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TSC2 binds TSC1. 1000 / 4486
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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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"Although we can not completely exclude the possibility that FIP200 could function to reduce the TSC1 and TSC2 complex formation under some conditions, the aforementioned consideration would suggest that FIP200 may inhibit TSC1 and TSC2 complex function through mechanisms other than disruption of the complex formation."
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"Consequently, this hypothesis provides an explanation for why TSC2-TSC1 complexes precipitated with TSC1 or TSC2 antibodies (as depicted in xref D and ( xref )) exhibit no discernible changes in GAP activity in response to insulin stimulation, as these antibodies predominantly capture the total pool of TSC2 complexes."
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"In mammalian cells, it is known that cytosolic acidification reduces the phosphorylation level of S6K, a homolog of Sch9, through the inhibition of mTORC1 via the TSC1-TSC2 complex. xref Unlike Sch9, S6K is a cytoplasm-localized protein, and its activity regulation via membrane localization has not been reported and is considered unlikely."
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"Because deficiency in either TSC1 or -2 leads to a very similar disease phenotype in humans with TSC ( xref ), and hamartin and tuberin form a complex in both mammalian cells ( xref ) and in Drosophila ( xref ; xref ), an important common function of the TSC1-2 complex has been sought that could explain its tumor suppressor activity."
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"Their gene products form the TSC1 and TSC2 complex (also named hamartin and tuberin complex) and, through its GAP (GTPase activating protein) activity towards the small G protein Rheb (Ras homolog enriched in brain), this complex is a negative regulator of mTORC1 (mammalian target of rapamycin complex 1) XREF_BIBR."
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"In 25 patients (13.6%), variations were identified in TSC1, whereas in 85 patients (46.2%), variations were observed in TSC2 ( TSC1:TSC2 ratio 1:3.4), and five patients (2.7%) suffered from a polycystic kidney disease with tuberous sclerosis (PKDTS), which is a contiguous gene deletion syndrome."
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"Recent work has indicated that the TSC1 and TSC2 complex plays a role in the pathobiology of a number of tumor predisposition syndromes, including tuberous sclerosis (TSC1/2), Peutz-Jeghers syndrome (LKB1), and Cowden 's syndrome (PTEN), in which the TSC/Rheb/mTOR axis is inappropriately active secondary to loss of tumor suppressor function."
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"Mutations in the gene for the SHANK3 protein of the postsynaptic membrane cause Phelan–McDermid syndrome; in
the gene for PTEN phosphatase, Cowden’s disease; for NF1,
type 1 neurofibromatosis; in the genes for GTPase, H-RAS,
RAF1, and MEK1 kinase, Costello and Noonan syndromes;
TSC2-TSC1, tuberous sclerosis; FMRP, fragile X syndrome;
UBE3A ubiquitin-protein ligase, Angelman syndrome; and in
genes for neuroligins NLGN3/4 and neurexin NRXN1, typical autism (Trifonova et al., 2016)."
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"DOCK7, with variants recently reported in AR EOEE, is a guanine nucleotide exchange factor known to activate small G proteins of the Rho family and may function as a GEF of Rheb downstream of the TSC1 and TSC2 complex (Nellist, Burgers, van den Ouweland, Halley, & Luider, 2005; Perrault et al., 2014)."
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"The authors did not propose a specific mechanism for the observed retinotopic changes upon Phr1 deletion, but this third mechanism is intriguing because PHR proteins are enriched in the CNS and have been demonstrated to interact and regulate activity of the hamartin and tuberin complex."
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"In response to growth factors, AKT directly phosphorylates TSC2 on several distinct residues [ xref ] that prevents the formation of TSC1-TSC2 complex, thus allowing GTPase Rheb to convert back into the GTP-bound active state [ xref ] which leads to mTORC1 activation [ xref , xref ]."
