Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inactivating mutations of the neurofibromatosis 2 (NF2) gene, NF2, result predominantly in benign neurological tumors, schwannomas and meningiomas, in humans; however, mutations in murine Nf2 lead to a broad spectrum of cancerous tumors. The tumor-suppressive function of the NF2 protein, merlin, a membrane-cytoskeleton linker, remains unclear. Here, we identify the mammalian target of rapamycin complex 1 (mTORC1) as a novel mediator of merlin's tumor suppressor activity. Merlin-deficient human meningioma cells and merlin knockdown arachnoidal cells, the nonneoplastic cell counterparts of meningiomas, exhibit rapamycin-sensitive constitutive mTORC1 activation and increased growth. NF2 patient tumors and Nf2-deficient mouse embryonic fibroblasts demonstrate elevated mTORC1 signaling. Conversely, the exogenous expression of wild-type merlin isoforms, but not a patient-derived L64P mutant, suppresses mTORC1 signaling. Merlin does not regulate mTORC1 via the established mechanism of phosphoinositide 3-kinase-Akt or mitogen-activated protein kinase/extracellular signal-regulated kinase-mediated TSC2 inactivation and may instead regulate TSC/mTOR signaling in a novel fashion. In conclusion, the deregulation of mTORC1 activation underlies the aberrant growth and proliferation of NF2-associated tumors and may restrain the growth of these lesions through negative feedback mechanisms, suggesting that rapamycin in combination with phosphoinositide 3-kinase inhibitors may be therapeutic for NF2.
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PMID:NF2/merlin is a novel negative regulator of mTOR complex 1, and activation of mTORC1 is associated with meningioma and schwannoma growth. 1945 Dec 25

Perinuclear aggresome formation is a key mechanism to dispose of misfolded proteins that exceed the degradative capacity of ubiquitin-proteasome and autophagy-lysosome systems. Functional blockade of either degradative system leads to an enhanced aggresome formation. The tuberous sclerosis complex-Ras homologue enriched in brain-mammalian target of rapamycin (TSC-Rheb-mTOR) pathway is known to play a central role in modulating protein synthesis and autophagy. However, in spite of the constitutive activation of mTOR and the abrogated autophagy activity in TSC1- or TSC2-deficient cells, the TSC mutant cells are defective in aggresome formation and undergo apoptosis upon misfolded protein accumulation both in vitro and in vivo. High Rheb activity in TSC mutant cells inhibits aggresome formation and sensitizes cell death in response to misfolded proteins. Surprisingly, this previously unrecognized function of Rheb is independent of TOR complex 1. Active Rheb disrupts the interaction between dynein and misfolded protein cargos, and therefore blocks aggresome formation by inhibiting dynein-dependent transportation of misfolded proteins. This study reveals a function of Rheb in controlling misfolded protein metabolism by modulating aggresome formation.
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PMID:Rheb controls misfolded protein metabolism by inhibiting aggresome formation and autophagy. 1945 66

The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) functions as a rapamycin-sensitive environmental sensor that promotes cellular biosynthetic processes in response to growth factors and nutrients. While diverse physiological stimuli modulate mTORC1 signaling, the direct biochemical mechanisms underlying mTORC1 regulation remain poorly defined. Indeed, while three mTOR phosphorylation sites have been reported, a functional role for site-specific mTOR phosphorylation has not been demonstrated. Here we identify a new site of mTOR phosphorylation (S1261) by tandem mass spectrometry and demonstrate that insulin-phosphatidylinositol 3-kinase signaling promotes mTOR S1261 phosphorylation in both mTORC1 and mTORC2. Here we focus on mTORC1 and show that TSC/Rheb signaling promotes mTOR S1261 phosphorylation in an amino acid-dependent, rapamycin-insensitive, and autophosphorylation-independent manner. Our data reveal a functional role for mTOR S1261 phosphorylation in mTORC1 action, as S1261 phosphorylation promotes mTORC1-mediated substrate phosphorylation (e.g., p70 ribosomal protein S6 kinase 1 [S6K1] and eukaryotic initiation factor 4E binding protein 1) and cell growth to increased cell size. Moreover, Rheb-driven mTOR S2481 autophosphorylation and S6K1 phosphorylation require S1261 phosphorylation. These data provide the first evidence that site-specific mTOR phosphorylation regulates mTORC1 function and suggest a model whereby insulin-stimulated mTOR S1261 phosphorylation promotes mTORC1 autokinase activity, substrate phosphorylation, and cell growth.
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PMID:Site-specific mTOR phosphorylation promotes mTORC1-mediated signaling and cell growth. 1948 63

