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TSC1 binds TSC2. 1000 / 2949
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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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"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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"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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"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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"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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"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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"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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"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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"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."
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"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 ]."
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"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 ]."
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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."
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"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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"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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"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."
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"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."
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"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."
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"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."
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"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 TSC1–TSC2 complex (an upstream negative regulator of mTORC1) (Gwinn et al., 2008; Inoki et al., 2003)."
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"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."
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"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]."
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"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]."
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"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."
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"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."
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"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."
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"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."
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"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]."
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"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)."
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"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."
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"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 ]."
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"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 (TSC1–TSC2), leading to mTOR inactivation and initiation of autophagy [ xref ]."
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"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."
"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)."
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"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."
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"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)."
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"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]."
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"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."
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"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."
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"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]."
"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."
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"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 )."
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"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."
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"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."
"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]."
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"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 TSC1–TSC2 complex on mTORC1, thus leading to increased mTORC1 signaling which phosphorylates eukaryotic initiation factor 4E-binding protein (4E-BP) and p70S6K [ xref ]."
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"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."
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"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 )."
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"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)."
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"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."
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"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 TSC1–TSC2 (TSC2; TSC2 signal = 1)."
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"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."
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"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."
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"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 ]."
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"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 ]."
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"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]."
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"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)."
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"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."
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"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 "
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"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)."
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"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."
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"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."
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"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."
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"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."
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"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 "
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"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."
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"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]."
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"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]."
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"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 ."
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"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 (Tsc1–Tsc2) complex, Forkhead box protein O3A (Foxo3A), p27, anti-Müllerian hormone (AMH), and Forkhead box L2 (FoxL2) [ xref ]."
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"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 ."
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"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."
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"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 TSC1–TSC2 complex regulates the differentiation of cells that are derived from the mesenchyme."
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"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."
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"DDIT4 was mainly applied to restrain mechanistic target of rapamycin 1 (mTORC1) by maintaining the TSC1‐TSC2 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."
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"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 ."
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"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."
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"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."
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"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."
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"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."
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"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]."
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"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."
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"TSC2 is a major signal integration point in the mTOR signaling pathway with growth factor receptor activity inhibiting TSC1–TSC2 complex formation via phosphorylation of TSC2 by AKT, and conversely, hypoxia inhibiting mTOR via induction of REDD1 which promotes TSC1–TSC2 complex formation and activity ( xref ; xref )."
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"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."
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"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]."
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"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 TSC1–TSC2 complex (an upstream negative regulator of mTORC1) ( xref ; xref )."
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"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."
sparser
"Both TORC1 and TORC2 complexes and their upstream regulators such as the TSC1–TSC2 (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)."