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"AMPK instead positively regulates macroautophagy upon its activation under conditions of energy deficiency (elevated AMP/ATP ratio), through a variety of mechanisms including direct phosphorylation of ULK1, RAPTOR and the TSC1-TSC2 complex to inhibit mTOR, of Beclin-1 to activate the Beclin-1–VPS34 complex required for autophagy initiation, and of FoxO3 to activate transcription of autophagy genes such as LC3B, GABARAPL1 and Beclin-1 ( xref )."
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"Hamartin–Tuberin complex, a TSC1 and TSC2 gene product, is involved in cell proliferation through mTOR inhibition, with resulting hamartoma formation in the skin, nervous system, kidney, lung, bone, and elsewhere, together with abnormalities in the TSC1 and TSC2 genes [102,103,104]."
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"We found that iNOS expression in human melanoma leads to nitrosylation of TSC2 which is associated with impaired dimerization of TSC2 with its inhibitory partner TSC1 and enhanced activation of its target, the small GTPase Rheb, and subsequent activation of downstream members of the mTOR pathway."
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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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"Immunoprecipitation experiments demonstrate that iNOS/NO modulates dimerization of TSC2 with its inhibitory partner TSC1, a critical checkpoint for downstream Rheb activation; thus modulating physical association of TSC1 and TSC2 is a plausible and novel mechanism by which iNOS/NO can control mTOR pathway activation."
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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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"It is evident that MAPK associated RSK activity contributed to S6 phosphorylation through two distinct mechanisms : (a) inhibition of TSC1 and TSC2 complex, which subsequently elevated mTORC activity toward S6 kinase/S6, or (b) direct phosphorylation of S6 at serine 235/236 sites XREF_BIBR - XREF_BIBR."
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"This short sequence motif contains several highly conserved positions, such as W347, P349, and C353, that are mapped to the interaction interface, suggesting that the interaction through this motif could be functionally important for the TSC1‐TSC2 complex.AlphaFold predicted the interaction between TSC1 and the protein kinase DYRK1A."
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"Genomic studies have not reported hereditary or somatic variants in TSC genes in patients with PPGL.13 14 The TSC1-TSC2 complex is known to inhibit mammalian target of rapamycin (mTOR) cascade, and TSC2 inactivation can activate mTOR.7 Its activation can lead to dysregulation of cell cycle, thereby causing tumor progression."
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"38 These findings suggest that the autophagic response is insufficient in the lungs of patients with COPD, which leads to accelerated epithelial cell senescence.Interestingly, mTOR signaling also has been linked to CS-induced COPD/emphysema.39 mTOR is an evolutionarily conserved serine-threonine kinase that acts as a sensor of environmental and cellular nutrition and energy status that also plays an important role in regulating autophagy.40 Rtp801, a stress-related protein triggered by adverse environmental conditions, was overexpressed in human emphysematous lungs and in lungs of mice exposed to CS.39 Rtp801 stabilized the assembly of the mTOR inhibitory complex TSC1-TSC2, resulting in exacerbation of oxidative stress-induced cell death."
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"In clinical, more attention has been paid on epithelial variant because it can undergo malignant transformation.Approximate 20% of renal AMLs is associated with tuberous sclerosis complex (TSC), an autosomal dominant multisystem disorder caused by the mutation of either TSC1 or TSC2.6,7 TSC2 and TSC1 complex is one central regulator of mTORC1 signaling pathway.8,9 TSC2 complexes with TSC1 to inhibit mTORC1 signaling via driving Rheb into GDP bound state, which acts as GTPase to activate mTORC1 when it is in GTP bound state.10,11 In the response to environmental stresses such as nutrients, oxygen, DNA damage, and growth factors, mTORC1 signaling is activated and controls cell growth and survival.12,13 In addition, mTORC1 is also implicated into cancer development due to its regulation on cell proliferation, angiogenesis, and metastasis.14-16 Therefore, mTORC1 is an appealing therapeutic target in clinic.Indeed, mTORC1 inhibitors such as deforolimus, everolimus and temsirolimus have been prevalently assessed in various cancers, alone or in combination with other targeted therapies or chemotherapies.17,18 Importantly, everolimus and temsirolimus were recently approved by the FDA for the treatment of renal cell carcinoma.Here, we report a rare case of epithelioid renal AML."
