorylation decreases the activity of tuberin; second, phosphorylation destabilizes tuberin by disrupting the complex formation between hamartin and tuberin resulting in ubiquitination of free tuberin and its degradation by the proteosome [XREF_BIBR]."

sparser
"At high nutrition levels, the elevated insulin and growth factor levels promote the phosphorylation of Akt, which inhibits TSC1-TSC2 and activates mTORC1."

reach
"Since TSC1 and TSC2 complex is an upstream negative regulator of mTORC1, loss of Tsc1 or Tsc2 will result in hyperactivation of mTORC1."

reach
"To further delineate the feedback inhibition pathway mediated by the Tsc1 and Tsc2 complex, we analyzed the requirement of TORC1 in the downregulation of dAkt phosphorylation."

reach
"Several proteins have been shown to interact with TSC2 and thus regulate the TSC1 and TSC2 complex function."

reach
"We also demonstrate that the TSC1 and TSC2 complex can directly stimulate the in vitro kinase activity of mTORC2."

reach
"Hamartin and Tuberin complex is involved in the phosphoinositide 3-kinase-protein kinaseB-mammalian target of rapamycin signal transduction pathway, and suppresses mammalian target of rapamycin complex1 activity, which is a center for various functions."

reach
"Once activated, the TSC1 and TSC2 complex inhibits mTOR resulting in a decrease in protein synthesis."

reach
"Disruption of TSC1 and TSC2 complex suppression on mammalian and mechanistic target of rapamycin (mTOR) signalling causes TSC."

reach
"Activation of mTORC1 is opposed by the Tsc1 and Tsc2 complex and in turn attenuates Akt signalling through a negative feedback loop."

reach
"However, the function of the TSC1 and TSC2 complex remained unclear until genetic studies in Drosophila ascribed a role for the complex in cell size control and placed it in a pathway that converges the insulin signaling from Akt to mTOR and S6K [XREF_BIBR - XREF_BIBR]."

reach
"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."

reach
"Although several regulatory phosphorylation sites are known to exist for TSC1, phosphorylation of TSC2 by Akt, extracellular signal regulated kinases (ERKs), activating protein p90 ribosomal S6 kinase 1 (RSK1), AMP activated protein kinase (AMPK), or glycogen synthase kinase -3 beta (GSK-3beta) appear to be more significant for controlling the TSC1 and TSC2 complex."

reach
"In addition, like the mammalian system, the Tsc1 and Tsc2 complex and Rhb1 are also involved in the TORC1 signaling that plays a critical role in the switch between cell proliferation and differentiation in response to nutrient availability and controls the phosphorylation and activity of Psk1, an ortholog of p70 S6 kinase, which, in turn, regulates the phosphorylation of ribosomal protein S6."

sparser
"However, by Western blot analysis there was no significant age- or alcohol-induced change in either the total amount of TSC1 and TSC2, or the association of TSC1 with TSC2 (data not shown)."

sparser
"We show that TSC1 and TSC2 form a complex and function in a common pathway to control cellular growth."

reach
"Consequently, active AKT phosphorylates a wide range of downstream targets involved in cell metabolism, such as forkhead box protein O1 (Foxo1), glycogen synthase kinase 3 (GSK3), and tuberous sclerosis 2 (TSC2) within TSC1 and TSC2 complex XREF_BIBR, XREF_BIBR."

sparser
"TSC2 forms a heterodimeric complex with TSC1, and phosphorylation of TSC2 at these sites inhibits the GAP (GTPase-activating protein) activity of this complex."

reach
"In tumor like cells, ERK phosphorylates TSC2 leading to the dissociation of TSC1 and TSC2 complex with subsequent up-regulation of mTORC1 XREF_BIBR."

reach
"Analogical to the TSC1 and TSC2 complex, PTEN is another negative regulator of the mTOR pathway."
| PMC

reach
"In this report, we show that one of the key mechanisms of cell survival mediated by the TSC1 and TSC2 complex involves the activation of NF-kappaB."

reach
"The tuberin and hamartin complex negatively regulates beta-catenin signaling activity."

reach
"TSC1 has limited homology with other proteins [2] and the exact role of TSC1 in the TSC1 and TSC2 complex is not completely clear."

sparser
"The functional complex of hamartin and tuberin acts as a GTPase that activates Ras homolog enriched in brain (Rheb) protein."

reach
"Yet, the presence of TSC1 is necessary for optimal TSC2 activity because formation of a TSC1 and TSC2 heterodimeric complex stabilizes TSC2."

reach
"The tumor-suppressor proteins TSC1 (hamartin) and TSC2 (tuberin) form a heterodimer to inhibit cell growth and proliferation."

sparser
"We also observed that overexpression of FIP200 alone increased S6K phosphorylation, possibly through its interaction with the endogenous TSC1TSC2 complex ( xref A, compare lanes 1 and 2)."

reach
"The product of the gene is the third subunit of the TSC1 and TSC2 complex with a Rheb-GAP activity, and is ubiquitously present in the complex."

reach
"Multiple upstream pathways activate or inhibit the mTOR pathway either directly or by interacting with the hamartin and tuberin complex."

sparser
"These disorders are associated with mutations of TSC1 or TSC2 that lead to overactivation of mTOR complex 1 (mTORC1), suggesting an opportunity for targeted therapy by using mTORC1 inhibitors."

reach
"This enzyme phosphorylates AMP kinase, which in turn activates the TSC2 and TSC1 complex."

sparser
"The TSC1TSC2 complex has inhibitory effects on the function of Rheb."

reach
"Thus, it is not surprising to learn that regulation of mTOR activation through Rheb could have more than one proteins involved : TSC1 and TSC2 complex and RGS10."

reach
"Indeed, label-free quantitative mass spectrometry based analyses to estimate the relative stoichiometry of TSC1 and TSC2 that co-immunoprecipitated with endogenous TBC1D7 yielded a near 1:1 ratio of TSC1 and TSC2 (XREF_FIG), providing further evidence that TBC1D7 primarily binds to the TSC1 and TSC2 complex."

reach
"The TSC1 and TSC2 heterodimer, in turn, blocks mTORC1 by inactivating the GTP binding protein Ras homolog enriched in brain (Rheb), which directly phosphorylates mTORC1 [XREF_BIBR, XREF_BIBR] (XREF_FIG)."

sparser
"The N-terminal region of tuberin contributed to the interaction of hamartin and tuberin ( xref )."

sparser
"Indeed, Oded Meyuhas (Hebrew University-Hadassah Medical School, Jerusalem, Israel) discussed the hypothesis that the unrestrained cell proliferation associated with a deficiency in TSC1 or TSC2 in cultured mammalian cells may result from the derepression of TOP mRNA translation."

sparser
"mTOR-dependent signalling in normal cells appears to be restrained by its association with the tumour-suppressor proteins TSC1 (hamartin) and TSC2 (tuberin)."

reach
"The function of TBC1D7 is not yet fully understood but, as a core subunit of the TSC complex, its loss leads to a decreased association between TSC1 and TSC2 resulting in decreased total cellular Rheb-GAP activity [XREF_BIBR]."

sparser
"Until now, over 50 proteins have been demonstrated to interact with hamartin and/or tuberin."

reach
"Growth factors, such as insulin and insulin like growth factor 1 (IGF1), that stimulate the PI3K and Ras pathways, directly phosphorylate the TSC1 and TSC2 complex to inactivate it and thus activate m[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

No evidence text available

reach
"Contrary to their findings in younger mice, Shigeyama et al. report that older mice lacking the TSC1 and TSC2 complex in beta-cells (> 40 weeks) have decreased beta-cell number and progressive hypoinsulinemia and hyperglycemia [XREF_BIBR], similar to what is observed in the progression of type 2 diabetes [XREF_BIBR]."

reach
"The latter being an important positive regulator of mTOR via pathways involving the TSC1 and TSC2 complex."

sparser
"Despite these uncertainties surrounding the pathway’s details, mTOR signaling during ischemia/hypoxia is known to depend on hamartin-tuberin complex formation ( xref ; xref )."

reach
"Differential accumulation of hamartin and tuberin in separate cellular compartments of giant cells may prevent formation of the hamartin and tuberin complex, resulting in increased S6 phosphorylation."

sparser
"One mechanism whereby AMPK decreases protein synthesis is via the TSC complex, as increased TSC2 phosphorylation as well as enhanced formation of the TSC1 00B7 TSC2 heterodimer can negatively regulate mTOR activity ( xref )."

sparser
"TSC1 and TSC2 form a complex that integrate different signalling cues to control mTOR activity. xref , xref TSC2 contains a GTPase Activating Protein domain that stimulates the GTPase of Rheb (which in its GTP-bound form is an activator of mTOR Complex I)."

reach
"Hamartin and tuberin form a heterodimer, which converts Rheb-GTP to the inactive Rheb-GDP."

No evidence text available

reach
"Downstream of phosphoinositide-3 kinase (PI3K), mTORC1 is activated by Akt, at least in part, through inhibitory phosphorylation of the TSC1 and TSC2 complex."

reach
"As is known, Akt phosphorylates and thereby inhibits the heterodimer TSC1/TSC2, which in turn inhibits activation of the small GTPase Rheb, thus promoting mTORC1 activation [41]."

reach
"Intriguingly, it has also been reported that FIP200, by inhibiting the TSC1 and TSC2 complex, can release their negative function on mTOR, thus blocking autophagy [XREF_BIBR]."

reach
"Akt activates mTORC1 by directly phosphorylating the TSC1 and TSC2 complex thereby inhibiting its GAP activity and releasing GTP bound Rheb to activate mTORC1 XREF_BIBR - XREF_BIBR."

sparser
"Although TR3 interacts with the N-terminal region of TSC2 (1-418), which is the same domain to which TSC1 binds, the binding of TR3 did not perturb the interaction between TSC1 and TSC2 (unpublished observations)."

reach
"Here we demonstrate that the Tsc1 and Tsc2 complex is required for ephrin-A-induced growth cone collapse and elucidate a mechanism by which ephrins regulate the Tsc-mTOR pathway in axons."

reach
"Akt regulates cell growth (XREF_FIG) through its effects on the TSC1 and TSC2 complex and mTORC signaling and acts as a major mediator of cell survival through the direct inhibition of pro apoptotic proteins, such as Bad or through the inhibition of pro apoptotic signals generated by transcription factors, such as Forkhead box protein O1 (FoxO)."

reach
"Growth factors and hormones, such as insulin, regulate mTORC1 signalling by the activation of class I PI3K and its downstream effector AKT, which reverses the inhibitory effect of TSC1 and TSC2 complex and PRAS40 on mTORC1 signalling [XREF_BIBR]."

reach
"TSC2 forms a heterodimeric complex with TSC1, and phosphorylation of TSC2 at these sites inhibits the GAP (GTPase activating protein) activity of this complex."

trips
"As overexpression of tuberin inhibits cell growth, and hamartin is known to bind tuberin, these results suggested that hamartin stabilizes tuberin and this contributes to the inhibition of cell growth."

reach
"AMPK, a cellular energy sensor and signal transducer, is a key player to switch off mTOR pathway through phosphorylating and thereby activating tuberous sclerosis protein (TSC) 2, leading to association of TSC1 and TSC2 complex and inhibition of mTOR pathway."

reach
"Similar dysfunctions were identified in TSC brain lesions in vivo, identifying a new role for the TSC1 and TSC2 complex in the neuronal stress response."

reach
"This study suggests that an increase in the steady state level of resident TSC1 and TSC2 complex is sufficient to reduce muscle mass and cause atrophy."

No evidence text available

sparser
"Hamartin and tuberin form a complex that exhibits guanosine triphosphatase (GTPase)-activating protein (GAP) activity toward Rheb, a Ras-like small G-protein xref xref xref ."

reach
"Moreover, binding of TSC1 to TSC2 appears to stabilize intracellular TSC2 levels since uncomplexed TSC2 is subject to ubiquitin mediated degradation."

sparser
"Hamartin and tuberin form a protein complex that helps regulate cellular hyperplasia."

sparser
"Akt accomplishes this by downregulating the tuberous sclerosis complex (TSC) protein, TSC2 that forms a complex with TSC1: a complex that otherwise inhibits Rheb a normal activator of mTOR."

reach
"Given the down-regulation of these proteins in cells lacking the TSC1 and TSC2 complex XREF_BIBR, XREF_BIBR, XREF_BIBR, we hypothesized that constitutive mTORC1 activation would allow these cells to differentiate independent of insulin signaling."

reach
"Another possibility is that the interaction between mTOR and S6K1, and tuberin and hamartin is quite complex and involves other signalling molecules, such as raptor [92,93] or PP2A [95-98], which may [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Although there is clear evidence that loss of a single allele of Tsc1or Tsc2 can affect global brain function XREF_BIBR, XREF_BIBR, both tuber giant cells and SEGA cells show evidence of complete loss of the TSC1 and TSC2 complex with constitutive activation of mTORC1, augmented protein translation XREF_BIBR, reduced autophagy XREF_BIBR, XREF_BIBR, and endoplasmic reticulum (ER) and oxidative stress XREF_BIBR."

sparser
"TSC1 and TSC2, which form the tuberous sclerosis complex (TSC), have been studied mainly in mammalian cells where TSC regulates TORC1 activity via the small G protein Rheb (Ras homolog enriched in brain) in response to various cues including specific nutrients and growth factors [ xref ]."

sparser
"Hamartin and tuberin form a complex that is thought to negatively regulate the cell cycle."

reach
"We found that TSC1 p.Arg22Trp and p.Arg204Cys profoundly inhibited TSC1 binding to TSC2."

"Inferred from SIGNOR complex SIGNOR-C101"

reach
"The effector kinases of these pathways are : protein kinase B (Akt and PKB), extracellular-signal-regulated kinase 1/2 (ERK1/2), and ribosomal protein S6 kinase (RPS6) which directly phosphorylate the[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"We have shown that loss of TSC1 and TSC2 complex reduced the expression of PDGFRalpha and PDGFRbeta [XREF_BIBR], and restoration of PDGFRbeta enhanced tumorigenic potential of TSC1 and TSC2 complex deficient cells [XREF_BIBR]."

sparser
"Adenosine monophosphate-activated protein kinase (AMPK) as upstream regulators of the mammalian target of rapamycin (mTOR) pathway senses nutrient and energy depletion and activates the tuberous sclerosis complex (TSC1TSC2), leading to mTOR inactivation and initiation of autophagy [ xref ]."

reach
"XREF_BIBR - XREF_BIBR TSC1 and TSC2 proteins form a heterodimeric complex that negatively regulates mTORC1."

reach
"These tumors represent a novel subset of sporadic RCC characterized by alterations in TSC1 and TSC2 complex or the mTOR complex 1 pathway."

reach
"The phosphorylation represses the function of the TSC1 and TSC2 complex, resulting in mTORC1 activation."

reach
"The Tsc1 and Tsc2 complex influences neuronal polarity by modulating TORC1 activity and SAD levels."

reach
"Together, these results suggest a cellular function of FIP200 in the regulation of cell size by interaction with the TSC1 and TSC2 complex."

sparser
"The TSC1 and TSC2 gene products form a protein complex that integrates multiple metabolic signals to regulate the activity of the target of rapamycin (TOR) complex 1 (TORC1) and thereby control cell growth."

sparser
"TSC1 and TSC2 form a complex that inhibits mammalian target of rapamycin complex 1 (mTORC1), a key regulatory hub in cell signaling."

reach
"Activation of AKT leads to disruption of the hamartin/tuberin complex (TSC1/TSC2) and may contribute to hyperactivation of mTOR [24]."

reach
"Formation of TSC1 and TSC2 complex is mandatory for p53 dependent mTORC1 inhibition."

reach
"Phosphorylation of TSC2 by AKT inhibits inactivation of rheb through the rheb-GTPase function of the TSC1 and TSC2 complex."

reach
"It would thus be interesting to determine the functional relationship between these proteins and the TSC1 and TSC2 complex.We have shown that Tsc1 is a potent regulator of cell growth, cell proliferat[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Five of 6 SEGAs also showed evidence of biallelic mutation of TSC1 or TSC2, suggesting that SEGAs develop due to complete loss of a functional tuberin and hamartin complex."

reach
"Under conditions of energy depletion, the highly conserved energy sensing protein kinase AMPK (5 ' AMP activated protein kinase) is activated and phosphorylates TSC2, which by still unclear mechanisms, enhances the ability of the TSC1 and TSC2 complex to turn off the mTOR pathway."

reach
"For instance, in the absence of growth factors, GSK-3, a regulator of beta -catenin, may negatively regulate the mTOR pathway by stimulating the TSC1 and TSC2 complex; however, under certain condition[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

"The tuberous sclerosis complex (TSC1/2), consisting of a heterodimer of TSC1 and TSC2, is an upstream negative regulator of mTORC1. TSC1/2 is the GTPase-activating protein for the Ras-family GTP-binding protein Rheb, which directly binds and activates mTORC1 (Guertin and Sabatini, 2009)."