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease characterized by the formation of renal cysts. This disease can be caused by mutations in two genes, PKD1 and PKD2, which encode polycystin-1 (PC-1) and -2 (PC-2), respectively.PC-1 is a large plasma membrane receptor involved in the regulation of several biological functions and signaling pathways, and PC-2 is a calcium channel of the TRP family. The two proteins associate in a complex to prevent cyst formation, but the precise mechanism(s) involved remain largely unknown.This review will focus on recent advances in our understanding of the functions of polycystins and their role in signal transduction.Increased activity of the mammalian target of rapamycin (mTOR) kinase has been observed in cysts found in ADPKD tissues. Rapamycin has been shown to have beneficial effects in rodent models of polycystic kidney disease, prompting the initiation of pilot clinical trials with human patients. Furthermore, a direct role for PC-1 in the regulation of cell growth (size) via mTOR has recently been demonstrated.Major advancements in the study of mTOR biology have highlighted that this kinase exists in association with two different complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The mTORC1 complex regulates cell growth (size), proliferation, translation and autophagy, and mTORC2 regulates the actin cytoskeleton and apoptosis. Interestingly, mTORC2 has been shown to contain the kinase responsible for the phosphorylation of Akt at Serine 473. Previous studies have shown that PC-1 controls the PI 3-kinase/Akt cascade to regulate apoptosis and the actin cytoskeleton, suggesting that this receptor might regulate mTOR at several levels.This review aims to discuss three different, inter-related themes emerging from the literature: (i) studies performed in our and other laboratories collectively suggest that PC-1 might be able to differentially regulate the two mTOR complexes; (ii) several studies point to genetic and functional cross-talk between the PKD and TSC genes, although the molecular details remain obscure; and (iii) studies performed in mammals and in the unicellular algae Chlamidomonas Reinhardtii might highlight a link between cilia, regulation of cell size and regulation of the cell cycle.
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PMID:Emerging evidence of a link between the polycystins and the mTOR pathways. 1986 83

The rapamycin-sensitive mTOR complex 1 (mTORC1) promotes protein synthesis, cell growth, and cell proliferation in response to growth factors and nutritional cues. To elucidate the poorly defined mechanisms underlying mTORC1 regulation, we have studied the phosphorylation of raptor, an mTOR-interacting partner. We have identified six raptor phosphorylation sites that lie in two centrally localized clusters (cluster 1, Ser(696)/Thr(706) and cluster 2, Ser(855)/Ser(859)/Ser(863)/Ser(877)) using tandem mass spectrometry and generated phosphospecific antibodies for each of these sites. Here we focus primarily although not exclusively on raptor Ser(863) phosphorylation. We report that insulin promotes mTORC1-associated phosphorylation of raptor Ser(863) via the canonical PI3K/TSC/Rheb pathway in a rapamycin-sensitive manner. mTORC1 activation by other stimuli (e.g. amino acids, epidermal growth factor/MAPK signaling, and cellular energy) also promote raptor Ser(863) phosphorylation. Rheb overexpression increases phosphorylation on raptor Ser(863) as well as on the five other identified sites (e.g. Ser(859), Ser(855), Ser(877), Ser(696), and Thr(706)). Strikingly, raptor Ser(863) phosphorylation is absolutely required for raptor Ser(859) and Ser(855) phosphorylation. These data suggest that mTORC1 activation leads to raptor multisite phosphorylation and that raptor Ser(863) phosphorylation functions as a master biochemical switch that modulates hierarchical raptor phosphorylation (e.g. on Ser(859) and Ser(855)). Importantly, mTORC1 containing phosphorylation site-defective raptor exhibits reduced in vitro kinase activity toward the substrate 4EBP1, with a multisite raptor 6A mutant more strongly defective that single-site raptor S863A. Taken together, these data suggest that complex raptor phosphorylation functions as a biochemical rheostat that modulates mTORC1 signaling in accordance with environmental cues.
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PMID:Regulation of mTOR complex 1 (mTORC1) by raptor Ser863 and multisite phosphorylation. 1986 31