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"Its interaction with the mTOR1 inhibitors TSC1 and TSC2, both also identified as interactors in this study, links the BAG3 protein to the mTOR signaling pathway, whereby it is able to coordinate macroautophagy and protein synthesis ( xref C, Cluster 6; xref C, Cluster 2 and 3; xref ) [ xref ]."
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"Low cellular ATP levels result in the activation of the adenosine monophosphate activated kinase (AMPK), which can phosphorylate and activate TSC2, of the TSC1–TSC2 inhibitory complex, on Thr1227 and S1345; and/or phosphorylate Raptor on Ser722 and Ser792, promoting its interaction with 14-3-3 proteins and the inhibition of mTORC1 ( xref ) [ xref , xref ]."
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"Genomic studies have not reported hereditary or somatic variants in TSC genes in patients with PPGL. xref , xref The TSC1-TSC2 complex is known to inhibit mammalian target of rapamycin (mTOR) cascade, and TSC2 inactivation can activate mTOR. xref Its activation can lead to dysregulation of cell cycle, thereby causing tumor progression."
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"The breast cancer cell-macrophage-adipocyte relationship is interconnected via multiple reactive processes, notably: release of inflammatory factors, TSC1-TSC2 complex crosstalk with mTOR, insulin resistance, endoplasmic reticulum stress, oxidative stress, and elevated estrogen levels ( xref )."
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"The molecular mechanisms underlying PEComa remain elusive; however, the TSC1-TSC2/mTOR signaling pathway has been identified as a significant molecular pathway implicated in tumorigenesis by promoting the dysfunction of TSC1-TSC2, with particular emphasis on TSC2 mutations that activate mTOR."
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"This activation of PI3K results in a cascade of phosphorylation events, resulting in the activation of Akt, which in turn inhibits the TSC1 and TSC2 complex, which negatively regulates mTOR by acting as a GTPase activating protein toward Ras homolog enriched in brain (Rheb), a direct and positive regulator of mTOR."
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"Knowledge of the implications of mTOR in carcinogenesis comes essentially from evidence obtained from familial cancer syndromes that develop as a consequence of mutations of negative regulators of mTOR, such as TSC1-TSC2 and PTEN [ xref ], as well as from experimental studies in mouse models of lymphoma involving alterations of eIF4E [ xref ]."
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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 [16] and the TSC-1-TSC2 complex [17], allowing rapid autophagy induction."
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"The mTOR upstream consists of varying growth factors and signaling molecules related to mitosis, such as PI3K, PDK1 (phosphoinositide-dependent kinase 1), TSC1-TSC2 complex, and Rheb, etc. Therefore, mTOR involves multiple life activities and links multiple signaling pathways, of which one of the most important is the PI3K-Akt-mTOR signaling pathway (Figure 1) [28]."
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"Briefly, Akt and PKB and AMPK antagonistically regulate the activity of a TSC1 and TSC2 complex, another human tumor suppressor [XREF_BIBR], through direct phosphorylation of TSC2 [XREF_BIBR, XREF_BIBR - XREF_BIBR], such that when insulin signaling is elevated and the AMP : ATP ratio is low, the TSC complex is antagonized by Akt and PKB, and is not activated by AMPK."
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"AMPK activation can inhibit the mTORC1 pathway through two main mechanisms : phosphorylation of tuberous sclerosis complex (TSC) 2 at Ser 1387, which activates the upstream mTOR inhibitor TSC1 and TSC2 complex [XREF_BIBR, XREF_BIBR] or direct inhibition by phosphorylating Raptor [XREF_BIBR]."
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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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"A possible mechanism by which AMPK might cause mTOR dysregulation involves its inhibition of AKT-dependent phosphorylation of TSC2 and/or the binding of TSC2 with its homolog TSC1 which increases the binding of GDP to Rheb (Ras homolog enriched in brain) and thereby inhibits mTOR activity."