sparser
"Differential phosphorylation sites on the hamartin protein may serve as the basis for a “molecular switch” that regulates the formation of its functional complex with tuberin. xref demonstrated that endogenous hamartin was threonine-phosphorylated at three sites (Thr 417, Ser 584, and Thr1047) in a reaction catalyzed by cyclin-dependent kinase 1 (CDK1), one of which (Thr417) is located in the hamartin-tuberin interaction domain ( xref ); the authors proceed to conclude that hamartin phosphorylation controls the activity of the complex during the cell cycle at the G2/M phase."

reach
"As described above, hamartin and tuberin form a complex containing a GTPase activate protein (GAP) domain that inactivates the small GTPase Rheb, thereby turning off mTOR activity [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR]."

sparser
"The tuberous sclerosis tumor suppressors TSC1 and TSC2 form a protein complex that integrates and transmits cellular growth factor and stress signals to negatively regulate TOR activity."

reach
"Previous studies have demonstrated that the TSC1/TSC2 complex, the pivotal negative modulator of mTOR, was tightly involved in autophagy regulation [36]."

reach
"The widely studied functions of both TSC1 and TSC2 are attributed to the TSC1 and TSC2 complex that regulates mTOR activity via RHEB."

reach
"In line with this, mTOR activation through conditional inactivation of Tsc1 (which encodes for a component of the TSC1/TSC2 complex that negatively regulates PI3K-mTOR signaling, as discussed above) in the HSCs of young mice mimics the phenotype of HSCs from aged mice; that is, there is a relative reduction in generation of lymphocytes and impaired capacity for hematopoiesis reconstitution in the context of transplantation (Chen et al., 2009)."

sparser
"In our immunoprecipitation assay, the full-length and CC of TSC1 shows comparable binding to TSC2 (Supplementary Fig.  xref ), consistent with the maintenance of TSC1TSC2 upon deletion of TSC1 several N-terminal fragments xref ."

reach
"Collectively, these data demonstrate that the TSC1 and TSC2 complex promotes mTORC2 activity in a manner that is independent of Rheb, mTORC1, and mTORC1 mediated feedback effects on PI3K."

sparser
"These data suggest that the interaction of TSC1 with TSC2 may be important for TSC1-dependent Rho activation and cell adhesion."

sparser
"The hamartin-tuberin complex regulates cell growth and proliferation by inhibiting the mammalian-target-of-rapamycin (mTOR)."

reach
"As a protein kinase, mTOR is released from the TSC1 and TSC2 complex, which acts as a negative regulator of mTOR, by upstream PI3K and Akt signaling."

reach
"One of the key downstream targets of AKT is the tuberin and hamartin complex (TSC1 and TSC2), mutations of which are associated with the hamartomatous syndrome tuberous sclerosis (TS) 82."

reach
"The TSC1 and TSC2 complex seems to be a GAP for Rap1 in the stimulation of mTORC1, although the Rheb protein is the best described and best known studied target of the tuberin and hamartin complex [XREF_BIBR]."

reach
"Some studies have suggested that binding with 14-3-3 prevents TSC2 from associating with TSC1 and thus reduces the function of the TSC1 and TSC2 complex toward Rheb [XREF_BIBR, XREF_BIBR], while others show that 14-3-3 may directly inhibit TSC2 function without disrupting the TSC1 and TSC2 complex [XREF_BIBR, XREF_BIBR]."

sparser
"Most TSC patients present with mutations in the TSC1 or TSC2 genes, which encode proteins that form the TSC1-TSC2 complex that serves to antagonize the signaling pathway downstream of mammalian target of rapamycin (mTOR) by promoting the activation of the small GTPase Rheb and thereby inhibiting cellular growth and proliferation."

reach
"XREF_BIBR Subsequently, the role of TSC1 and TSC2 complex in relation to inhibition mechanism of mTOR was demonstrated."

reach
"However, the precise mechanism by which Akt phosphorylation affects the function of TSC1 and TSC2 heterodimer is not clear [XREF_BIBR]."

reach
"TSC1 and TSC2 form a dimer and function as a GTPase activating protein (GAP) to inactivate the small GTPase " Ras homolog enriched in brain " (Rheb), which directly binds to mTORC1 and activates kinas[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"Hamartin and tuberin form a complex providing a tentative explanation for the similar disease phenotype in TSC patients with mutations in either of these genes."

reach
"The TSC1 and TSC2 heterodimer is a major upstream inhibitor of mTORC1, which can be phosphorylated and inhibited by AKT to activate mTORC1."

reach
"TSC1 and TSC2 dimerization is a critical checkpoint for downstream Rheb activation required for mTOR pathway signaling."

sparser
"Together, these results suggested a novel function for FIP200 in the regulation of cell size, possibly through its interaction with the TSC1TSC2 complex."

reach
"The ability of 14-3-3 proteins to bind and regulate various oncogenic gene products as well as various tumor suppressor gene products points to a potential role in cancer As such 14-3-3 has been shown to inhibit TSC1 and TSC2 complex functions and overexpression of either TSC1 or TSC2 in Hela cells has been reported to increase the expression of various 14-3-3 isoforms [XREF_BIBR] suggesting that deregulated expression of 14-3-3 and TSC can be associated with leiomyoma pathogenesis."

reach
"In addition, the loss of TSC1 and TSC2 complex impedes mTORC2 phosphorylation of Akt (Ser473) [XREF_BIBR]."

reach
"However, only CD44-CP1, in addition to enhancing membrane retention of TSC2, significantly enhanced the interaction between TSC2 and TSC1, as determined by immunoprecipitation assays where TSC1 was co-immunoprecipitated with TSC2 (XREF_FIG, lanes 4 and 5) (n = 3)."

reach
"mTOR is activated by the GTPase Rheb which in turn is controlled by the TSC1 and TSC2 complex."

reach
"Because of its central role in regulating mTORC1, 34 species depicting extensive details about the TSC1 and TSC2 complex (post-translation modifications, interactors, cellular locations) were represented in the comprehensive mTOR map."

reach
"mTORC2 activation requires PI3K and the TSC1 and TSC2 complex, but is independent of Rheb and is largely insensitive to either nutrients or energy conditions [XREF_BIBR]."

reach
"In addition, Akt promotes the mammalian target of rapamycin (mTOR) activity by relieving inhibition of RhebGTP by the TSC1 and TSC2 complex [XREF_BIBR]."

reach
"In fact, although the hamartin and tuberin complex is a potent inhibitor of the mTORC1 complex, it can regulate the activation state of mTORC2 on at least two different levels : (i) it directly binds to and stimulates the activity of mTORC2 [XREF_BIBR]; and (ii) it can act on mTORC2 activity indirectly, via the S6K mediated feedback loop [XREF_BIBR]."

reach
"The Akt dependent phosphorylation of tuberin has a differential effect on the stability of the hamartin and tuberin complex in mammalian and Drosophila cells."

reach
"Examination of the major upstream pathways converging on the TSC1 and TSC2 complex showed that Akt signaling was unaffected by pH but that the Raf/MEK/ERK pathway was inhibited."

reach
"Upregulation of TNFalpha or downregulation of AMPK signaling can also activate mTOR through inhibition of the tuberin and hamartin complex."

reach
"This is supported by the observation that the tuberin-hamartin complex is essential in the regulation of the insulin receptor signal transduction."

reach
"Over the past decade, their gene products, TSC1 and TSC2 heterodimer, have emerged as a critical integrator of growth factor, nutrient and stress signals to control protein synthesis, cell growth and other cellular processes [XREF_BIBR]."

reach
"Furthermore, the kinase RSK, a direct downstream substrate of ERK, can also phosphorylate TSC2 on serine 1798 to inhibit the function of TSC1 and TSC2 complex [XREF_BIBR]."

reach
"These findings correlate well with recently published Drosophila genetic epistasis analyses of dPI3K, dPKB, dTSC1, and dTSC2, which place the tuberin and hamartin complex either downstream of PI3K and[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Both hamartin and tuberin contain predicted coiled-coil domains that bring them together to form the tuberin and hamartin complex (THC)."

reach
"Loss of TSC2 GAP activity or disruption of the TSC1 and TSC2 complex dysregulates S6K1 activation, which leads to abnormal cell proliferation associated with LAM disease."

reach
"Hamartin and tuberin form a heterodimer that inhibits the mammalian target of rapamycin complex 1 (mTORC1) kinase, a major cellular regulator of protein translation, cell growth and proliferation."

reach
"These results raised the possibility that FIP200 may reduce the formation of the TSC1 and TSC2 complex to negatively regulate its function."

reach
"Rheb is a small GTPase molecule that stimulates the mTOR/S6 kinase (S6K)/factor 4E binding protein (4E-BP)-1 signaling cascade, which is critical for cell size and proliferation control and is negatively regulated by the tuberin-hamartin complex."

reach
"We propose that the Tsc1 and Tsc2 complex antagonizes the TOR mediated response to amino acid availability."

reach
"It is important to note that although TBC1D7 can bind TSC1 in the absence of TSC2, our collective data indicate that TBC1D7-TSC1 complexes lacking TSC2 are rare, or nonexistent, in wild-type cells and that TBC1D7 primarily binds to the TSC1 and TSC2 complex."

"Furthermore, tsc2 is directly phosphorylated by akt, which is involved in stimulating cell growth and is activated by growth stimulating signals, such as insulin. Tsc2 is inactivated by akt-dependent phosphorylation, which destabilizes tsc2 and disrupts its interaction with tsc1."

reach
"Akt mediated phosphory lation of TSC2 disrupts the TSC1 and TSC2 complex, allowing unrestrained mTOR kinase activity."

sparser
"Although both hamartin and tuberin may have distinct functions outside of their combined complex, hamartin binding to tuberin stablilizes the latter ( xref ; xref ), allowing the complex to proceed to function as the GTPase activating protein (GAP) for the ras homolog RheB, which is highly expressed in the brain ( xref )."

reach
"TSC1 and TSC2 form a heterodimeric complex (TSC1/2) that receives signals from protein kinase B (Akt) XREF_BIBR - XREF_BIBR, extracellular signal regulated kinase (Erk1/2) XREF_BIBR, XREF_BIBR, 5 ' adenosine monophosphate activated protein kinase (AMPK) XREF_BIBR, TNFalpha-IkappaB kinase beta signaling XREF_BIBR, and glycogen synthase kinase-3beta (GSK3beta) XREF_BIBR."

reach
"Together, these data suggest that FIP200 interaction with the TSC1 and TSC2 complex is not required for FIP200 regulation of cell cycle progression."

sparser
"PEComas are associated with mutations or deletions of tuberous sclerosis associated genes TSC1 or TSC2 , which act as tumor suppressor genes by regulating mTOR."

reach
"Indeed, the FIP200 N1-859 fragment, which can interact with the TSC1 and TSC2 complex (XREF_FIG A), showed similar activity as the full-length FIP200 in the inhibition of cell cycle progression as measured by BrdU incorporation (not depicted)."

sparser
"The PIP 3 second messenger has many functions but classically activates the downstream kinase, AKT, which negatively regulates TSC1 and TSC2 heterodimers to modulate mTORC1 activity ( xref ) [ xref ]."

reach
"Defective activity of the TSC1 and TSC2 complex in the heart triggers development of rhabdomyosarcomas at embryonic stages that halt or regress after birth."

reach
"Active AKT, and extracellular regulated kinase 1 and 2 (ERK1/2), phosphorylate TSC2 which inhibits the GTPase activating protein (GAP) activity of the TSC1 and TSC2 complex towards Ras homologue enriched in brain (RHEB)."

reach
"Therefore, we examined the possible effect of FIP200 on TSC1 and TSC2 complex mediated inhibition of S6K to determine the mechanisms by which FIP200 interaction with the TSC1 and TSC2 complex regulated cell size."

sparser
"The interaction of Tsc1:Tsc2 was also not disrupted with GB (Fig  xref H)."

reach
"Dysregulation of the TSC1 and TSC2 complex by mutation compliments HIF-1alpha polymorphisms in the expression of HIF-1alpha in SCC of the head and neck, and may provide biomarkers to predict responses to specific therapies and overall disease prognosis."

reach
"Coexpression of cyclin D1-CDK4/6 in cultured cells leads to increased phosphorylation and decreased detection of both TSC2 and TSC1, and promotes the phosphorylation of the mTOR substrates, 4E-BP1 and S6K1, two key effectors of cell growth that are negatively regulated by the TSC1 and TSC2 complex."

sparser
"These results indicate that Rictor is the essential component of mTORC2 for its physical association with the TSC1-TSC2 complex."

sparser
"The TSC1-encoded protein hamartin and TSC2-encoded protein tuberin bind to each other to form a functional heterodimer (TSC2: TSC1)."

reach
"Furthermore, both the Wnt and TNFalpha pathways, which contribute to the development and progression of some malignancies, have inputs into the TSC1 and TSC2 complex that could result in mTORC1 activation in tumors."

"Genetic support for a linear Akt1-mTOR-p70S6K pathway has recently come from reports demonstrating that the tuberous sclerosis complex 1 and 2 proteins (Tsc1 and Tsc2) can inhibit mTOR (Fig. 1). Akt1 phosphorylates Tsc2, thereby activating mTOR at least in part by disrupting the Tsc1-Tsc2 complex [54]."

reach
"Activated ERK binds to TSC2 and phosphorylates it on Ser664, stimulating dissociation of the TSC1 and TSC2 complex and removal of its repression of Rheb, resulting in increased cell proliferation and transformation."

sparser
"Hamartin and tuberin form a heterodimer which converts Rheb-GTP to Rheb-GDP, thereby inactivating Rheb."

sparser
"As expected, WT TSC1 and TSC2 formed a stable complex."

sparser
"The hamartin-tuberin complex inhibits mTORC1 by acting on RheB when the cell is subjected to hypoxic or energy-poor conditions, and thereby enacts downstream control over protein synthesis and cell growth through regulation of p70S6K, 4E-BP1, and EEF2K ( xref )."

reach
"The TSC1 and TSC2 complex is often inhibited under growth conditions to facilitate mTOR activation."

reach
"However, how mTORC2 is regulated and whether the TSC1 and TSC2 complex is involved are unknown."

reach
"The Akt kinase is located upstream of the TSC1 and TSC2 complex in this pathway and has a critical role in promoting cell growth."

reach
"On the other hand, p-AMPK can activate TSC1 and TSC2 complex, indirectly suppressing the activity of mTORC1 and concurrently initiating autophagy [XREF_BIBR]."

sparser
"The epitope-tagged TBC7 was expressed in HEK293 cells and its association with the endogenous TSC1 and TSC2 was examined (B)."

sparser
"TSC1 and TSC2 form a functional complex that is a suppressor upstream of mTORC1 [ xref , xref ]."

sparser
"Given the above observations it was initially somewhat surprising that deletion of exon 22, encoding heptads 24 – 29 of the coiled coil region, did not significantly affect TSC1 immunoprecipitation or the TSC1-TSC2 interaction as assayed by coimmunoprecipitation of TSC2."

sparser
"TSC2, the second target of PKB, forms a complex with TSC1 and acts as a negative regulator of growth in Drosophila , and as a tumor suppressor in mammals."

reach
"Increased pAkt activity increases phosphorylation of hamartin and tuberin complex (TSC1 and TSC2), which attenuates its inhibitory effect on mTORC1 (i.e., increases mTORC1 activity) [XREF_BIBR, XREF_BIBR]."

reach
"It has been shown that RB1CC1 and FIP200 interacts with the middle region of TSC1 including the coiled-coil domain and induces the ubiquitin mediated degradation of TSC1 resulting in the reduction of [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Both PKB (Dan et al., 2002; Inoki et al., 2002; Manning et al., 2002; Potter et al., 2002) and p90RSK (Tee et al., 2003a; Roux et al., 2004) phosphorylate TSC2 and inhibit repressive GTPase activating[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"It has also been shown that hamartin can bind to tuberin to prevent tuberin ubiquitination and degradation. ."

isi
"The TSC1 and TSC2 genes are connected to multiple syndromes from Tuberous Sclerosis Complex (TSC) to autism spectrum disorder (ASD), with uncertainty if genetic variants cause all or subsets of phenotypes based on the location and type of change."

sparser
"A previous study identified that there are >1,300 types of TSC1 and TSC2 mutations ( xref ), which may be associated with the different clinical manifestations between patients with TSC."

sparser
"Inactivating mutations of the genes TSC1 or TSC2 are found in over 85% of TS patients. xref TSC1 and TSC2 proteins form a heterodimer complex that inhibits the mammalian target of rapamycin (mTOR) complex 1 (mTORc1)."

reach
"TSC proteins form a heterodimeric TSC1 and TSC2 complex and function to inhibit mTORC1 signaling, which critically regulates cell growth and proliferation."

reach
"Disruption of the TSC1 and TSC2 complex by inactivating mutations in either TSC1 or TSC2 leads to the accumulation of GTP bound Rheb, which in turn activates mammalian target of rapamycin complex 1 (mTORC1) [XREF_BIBR]."

reach
"Studies have shown that absence of the TSC1 and TSC2 complex leads to the loss of mTORC2 kinase activity in vitro."

sparser
"AKT and ERK are parallel signaling pathways activated by Growth factors & Mitogens, both phosphorylates tuberous sclerosis complex 2 (TSC2) to suppress the inhibitory effect of the TSC1TSC2 complex on mTORC1, thus leading to increased mTORC1 signaling which phosphorylates eukaryotic initiation factor 4E-binding protein (4E-BP) and p70S6K [ xref ]."
| PMC

reach
"Receptor tyrosine kinases have been shown to promote the accumulation of GTP bound Rheb via inhibition of the TSC1 and TSC2 complex by inducing the phosphorylation of TSC2."

sparser
"Hits included an upstream activator of PI3K (GRB2), two mTORC1/2 core components (RICTOR and TTI1), a direct activator of mTORC1 (RHEB), and HRAS, which can stimulate mTORC1 by inhibiting the TSC2-TSC1 complex xref ."

reach
"Furthermore, CPT did n't affect the expression of TSC1 when immunoprecipitates TSC2 in Rh30 cells, verifying no occurrence of disruption of TSC1 and TSC2 complex."

sparser
"The Tsc1 gene encodes hamartin protein (also known as tuberous sclerosis complex 1, TSC1), which forms a complex with TSC2 and regulates the mTORC1 signaling pathway."

reach
"29,31 Activity of mTORC1 depends not only on the activity of mTOR kinase and raptor protein level, but also on removal of an inhibitory complex TSC2 and TSC1."

reach
"Interestingly, the PI3K and PTEN signaling pathway regulates the TSC1 and TSC2 complex and its downstream targets, including the mammalian target of rapamycin (mTOR) [XREF_BIBR, XREF_BIBR]."

reach
"Nonetheless, we did not observe significant effects of the TSC1 Y948N, I954K or L963S variants on the ability of the TSC1 and TSC2 complex to inhibit TORC1 signaling in our standard assay (XREF_FIG)."

reach
"This result implies that one of the primary functions of the insulin pathway, at least in Drosophila, is to inhibit the hamartin and tuberin complex."

reach
"Thus, TSC2 mutation heterozygosity may have an impact on intracellular localization of the TSC1 and TSC2 complex, potentially affecting its physiological role."

sparser
"Notably, in breast cancer, relative low expression of hamartin and tuberin ( TSC1 and TSC2 products, respectively) is associated with poor clinical outcome [ xref ], and depletion of tuberin promotes metastasis [ xref ]."

reach
"In P15 mutant cortex, loss of Tsc1 and concurrent reduction in Tsc2 protein, which is in line with TSC2 dependence on TSC1 expression for stabilization of the TSC1 and TSC2 complex, led to a marked increase in pS6 S235/6 (XREF_FIG)."