Disturbance to endoplasmic reticulum (ER) homeostasis that cannot be rescued by the unfolded protein response (UPR) results in autophagy and cell death, but the precise mechanism was largely unknown. Here we demonstrated that ER stress-induced cell death was mediated by autophagy which was partly attributed to the inactivation of the mammalian target of rapamycin (mTOR). Three widely used ER stress inducers including tunicamycin, DTT and MG132 led to the conversion of LC3-I to LC3-II , a commonly used marker of autophagy, as well as the downregulation of mTOR concurrently. TSC -deficient cells with constitutive activation of mTOR exhibited more resistance to ER stress-induced autophagy, compared with their wild-type counterparts. Furthermore, our studies showed that ER stress-induced deactivation of mTOR was attributed to the downregulation of AKT/TSC /mTOR pathway. Phosphatase and tensin homolog (PTEN) and AMP-activated protein kinase (AMPK) as two regulators in this pathway seemed to be absent in this regulation. As a chemical chaperone helping the correct folding of proteins, 4-phenylbutyric acid (4-PBA) partly rescued the AKT/TSC/mTOR pathway in drug-induced acute ER stress. Moreover, constitutively-activated mTOR-induced long-term ER stress attenuated the RTK/PI3K/AKT signaling pathway in response to the stimulation by various growth factors, which could also be partly restored by 4-PBA.
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PMID:ER stress negatively regulates AKT/TSC/mTOR pathway to enhance autophagy. 2010 19

Tuberous sclerosis complex proteins 1-2 (TSC1-TSC2) complex integrates both nutrient and hormonal signaling and is a critical negative regulator of mammalian target of rapamycin (mTOR) complex 1. The use of different beta-cell lines expressing or not the insulin receptor (IR(+/+) and IR(-/-)) or with a reconstituted expression of IR isoform A or B (Rec A and Rec B) revealed that both phosphatidylinositol 3-kinase/Akt/TSC/mTOR complex 1 and MAPK kinase/ERK pathways mediate insulin signaling in IR(+/+)-, IRA-, or IRB-expressing cells. However, glucose signaling was mediated by MAPK kinase/ERK and AMP-activated protein kinase pathways as assessed in IR(-/-) cells. The effect of insulin on Akt phosphorylation was completely inhibited by the use of the phosphatidylinositol 3-kinase inhibitor wortmannin in IR(+/+) and Rec B cells, a partial inhibitory effect being observed in Rec A cell line. The knockdown of TSC2 expression up-regulated the downstream basal phosphorylation of 70-kDa ribosomal protein S6 kinase (p70S6K) and mTOR. More importantly, upregulation of p70S6K signaling impaired insulin-stimulated phosphorylation of Akt Ser(473) and p70S6K in IR(+/+) and Rec B but not in Rec A cell lines. In fact, insulin receptor substrate-1 Ser(307) phosphorylation signal in Rec B was stronger than in Rec A cell line during insulin action. Rec A cells induced a higher proliferation rate compared with Rec B or IR(+/+) during serum stimulation. Thus, we propose that the regulation of TSC2 phosphorylation by insulin or glucose independently integrates beta-cell proliferation signaling, the relative expression of IRA or IRB isoforms in pancreatic beta cells playing a major role.
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PMID:Role of the TSC1-TSC2 complex in the integration of insulin and glucose signaling involved in pancreatic beta-cell proliferation. 2042 78