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"When AKT is phosphorylated, this can inhibit the dimeric protein complex TSC1/TSC2, resulting in the subsequent activation by phosphorylation of mTORC1 (p-mTOR), which induces increased activity of other downstream regulators such as P70S6K1, eIF4E, and 4E-BP1 that have specific cellular roles primordially—but not exclusively—related to cell proliferation, cell growth, and cell cycle progression [27,30,31,32,33,34,35]."
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"mTORC1 inhibition by REDD1 requires the TSC1 and TSC2 complex (XREF_FIG), but REDD1 does not appear to interact with TSC1 and TSC2; in reciprocal immunoprecipitation experiments, and under conditions in which TSC1 was recovered bound to TSC2, REDD1 was not found in the complex (XREF_FIG)."
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"Phosphorylation of tuberin by Akt 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."
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"The TSC1/TSC2 tumor suppressor gene complex, also known as the Hamartin and Tuberin protein complex, negatively regulates mechanistic target of rapamycin (mTOR) complex 1 (mTORC1), a master regulator of cellular biosynthesis, resulting in proliferation, angiogenesis and uncontrolled cell growth."
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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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"XREF_BIBR Both sestrins can trigger the AMPK and target it to phosphorylate and activate TSC1 and TSC2 complex, thereby inhibiting the signaling of mTOR, a critical autophagy inhibitor of cells, XREF_BIBR, XREF_BIBR and so CX-5461-induced autophagy through AMPK and mTOR signaling pathway in U2-OS cells might arise from the upregulation of Sesn1/2 by p53."
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"mTOR is mechanistically tightly interconnected with the TSC1/TSC2 complex; therefore, it has been found upregulated in patients with TSC—an autosomal dominant disorder caused by loss-of-function mutations of either TSC1 or TSC2 genes—who develop neurological manifestations, including epilepsy, neuropsychiatric disorders, autism, and brain tumors [20,21]."
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"While early reports proposed that Akt-mediated phosphorylation destabilizes the TSC1-TSC2 complex, leading to dissociation of TSC1 from TSC2 and subsequent activation of mTORC1 signaling ( xref , xref ), more recent studies have suggested that there was no destabilization of endogenous TSC1 and TSC2 protein complexes before or after TSC2 phosphorylation."
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"The formation of hamartin–tuberin is able to suppress the activity of mTORC1, regulating cell growth and proliferation under a normal state.[ xref , xref ]The mutations in TSC1 or TSC2 induce hyperactivity of mTORC1, promoting abnormal cell growth and suppressing autophagic cell death.[ xref , xref ]"
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"Interestingly, Akt appears to have a complex dual role on mTOR, being both an (i) upstream regulator of mTORC1 (indirect activation through phosphorylation and inactivation of TSC1/TSC2 complex, who constitutively suppress mTORC1 activity through Rheb GTPase inhibition) and a (ii) downstream target of mTORC2 [10, 22]."
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"Patients with TSC have pathogenic variants in either TSC1 or TSC2, not both genes; these pathogenic variants functionally inactivate TSC1 or TSC2 or leads to the loss of the ideal conformation of the hamartin-tuberin complex causing aberrant activation of mTOR and resulting in heightened cell proliferation and growth (Figure 1) ."
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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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"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 [35]."
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"A recent study has provided evidence that the TSC1-TSC2 complex plays a role in regulating b-catenin signaling.[76] Using Wnt-responsive 293T cells, cotransfection of TSC1 and TSC2 significantly suppressed bcatenin – dependent TCF/Lef transcription activation upon Wnt stimulation."
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"Others regulators that induce AP include tumor suppressors, such as PTEN, TSC1 and TSC2 complexes, and the death associated kinase (DAPK); stress activated signaling molecules, such as c-Jun N-terminal kinase 1 (JNK1), and those that respond to endoplasmic reticulum (ER) stress (PERK, eIF2alpha-kinase, and IRE1), and molecules involved in innate immune signaling, such as TLRs and immunity related GTPases [XREF_BIBR]."