No evidence text available

reach
"Although we could not confirm our previous estimate of the size of the TSC1 and TSC2 complex, our new data support the proposal that the TSC1 and TSC2 complex can contain multiple TSC1 and TSC2 subunits [XREF_BIBR, XREF_BIBR]."

reach
"Previous studies suggested that TSC1 and TSC2 complex formation is critical for its function."

reach
"C. elegans also lacks key components of the Tor pathway, including the Tsc1 and Tsc2 complex [XREF_BIBR], and 4E-BP [XREF_BIBR]."

reach
"In the absence of Akt, the TSC1 and TSC2 complex is a negative regulator of mTORC1."

reach
"In addition to being inhibited by growth factor signaling, the TSC1 and TSC2 complex can be activated by AMPK, a kinase that is activated by decreases in cellular ATP, usually brought about by glucose[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"The I820del and L1511H changes therefore had similar effects to other pathogenic TSC2 missense mutations, disrupting the function of the TSC1 and TSC2 complex in vitro."

reach
"The mTOR is negatively regulated by TSC1 and TSC2 complex."

sparser
"Thus, TSC1-PDGFRB fusion may upregulate the downstream mTOR pathway by interrupting the TSC1-TSC2 activity due to TSC1 translocation."

reach
"The TSC1 and TSC2 complex acts as an inhibitor of mTORC1, but the exact role of these proteins, especially TSC1, remains unclear."

reach
"Indeed, although all TSC1 and TSC2 complex subunits have managed to copurify RUVBL1 and RUVBL2, which are not exclusive to R2TP and PFDL, other R2TP and PFDL component have solely been detected in TSC1 and TBC1D7 purifications."

sparser
"Activated AKT directly phosphorylates TSC2, disrupting and inactivating the TSC1-TSC2 complex."

reach
"DAPK1 promotes TSC2 phosphorylation resulting in TSC1 and TSC2 complex dissociation and mTORC1 signaling activation [XREF_BIBR]."

reach
"Mechanistically, Plk1 phosphorylation of TSC1 at S467 and S578 interfered with TSC1 and TSC2 binding, destabilized TSC1, promoted dissociation of the TSC complex from the lysosome, and eventually led to mTORC1 activation."

sparser
"The TSC1 gene maps to chromosome 9q34 and encodes the protein hamartin. ( xref , xref ) The TSC2 gene maps to chromosome 16p13.3 and encodes the tuberin protein. ( xref , xref ) Hamartin and tuberin together form a complex that acts to negatively regulate the cell cycle. ( xref ) TSC functions as a tumor suppressor gene, as evidenced by the presence of inactivating mutations of TSC and loss of heterozygosity of TSC1 and TSC2 in tumors associated with TSC. ( xref , xref ) Loss-of-function mutations of the tuberin-hamartin complex impair GTPase activity, leading to constitutive activation of these proteins."

sparser
"However, consistent with previous findings showing that the TSC1-TSC2 interaction is mediated through multiple regions of TSC1, TSC2 could still be coimmunoprecipitated with the TSC1 delex9, delex18 and delex23 proteins."

reach
"Tuberin and hamartin form a complex in vivo [6,7] and function within the same pathway regulating cell growth [8-10]."

reach
"PKCalpha levels are decreased in mouse and human tumors lacking a functional TSC1 and TSC2 complex."

sparser
"In mammalian cells, tuberous sclerosis complex 1 (Tsc1) is part of the Tsc1-Tsc2 GTPase-activating complex that stimulates a small GTPase, Rheb."

reach
"Collectively, these data demonstrate that the TSC1 and TSC2 complex promotes both PI3K dependent functions of mTORC2 (i.e., Akt-S473 phosphorylation) and the basal constitutive activities of mTORC2 (i.e., PKC-S657 and Akt-T450 phosphorylation)."

sparser
"The proposed model of cortical tuber formation is that somatic “second-hit” mutations in patients with heterozygous germ line mutations result in loss of function of the TSC1-TSC2 complex and hyperactivation of mTORC1 signaling in a subset of cortical progenitor cells ( xref ; xref )."

sparser
"TBC1D7 has been identified as a stably associated and ubiquitous subunit of the TSC1TSC2 complex [ xref ]."

reach
"PC1 decreases mTOR activity by stabilizing the functional TSC1 and TSC2 complex via two distinct mechanisms."

sparser
"The substitution of a basic histidine residue for a nonpolar leucine residue at position 1511 did not affect the TSC1TSC2 interaction, but did abrogate the rheb GAP activity of the TSC1TSC2 complex."

reach
"Since Tsc1 and Tsc2 can bind in vitro, we hypothesized that they might function together in vivo."

reach
"To determine whether Pas1 links nutrient availability to cell cycle progression downstream of the Tsc1 and Tsc2 complex, we examined the kinetics of G1 arrest in single and double mutant strains."

reach
"We found that association of FIP200 with the TSC1 and TSC2 complex correlated with its ability to increase cell size and up-regulate S6 kinase phosphorylation but was not involved in the regulation of cell cycle progression."

sparser
"Tsc1 and Tsc2 proteins form a complex and serve as a GTPase-activating protein (GAP) for Rheb, a GTPase regulating a downstream kinase, mTOR."

reach
"These results indicate that Rictor is the essential component of mTORC2 for its physical association with the TSC1 and TSC2 complex."

reach
"ERK dependent phosphorylation of tuberin prevents its association with hamartin and the inhibition of Rheb and mTOR by the tuberin and hamartin complex."

reach
"It has been posited that Redd1 inhibits mTORC1 by controlling the release of TSC2 from its growth-factor-induced association with 14-3-3, thereby stabilizing the interaction between TSC1 and TSC2."

reach
"The identification of the TSC1 and TSC2 complex as an inhibitor of mTORC1 has paved the way for a novel medical treatment of TSC."

reach
"To establish whether the separation of TBC1D7 into high-density fractions (XREF_FIG) reflects binding to the TSC1 and TSC2 heterodimer through TSC1, we repeated the sucrose density fractionations following siRNA mediated knockdown of the three complex components."

reach
"Absence of tuberin, as occurs with TSC2 gene mutations, loss of heterozygosity, or inhibition of the hamartin and tuberin complex by growth factors either through the mitogen activated protein kinase (MAPK) or insulin signalling pathways, leads to accumulation of active Rheb-GTP, stimulation of mTOR, phosphorylation of S6 kinase and eukaryotic initiation factor 4E binding protein, and increased translation, cell size and proliferation [XREF_BIBR] (XREF_FIG)."

sparser
"Many studies have shown that, in addition to mTORC1 upregulation, the activity of some mTORC2 substrates in TSC1-TSC2 deficient cells (e.g., Akt) decreases (see also Fig.  xref and 6)."

reach
"Conversely, tumor suppressor gene products upstream of mTOR signaling, such as PTEN (phosphatase and tensin homolog deleted on chromosome ten) and TCSs (tuberous sclerosis complex TSC1 and TSC2), antagonize PI3-K activation and promote autophagy by down-regulation of mTOR XREF_BIBR."

reach
"Therefore, like cell culture models lacking a functional TSC1 and TSC2 complex, tumor cells from TSC patients display elevated mTORC1 signaling and PPARgamma expression."

reach
"Multiple upstream pathways stimulate or inhibit the mTOR pathway by interacting with the hamartin and tuberin complex to control important physiological functions."

reach
"Functional characterisation of the TSC1 and TSC2 complex to assess multiple TSC2 variants identified in single families affected by tuberous sclerosis complex."

No evidence text available

sparser
"TBC1D7, a candidate found in T47D cells, is a subunit of the TSC1-TSC2 complex and maintains the association of the complex ( xref )."

reach
"Although the molecular mechanism is not well understood, these phosphorylation events relieve the inhibitory effects of the TSC1 and TSC2 complex on Rheb and mTORC1 [mTOR (mammalian target of rapamycin) complex] 1, thereby activating mTORC1 in response to growth factors."

sparser
"From these two screens, 288 genes that had SS/L interactions with TSC1 and/or TSC2 were identified ( xref and xref )."

reach
"Several kinases can inactivate the hamartin and tuberin complex, thus increasing mTOR activity and cell growth."

reach
"However, the regulatory mechanism of amino acid uptake in which the Tsc1 and Tsc2 complex and Pub1 are involved remains largely unclear."

reach
"The growth factor stimulated kinase activity of mTOR complex 2 (mTORC2 or the mTOR and Rictor complex), which normally enhances Akt signalling by phosphorylating its hydrophobic motif (Ser473), was found to be defective in cells lacking the TSC1 and TSC2 complex."

reach
"The phosphorylation of the TSC2 and TSC1 complex by AMPK leads to the inactivation of Rheb, a GTPase that activates mTORC1."

reach
"The tuberous sclerosis 1 and 2 complex (Tsc1 and Tsc2 complex) negatively regulates mTOR activity [XREF_BIBR - XREF_BIBR]."

reach
"Therefore our identification of the interaction between FIP200 and the TSC1 and TSC2 complex raises the interesting possibility that FIP200 may regulate cell size through interaction with the TSC1 and TSC2 complex."

reach
"The TSC1 and TSC2 complex can negatively-regulate proliferation through mTORC1 inhibition and GSK-3beta activation."

sparser
"Our results further suggest that endogenous TSC1 and TSC2 proteins form a stable complex in each of these compartments and, in the absence of tuberin, endogenous hamartin does not appear to self-aggre[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Many factors (e.g., nutrients and growth factors) activate mTORC1 [XREF_BIBR] through the PI3K-PDK1-AKT pathway with the inactivation of the TSC1 and TSC2 complex."

reach
"Thus, AKT activates mTORC1 by inhibiting the TSC1 and TSC2 complex."

sparser
"Indeed, rapid degradation of the mutant TSC1 isoforms in vivo removed the suppressive effects of TSC1-TSC2 -variants on mTOR signaling ( xref ), promoting the progression of TSC."

sparser
"TSC subunit 1 (TSC1) stabilizes TSC2 by inhibiting the interaction between TSC2 and HERC1, forming a TSC1-TSC2 complex that negatively regulates mTORC1."

reach
"The TSC1 and TSC2 complex, and in particular TSC2 is extensively phosphorylated in response to upstream signals and these phosphorylation events play a very important role in the relay of signals to mTORC1."

reach
"In flies, as in mammals, TOR activity is negatively regulated by the amino-acid responsive protein complex TSC1 and TSC2."

sparser
"The Tsc1:Tsc2 complex has a well-established function inhibiting the mTOR pathway via Rheb inhibition."

reach
"Phosphorylation of the TSC1 and TSC2 complex abolishes its (indirect) inhibitory action on the " target of rapamycin " (TOR)."

reach
"As a result, inhibition of the TSC1 and TSC2 complex results in the overactivation of mTOR, leading to cell growth and proliferation [XREF_BIBR - XREF_BIBR]."

reach
"The TSC1 and TSC2 complex is encoded by the two tumor suppressor genes mutated in the genetic tumor syndrome tuberous sclerosis complex (TSC)."

trips
"We observed that the interaction of TSC1 with TSC2 appears to exclude TSC2 from interacting with HERC1."

reach
"TSC1 and TSC2 complex exerts negative regulation on mTORC1 signaling."

reach
"The AKT oncogene promotes proliferation via inhibition of the TSC1 and TSC2 complex upstream of the mTOR and P70S6K pathway."

reach
"Our results uncovered further molecular links between axon guidance cues and local mRNA translation in the axon, including the Tsc1 and Tsc2 complex and Rheb."

reach
"The physical association between the C terminus of TSC2 (amino acids 1280-1499) and FoxO1 degrades the TSC1 and TSC2 complex and inhibits GTPase activating protein activity of TSC2 toward Rheb."

reach
"Akt regulates protein synthesis by phosphorylating the tuberous sclerosis complex 2 (TSC2) protein tuberin, thus inhibiting the GAP (GTPase activating protein) activity of the TSC1 and TSC2 complex toward Rheb (small G protein Ras homologue enriched in brain)."

reach
"TSC1 and TSC2 complex relays signals from diverse cellular pathways to properly modulate mTORC1 activity [XREF_BIBR, XREF_BIBR]."

reach
"TSC1 and TSC2 form a complex that negatively regulates the activity of mammalian target of rapamycin (mTOR) by inhibiting Ras homolog enriched in brain (Rheb)."

sparser
"Variants classified in Group 1 (no effect on TSC complex function) are shown in black, Group 2 variants (disrupt TSC complex activity) are in gray, and Group 3 variants (inactivate TSC complex) are in white (see main text for details). (b) Mean signals for the TSC2 variants, relative to wild‐type TSC1TSC2 (TSC2; TSC2 signal = 1)."

reach
"XREF_BIBR, XREF_BIBR Phosphorylation of TSC2 by Akt may inhibit the function of the TSC2 : TSC1 complex either by decreasing the interaction between TSC2 and TSC1 or enhancing the degradation of the heterodimeric complex by the ubiquitin-proteasome pathway."

reach
"Mutations in neurofibromin lead to overactivation of Ras activity, followed by enhanced activation of the Ras-MAPK signaling pathway as well as PI3K and ERK 1/2 which both inactivate the TSC1 and TSC2 complex releasing inhibition of Rheb and allowing activation of mTOR."

reach
"Most TSC patients present with mutations in the TSC1 or TSC2 genes, which encode proteins that form the TSC1-TSC2 complex that serves to antagonize the signaling pathway downstream of mammalian target of rapamycin (mTOR) by promoting the activation of the small GTPase Rheb and thereby inhibiting cellular growth and proliferation."

reach
"Redd1 is a new stress induced protein and is known as a negative regulator of mTOR through TSC1 and TSC2 complex [XREF_BIBR - XREF_BIBR]."

sparser
"Besides their association with TSC1 and TSC2 mutations, and those harboring TFE3 rearrangements, little is known about the molecular phenotype of uterine PEComas."

reach
"Increased levels of ROS activate AMP activated protein kinase (AMPK), which causes TSC2 phosphorylation and activates the TSC1 and TSC2 complex, thus inhibiting mTORC1 and stimulating ULK (an important initiator of the autophagy complex) to induce autophagy."

reach
"Huang and co-authors proposed that the TSC1 and TSC2 complex, the upstream negative regulator of mTORC1, may also bind to and regulate mTORC2 activity by direct binding to mTORC2 [XREF_BIBR]."

reach
"A primary mechanism by which Akt activates mTORC1 is through phosphorylation and inhibition of TSC2 within the TSC1 and TSC2 complex."

reach
"Taken together, hyperactivated mTORC1 is responsible for the downregulation of PDGFRalpha due to loss of TSC1 and TSC2 complex."

reach
"All components of mTORC2 co-immunoprecipitated with the TSC1 and TSC2 complex (XREF_FIG)."

reach
"Considering that TSC2 mRNA was unchanged in LV-miR-19a OB-6 cells, TSC2 downregulation by miR-19a should be due to the disruption of the TSC1 and TSC2 complex."

sparser
"Hamartin has been shown to significantly enhance tuberin's GAP activity toward Rheb GTPase ( xref ; xref ), and our observations also emphasize the importance of the interaction between tuberin and hamartin as a functional unit."

reach
"GSK3beta is upstream regulator of the TSC1 and TSC2 complex which regulates mTOR signaling through mTORC1 based on Rheb GDP loading XREF_BIBR XREF_BIBR."

reach
"The activated TSC1 and TSC2 complex regulates the activity of mTORC1 and raptor, which controls cell growth mainly through the regulation of protein translation."

reach
"PI3K mediated activation of mTORC1 via AKT, occurring due to inhibitory phosphorylation of the TSC1 and TSC2 complex, links mTORC1 to PI3K signaling and the regulation of protein synthesis, cell size and proliferation XREF_BIBR."

reach
"In respect to energy status, the decreased ATP levels activate AMPK, which in turn activates the TSC1 and TSC2 complex, resulting in mTORC1 inactivation."

reach
"TSC2 forms a complex with TSC1 that functions to integrate growth factor signals with the cell growth regulatory apparatus (Marygold and Leevers, 2002)."