Tuberous sclerosis, caused by germline mutations in the TSC1 or TSC2 genes, is associated with aberrant upregulation of the mammalian target of rapamycin (mTOR) signalling pathway, resulting in growth of tumours, including renal angiomyolipomas (AMLs). AMLs may cause hypertension, renal failure and spontaneous life-threatening haemorrhage. Previously, invasive interventions were required to treat AMLs. More recently, mTOR inhibitors have been used as molecularly targeted treatment to treat AMLs. We present here the case of a paediatric patient with TSC in whom sirolimus has been used successfully to halt growth of renal AMLs.
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PMID:Sirolimus and tuberous sclerosis-associated renal angiomyolipomas. 2045 4

The recent progress of the biology of the locally aggressive sarcomas of soft tissues and related connective tissue tumors enabled to reclassify molecular and histological entities of the disease. Six subgroups of sarcomas are identified with specific molecular alterations, the targeted treatments of which are the object of this article: 1) sarcomas with specific translocations with fusion oncogenes (DFSP, PVNS); 2) sarcomas with tyrosine kinase mutations (KIT in GIST); 3) tumors with deletion of tumor suppressor genes (TSC in the PEComes, NF1 involved in type 1 neurofibromatosis; 4) sarcomas with MDM2/CDK4 amplification in the 12q13-15 amplicon, i.e. well differentiated or dedifferentiated liposarcomas; 5) sarcomas with complex genetics present more unrefined genetic changes (leiomyosarcomas, osteosarcomas). On top these 5 groups, desmoids tumors characterized by alterations of the Wnt, beta catenin, APC, and giant cell tumors of the bone, in which RANK/RANKL operates a complex interaction between the cellular stroma and giant tumor cells. The identification of these abnormal ways of road marking to licence the development of effective targeted therapeutic agents against certain rare histological connective subcategories of sarcomas and tumors with local aggressiveness, in particular DFSP, PVNS, GCST, PEComes, endometrial stromal sarcomas, Ewing sarcomas, etc. Imatinib is used in the treatment of DFSP, characterized by a translocation of the gene PDGF, or in pigmented villonodular synovitis (PVNS), a tumor of soft part also locally aggressive, caused by an abnormality of the gene coding for the M-CSF. Several clinical trials of phase I and II trials demonstrated the antitumor activity of anti-IGF1R antibodies in Ewing, whose fusion gene downregulates IGFBP3. Inhibitors of MDM2 are in the course of clinical evaluation in liposarcomas. Inhibitors of mTOR (sirolimus, temsirolimus) demonstrated an antitumoral activity in the PEComas. The molecular characterization of sarcomas allowed to develop therapeutic targeted to correct the responsible abnormalities. Translational research is and will be an essential tool for the development of new treatments and the identification of the mechanisms of answer and resistance set up by these tumors.
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PMID:[Targeted treatment of rare connective tissue tumors and sarcomas]. 2049 11

Inhibition of mTOR by rapamycin has been shown to suppress seizures in TSC/PTEN genetic models. Rapamycin, when applied immediately before or after a neurological insult, also prevents the development of spontaneous recurrent seizures (epileptogenesis) in an acquired model. In the present study, we examined the mTOR pathway in rats that had already developed chronic spontaneous seizures in a pilocarpine model. We found that mTOR is aberrantly activated in brain tissues from rats with chronic seizures. Furthermore, inhibition of mTOR by rapamycin treatment significantly reduces seizure activity. Finally, mTOR inhibition also significantly suppresses mossy fiber sprouting. Our findings suggest the possibility for a much broader window for intervention for some acquired epilepsies by targeting the mTOR pathway.
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PMID:Pharmacological inhibition of the mammalian target of rapamycin pathway suppresses acquired epilepsy. 2056 81


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