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"Previous studies have also shown that RB1CC1 plays important roles in controlling G 1 -S cell cycle progression through up-regulation of p21 WAF together with down-regulation of cyclin D1, cell size control through the inhibition of the TSC1 and TSC2 complex, regulation of TNF-alpha-induced apoptosis through the modulation of TRAF2-ASK1 signal transduction, and autophagosome formation together with ULK kinases."
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"DNA damage‐inducible transcript 4 (DDIT4), variously termed REDD1 or RTP801, is induced by a variety of stress conditions, including oxidative stress, endoplasmic reticulum stress, hypoxia, and starvation. [ xref ] Over the past decades, DDIT4 dysregulation has been observed in numerous human malignancies, such as prostate cancer, ovarian cancer, gastric cancer, and breast cancer. [ xref , xref ] Moreover, DDIT4 inhibits mammalian target of rapamycin complex 1 (mTORC1) by stabilizing the tuberous sclerosis complex (TSC1–TSC2)."
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"In this setting, R204H could be interpreted as a “non-severe” variant that could have some gain-of-function effects on the hamartin-tuberin complex, thus justifying the clinical phenotype seen in our patient, which comprised primary microcephaly (a malformation with reduced cellular growth/increased apoptosis), simplified gyration, and stunted overall growth (weight and height)."
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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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"Also, the rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (Raf)/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK)/p90 ribosomal S6 kinase 1 (p90RSK1) cascade impinges on mTORC1, as both ERK and p90RSK1 phosphorylate TSC2 (at Ser664 and Ser1798, respectively), thereby inhibiting the TSC1/TSC2 complex and triggering Rheb-dependent mTORC1 activation [20]."
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"Particularly relevant in cancer is stimulation of tuberous sclerosis complex 2 (TSC2) protein, which associates with tuberous sclerosis 1 (TSC1) and is a key mediator of the mammalian target of rapamycin (mTOR). xref Akt further regulates transcriptional control of apoptosis through regulation of IKK-, MDM2-, and CREB-mediated signaling. xref More direct regulation of apoptosis occurs via the mediators BAD and caspase-9."
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"In this setting, R204H could be interpreted as a “non-severe” variant that could have some gain-of-function effects on the hamartin-tuberin complex, thus justifying the clinical phenotype seen in our patient, which comprised primary microcephaly (a malformation with reduced cellular growth/increased apoptosis), simplified gyration, and stunted overall growth (weight and height)."
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"In two families with a severe form of sarcoidosis, we demonstrated deleterious mutations in DDIT4 (DNA damage inducible transcript 4 gene), also called Rtp801, encoding a factor that turns off the metabolic activity triggered by mTOR by stabilizing the TSC1–TSC2 inhibitory complex [ xref ]."
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"The tuberous sclerosis (TSC1–TSC2) heterodimeric protein complex xref stimulates TSC2 GTPase-activating protein (GAP) activity toward Rheb, converting Rheb-GTP (active form) to Rheb-guanosine diphosphate (GDP_ xref , xref (inactive form), which in turn limits mTORC1 activity. xref TSC2-GAP activity on Rheb is regulated by extracellular signals through the phosphorylation of TSC1 and TSC2 by protein kinase B (AKT), AMP-activated protein kinase (AMPK), glycogen synthase kinase 3 (GSK3), ERK, serum and glucocorticoid (SGK), or ribosomal s6 kinase (RSK). xref , xref , xref , xref , xref Notably, stimulation of Pirb -/- naïve CD4 + T cells under Th17 polarizing conditions lead to significantly increased phosphorylation of the mitogen-activated protein kinase ERK, compared with WT naïve CD4 + T cells ( xref D )."