No evidence text available

sparser
"Tuberin forms a complex with hamartin, via its N-terminal domain ( Hodges et al., 2001 )."

reach
"The hamartin and tuberin complex also negatively regulates beta-catenin stability and activity, by participating in beta-catenin degradation complex [XREF_BIBR]."

reach
"The tuberin and hamartin complex was shown to protect p27 from protein degradation."

reach
"The TSC1 and TSC2 complex inhibits primarily mTORC1 signaling; destruction and inhibition of the TSC1/2 complex due to growth factors leads to activation of mTORC1 signaling."

reach
"Nevertheless, our results establish that there is a crosstalk between the TSC/Rheb/mTOR and the NF-kappaB pathways that modulates cell survival.In conclusion, our results demonstrate that the TSC1 and[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

No evidence text available

reach
"The documentation of the first clinical case of fulminant SLE in a patient with tuberous sclerosis also support a fundamental role of mTOR pathway activation in the pathogenesis of both these diseases 118 : in accordance with a negative regulatory role for the TSC1 and TSC2 complex, all lymphocyte subsets of this patient exhibited robust mTORC1 activation 118."

sparser
"TSC1 and TSC2 form a heterodimeric tumor suppressor complex that negatively regulates the activity of mTORC1, a central hub for the regulation of protein synthesis, cell growth and proliferation xref , xref ."

reach
"For example, the TSC1 and TSC2 complex inhibits mTOR functions by inactivating Rheb; Rheb binds and activates mTOR only when the former is in its GTP bound form."

sparser
"Abnormal mammalian target of rapamycin (mTOR) complex signaling and defects in TSC1 and TSC2 have been associated with the development of sub-ependymal giant cell astrocytomas (SEGAs) in tuberous sclerosis complex (TSC) patients."

sparser
"Hamartin and tuberin form a complex that inhibits mTORC1; immune profiling of one of the described tuberous sclerosis patients with SLE demonstrated significant mitochondrial hyperpolarization and increased mTOR activity in vitro [ xref ]."

reach
"TSC1 and TSC2 complex maintains quiescence of naive T cells by regulating cell size, cell cycle entry, and cell survival."

reach
"Hamartin and tuberin form a heterodimer that functions as a major cellular inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) kinase."

reach
"It has recently been shown that ERK phosphorylates the tumor suppressor TSC2, leading to the disruption of the TSC1 and TSC2 complex and ultimately unleashing mTOR kinase activity [30], an important s[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"Together with a small third subunit TBC1D7, xref TSC1 and TSC2 assemble to form the TSC protein complex (TSCC)."

reach
"REDD1 negatively regulates mTORC1 via the TSC1 and TSC2 complex through unknown mechanisms or a mechanism involving 14-3-3, a cytosolic anchor protein [XREF_BIBR]."

reach
"These two genes are located on chromosomes 9 and 16, encoding hamartin and tuberin, respectively, which form the TSC1 and TSC2 complex to inhibit the mTOR signaling pathway and regulate cell growth and function [XREF_BIBR]."

reach
"The mTOR pathway can also be activated downstream of RAS via ERK mediated negative regulation of the TSC1 and TSC2 complex [XREF_BIBR]."

reach
"AMPK, activated by LKB1, inhibits AKT signaling turning off mTOR by activating the tumor oncosuppressor complex TSC2 and TSC1 [101]."

reach
"AKT mediated phosphorylation of TSC2 inhibits the TSC1 and TSC2 complex function, and thus activates mTORC1 signaling."

reach
"Activation of TSC1/TSC2 complex decreases MTOR activity by inhibiting RHEB, a positive MTOR regulator."

reach
"Under oxidative and bioenergetic stress or hypoxia the hamartin and tuberin heterodimer is positively regulated by AMPK and REDD1, respectively."

reach
"The TSC1 and TSC2 complex has recently been implicated in cell survival responses."

sparser
"Regulation of ciliary formation by Tsc1 and Tsc2 is rapamycin-insensitive."

reach
"The TSC1 and TSC2 complex : a molecular switchboard controlling cell growth."

reach
"However, the regulation of the hamartin and tuberin complex in the context of the physiologic role as tumor suppressor genes has not been documented."

sparser
"TSC1 and TSC2 complex negatively regulate the activity of mTOR1 and connection between TSC and the mTORC1 pathway revealed very first molecular link between mTOR and cancer, although, AKT based phosphorylation and inhibition of TSC2 is the clearest link between mTORC1 and dysregulated pathway of cancer [ xref ]."
| PMC

reach
"The overexpression of 14-3-3beta compromises the ability of the TSC1 and TSC2 complex to reduce S6K phosphorylation."

reach
"DAPK dependent phosphorylation leads to TSC1 and TSC2 complex dissociation, and consequently manipulation of DAPK by transfection or short interfering RNA demonstrated that DAPK is a positive regulator of mTORC1 in response to growth factor activation."

reach
"LPS has been shown to induce TSC2 phosphorylation, which inactivates the TSC1 and TSC2 heterodimer, leading to mTOR activation [XREF_BIBR], and AKT inhibitors, which blunt TSC2 phosphorylation [XREF_BIBR]."

reach
"TSC2 phosphorylation by Akt represses GAP activity of the TSC1 and TSC2 complex, allowing Rheb to accumulate in a GTP bound state."

reach
"mTORC1 activity is negatively regulated by the heterodimer TSC1/TSC2 (tuberous sclerosis 1 and 2)."

sparser
"Hamartin and tuberin interact with each other through their coiled-coil domains to form a stable and functional heterodimer that promotes the GTPase activity of Rheb protein, thus preventing the Rheb-GTP-dependent stimulation of cell proliferation, adhesion, growth, differentiation and migration, through the mTOR pathway [ xref , xref – xref ]."

reach
"Expression of these mutants confers resistance to canavanine and thialysine, phenotypes which are similar to phenotypes exhibited by cells lacking the Tsc1 and Tsc2 complex that negatively regulates Rhb1."

reach
"Furthermore, Akt phosphorylated cytoplasmic FoxO1 binds to TSC2 and thereby dissociates the TSC1 and TSC2 complex, which activates mTORC1 XREF_BIBR."

reach
"TSC1 and TSC2, mutated in tuberous sclerosis, form a complex which permits the functioning of a TSC2 GTPase activating protein for Rheb GTPase which inhibits the mTOR pathway."

reach
"The TSC1 and TSC2 proteins form a complex that lies at the crossroad of many signalling pathways integrating the energy status of the cell with signals induced by nutrients and growth factors."

sparser
"The TSC1 and TSC2 proteins form a physical and functional complex in which TSC2 is the catalytic subunit having GTPase-activating protein (GAP) activity toward Rheb, a Ras family GTPase ( Manning and [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"Indeed, none of the exon-specific deletion proteins completely prevented TSC1-TSC2 binding ( xref ; see below)."

reach
"Biochemical analyses confirmed Rheb as a bona fide effector of the TSC1 and TSC2 complex [XREF_BIBR - XREF_BIBR]."

reach
"TSC1 and TSC2 complex negatively regulate the activity of mTOR1 and connection between TSC and the mTORC1 pathway revealed very first molecular link between mTOR and cancer, although, AKT based phosphorylation and inhibition of TSC2 is the clearest link between mTORC1 and dysregulated pathway of cancer [116]."
| PMC

reach
"As mTORC1 is known to control axonal guidance and synaptic plasticity [XREF_BIBR, XREF_BIBR], it is possible that these counterintuitive phenotypes reflect defects in neuronal morphology upon disruption of the TSC1 and TSC2 complex."

reach
"The growth suppressor genes TSC1 and TSC2 encode proteins that function together as an intrinsic modulator of cell growth by forming the TSC1 and TSC2 complex that inhibits mTORC1 signaling [11,12]."

reach
"The effector kinases of these pathways -- protein kinase B (Akt and PKB), extracellular-signal-regulated kinase 1/2 (ERK1/2), and ribosomal S6 kinase (RSK1) -- directly phosphorylate the TSC1 and TSC2 complex to inactivate it and thus activate mTORC1."

sparser
"Flies with reduced TOR levels, or expressing dominant negative forms of S6K, TSC1, or TSC2 (suppressors of the TOR pathway) are long-lived [ xref , xref ]."

sparser
"Upstream pathways activate or inhibit the mTOR pathway either directly or by interacting with the hamartintuberin complex."

reach
"In contrast to mTORC1, the TSC1 and TSC2 complex appears to promote the activity of mTORC2 [XREF_BIBR]."

sparser
"Tsc1 and Tsc2 form a physical and functional complex that ultimately inhibits mTOR."

reach
"Active MAP kinase can inhibit the TSC1 and TSC2 complex by specifically phosphorylating TSC2, or indirectly through activation of RSK, and thereby activating mTOR1."

reach
"Although mutations that prevent tuberin tyrosine phosphorylation also inhibit tuberin-hamartin binding and the chaperone function, our results indicate that only hamartin is phosphorylated in the tuberin and hamartin complex."

reach
"p53 also transactivates Sestrin1 and Sestrin 2, which can repress mTORC1 via AMPK dependent regulation of the TSC1 and TSC2 complex (XREF_FIG)."

reach
"In support of the established mechanism by which the TSC1 and TSC2 complex inhibits mTORC1 by acting as a GAP for Rheb, the stimulation of mTORC1 signaling by TBC1D7 knockdown was inhibited by siRNAs targeting Rheb1, with a minor contribution from Rheb2 (also known as RhebL1; XREF_FIG)."

reach
"The hamartin and tuberin complex inhibits the mammalian target of rapamycin pathway, which controls cell growth and proliferation."

sparser
"In the resting cell, TSC-1 and TSC-2 form a heterodimer; TSC2 is a GTPase activating protein that suppresses activation of (Ras homolog enriched in brain) Rheb[ xref ]."

reach
"Second, Akt phosphorylates and inhibits TSC2 thereby relieving the inhibitory effects of the TSC1 and TSC2 complex on mTORC1 [XREF_BIBR - XREF_BIBR]."

reach
"Together, these observations highlighted that p53 inhibits mTOR by regulating a pathway that is used to detect nutrient and energy deprivation such as AMPK, and subsequently the TSC1 and TSC2 complex [XREF_BIBR]."

reach
"As Tuberin forms a complex with TSC1 and Hamartin, it has been argued that complex formation between Tuberin and Hamartin is necessary for Rheb-GAP activity."

reach
"REDD1 releases Tsc2 from the growth-factor induced association with 14-3-3 proteins, thereby activating the Tsc1 and Tsc2 complex and leading to the inhibition of TORC1 activity."

sparser
"50. van Slegtenhorst M, Nellist M, Nagelkerken B, Cheadle J, Snell R, van . den Ouweland A, Reuser A, Sampson J, Halley D, van der Sluijs P: Interaction between hamartin and tuberin, the TSCI and [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

No evidence text available

reach
"Extracellular signal regulated kinases (ERKs), protein p90 ribosomal S6 kinase 1 (RSK1), glycogen synthase kinase -3 beta (GSK-3beta), and AMP activated protein kinase (AMPK) also can modulate the activity TSC1 and TSC2 complex."

reach
"Recent work suggests that this may involve the components of the tuberous sclerosis complex TSC1 and TSC2, TSC2 being a direct substrate for Akt [5]."

reach
"Initial studies characterizing the function of TSC1 and TSC2 complexes in the brain identified important roles in regulating neuronal growth and neural network homeostasis."

reach
"Taken together, both expression level and activity of FOXO3a were negatively regulated by mTORC1 in cells lacking TSC1 and TSC2 complex."

reach
"Binding of TSC1 to TSC2 appears to stabilize intracellular TSC2 levels since uncomplexed TSC2 is subject to ubiquitin mediated degradation."

reach
"Rheb is negatively regulated by the GAP activity of the TSC1 and TSC2 complex 7."

reach
"This tag did not interfere with either the TSC1-TSC2 interaction, or with the function of the TSC1 and TSC2 complex [15-19]."

reach
"Therefore, like other mTORC2 targets (i.e., Akt and PKCalpha), SGK1 activation is defective upon loss of the TSC1 and TSC2 complex."

isi
"Mutational analysis of TSC1 and TSC2 in Danish patients with tuberous sclerosis complex."

reach
"ERK activated kinase, p90 RSK1, phosphorylates TSC2 on serine 1798, inhibits the function of the TSC1 and TSC2 complex, and leads to an increase in activity of mTOR and p70S6K phosphorylation."

sparser
"Hamartin and tuberin form a complex, of which tuberin is assumed to be the functional component."

sparser
"Loss-of-function mosaic mutations in negative regulators of mTOR kinase, as TSC1 and TSC2 , induce mTOR hyperactivation by disturbing the function of the TSC1TSC2 complex (Lim et al., xref ; Baldassari et al., xref )."

sparser
"Finally, Decreased protein levels of TSC1 and TSC2 in GBMs were associated with decreased mRNA levels."

reach
"Role of the TSC1 and TSC2 complex in the integration of insulin and glucose signaling involved in pancreatic beta-cell proliferation."

reach
"However, a perfectly circular dAkt-TOR pathway predicts that increased Tsc1 and Tsc2 levels should trigger high dAkt activity, which in turn should inactivate the Tsc1 and Tsc2 complex by direct phosphorylation of Tsc2 XREF_BIBR, XREF_BIBR, XREF_BIBR."

reach
"AMPK activation exerts an inhibiting effect on mTORC1 via the TSC1 and TSC2 complex, or in direct phosphorylation of ULK-1, both resulting in the initiation of autophagy [XREF_BIBR]."

reach
"TSC2 and TSC1 form a heterodimer to suppress cell proliferation."

reach
"Like the PI3K and Atk complex, AMPK interacts with the TSC1 and TSC2 complex leading to the downstream activation of mTORC1 [XREF_BIBR, XREF_BIBR]."

reach
"Akt-mediated TSC1/TSC2 complex inhibition consequently allows Rheb to accumulate in a GTP-bound state, whereby Rheb-GTP binds and activates mTORC1 [18]."

reach
"However, Akt can phosphorylate TSC2 and thereby disrupts TSC1 and TSC2 complex formation [XREF_BIBR]."

reach
"These findings suggest that the TSC1 and TSC2 complex plays opposing roles in tumor progression, both blocking and promoting specific oncogenic pathways through its effects on mTORC1 inhibition and mTORC2 activation, respectively."

sparser
"We also show that the Tsc1 protein binds to Drosophila Tsc2 in vitro."

reach
"On the other hand, it has been found that TORC1 is activated by the Ras family Rheb GTPase, which is negatively regulated by the Tsc1 and Tsc2 complex that acts as Rheb GTPase activating protein (GAP) [XREF_BIBR]."

sparser
"Phosphorylation of Tuberin at these sites does not disrupt the Tuberin-Hamartin interaction but are key modifications in inhibiting Tuberin GTPase function, thereby permitting mTOR activity [ xref ]."

sparser
"The hamartintuberin complex normally inhibits mammalian target of rapamycin complex 1 (mTORC1) in a cell."

reach
"Functionally, the TSC1 and TSC2 complex is positioned downstream of AKT where TSC2 is directly phosphorylated and inactivated by AKT."