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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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"Consistent with this, diminished mTORC1 activation and signaling, such as that observed by genetic deletion of mTOR or S6 kinase, results in a failure of naïve CD4 + T cells to differentiate into Th17 cells. xref , xref , xref Conversely, exaggerated mTORC1 signaling as observed by deletion of TSC1 and loss of the TSC1–TSC2 heterodimeric protein inhibitory complex also results in impaired CD4 + T-cell survival. xref "
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"Stimulation of Rheb-GTP hydrolysis by the TSC1-TSC2 complex inhibits the downstream mechanistic target of rapamycin complex 1 (mTORC1) activity and its targets, including p70 S6 kinase (S6K) and eukaryotic translation-initiation factor 4E-binding protein 1 (4E-BP1), necessary for cell growth, metabolism, and protein synthesis regulation. xref , xref Mutations in Tsc1/2 genes impair the inhibitory function of the TSC1-TSC2 complex on mTORC1 activity resulting in cell cycle dysregulation and tumorigenesis."
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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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"TSC is caused by a single heterozygous TSC1 or TSC2 mutation, and a somatic “second-hit” mutation in the unaffected allele is required for loss of the hamartin-tuberin complex and activation of the mammalian rapamycin complex 1 target (mTORC1), which results in hamartoma development ."
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"By activating the tuberous sclerosis complex TSC1 and TSC2 leading the activation of mTOR, Akt may represent a mechanistic link between S1P signaling and mTOR signaling as S1P regulates Akt phosphorylation as a ligand for five high-affinity G coupled receptors (S1P 1-5) 46 in various physiological conditions."
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"It has been shown that TRIM31 expression is significantly higher in HCC tissues than in distal non-cancerous liver tissues of HCC patients, and TRIM31 overexpression possibly correlates with HCC progression (Guo et al., xref ; Wang et al., xref ), and that TRIM31 contributes to the activation of the mTORC1 pathway by promoting the ubiquitin-dependent degradation of the TSC1-TSC2 complex, an upstream repressor of the mTORC1 pathway (Guo et al., xref )."
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"125 If the TSC complex is disrupted, Rheb will not shift from the active form (GTP-bound Rheb) to the inactive form (GDP-bound Rheb) and fail to inhibit mTORC1.124 126 AKT can directly phosphorylate TSC2, which destabilizes TSC2 and disrupts its interaction with TSC1.127 Also, the phosphorylation of TSC2 by GSK-3β may be relevant for inhibiting the TSC1/TSC2 complex."
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"Patients with TSC have pathogenic variants in either TSC1 or TSC2 , not both genes; these pathogenic variants functionally inactivate TSC1 or TSC2 or leads to the loss of the ideal conformation of the hamartin-tuberin complex causing aberrant activation of mTOR and resulting in heightened cell proliferation and growth ( xref ) xref , xref , xref ."
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"Indeed, the Ref(2)P-ubiquitin-positive aggregates were gone when InR DN , akt RNAi, TOR RNAi, or TSC1-TSC2 (forming a negative regulator complex of TOR) was expressed in AMPK RNAi neurons (), in contrast to the Ref(2)P-ubiquitin aggregates that robustly accumulated in AMPK RNAi neurons alone ()."
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"For immunoprecipitation of mTOR–Raptor and TSC1‐TSC2 complexes, HCT‐116, HCT‐15, and LS174T cells were seeded in 100 mm × 20 mm dishes and incubated for 24 h. Vehicle or gedatolisib was added to a final concentration of 1 μM and the cells were incubated for an additional 12 h and then harvested."
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"Previous studies have suggested links between the DDR and the mTOR signalling pathway potentially via protein kinase B (PKB and Akt) phosphorylation : firstly, Akt has been shown to activate mTORC1 by directly phosphorylating the TSC1 and TSC2 complex (Inoki etal, 2002) or by dissociation of PRAS40 from the essential mTORC1 component RAPTOR (Thedieck etal, 2007)."
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"For instance, the ubiquitous growth factor regulated protein kinases Akt, ERK, and RSK all directly phosphorylate TSC2 and, through unknown molecular and cellular mechanisms, inhibit the TSC1 and TSC2 complex, thereby stimulating an increase in Rheb-GTP levels and activation of mTORC1."
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"Both traditionally known pathways of mTORC1 and mTORC2 that involve p70S6K, 4EBP1, PI 3-K, Akt, AMPK, GSK-3beta, REDD1, and the TSC1 and TSC2 complex and newly recognized pathways that include wingless, growth factors, and forkhead transcription factors can significantly influence the biological outcome of mTOR signaling."
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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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"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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"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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"We investigated whether CaM binding-mediated inhibition of the TSC2-Rheb interaction was affected by a change in the interaction between TSC1 and TSC2.To evaluate the effect of CaM addition on TSC1–TSC2 binding and TSC2–Rheb binding simultaneously, myc-tagged TSC1 (TSC1-myc) was co-expressed with HiBiT-Rheb and subjected to a TSC2-Rheb binding assay by mixing with cell lysates containing GFP-TSC2."
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"These results suggest that CaM binding to TSC2 does not affect TSC1–TSC2 complex formation, and the CaM-mediated reduction of TSC2-Rheb interaction is not mediated by the change of TSC1-TSC2 complex.Previously, we demonstrated that treatment with BAPTA-AM, an intracellular Ca chelator, and CaM inhibitors like calmidazolium (CMDZ) and W-7, resulted in a decrease of the phosphorylation of ribosomal protein S6 kinase 1 (S6K1), a readout of mTORC1 activity (16)."
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"Although the oncogenic events that have been associated with mTOR upregulation of HIF have included persistent activation of Akt, overexpression of HER2 and the BCR-ABL, and inactivation of PTEN, similar effects may also be achieved by dysregulation of the TSC1 and TSC2 complex by mutation, promoter hypermethylation [XREF_BIBR], or by binding with HPV16 E6, which results in the proteasome mediated degradation of TSC2 [XREF_BIBR]."
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"Whether such alterations in the TSC1 and TSC2 complex coupled with HIF-1alpha polymorphisms influence the progression to SCC of the head and neck needs to be further assessed in a larger number of cases and may provide biomarkers to predict responses to specific therapies and overall disease prognosis."
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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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"Indeed, there appears to be a correlation between tyrosine phosphorylation, TSC1-TSC2 interaction, and negative regulation of mTOR activity since the TSC2Y1571H mutant failed to suppress phosphorylation at the T-loop and H-motif of p70S6K.[87] To date, upstream tyrosine kinases that act on tuberin have not been elucidated."
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"The tuberous sclerosis complex (TSC) constitutes a genetic disorder that is caused by mutations in TSC1 or TSC2 , which encode proteins that form the hamartin–tuberin complex that is a key negative regulator of the mTORC1 pathway, which controls cell growth and metabolism [ xref ]."
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"Furthermore, the loss of the C-terminal GTPase activating protein (GAP) domain of TSC2 would also be predicted to disrupt the action of the TSC1 and TSC2 complex on the GTPase Ras homolog expressed in brain (RHEB), thus activating RHEB-GTP-dependent stimulation of the mammalian target of rapamycin complex 1 (mTORC1) [XREF_BIBR]."
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"Loss of either TSC1 or TSC2 prevents formation of a functional TSC1 and TSC2 complex resulting in constitutive activation of mTORC1 and phosphorylation of its downstream targets S6K and 4E-BP1, with net effects of abnormal translational activation leading to cell growth and proliferation."
sparser
"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 [ xref – xref ]."
reach
"The major breakthrough in understanding the functions of TSC1 and TSC2 came with identifying that TSC2 binds TSC1 via its N-terminal domain and forms the TSC1 and TSC2 tumor suppressor complex that acts as a negative regulator of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), a key regulator of cell growth, proliferation, metabolism, and autophagy XREF_BIBR - XREF_BIBR."
reach
"While early reports proposed that Akt-mediated phosphorylation destabilizes the TSC1-TSC2 complex, leading to dissociation of TSC1 from TSC2 and subsequent activation of mTORC1 signaling (16, 18), more recent studies have suggested that there was no destabilization of endogenous TSC1 and TSC2 protein complexes before or after TSC2 phosphorylation."