"Hypoxia results in energy starvation and activation of the AMPK/TSC2/Rheb/mTOR pathway"

reach
"Therefore, it appears that the TSC1 and TSC2 complex has direct effects on mTORC2 kinase activity, the molecular nature of which is currently unknown."

reach
"The second variant identified in family 1, TSC2 R1772C, did not have a deleterious effect on the activity of the TSC1 and TSC2 complex."

sparser
"TSC1 associates with TSC2 to form a heterodimer."

reach
"In cell line models, the TSC1 and TSC2 complex can associate with mTORC2 to promote mTORC2 signaling [XREF_BIBR]."

reach
"This discrepancy could be explained by the findings that mTORC2 activity has been inhibited by loss of TSC1 and TSC2 complex [XREF_BIBR, XREF_BIBR], and therefore knockdown of Rictor, a specific component of mTORC2, can no longer reduce mTORC2 activity as well as its downstream targets in Tsc1- or Tsc2-null MEFs."

sparser
"Conversely, absence of a nitrogen source suppresses TORC1 in a manner dependent on GATOR1 as well as the Tsc1-Tsc2 complex, whose mammalian equivalent functions as a growth-factor sensitive TORC1 inhibitor."

reach
"Recent studies suggested that TSC2 functions as the GTPase activating protein of the small G protein Rheb, an upstream activator of mTOR, and that the TSC1 and TSC2 complex antagonizes the mTOR signaling pathway via stimulation of GTP hydrolysis of Rheb."

reach
"Lack of functional TSC1 and TSC2 complex in cells results in the loss of the mTORC2 kinase activity in vitro."

sparser
"The Tsc1 and Tsc2 proteins form a complex but little is currently known about their biological function."

sparser
"Upon glucose starvation AMPK inhibits mTORC1 either via the TSC1–TSC2 (hamartin-tuberin) complex or by direct phosphorylation of Raptor xref , xref , xref – xref ."
| PMC

sparser
"Other genetic manipulations causing more severe Tsc2 deficiency, or dysfunction of the TSC1-TSC2 complex, lead to abnormal social behaviors in mice [ xref , xref ]."

reach
"Tumor suppressor complex TSC1 and TSC2 represents a key negative regulator of mammalian target of rapamycin (mTOR)-S6 kinase 1 signaling."

reach
"Tuberin and hamartin complex has also strong and highly specific GAP activity toward Rheb (Ras homolog enriched in brains), which activate mammalian target of rapamycin (mTOR) [7,15,16]."

sparser
"As the inhibitors of the mTOR signaling pathway, TSC1 and TSC2 form as the heterodimer to inhibit mTOR signaling and subsequently attenuate cell growth, proliferation, division, and survival xref ."

sparser
"This disease is mainly caused by inactivating mutations of either TSC1 or TSC2 tumor suppressor genes. xref TSC1 and TSC2 form a physical and functional protein complex that negatively regulates mammalian target of rapamycin (mTOR) through inactivation of a small GTPase, RAS homolog enriched in brain. xref mTOR exists in rapamycin-sensitive mTOR complex 1 (mTORC1, composed of mTOR, DEPTOR, mLST8, PRAS40, and raptor) and rapamycin-insensitive mTOR complex 2 (mTORC2, composed of mTOR, DEPTOR, mLST8, mSin1 and rictor). xref mTORC1 can integrate various inputs, including growth factors, energy, nutrient, stress and oxygen to control cell survival, growth, proliferation and differentiation, while the mTORC2 pathway is insensitive to nutrients, but can be regulated by insulin-PI3K signaling and functions through several members of the AGC subfamily of kinases including AKT, SGK1 and PKCα. xref , xref "

reach
"TSC1 and TSC2 form a heterodimeric tumor suppressor complex that negatively regulates the activity of mTORC1, a central hub for the regulation of protein synthesis, cell growth and proliferation XREF_BIBR, XREF_BIBR."

sparser
"FIP200 regulation of S6K phosphorylation through its association with the TSC1TSC2 complex."

reach
"In this report, we demonstrate an interaction between hamartin and tuberin, which is detectable at endogenous protein levels."

reach
"Therefore, Akt mediated inhibition of the TSC1 and TSC2 complex serves to activate Rheb and mTORC1."

reach
"XREF_BIBR Hamartin and tuberin form a heterodimer that inhibits the mammalian target of rapamycin (mTOR) protein kinase, which is a key regulator of several cellular functions, including nutrient sensing, protein synthesis, and cellular growth and proliferation."

sparser
"Normally, TSC2 forms heterodimers with TSC1; together, they regulate the activity of Rheb, a GTPase for mTORC1."

reach
"Loss of function of either TSC1 or TSC2 due to inactivating mutations promotes the degradation of the TSC1 and TSC2 complex and deregulation of Rac1 and Rho activities."

reach
"Thus, the Tsc1 and Tsc2 complex may serve as a hub to integrate growth signals."

sparser
"However, all three mutants retained interaction with the TSC1:TSC2 complex ( xref )."

reach
"The tuberin and hamartin complex is a nodal point for several polycystin dependent pathways."

reach
"CTuberin binds to hamartin and Rheb and inhibits mTOR activation."
| PMC

reach
"One would therefore expect diminished Akt activity to be associated with enhanced TSC1 and TSC2 complex formation."

sparser
"The hamartin-tuberin complex plays diverse roles in cell cycle regulation, chiefly through inhibition of the mammalian target of rapamycin (mTOR) cascade [ xref – xref ]."

sparser
"In C2C12 myotubes, however, we found no effect of IGF-1 stimulation on the functional interaction between TSC1 and TSC2, even though the phosphorylation level of TSC2 was altered."

reach
"How mutations in TSC1 and TSC2 contribute to HNSCC may be revealed by the function of the TSC1 and TSC2 complex."

reach
"Through its GAP activity, the TSC1 and TSC2 complex inhibits the ability of Rheb to activate mTOR complex 1 (mTORC1 or the mTOR, Raptor, and mLST8 complex), a critical promoter of cell growth and proliferation."

reach
"mTORC1 signalling is inhibited on HIF-1 activation, through transcription of REDD1, which activates the TSC1 and TSC2 complex, resulting in mTORC1 inhibition."

reach
"In this study, we showed that FIP200 can also regulate cell size through interaction with the TSC1 and TSC2 complex and activation of S6K."

sparser
"The TSC1 and TSC2 complex is known to interact with several protein-binding partners."

reach
"The TSC-1/TSC-2 protein complex (Plank et al., 1998; van Slegtenhorst et al., 1998) negatively regulates the mammalian target of rapamycin (mTOR) pathway, which is triggered by growth factors as well as nutrients and regulates protein synthesis, autophagy, transcription cell growth, cell proliferation, cell motility (Hay and Sonenberg, 2004; Sarbassov et al., 2005)."

reach
"The activation of AKT suppresses the TSC1 and TSC2 heterodimer, which is an upstream regulator of mTOR."

sparser
"The TSC1 and TSC2 gene products form a functional complex and inhibit phosphorylation of S6K and 4EBP1."

sparser
"They manifest in about 84% of mutated patients (47.2% with mutated TSC1 gene and 52.8% with mutated TSC2 gene), but only in 14% of patients without TSC1 or TSC2 mutations [ xref ], suggesting that the inactivation of the hamartin-tuberin complex, and the subsequent hyper-activation of mTOR signaling, may have a direct role in the development of SBLs, as the studies described above also appear to confirm."
| PMC

reach
"In the fission yeast Schizosaccharomyces pombe, the Tsc1 and Tsc2 complex is a homologous protein complex of human tuberous sclerosis complex (TSC), TSC1 and TSC2, a GTPase activating protein for the Rheb small GTPase, which is involved in cell growth through the regulation of mechanistic target of rapamycin complex (mTORC1) signaling."

reach
"This GTPase is under the negative control of the heterodimeric tumor suppressor complex TSC1 and TSC2."

reach
"First, AMPK phosphorylates TSC2, enhancing the Rheb-GTPase activator function of the TSC1 and TSC2 complex and thus converting the G protein Rheb, an upstream activator of mTORC1, to its inactive GDP bound form."

reach
"Tuberin, the protein product of tuberous sclerosis gene 2 (TSC2), is the functional component of the TSC1 and TSC2 complex and regulates cell cycle through activation of the cyclin dependent kinase inhibitor p27."

reach
"Hamartin and tuberin form a complex that activates the GTPase activating protein Rheb to inhibit the mammalian target of rapamycin (mTOR)."

reach
"Inactivation of the TSC1 and TSC2 complex results in activation of mTOR and phosphorylation of the mTOR targets p70 S6 kinase (S6K), ribosomal protein S6 and 4E-BP1 [XREF_BIBR]."

reach
"These two proteins interact in the Golgi complex, and the hamartin and tuberin complex acts as a tumor-suppressor protein through the Ras homologue enriched in brain protein to limit activation of the mammalian target of rapamycin (mTOR) complex 1."

sparser
"Akt-driven phosphorylation prevents TSC1TSC2 localization to intracellular membranes."

reach
"The hamartin and tuberin complex converts the active guanosine triphosphate bound form of Rheb into its guanosine diphosphate bound state, preventing it from interacting and stimulating mTOR complex 1 [XREF_BIBR]."

sparser
"Tsc1 forms a complex with Tsc2 that functions as a GAP towards the obligatory activator of mTORC1 Rheb."

reach
"As a result of this effect, a feedback loop is initiated whereby activation of mTORC1 results in activation of S6K, which in turn downregulates the IRS, PI3K and Akt, and Ras and ERKs, thus diminishing their effect on the TSC1 and TSC2 complex and ultimately restoring the basal activity of mTORC1."

reach
"As TSC1 and TSC2 complex is an activator of mTORC2 signaling and a repressor of mTORC1 and Rheb is an activator of mTORC1 signaling, this data suggests that mTORC2 signaling may be more prominent in ERalpha + and mTORC1 signaling may be more prevalent in ERalpha - breast carcinomas."

sparser
"Studies using yeast two-hybrid analysis and coimmunoprecipitation have provided evidence that TSC1 and TSC2 proteins interact in a complex ."

reach
"ERK is activated in response to growth factors and can directly phosphorylate TSC2, disrupting the TSC1 and TSC2 complex, thereby increasing mTOR activity XREF_BIBR."

reach
"To address this issue, we examined the influence of chronic unpredictable stress (CUS) on REDD1 (DDIT4, RTP801), which stabilizes the TSC1 and TSC2 complex, inhibiting mTORC1 dependent protein synthesis and cell growth (10) (XREF_FIG)."

reach
"TR3 interacts with the TSC1 and TSC2 complex to regulate mTORC1 activity."

reach
"We also observed that overexpression of FIP200 alone increased S6K phosphorylation, possibly through its interaction with the endogenous TSC1 and TSC2 complex (XREF_FIG A, compare lanes 1 and 2)."

reach
"AKT mediated phosphorylation of TSC2 results in the degradation of the TSC1 and TSC2 complex, which regulates mTOR and thereby S6K [68]."

reach
"As the TSC1 and TSC2 complex is required for REDD1 induced mTORC1 inhibition, these results would provide an explanation for mTORC1 activation in these cells despite high REDD1 levels."

reach
"Since the TSC1 and TSC2 complex promotes conversion of RHEB-GTP to RHEB-GDP, this results in the cessation of mTORC1 activity."

reach
"Control of the TSC1 and TSC2 complex also is overseen through Akt and its phosphorylation of TSC2."

reach
"The formation of VPS34 and TSC1 complex at the plasma membrane disengages TSC2 from the TSC1 and TSC2 heterodimer, leading to TSC2 ubiquitination and degradation."

sparser
"According to some studies, 70–90% of children with CR have TSC, a multi-system autosomal dominant disorder. xref Tuberous sclerosis complex is reported in 1/6000 to 1/10 000 live births. xref Mutations in TSC1 and TSC2 genes (encoding for hamartin and tuberin , respectively) account for the majority of cases. xref , xref Abnormal hamartin-tuberin tumour suppressor proteins imply in ubiquitous loss of control over cell cycle progression. xref , xref Indeed, TSC most common findings are benign tumours (hamartomas) in the skin, brain, heart, lung, and kidneys. xref However, clinical spectrum is wide and syndrome’s recognition relies on diagnostic criteria ( xref ). xref "

sparser
"Tuberin and hamartin form a complex that regulates signaling through the mammalian target of rapamycin (Rheb/mTOR/p70S6K) pathway, which controls processes such as cell growth, cell cycle progression and apoptosis."

reach
"S. pombe contain homologues for Rheb, a GTP binding protein, and an upstream activator of mTOR [XREF_BIBR], as well as the TSC1 and TSC2 complex that negatively regulates Rheb [XREF_BIBR, XREF_BIBR, XREF_BIBR]."

reach
"As a result, the TSC1 and TSC2 complex is phosphorylated inhibiting its GAP activity towards Rheb, thus freeing it for mTORC1 activation."

reach
"Thus the Ser20Asn and Asp60Ile mutations markedly reduce and may eliminate Rheb binding of guanyl nucleotide.Biochemical and genetic evidence establish that the ability of the TSC1 and TSC2 heterodime[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Conversely, the Akt, ERK1/2 and IKKbeta pathways inhibit the TSC1 and TSC2 complex in response to growth factors and cytokines XREF_BIBR - XREF_BIBR."

reach
"The importance of these proteins is confirmed by their ubiquitous character and by the fact that TSC1 and TSC2 complex is involved in the regulation of the activity of mTOR, a master controller of protein translation."

sparser
"In this report, we demonstrate an interaction between hamartin and tuberin, which is detectable at endogenous protein levels."

sparser
"It has been shown that human TSC1 protein binds to the TSC2 protein (Plank et al., 1998; van Slegtenhorst et al., 1998) ."

sparser
"Similar experiments showed that overexpression of the FIP200 N1-859 segment can also decrease TSC1TSC2 interaction, whereas overexpression of the N1-638 segment did not ( xref B)."

reach
"Pengbo Guo and colleges reported that TRIM31 exerted its oncogenic effect and promotes anoikis resistance through promoting the E3 ligase-mediated K48-linked ubiquitination of the TSC1TSC2 complex or regulation of the p53-AMPK axis, respectively (15, 16)."

reach
"Importantly, within the network of signaling pathways that regulate mTORC1 activity upstream of the TSC1 and TSC2 complex are numerous oncogenes and tumors suppressors, including those most commonly affected in human malignancies (XREF_FIG)."

reach
"This makes the TSC1 and TSC2 complex unable to inactivate Rheb, promoting mTORC1 activation."

reach
"TSC1 exists in a complex with TSC2 and functions primarily as a key negative regulator of mammalian target of rapamycin complex 1 (mTORC1) signaling and protein synthesis, although the TSC1 and TSC2 complex also shows mTORC1 independent outputs to other pathways."

reach
"By phosphorylating TSC2, AKT makes the complex TSC1 and TSC2 inactive, thus indirectly stimulating mTor kinase activity."

sparser
"This parallel dimerization of TSC1 leads to an asymmetric formation of TSC1TSC2 tetramer and recruitment of a single TBC1D7 molecule, generating a unique and characteristic modular organization (Fig.  xref and Supplementary Fig.  xref )."

reach
"Indeed transgenic expression of TSC1 stabilizes the TSC1 and TSC2 complex and causes muscle wasting."

reach
"TBC1D7 (a third subunit of the TSC1 and TSC2 complex 23) was also found in the peroxisome fraction (XREF_FIG and XREF_SUPPLEMENTARY), whereas AKT was detected in cytosolic (primarily) compartments (XREF_FIG and XREF_SUPPLEMENTARY)."

reach
"Tuberin and Hamartin form a heterodimer that inhibits cell growth and proliferation [3-6]."

reach
"This is achieved through AMPK phosphorylation of the ULK1 and TSC1 and TSC2 complex that consequently acts on mTORC1 activation as we described earlier [XREF_BIBR, XREF_BIBR]."

reach
"These results imply that Tsc1 and Tsc2 complex plays a role in regulating the quiescence and activation of follicles."

reach
"Following growth-factor stimulation, activated Akt suppresses the GTPase activating protein (GAP) activity of the tumor suppressor TSC2 and TSC1 complex by phosphorylating TSC2 (Gao et al., 2002; Inok[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"The disease is caused by heterozygous mutations in the genes encoding TSC1 or TSC2 proteins that together form the TSC1/2 complex."

reach
"The hamartin and tuberin complex is involved in at least three signaling pathways : the PI3K-Akt pathway, the ERK1/2-RSK 1 pathway, and the LKB1-AMPK pathway."

reach
"Genetic studies in mammalian systems [XREF_BIBR] and Drosophila [XREF_BIBR, XREF_BIBR] showed that the TSC1 and TSC2 complex inhibits cell growth in both mass or size and cellular proliferation thus exerting a positive control of apoptosis [XREF_BIBR, XREF_BIBR]."

reach
"Consistent with the in vivo interaction, we also found that Erk phosphorylation of TSC2 could directly cause disruption of the TSC1 and TSC2 complex, but not the TSC1-TSC2 S664A and S540A complex in v[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"The hamartin and tuberin complex regulates mTORC1 negatively through its actions on Rheb (Ras homolog enriched in brain)."

No evidence text available

reach
"Signaling pathways, comprised of a number of oncogenes and tumor suppressors, converge on the TSC1 and TSC2 complex to properly regulate Rheb and mTORC1."

reach
"The mechanism by which mTORC1 is regulated by tumor suppressor complex TSC1 and TSC2, LKB1 and PTEN signaling led to a growing appreciation that mTORC1 mediates three major inputs from growth factors, amino acids and ATP, and is a master regulator of cell growth and metabolism."

reach
"TSC2 phosphorylation by AKT inhibits the GTPase activity of the TSC2 and TSC1 heterodimer allowing the Rheb and GTP complex to bind and activate mTOR (XREF_FIG)."

reach
"A possible function of the interaction between 14-3-3 proteins and phosphorylated tuberin is to inhibit the formation of tuberin and hamartin complex, in order to decrease the stability of tuberin and release of the activated mTOR [XREF_BIBR]."

reach
"ERK phosphorylates TSC2 on Ser 664 in vitro and in vivo, which leads to TSC1 and TSC2 complex disassembly and derepression of mTORC1 signalling [XREF_BIBR]."

reach
"However, the TAD construct, which does not interact with the TSC1 and TSC2 complex, had no effect on S6K1 phosphorylation (XREF_FIG)."

reach
"The effects of amino acid changes on TSC1 and TSC2 complex formation, on the activation of rheb GTPase activity by the complex, and on the phosphorylation status of S6K and S6, the downstream effectors of mTOR, can be determined [XREF_BIBR, XREF_BIBR]."

sparser
"Under energy stress conditions, AMPK activates autophagy phosphorylating the autophagy regulator ULK1, while inhibits mTORC1 phosphorylating Raptor and the TSC1-TSC2 complex ( xref )."

sparser
"These two proteins bind to each other, via their respective coiled-coil domains, to form an intracellular hamartin-tuberin complex that negatively regulates the Mammalian Target of Rapamycin Complex 1 (mTORC1) signaling, which is a major regulator of anabolic cell growth."
| PMC

reach
"This initiates a phosphorylation cascade, which activates the protein kinase B. Protein kinase B then inhibits the TSC1/TSC2 complex, resulting in cell growth and proliferation."

reach
"The activation of PI3K and phosphorylation of Akt at Thr308 lead to the phosphorylation and inhibition of TSC1 and TSC2 complex and PRAS40."

reach
"Association of FIP200 with the TSC1 and TSC2 complex."

reach
"Loss of mTORC2 activity in cells lacking the TSC1 and TSC2 complex, coupled with mTORC1 mediated feedback mechanisms, leads to strong attenuation of the growth factor stimulated phosphorylation of Akt on S473."

reach
"Here, we discuss the molecular relationship between Akt and the mTOR complexes, with a focus on the critical regulatory role of the TSC1 and TSC2 complex (summarized in XREF_FIG)."

"In turn, Akt phosphorylates the tuberous scleorisis complex, TSC1/TSC2 (hamartin/tuberin) that serves as a GTPase activating protein (GAP) for the small G protein, Ras homolog enriched in brain (Rheb)."

No evidence text available

reach
"Since mTORC2 has been implicated in the phosphorylation of hydrophobic motifs on a number of AGC family kinases, we examined the phosphorylation of these motifs in cells lacking either the TSC1 and TSC2 complex (Tsc2 -/- MEFs) or mTORC2 (Rictor -/- MEFs), using a phospho specific antibody that recognizes the phosphorylated hydrophobic motif."

reach
"TSC2 is phosphorylated and inactivated by Akt and the TSC1 and TSC2 complex negatively regulates the kinase mTOR."

reach
"The GTPase activating protein (GAP) for RHEB is the tumour suppressor tuberous sclerosis complex TSC1 and TSC2."

sparser
"The gene products Tsc1 and Tsc2 form a heterodimer and promote nutrient uptake, such as amino acids and nucleotides through regulation of localization and expression of transporters, such as amino acid transporter [ xref – xref ]."

reach
"In addition to AMPK, glycogen synthase kinase (GSK) 3β is a potent activator of the TSC1/TSC2 complex and so can also contribute to dampening of mTORC1 activity during times of cellular stress (see Figure 1 for summary of signaling)."

reach
"The other major role of Akt is to activate mTOR through a series of biochemical steps beginning with the phosphorylation of TSC2 in the TSC1 and TSC2 complex."

reach
"IR, PI3K, Akt, and PTEN, are sitting upstream of the TSC1 and TSC2 complex, while mTOR and S6K are sitting downstream of the complex, as shown in XREF_FIG [XREF_BIBR]."

reach
"These observations indicate that aberrant function of the hamartin and tuberin complex, but not overstimulation of growth factors, may play a major role in the tumorigenesis of FPs."

reach
"Growth factor stimulation inhibits the GAP activity of TSC1 and TSC2 complex to promote Rheb GTP binding, which activates mTORC1 signaling."

reach
"Collectively, TSC1 and TSC2 complex positively regulates miR-125b-5p expression."

No evidence text available

reach
"AKT signals through direct phosphorylation of the TSC1 and TSC2 complex to indirectly activate mTORC1."

reach
"Hypoxic oxygen levels inhibit mTORC1 by activating the TSC1 and TSC2 complex through two different pathways."

sparser
"In addition, AICAR increased the amount of TSC1 bound to TSC2 ( xref ), suggesting increased GTPase activity and inhibition of Rheb."

reach
"Co-depletion of CUL4A+ B resulted in prolonged stabilisation of TSC2 potentially reinforcing inhibitory signalling from TSC1 and TSC2 complex towards mTOR (Hu et al., 2008)."

sparser
"It is negatively regulated by a complex formed by TSC1 and TSC2, and somatically acquired TSC1 mutations occur in ~5% of sporadic ccRCCs ( xref )."

sparser
"Subsequent stabilization of TSC1-TSC2 complex suppressed levels of Ras homolog enriched in brain-GTP (Rheb-GTP) as TSC2 acts as a GTPase-activating protein (GAP) toward Rheb."

reach
"However, additional studies are needed to clarify whether these effects are solely dependent on the presence of a functional TSC1 and TSC2 complex."

reach
"Loss of a functional hamartin and tuberin complex leads to increased activation of mTOR signaling and subsequent unregulated cell growth and proliferation."

reach
"The TSC1 and TSC2 proteins form a heterodimer that stimulates GTP hydrolysis by the small G protein Rheb, a crucial activator of mTOR in a rapamycin sensitive complex termed TORC1 [XREF_BIBR - XREF_BIBR]."

reach
"In contrast, the overexpression of A1 paralleled with the presence of no Mg 2+ or physiological [Mg 2+] (1 mM) in the bath solution significantly attenuates the phosphorylation of Thr 308 and Ser 473 of Akt and PKB in the + tet cells, and, hence, under this condition, the attenuated Akt and PKB activity leads to the increased stability of the TSC1 and TSC2 complex and the silencing of mTOR signaling (when compared with [Mg 2+] (10 mM); Figure XREF_FIG) [XREF_BIBR]."

reach
"Purifications of the TSC1 and TSC2 complex also corroborated the association to R2TP and PFDL as a number of subunits were detected."

reach
"Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products."

sparser
"In cells, hamartin and tuberin form a complex which inhibits the mammalian target of rapamycin (mTOR), a central controller of cell growth and proliferation."

reach
"The hamartin and tuberin complex is a modulator of the mTOR signaling pathway, which is important in the regulation of cell growth."

reach
"The TSC1 and TSC2 complex is a critical player in the control of mTOR, a master regulator of cellular metabolism."

sparser
"Nevertheless, data presented in this study strongly suggest that FIP200 regulates cell size through its interaction with the TSC1TSC2 complex."

reach
"Interestingly, in TSC -/- cells, amino acid deprivation still impairs the mTORC1 signaling, suggesting that amino acid regulate the activity of mTORC1 through a mechanism that is independent of TSC1 and TSC2 complex [XREF_BIBR]."

reach
"As expected, delayed inactivation of mTORC1 in response to osmostress was also observed in MEFs lacking the TSC2 binding partner TSC1 (XREF_SUPPLEMENTARY)."

"Recently, it has been demonstrated that TSC1.TSC2 functions to inhibit ribosomal S6 kinase and negatively regulate cell size."

reach
"The TSC1 and TSC2 complex works as a GTPase activating protein (GAP) for RHEB (leading to GTP hydrolysis), a small GTPase that is required to activate mTORC1."

reach
"Moreover, CCL5/CCR5-mediated-PI3K/AKT phosphorylates TSC-2 at Thr1462, thereby prevent the formation of TSC-1/TSC-2 complex."

sparser
"TSC1 and TSC2 proteins form a physical and functional complex in vivo."

reach
"A role for the tuberin and hamartin complex in intracellular transport was suggested by recent findings that polycystin-1, an integral membrane component of basolateral adherens junctions, was misloca[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"In addition, the results confirm that phosphorylation may play an important role in the formation of the tuberin and hamartin complex."

reach
"The hamartin and tuberin complex functions normally as a tumor suppressor through negative regulation of translation."

sparser
"From there, AKT can phosphorylate a number of targets such as the tuberous sclerosis 1 and 2 (TSC1-TSC2) complex, mammalian target of rapamycin complex 1 (mTORC1) and Caspase 9, thereby promoting protein synthesis and survival ( xref , xref )."

reach
"In this study, we show that endoplasmic reticulum (ER) stress regulates TSC1 and TSC2 complex to limit mTOR activity."

reach
"The inhibitory function of the tuberin and hamartin complex results from tuberin 's GTP-ase activity on Rheb, which directly regulates mTOR kinase activity [XREF_BIBR]."

reach
"Interestingly, in the present study, we saw relatively little effect of Lkb1 deletion on mTOR signaling in the presence of Tcf7l2 despite the predicted activation of the downstream TSC1 and TSC2 complex in the absence of AMPK activity."

reach
"A heterodimer TSC1 and TSC2 consisting of the TSC1 and TSC2 gene products functions as a GTPase activating protein for Rheb converting GTP bound form to a GDP bound form."

sparser
"Demonstration of physical interaction by co-immunoprecipitation of tuberin and hamartin indicates that these genes were functional in SV7 tert cells (data not shown)."

No evidence text available

sparser
"These two genes encode for the proteins TSC1 and TSC2 that form a multimeric complex together with the protein TBC1D7 ( xref ), which represses mTOR complex 1 (mTORC1) signaling."

reach
"In TSC, loss of function of the TSC1 and TSC2 complex causes activation of mTORC1, inducing cellular growth."

sparser
"Because AMPK is located at the center of multiple established tumor suppressor networks including LKB1, TSC1TSC2 complex and p53, it is recognized to play a pivotal role in cancer progression xref ."

reach
"Fibroblasts deleted of the tuberous sclerosis complex TSC2 gene, a major negative regulator of mTORC1, were unable to inhibit mTORC1 in acidic extracellular conditions, showing that the TSC1 and TSC2 complex is required for this response."

reach
"mTOR activates p53 by either increasing its protein synthesis or its stability, which increases the GAP activity of the Tsc1 and Tsc2 complex via AMPK and sestrin 1/2 [XREF_BIBR, XREF_BIBR]."

reach
"Deletion, nonsense, or missense mutations of TSC1 and TSC2 lead to loss of function of the TSC1 and TSC2 complex and constitutive activation of mTOR signaling."

sparser
"With respect to the genetics of tuberous sclerosis complex, functional mutations in either TSC1 or TSC2 have been associated with the disease, and TSC1 and TSC2 are thought to have complementary roles [ xref ]."

sparser
"In this study, we showed that FIP200 can also regulate cell size through interaction with the TSC1TSC2 complex and activation of S6K. These results identify FIP200 as a regulator that plays roles in both cell proliferation and cell size control."

reach
"Although multiple regulatory phosphorylation sites are known to exist for TSC1, control of the TSC1 and TSC2 complex can be regulated though pathways that include Akt and AMP activated protein kinase (AMPK) that phosphorylate TSC2."

reach
"The identification of the role of the TSC1 and TSC2 complex in regulating signal transduction through mTOR has made it possible to assess the activity of different TSC1 and TSC2 variants."

sparser
"Study of cultured cell lines transiently expressing the mutant proteins showed that these missense variants affected the formation or function of the TSC1-TSC2 complex, thereby inducing hyperactivation of the mTOR pathway."

reach
"mTORC1 is activated by the Rheb GTPase, which, in turn, is inhibited by the TSC1 and TSC2 complex."

reach
"A study of tumor-suppressor genes used tsc1 and tsc2 as subjects to investigate whether the Rap1 could be a link between the hamartin and tuberin complex (TSC1-TSC2) and mTORC1."

reach
"When both alleles contain mutations, the result is biallelic inactivation, thus reducing the function of the TSC1 and TSC2 complex."

reach
"Wang et al., (2006) [XREF_BIBR], showed that dexamethasone increases REDD1 expression in skeletal muscle, which subsequently activates the tuberin and hamartin complex and suppresses mTOR activity."

reach
"This is consistent with our previous report that mitochondrial FAO deficiency induced a low-energy state in skeletal muscle of Cpt1b m-/- mice that activated AMPK (Wicks et al., 2015) but extends thes[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Most promisingly, the hamartin and tuberin complex has been shown to function as a negtive regulator of the insulin receptor and phosphoinositide 3-kinase/S6 kinase pathway."

reach
"Recent studies have identified the TSC1 and TSC2 complex as a key regulator of cell size control."

reach
"The phosphorylation of TSC2 at T1462 was also reduced promoting its inhibitory GTPase activating role within the mTORC1 regulatory complex TSC1 and TSC2."

reach
"In the brains of healthy individuals, phosphoinositide 3 kinase (PI3K) activates mTORC1 via AKT by phosphorylating the tuberous sclerosis complex (TSC2)-2, which in turn inhibits function of the TSC1 and TSC2 complex, negatively regulates conversion of Ras homolog enriched in brain (Rheb) [XREF_BIBR]."

sparser
"As a result, the TSC1TSC2 complex downregulates a small G-protein Rheb."

reach
"AKT, however, can inhibit TSC1 and TSC2 complex through phosphorylation."

reach
"NT mutations to this central region have been shown to affect the activity of the TSC1 and TSC2 complex, but do not appear to affect TSC1-TSC2 binding, and map outside the GTPase activating protein (G[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"Our data show for the first time that 1) tuberin is phosphorylated at tyrosine and serine residues, 2) TSC1-TSC2 interaction is regulated by tuberin phosphorylation, and 3) defective phosphorylation of tuberin is associated with loss of its tumor suppressor activity."

reach
"Because TSC and LAM disease severity is predominantly associated with the loss of TSC2 function, the perturbed balance between TSC2 and TSC1 interaction could be a key event in the pathobiology of TSC and LAM."

sparser
"TSC1 and TSC2 form a heterodimeric complex (TSC1/2) that receives signals from protein kinase B(Akt) xref – xref , extracellular signal-regulated kinase (Erk1/2) xref , xref , 5′ adenosine monophosphate activated protein kinase (AMPK) xref , TNFα-IκB kinase β signaling xref , and glycogen synthase kinase-3β (GSK3β) xref ."

sparser
"One direct substrate that is inhibited by Akt-mediated phosphorylation is the tuberous sclerosis complex 2 (TSC2) protein, which associates with TSC1 and acts as a critical negative regulator of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1)."

reach
"Downstream Akt lies the TSC1 and TSC2 complex (Tuberous Sclerosis Complex1/2) that constitutively represses mTORC1 activity."

sparser
"TSC1 forms a complex with TSC2 and its mutations were found in a number of bladder cancer cases as well xref ."

reach
"How the binding of TSC1 and TSC2 might result in an activity that neither alone contains is unclear."

sparser
"Hamartin and tuberin bind together to form a complex that normally inhibit the mTOR pathway and consequently prevent excessive cell growth and proliferation."

reach
"To avoid co-purification of endogenous mTORC2, we washed the immunoprecipitates with a high salt wash buffer found previously to disrupt binding of mTORC2 to the TSC1 and TSC2 complex."

reach
"The tuberin/hamartin complex can also associate with and positively regulate mTORC2 (Wullschleger et al., 2006; Dann et al., 2007; Guertin and Sabatini, 2007; Yang and Guan, 2007)."

reach
"However, a direct inhibition of TORC1 by Vps34, an essential gene which channels amino acid availability to the Tsc1 and Tsc2 complex, has been reported in yeasts and mammals [XREF_BIBR, XREF_BIBR]."

reach
"When the TSC1 and TSC2 complex is not functional, uncontrolled mTORC1 activity accelerates the cell cycle and triggers tumorigenesis."

sparser
"The quiescence of primordial follicles is maintained by several molecules including phosphatase and tensin homolog deleted on chromosome 10 (Pten), tuberous sclerosis complexes 1–2 (Tsc1Tsc2) complex, Forkhead box protein O3A (Foxo3A), p27, anti-Müllerian hormone (AMH), and Forkhead box L2 (FoxL2) [ xref ]."

reach
"Indeed, ERK1/2 can directly phosphorylate TSC2 on Ser664 leading to disruption of the TSC1 and TSC2 complex, TSC2 inactivation and mTOR activation [34]."

reach
"The TSC1 and TSC2 complex normally inhibits mTOR activity, with loss of function mutations resulting in overactive mTOR and consequential increased protein synthesis and decreased protein degradation [XREF_BIBR, XREF_BIBR, XREF_BIBR]."

reach
"TSC1 and TSC2 form a dimer (TSC1 and TSC2) that regulates mTOR activity indirectly."

sparser
"When expressed in HEK293 cells, TSC2-R622W did not bind to TSC1, in contrast to wild type TSC2, as assessed by a co-immunoprecipitation assay ( xref )."