reach
"These findings suggest that while the HBD in the N-terminus of TSC2 contributes to the interaction with CBAP, other regions of TSC2 may also be involved.To further investigate the effect of CBAP on the interaction between TSC2 and TSC1, we expressed equal amounts of exogenous GFP-tagged HBD with increasing amounts of Flag-tagged CBAP in CBAP-deficient HEK293T cells."
reach
"The different effects of MHY1485 and 3BDO compared to TSC1 deficiency on cytokine production suggests that the TSC1/TSC2 complex may be involved in other regulatory pathways in addition to mTORC1.It is interesting to note that there is evidence for the participation of the mTORC1-mediated signaling pathway in the process of MC granule biogenesis after degranulation [42]."
reach
"To further verify that it is indeed mTORC1 that mediates the positive regulation of STAT3 and the negative regulation of miR-125b-5p downstream of TSC1 and TSC2 complex, we examined STAT3 and miR-125b-5p level in Raptor (a specific component of mTORC1) or Rictor (a specific component of mTORC2)-knockdown Tsc2-/- MEFs."
reach
"Advances in understanding the molecular pathology underlying Tuberous Sclerosis Complex (TSC) and sporadic Lymphangioleiomyomatosis (LAM) led to the identification of the mechanistic target of rapamycin complex 1 (mTORC1) as a critical effector of the hamartin and tuberin heterodimer."
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
"Regulators that induce autophagy include tumor suppressors, such as PTEN, TSC1 and TSC2 complexes, and DAPk; stress activated signaling molecules, such as c-Jun N-terminal kinase 1 (JNK1), and those that respond to low energy (for example, AMP kinase) or endoplasmic reticulum (ER) stress (for example, PERK, eIF2alpha-kinase and IRE1), and molecules involved in innate immune signaling, such as toll like receptors and immunity related GTPases."
sparser
"The R2TP complex is known for its involvement in the assembly and stabilization of several multiprotein complexes such as L7Ae ribonucleoproteins, U5 small nuclear ribonucleoprotein, RNA polymerase II, phosphatidylinositol 3-kinase-related kinases (PIKKs), and the mTOR/tuberous sclerosis complex (TSC1-TSC2)."
sparser
"It is caused by a heterozygous TSC1 or TSC2 mutation that, in combination with a “second hit”, leads to a loss of the hamartin–tuberin complex and thereby to a constitutive activation of the mammalian target of rapamycin complex 1 (mTORC 1) effecting cell proliferation and tumorigenesis [ xref ]."
reach
"XREF_BIBR, XREF_BIBR Growth factor stimulation results in PI3K-Akt activation, and activated Akt promotes mTORC1 signaling through Akt mediated phosphorylation of both TSC2 and PRAS40, in which Akt mediated phoshorylation of TSC2 relieves the inhibitory effect of TSC1 and TSC2 complex on mTORC1 activation and cell growth."
reach
"The phosphorylation of TSC2 on the residues of serine 939, serine 981, and threonine 1462 can increase its binding to the anchor protein 14-3-3 and lead to the cellular sequestration by 14-3-3, disruption of the TSC1 and TSC2 complex, and subsequent activation of Rheb and mTORC1 [XREF_BIBR]."
reach
"In addition, the study also confirmed that in rat mesangial cell lines cultured in high glucose environment, mTOR regulates cell growth and proliferation by phosphorylating downstream proteins p70s6k and 4E-BP1, and DDIT4 inhibits cell proliferation by up regulating the expression of mTOR by up regulating TSC1/TSC2 complex (Chen et al., 2018a; Herb and Schramm, 2021)."
reach
"Nellist et al. (2005), studied other TSC2 variants, R905Q, and P1202H, which are similar to F1510del in that they do not involve the TSC1 interacting region within residues 70–530, and thus do not prevent TSC1-TSC2 complex formation, do not involve the so-called tuberin domain (555–903) and are N-terminal to the TSC2 GAP domain [37]."