reach
"For example, TRIM31 indirectly overactivates the mTORC pathway by ubiquitinating the TSC1 and TSC2 complex to promote hepatocellular carcinoma progression."

sparser
"22 In addition, the interaction of TSC1 and TSC2 genes is complicated."

reach
"Therefore, we investigated whether FIP200 could affect TSC1 and TSC2 complex formation to understand the mechanisms by which FIP200 regulates TSC1-TSC2 activity as shown in the aforementioned studies."

reach
"AMPK inhibits the TORC1 complex by increasing TSC1 and TSC2 complex activity through direct phosphorylation of TSC2, as well as inhibiting substrate recruitment to TORC1 via phosphorylation of Raptor [XREF_BIBR, XREF_BIBR]."

sparser
"TSC1 and TSC2 proteins bind to each other to form a complex that regulates protein synthesis and cell size ( xref )."

reach
"This TSC-Rheb-TOR trio has emerged as a core element of the pathway in metazoans, with the TSC1 and TSC2 complex in particular acting as a convergence point for multiple signals that govern TOR."

reach
"The serine/threonine kinase PKB and Akt is a key positive upstream regulator of mTORC1 that directly phosphorylates and inhibits the TSC1 and TSC2 complex."

reach
"To examine if the inhibition of the mTORC1 pathway in the absence of perlecan is growth factor dependent, we investigated the activation of the ERK1/2 pathway, which can be activated by insulin like g[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Moreover, some factors, such as low oxygen and energy levels, can also in some degree act on mTORC1 through TSC1 and TSC2 complex, which is controlled by LKB1 and SKT1-AMPK pathway (Yip, 2015)."

reach
"Activated AMPK phosphorylates TSC2 at Thr 1227 and Ser 1345 and increases the activity of TSC1 and TSC2 complex to inhibit mTOR XREF_BIBR."

sparser
"Hamartin and tuberin associate physically in vivo what makes it very likely that these two proteins function in the same complex [4,5] ."

reach
"AMPK phosphorylation of TSC1 activates the TSC1-TSC2 complex, in turn inhibiting mTORC1 through its Rheb-GAP activity [20,25]."
| PMC

reach
"XREF_BIBR, XREF_BIBR The hamartin and tuberin complex is an important inhibitor of tumor growth; its absence triggers the loss of proliferation and cell migration inhibition."

reach
"Previously, we demonstrated direct binding between tuberin and hamartin."

sparser
"TSC1 and TSC2 form a membrane-bound tumor suppressor complex, in which TSC1 functions as the regulatory component stabilizing TSC2 and facilitating the catalytic activity of TSC2 as a GAP for the small GTPase Rheb, a positive regulator of mTORC1, cell growth and proliferation xref , xref ."

reach
"Our results suggest that amino acid residues within the N-terminal region of TSC1 are important for TSC1 function and for maintaining the activity of the TSC1 and TSC2 complex."

reach
"In addition, DAPK1 is involved in activating the mTOR pathway by breaking the TSC1 and TSC2 complex in the p53-mutant triple receptor negative breast cancer [XREF_BIBR]."

reach
"In the present study, gel filtration experiments using cell extracts obtained by hypotonic lysis [XREF_BIBR] indicate that TSC1 and TSC2 form complexes up to ~ 1 MDa in size, suggesting that our previous analysis underestimated the size of the TSC1 and TSC2 complex."

reach
"Phosphorylation of TSC2 by Akt releases the inhibitory effect of the TSC1 and TSC2 complex on the Ras family GTPase, Rheb XREF_BIBR, XREF_BIBR."

sparser
"The TSC1 and TSC2 proteins form a heterodimeric complex, which regulates the mammalian target of rapamycin (mTOR) complex 1."

reach
"LKB1, AMPK, TSC1 and TSC2 complex, and PTEN in mTOR signaling pathways can induce autophagy, while Akt and Rheb have an inhibitory effect."

reach
"The TSC1 and TSC2 heterodimer functions as a negative regulator of the protein kinase mammalian target of rapamycin (mTOR), a key regulator of protein synthesis that is known to be critical for synaptic plasticity and memory."

reach
"Simultaneously, DAPK1 could regulate cell growth by modulating TSC1 and TSC2 complex formation via the mechanistic target of rapamycin (mTOR) pathway."

reach
"den Ouweland A, Reuser A, Sampson J, Halley D, van der Sluijs P : Interaction between hamartin and tuberin, the TSCI and TSCP gene products."

reach
"We have shown that Akt regulates the Tsc1 and Tsc2 complex by directly phosphorylating Tsc2."

reach
"PI3K signaling connected via Akt, by direct phosphorylation of TSC2, can block the TSC1 and TSC2 complex inhibitory action on mTORC1 activity."

reach
"Among identified interactors of the R2TP and PFDL complex were several protein subunits of the U5 snRNP (AAR2, EFTUD2, PRPF8 and SNRNP200) and the TSC1 and TSC2 complex (TSC1, TSC2 and TBC1D7)."

reach
"The TSC1-TSC2 complex, a tumor suppressor, forms when TSC1 and TSC2 bind via their coiled-coil domains to form an intracellular complex, which helps switch the protein Ras homolog enriched in brain (Rheb) from its active state, Rheb-GTP, to its inactive state [10]."
| PMC

reach
"The TSC1 and TSC2 complex is negatively regulated by Akt1 function and this complex in turn negatively attenuates RHEB function in its activation of TOR."

reach
"Therefore, AKT functions in the activation of mTOR signaling through both direct phosphorylation of mTOR protein and inhibition of the TSC1/TSC2 complex.Over the past several decades, strenuous efforts have been made in the development of new targeted therapy using small molecule inhibitors against the PI3K/AKT pathway, which specifically targets toward PI3K, AKT, or mTOR."

reach
"Another HIF1 dependent gene, bNIP3, has also been implicated in hypoxia dependent mTORC1 inhibition, because it decreases the activity of RHEB (Li et al., 2007), a small GTPase necessary for mTORC1 ac[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Activated Akt phosphorylates several downstream substrates, including TSC1 and TSC2 complex, thereby activating mTORC1 and downstream effectors of mTORC1 [XREF_BIBR, XREF_BIBR]."

reach
"Consequently, the inactivation of TSC1/TSC2 complex caused by phosphorylation of TSC2 induces mammalian target of rapamycin complex (mTORC1), another key mediator of PI3K/Akt pathway [43,46,47]."

reach
"DDIT4 Inhibits the Activity of mTOR VIA Tuberous Sclerosis Complex (TSC1 and TSC2 Complex)."

reach
"Since the TSC1 and TSC2 complex and RHEB are the upstream molecules responsible for the regulation of mTOR activity, we investigated whether the regulation of mTOR function by TNFalpha and IKKbeta sig[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"The hamartin and tuberin complex inhibits the mammalian target of rapamycin pathway, which controls cell growth and proliferation."

reach
"Collectively, these results demonstrate that endocytosis is critical for Slimfast down-regulation in response to reduced TOR signaling, resulting either from poor nutrient conditions or inactivation by the TSC1 and TSC2 complex."

No evidence text available

sparser
"Loss of heterozygosity at the TSC1 or TSC2 locus and hyperphosphorylation of ribosomal protein S6 has been documented in each of the three cellular components of angiomyolipomas [ xref ], suggesting that they may arise from a common progenitor and that the TSC1TSC2 complex regulates the differentiation of cells that are derived from the mesenchyme."

reach
"AKT regulate protein synthesis by phosphorylating the tuberous sclerosis complex 2 (TSC2) protein tuberin, and therefore inhibits the GTPase activating protein (GAP) activity of the TSC1 and TSC2 complex toward Rheb."

sparser
"Mutations in TSC1 or TSC2 are associated with the disease tuberous sclerosis complex (TSC), characterized by the formation of hamartomas in multiple organs."

reach
"Furthermore, in insulin- or serum stimulated cells, activation of p70S6K is inhibited by expression of the Tsc1 and Tsc2 complex [54,55]."

No evidence text available

sparser
"Thus, AMP-independent activation of AMPK on lysosomes may be an early event following glucose starvation that is important not just to activate catalytic pathways, but to induce mTORC1 inactivation through AMPK-dependent phosphorylation of the mTORC1 subunit Raptor [ xref ] and the TSC-1-TSC2 complex [ xref ], allowing rapid autophagy induction."

reach
"A negative regulation of mTOR activity involves AMPK (5 '-AMP-activated protein kinase), which inhibits mTOR actions through phosphorylation and activation of TSC1 and TSC2 complex [XREF_BIBR, XREF_BIBR]."

sparser
"Under conditions of energy depletion, 5′-AMP-activated protein kinase (AMPK) is a central energy sensor that participates in the inhibition of MTORC1 by TSC1-TSC2, and AMPK has also been found defective in a variety of human cancers [ xref ]."

reach
"Similar to the other small GTPases, Rheb1 protein has two forms of existence : inactive GDP bound and active GTP bound states, and may be deactivated by Tsc1 and Tsc2 complex XREF_BIBR, XREF_BIBR."

reach
"Activated PKB and AKT further activates mTOR (an autophagy inhibitor) through inhibiting the TSC1 and TSC2 complex, a repressor of the mTOR activating protein Rheb."

sparser
"It inhibits mTORC1 indirectly through the phosphorylation of Tuberous sclerosis 2 (TSC2), thus favoring a TSC1-TSC2 association, an upstream inhibitor complex of mTORC1."

reach
"Together, our data reveal that FoxOs operate in parallel to the TSC1 and TSC2 complex to regulate mTORC1 and cell survival under energy stress."

sparser
"TSC2 forms a heterodimeric complex with TSC1 and negatively regulates mTOR ( xref )."

reach
"In contrast, the three TSC2 GAP domain point mutants were unable to repress Rheb induced S6K1 activation, revealing that the GAP domain of Tuberin is critical for Tuberin 's ability to repress Rheb me[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"The TSC1 and TSC2 complex suppresses mTOR activity through its interaction with Rheb by an Akt independent mechanism [148]; TSC2 accomplishes this by functioning as a Rheb GTPase, resulting in the ina[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Oversight of the TSC1 and TSC2 complex also is controlled through phosphoinositide 3-kinase (PI 3-K), Akt, and its phosphorylation of TSC2."

reach
"Other studies have shown that ERK activation, downstream from PKA activation, leads to phosphorylation of tuberin preventing its association with hamartin and the inhibition of Rheb and mTOR by the tuberin and hamartin complex [XREF_BIBR, XREF_BIBR]."

reach
"The activity of the TSC1 and TSC2 complex towards Rheb and mTORC1 is tightly regulated through phosphorylation of both proteins."

reach
"The TSC1 and TSC2 complex is the only known GTPase for Rheb, serving to reduce Rheb-GTP levels, and thereby inhibit activation of mTORC1, a protein complex consisting of mTOR, RAPTOR, and mLST8."

reach
"Inhibition of Tsc1 and Tsc2 heterodimers preserves an active GTP bound state of the protein Rheb (Ras homolog enriched in brain) and leads to an increase in mTORC1 activity [XREF_BIBR]."

sparser
"TSC1 and TSC2 form a complex that negatively regulates mTORC1."

sparser
"DDIT4 was mainly applied to restrain mechanistic target of rapamycin 1 (mTORC1) by maintaining the TSC1TSC2 inhibitory complex. xref The up‐regulation of DDIT4 has been reported as prognostic biomarker in AML. xref , xref SOCS2 was expressed in both normal HSC and AML‐LSC, xref and did its job by inhibiting the JAK/STAT pathway. xref Overexpression of SOCS2 was mostly associated with the advanced stages of chronic myeloid leukaemia. xref , xref , xref However, there were also studies showing that high expression of SOCS2 in paediatric AML patients had an inferior prognosis. xref Although not reported to be associated with the prognosis of AML patients, ADGRG1, NDST1, FHL1, FAM124B, NYNRIN and CALCRL had been reported to be related with several other cancers xref , xref , xref and might be potential novel prognostic factors of AML."

reach
"Activated AKT-mediated inhibition of TSC1-TSC2 complex also activates mTOR signaling [9, 38, 39]."

reach
"While in mammals AMPK phosphorylates the TSC2 and TSC1 complex and Raptor, TSC2 and the AMPK phosphorylation site in Raptor are missing in Arabidopsis and it is not yet clear whether TOR and SnRK1 pathways interact in a similar way."

reach
"Recent studies revealed that metabolism and excitability (in the case of neurons) of cells lacking Tsc1 and Tsc2 complex are changed, and these features may potentially be used to treat some of TSC symptoms."

sparser
"TSC1 and TSC2 form an obligate heterodimeric protein complex that functions downstream of PI3K/Akt signaling, and is a key regulator of the serine-threonine kinase TOR (Target of Rapamycin) xref , xref ."

reach
"TSC1 and TSC2 proteins form a complex in vivo which negatively regulates mTORC1 by acting as Rheb GAP (GTPase activation protein) that converts Rheb into an inactive GDP bound form [XREF_BIBR, XREF_BIBR]."

reach
"It is likely therefore, that silencing of the TSC1 and TSC2 complex constitutes a critical step toward translational activation of TOP mRNAs by amino acids."

sparser
"Activation of LKB1 and AMPK, AMPK-induced stabilization of TSC1-TSC2 (inhibitor of Rheb, an mTORC1 activator), and activation of the tumor suppressor p53[ xref ]."

sparser
"TSC1 and TSC2 proteins form a cytosolic heterodimer and exert their function as negative regulators of the mammalian target of rapamycin (mTOR) signaling pathway ( xref ; xref ; xref )."

reach
"Growth factors activate mTORC1 via phosphatidylinositol 3-kinase (PI3K), PDK1, Akt, the TSC1 and TSC2 complex, and Rheb, a small guanosine triphosphate (GTP)-binding protein that binds and activates m[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"To this end, it is interesting to note that 2 recent papers show that lack of amino acids triggers a rapid deactivation of MTORC1 by a mechanism involving the recruitment of its negative regulator, the tumor suppressor complex TSC1 and TSC2."

reach
"The TSC1 and TSC2 gene products, TSC1 and TSC2, form a complex that inhibits the mammalian target of rapamycin (mTOR) complex 1 (TORC1)."

sparser
"Furthermore, hypoxia also affects mTORC1 in AMPK-independent ways by inducing the expression of REDD1, which inhibits mTORC1 by promoting the assembly of TSC1TSC2 ( xref ) ( xref )."

reach
"Hamartin with alanine mutations in the three cyclin dependent kinase 1 phosphorylation sites increased the inhibition of p70S6 kinase by the hamartin and tuberin complex."

reach
"Here, we report that Drosophila melanogaster Akt and PKB stimulates growth by phosphorylating the tuberous sclerosis complex 2 (Tsc2) tumour suppressor and inhibiting formation of a Tsc1 and Tsc2 complex."

reach
"GTP bound RHEB is known to activate mTOR, whereas GDP bound RHEB loses its ability to activate mTOR, suggesting that the TSC1 and TSC2 complex can downregulate the mTOR pathway through suppressing RHE[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

sparser
"Deletion of exon 9 alone has been shown to disrupt TSC1TSC2 dimer formation and downstream inhibition of mTORC1 kinase activity ( xref ), supporting this fusion as indeed a loss of function variant."

reach
"Contradictory to these findings, we demonstrate that loss of TBC1D7 partially disrupts the association between TSC1 and TSC2, resulting in a decrease in Rheb-GAP activity."

reach
"Acting in the brain, the hamartin and tuberin complex is involved in neuronal arborization, which constitutes the regulation of spine density as a part of the PI3K-Akt-mTOR pathway [XREF_BIBR]."

reach
"By stimulating Rheb GTP hydrolysis, the TSC1 and TSC2 complex inactivates mTORC1 and restrains cell growth."

reach
"These results suggested that the TSC1 and TSC2 complex and its downstream target mTOR are required for FIP200 regulation of S6K phosphorylation."

sparser
"Recent evidence indicates that gliomas are formed by biallelic TSC1 or TSC2 gene inactivation, reflecting a double-hit mechanism according to which a germline or a somatic mutation (likely occurring during development) affects the non-mutated allele, producing ‘loss of heterozygosity’ xref ."

reach
"AMPK is a known autophagy promoting factor by activating the TSC1 and TSC2 complex XREF_BIBR - XREF_BIBR."

No evidence text available

sparser
"It is also of note to observe that the complex TSC1-TSC2 exerts its physiological action by negatively regulating Mammalian Target of Rapamycin (mTOR) signaling [ xref ], and that the ultimate target of the mTOR signaling pathway is the ribosome [ xref ]."

reach
"The binding of the 14-3-3 protein to the TSC1 and TSC2 complex prevents an inhibition of S6 kinase and the non phosphorylation of 4E binding protein 1, i.e., it causes a weakening of the PI3K/PKB/TOR pathway signaling [XREF_BIBR]."

sparser
"The activation of the TSC1-TSC2 complex may occur via the activation of AMP-activated protein kinase (AMPK) [ xref ] or regulated in development and DNA damage responses 1 (REDD1) [ xref ]."

reach
"Substantial breakthrough in mTOR research led to the identification of the Tuberous Sclerosis Complex (TSC1 and TSC2) as upstream negative regulators of mTOR [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR] TSC1 and TSC2 complex is negatively regulated by the serine/threonine kinase PKB and AKT downstream of the insulin signaling pathway (XREF_FIG) and has GTPase activating domain (GAP) in the C-terminus."

sparser
"Multiple upstream pathways stimulate or inhibit the mTOR pathway by interacting with the hamartin and tuberin complex to control important physiological functions."

reach
"First, knockdown of endogenous FIP200 by RNAi did not significantly promote endogenous TSC1 and TSC2 complex formation (XREF_FIG C)."

sparser
"Hamartin and tuberin form an intracellular complex which interacts with numerous cellular pathways."

reach
"However, FOXO proteins are not phosphorylated and remain nuclear, even in the presence of growth factors, in cells, tumors, and tissues lacking the TSC1 and TSC2 complex [XREF_BIBR, XREF_BIBR - XREF_BIBR]."

reach
"When mutations occur in TSC1 or TSC2, the hamartin and tuberin complex is nonfunctional, Rheb-GTP is favored, and mTOR kinase is constitutively activated causing hyperphosphorylation of the downstream effectors (p70 S6 kinase and 4E binding protein1) resulting in increased protein translation, cell growth, proliferation, and survival."

reach
"When a nonphosphorylatable form of TSC2 (S939A) was overexpressed, phosphorylation dependent binding of the scaffold protein 14-3-3 to TSC2 was diminished and no redistribution of the TSC1 and TSC2 complex was observed after IGF-1 stimulation."

reach
"One of the substrates of AMP kinase is the TSC-1 and TSC-2 protein complex and the phosphorylation of these proteins enhances a GTPase activity that converts GTP (active form) to GDP (inactive form) that is associated with the RHEB G protein [XREF_BIBR]."

reach
"TSC is caused by the lack of functional Tsc1 and Tsc2 complex, which serves as a major cellular inhibitor of mammalian Target of Rapamycin Complex 1 (mTORC1)."

sparser
"Co-expression of TSC2 prevents TSC1 aggregation due to the formation of soluble TSC1-TSC2 complexes [ xref , xref ]."

reach
"Therefore, most, if not all, of the Rheb-GAP activity of the TSC1 and TSC2 complex is in association with TBC1D7."

reach
"TBC1D7 is a third subunit of the TSC1 and TSC2 complex upstream of mTORC1."

sparser
"TSC1 and TSC2 form a dimer and function as a GTPase-activating protein (GAP) to inactivate the small GTPase “Ras homolog enriched in brain” (Rheb), which directly binds to mTORC1 and activates kinase [MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"Hamartin and tuberin associate physically in vivo what makes it very likely that these two proteins function in the same complex [4,5]."

sparser
"Toward this goal, we reported previously the use of a cross-species screening approach to identify SS/L interactions with TSC1 and TSC2 , the two tumor suppressor genes underlying tuberous sclerosis complex (TSC) ( xref , xref )."

sparser
"Univariate logistic regression was conducted to evaluate the association of the TSC1 and TSC2 gene mutations with patient and disease characteristics."

reach
"The hamartin and tuberin complex inhibits the mammalian-target-of-Rapamycin (mTOR) pathway, which controls cell growth and proliferation."

reach
"TSC1 and TSC2 complex functions as a GAP for Rheb and this involves the use of the asparagine thumb mechanism."

reach
"Here we showed that loss of TSC1 and TSC2 complex downregulated PDGFRalpha expression via activation of mTORC1."

reach
"Intriguingly, hamartin has recently been localized to the basal body of cilia in mammalian cells [XREF_BIBR], and absence of the hamartin and tuberin complex has been linked to a long ciliary phenotype [XREF_BIBR]."

sparser
"The proteins they encode, hamartin and tuberin respectively, interact and form a heterodimer that inhibits the activation of mTORC1, a master regulator of nutrient and growth-factor-induced signaling. xref , xref In RCC, mTOR inhibitors represent an important therapeutic approach for advanced disease. xref Interestingly, while inactivating mutations of TSC1 / TSC2 or activating mutations of MTOR occur in the common subtypes of RCC, their reported frequencies are typically low (e.g. TSC1 / TSC2 at about 1–3%, MTOR 3–5%) and often co-occur with other characteristic molecular alterations of the corresponding histologic subtype. xref – xref Although believed to be an important pathway implicated in the pathogenesis of RCC, it remains unclear whether these mutations alone drive the development of renal cell tumors in sporadic settings."

sparser
"Both protein products of TSC1 and TSC2 form an intracellular complex exerting GTPase-activating (GAP) activity towards a small G protein Rheb (Ras homologue enriched in brain)."

reach
"Hamartin and tuberin, the TSC1 and TSC2 gene products, interact and the tuberin and hamartin complex inhibits cell growth by antagonising signal transduction to downstream effectors of the mammalian target of rapamycin (mTOR) through the small GTPase rheb."

sparser
"The overall architecture of TSC1TSC2 and TSC1–TBC1D7 interactions together allows one TBC1D7 to be assembled into TSC complex and this subunit stoichiometry is consistent with previous structural and biochemical analyses xref , xref ."

reach
"Therefore, loss of TSC1 and TSC2 complex led to mTOR independent inhibition of AKT at least partially through downregulation of the SOX9-OPN signalling cascade."

sparser
"The TSC2 N-terminal region and multiple regions of TSC1 are important for the TSC1-TSC2 interaction [ xref , xref ]."

reach
"52 The TSC1 and TSC2 complex inactivates the mTORC1 complex through the hydrolysis of guanosine triphosphate, which is required for Rheb to activate mTORC1."

sparser
"Tsc1 and Tsc2 form an integral TSC complex that inhibits mTOR signalling through their GTPase-activating activity on Rheb xref ."

reach
"AKT activation is also involved with inactivation of the TSC1 and TSC2 complex (tumor suppressor 6 genes)."

sparser
"These data suggest that the interaction of hamartin with tuberin facilitates its localization to the membrane, implying that the tuberinhamartin heterodimer functions in this subcellular compartment."

reach
"Other example such as TSC1 and TSC2 complex was shown to associate with the mTORC2 complex and activate Akt kianse activity (Akt Ser 473 phosphorylation) XREF_BIBR."

sparser
"RheB-GTP can interact with the target of rapamycin (TOR) complex 1 (TORC1) to precipitate phosphorylation of TORC1 targets, including p70 S6 kinase and elongation factor 4E binding proteins ( xref ); thus, formation of the hamartin-tuberin complex is a crucial means by which to inhibit the mTOR pathway."

sparser
"TSC1-TSC2 acts as a GTPase activating protein (GAP) for RHEB, thereby inactivating RHEB."

reach
"Similarly, expression of FIP200 reversed inhibition of endogenous S6K phosphorylation by overexpression of the TSC1 and TSC2 complex (XREF_FIG B, left) and expression of FIP200 alone also increased endogenous S6K phosphorylation (XREF_FIG B, right)."

sparser
"TSC1 and TSC2 associate with each other to form a heterodimeric complex as a regulatory unit and a catalytic unit, respectively."

sparser
"TSC1 maintains stability, activity, and transportation of the TSC1-TSC2 complex ( xref )."

reach
"In this regard, tuberin, when associated with hamartin in the THC, functions as a GAP for Rheb, and converts it from its active GTP bound conformation to an inactive GDP bound form."

reach
"We have used a combination of different assays to characterise the effects of a number of pathogenic TSC2 amino acid substitutions on TSC1 and TSC2 complex formation and mTOR signalling."

sparser
"Inhibition of TSC1-TSC2 by Akt phosphorylation allows Rheb-GTP to accumulate and activates mTOR (Proud, 2007) ."

sparser
"In contrast, the U0126 effect on TSC1-TSC2 S664A/S540A interaction was much smaller ( Figure 4 C)."

reach
"In 293T cells, increasing concentration of BS 3 resulted in formation of cross linked hamartin and tuberin complex not seen in cells devoid of tuberin (EEF155-4A and EEF126-8)."

reach
"An upstream activator of TORC1 is Rheb GTPase XREF_BIBR, the activity of which can be switched off by the GTPase activating protein complex TSC1 and TSC2."

reach
"Loss of the TSC1 and TSC2 complex leads to Akt suppression and its activity is rapidly reversed by rapamycin, an inhibitor of mTORC1."

isi
"Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder caused by deletions in the TSC1 or TSC2 genes that is associated with epilepsy in up to 90% of patients."

reach
"Interestingly, coexpression of FIP200 reversed the inhibition of S6K phosphorylation by the TSC1 and TSC2 complex (XREF_FIG A, compare lane 4 with lanes 1 and 3)."

reach
"A variety of signaling pathways act on the mTORC1 cascade by regulating the assembly or the activity of the tuberin and hamartin complex."

sparser
"The substitution of a polar threonine for nonpolar methione at position 993 had no deleterious effect on the TSC1TSC2 interaction or on the activity of the complex."

reach
"In response to energy stress, AMPK inactivates mTORC1 and represses protein synthesis via AMPK phosphorylation of Raptor, a component of mTORC1, and the TSC1 and TSC2 complex, a negative regulator of mTORC1 XREF_BIBR, XREF_BIBR."

reach
"The interaction between these two proteins, the tuberin and hamartin complex, has been shown to be critical to multiple intracellular signalling pathways, especially those controlling cell growth and proliferation."

reach
"AKT is the main upstream activator of mTOR, and its activation relieves the inhibitory effects of the TSC1 and TSC2 complex on Rheb and mTORC1, thereby activating mTORC1 in response to growth factor stimulations."

sparser
"Huang et al. ( xref ) had previously reported the presence of the TSC1-TSC2 complex in physical association with mTORC2 but not mTORC1 in several cell lines."

reach
"XREF_BIBR, XREF_BIBR Therefore, the ability of a variety of upstream pathways to affect mTORC1 activity is dependent on modifications that functionally inhibit or activate the TSC1 and TSC2 complex."

reach
"Thus, TSC1 and TSC2 complex is more available to inhibit the mTOR pathway, demonstrated for the first time in rat primary neuronal cultures."

sparser
"Therefore our identification of the interaction between FIP200 and the TSC1TSC2 complex raises the interesting possibility that FIP200 may regulate cell size through interaction with the TSC1TSC2 complex."

reach
"Loss of function of the TSC1 and TSC2 complex results in constitutive mTORC1 signaling and, through mTORC1 dependent feedback mechanisms and loss of mTORC2 activity, leads to a concomitant block of Akt signaling to its other downstream targets."

reach
"Since some of the most severe manifestations of TSC disease are in the CNS, we investigated the role of the TSC1 and TSC2 complex in the neuronal response to ER stress."

reach
"Lastly, in mammalian cells the Tsc1 and Tsc2 complex is required for proper TORC2 activation, independently from its role in negative feedback signaling XREF_BIBR."

reach
"It is caused by an inactivating mutation in tumor suppressor genes coding the TSC1 and TSC2 complex, resulting in the hyperactivation of mTOR- and Raf/MEK/MAPK dependent signaling that stimulates tumor cell proliferation and metastasis."

reach
"Complete loss of either TSC1 or TSC2 due to a second hit to either TSC locus leads to a dysfunctional TSC1 and TSC2 complex and unchecked cell proliferation through unregulated mammalian target of rapamycin complex 1 (mTORC1) activation [XREF_BIBR] and impaired mammalian target of rapamycin complex 2 (mTORC2) activation [XREF_BIBR]."

sparser
"Recently, it has been shown that TSC1 and TSC2 form a complex that inactivates mTOR and so inhibits the activity of S6K [68] ."

reach
"Next, to examine the molecular mechanism underlying the effects of these mutations on the TSC complex, we first tested whether mutations in TSC1 and TSC2 disrupt the formation of the TSC1 and TSC2 com[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"

reach
"LKB1 is a serine/threonine kinase that has multiple targets, including AMPK which phosphorylates and activates the TSC1 and TSC2 complex."

reach
"The TSC1 and TSC2 genes encode for proteins to form the TSC1 and TSC2 complex."

reach
"Finally, it is now clear that the role of the TSC1 and TSC2 complex in normal cell physiology extends beyond cell growth suppression through inhibition of mTORC1."

reach
"In contrast to the TSC1 and TSC2 complex inhibiting mTORC1 activity, mTORC2 activity is increased during activation of the TSC1 and TSC2 complex through the amino (N)-terminal region of TSC2 and the C-terminal region of Rictor (Huang et al., 2008)."

reach
"In neuronal translation, mTORC1 signaling is a regulator of long-lasting synaptic plasticity and memory as it integrates signals from neuronal surface receptors/channels via MEK/ERK- and PI3K/AKT-mediated phosphorylation and inactivation of the TSC1-TSC2 complex [4–6]."

reach
"Moreover, fisetin increased the total protein levels of TSC1 and TSC2 and stabilized the binding of TSC1 to TSC2 (XREF_FIG & XREF_FIG)."

sparser
"This finding led to further investigations on the possible interaction between TSC1TSC2 and AKT/PTEN."

sparser
"Additionally, tuberin-ERalpha interactions were found to be modulated by the presence of tuberin's predominant intracellular binding partner hamartin, suggesting that tuberin-hamartin interactions negatively impact the ability of tuberin to modulate ERalpha-mediated gene transcription events."

sparser
"TSC2 is a major signal integration point in the mTOR signaling pathway with growth factor receptor activity inhibiting TSC1TSC2 complex formation via phosphorylation of TSC2 by AKT, and conversely, hypoxia inhibiting mTOR via induction of REDD1 which promotes TSC1TSC2 complex formation and activity ( xref ; xref )."

reach
"Akt and PKB phosphorylates tuberin, thereby promoting dissociation of the hamartin and tuberin complex (XREF_FIG) [XREF_BIBR, XREF_BIBR]."

reach
"TSC2 loss or mutation leads to disruption of the tuberin and hamartin heterodimer."

reach
"Meanwhile, PPIs also could inhibit the expressions of TSC1 and TSC2 complex and Rheb which might be involved into regulating the signaling pathway intermediately."

sparser
"To investigate their effects on TSC complex formation we coexpressed the TSC2 variants with myc‐tagged wild‐type TSC1 in the TSC1:TSC2 DKO HEK 293T cells and isolated TSC complexes by immunoprecipitation using antibodies specific for either the TSC2 (Figure xref a) or TSC1 (Figure xref d) subunit."

reach
"The stimulation of these two pathways by growth factors increases the phosphorylation of tuberin (TSC2) and this way inactivate hamartin and tuberin complex."

sparser
"TSC1 and TSC2 code for the proteins hamartin and tuberin to form an inhibitor complex of mTORC1 activation [ xref ]."

reach
"As mentioned above, the TSC2 and TSC1 complex suppresses mTORC1 by inactivating mTORC1 interacting protein, Rheb."

reach
"Elucidation of the role of the TSC1 and TSC2 complex in TORC1 signaling has provided new insights into basic cell biology and, importantly for TSC patients, has led to the development of promising new therapies based on the use of specific TORC1 inhibitors such as rapamycin and its derivatives [XREF_BIBR]."

sparser
"Phenotypes that are related to the loss of Tsc2 have been postulated to be more severe for several reasons, including stronger mTORC1 pathway activation or the engagement of TSC1 in protein complexes that are different from Tsc1- Tsc2 complex."

sparser
"For example, in response to energy stress, AMPK activates autophagy, a catabolic process that recycles intracellular nutrients to maintain cell survival under nutrient-deprived conditions, through phosphorylating autophagy regulators such as ULK1 ( xref ; xref ), while inhibits mechanistic target of rapamycin complex 1 (mTORC1)-mediated protein synthesis by phosphorylating Raptor (an mTORC1 component) and the TSC1TSC2 complex (an upstream negative regulator of mTORC1) ( xref ; xref )."

sparser
"The TSC1 and TSC2 proteins form a tumor suppressor complex that transmits growth factor and energy signals to mTORC1 by regulating the GTP-loading state of Rheb, a Ras-related GTP-binding protein."

reach
"A second key mechanism by which Akt may alter the TSC1 and TSC2 complex is by phosphorylating TSC2 on S939 and S981."

reach
"It was thus proposed that the Tsc1 and Tsc2 complex antagonizes the TOR mediated response to amino acid availability [XREF_BIBR]."

reach
"This has been attributed to a variety of feedback mechanisms, including suppression of IRS function, reduced PDGFR expression, and most recently elucidation of a functional role for the TSC1 and TSC2 complex as a co-factor for the kinase activity of mTORC2, the AKT S473 kinase."

reach
"Interestingly, the Rho activating domain of TSC1 (amino acids 145-510) overlaps with the domain that binds TSC2 : the amino acids 302-430 of TSC1 associate with amino acids 1-418 of TSC2 and are required for TSC1 and TSC2 complex formation, which potentially stabilizes each protein."

reach
"The interaction between TSC1 and TSC2 appears to be important in maintaining the stability of each of the proteins."

sparser
"Both TORC1 and TORC2 complexes and their upstream regulators such as the TSC1TSC2 (hamartin and tuberin, respectively) protein complex that represses TORC1 by affecting Rheb, a G-protein that acts as positive regulator of this complex [ xref ], show great conservation within eukaryotes ( xref B)."