UNIPROT:P42345 - FACTA Search

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Query: UNIPROT:P42345 (mTOR)
26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The eukaryotic initiation factor 4E (eIF-4E)-binding proteins PHAS-I and PHAS-II were found to have overlapping but different patterns of expression in tissues. Both PHAS proteins were expressed in 3T3-L1 adipocytes, in which insulin stimulated their phosphorylation, promoted dissociation of PHAS.eIF-4E complexes, and decreased the ability of both to bind exogenous eIF-4E. The effects of insulin were attenuated by rapamycin and wortmannin, two agents that block activation of p70(S6K). Unlike PHAS-I, PHAS-II was readily phosphorylated by cAMP-dependent protein kinase in vitro; however, the effects of insulin on both PHAS proteins were attenuated by agents that increase intracellular cAMP, by cAMP derivatives, and by phosphodiesterase inhibitors. These agents also markedly inhibited the activation of p70(S6K). In summary, our results indicate that PHAS-I and -II are controlled by the mammalian target of rapamycin and p70(S6K) signaling pathway and that in 3T3-L1 adipocytes this pathway is inhibited by increased cAMP.
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PMID:Control of the translational regulators PHAS-I and PHAS-II by insulin and cAMP in 3T3-L1 adipocytes. 893 71

PHAS-I and PHAS-II are members of a newly discovered family of proteins that regulate translation initiation. PHAS-I is expressed in a wide variety of cell types, but it is highest in adipocytes, where protein synthesis is markedly increased by insulin. PHAS-II is highest in liver and kidney, where very little PHAS-I is found. PHAS proteins bind to eIF-4E, the mRNA cap-binding protein, and inhibit translation of capped mRNA in vitro and in cells. In rat adipocytes PHAS-I is phosphorylated in at least five sites, all of which conform to the consensus, (Ser/Thr)-Pro. Both PHAS proteins are phosphorylated in response to insulin or growth factors, such as EGF, PDGF and IGF-1. Phosphorylation in the appropriate site(s) promotes dissociation of PHAS/eIF-4E complexes. This allows eIF-4E to bind to eIF-4G (p220), thereby increasing the amount of the eIF-4F complex and the rate of translation initiation. Increasing cAMP promotes PHAS-I dephosphorylation and increases binding to eIF-4E. Unlike PHAS-I, PHAS-II is readily phosphorylated by PKA in vitro, suggesting that regulation of the two proteins differs. However, increasing cAMP in cells also promotes dephosphorylation of PHAS-II. Thus, PHAS proteins appear to be key mediators not only of the stimulatory effects of insulin and growth factors on protein synthesis, but also of the inhibitory effects of cAMP. Moreover, by controlling eIF-4E PHAS proteins may be involved in the control of cell proliferation, as increasing eIF-4E is mitogenic and can even cause malignant transformation of cells. MAP kinase readily phosphorylates both PHAS-I and PHAS-II in vitro, but inhibiting activation of MAP kinase does not attenuate the effects of insulin on increasing phosphorylation of the PHAS proteins in adipocytes or skeletal muscle. MAP kinase phosphorylates neither PHAS-I nor PHAS-II at a significant rate when the proteins are bound to eIF-4E. Therefore, the role of MAP kinase in promoting the dissociation of PHAS/eIF-4E complexes is not clear. Of several protein kinases tested, only casein kinase-II phosphorylated PHAS-I when it was bound eIF-4E. Indeed, the bound form of PHAS-I was phosphorylated more rapidly than the free form. However, it is unlikely that casein kinase II regulates either PHAS protein, as the major site (Ser111) in PHAS-I phosphorylated by casein kinase II in vitro is not phosphorylated in adipocytes, and PHAS-II is not a substrate for casein kinase-II. Pharmacological and genetic evidence indicates that the mTOR/p70S6K pathway is involved in the control of PHAS-I and -II. Thus, PHAS proteins may be mediators of the effects of this pathway on protein synthesis and cell proliferation.
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PMID:PHAS proteins as mediators of the actions of insulin, growth factors and cAMP on protein synthesis and cell proliferation. 938 73

Incubating 3T3-L1 adipocytes with forskolin, which increases intracellular cAMP by activating adenylate cyclase, mimicked rapamycin by attenuating the effect of insulin on stimulating the phosphorylation of four (S/T)P sites in PHAS-I, a downstream target of the mammalian target of rapamycin (mTOR) signaling pathway. To investigate the hypothesis that increasing cAMP inhibits mTOR, the protein kinase activity of mTOR was measured in an immune complex assay with recombinant PHAS-I as substrate. Both forskolin and 8-(4-chlorophenylthio)adenosine 3'-5'-monophosphate (CPT-cAMP) prevented the activation of mTOR by insulin in adipocytes, but neither agent affected mTOR activity when added directly to the immunopurified protein. In contrast, the cAMP phosphodiesterase inhibitor, theophylline, inhibited mTOR activity not only when added to intact adipocytes but also when added to immunopurified mTOR in vitro, demonstrating that certain methylxanthines are able to inhibit mTOR independently of increasing cAMP. Forskolin and CPT-cAMP blocked the effect of insulin on increasing mTOR phosphorylation, which was assessed using mTAb1, an antibody whose binding is inhibited by phosphorylation of mTOR. Although the mTAb1 epitope contains a consensus site for protein kinase B, neither agent inhibited the activation of protein kinase B produced by insulin. These findings support the interpretation that increasing cAMP attenuates the effects of insulin on PHAS-I, p70(S6K), and other downstream targets of the mTOR signaling pathway by inhibiting the phosphorylation and activation of mTOR.
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PMID:Attenuation of mammalian target of rapamycin activity by increased cAMP in 3T3-L1 adipocytes. 985 18

The intracellular signaling mechanisms by which cholecystokinin (CCK) and other secretagogues regulate pancreatic acinar function are more complex than originally realized. CCK couples through heterotrimeric G proteins of the Gq family to lead to an increase in intracellular free Ca2+, which shows spatial and temporal patterns of signaling. The actions of Ca2+ are mediated in part by activation of a number of Ca2+-activated protein kinases and the protein phosphatase calcineurin. By the process of exocytosis the intracellular messengers Ca2+, diacylglycerol, and cAMP activate the release of the zymogen granule content in a manner that is poorly understood. This fusion event most likely involves SNARE and Rab proteins present on zymogen granules and cellular membrane domains. More likely related to nonsecretory aspects of cell function, CCK also activates three MAPK cascades leading to activation of ERKs, JNKs, and p38 MAPK. Although the function of these pathways is not well understood, ERKs are probably related to cell growth, and through phosphorylation of hsp27, p38 can affect the actin cytoskeleton. The PI3K (phosphatidylinositol 3-kinase)-mTOR (mammalian target of rapamycin) pathway is important for regulation of acinar cell protein synthesis because it leads to both activation of p70S6K and regulation of the availability of eIF4E in response to CCK. CCK also activates a number of tyrosyl phosphorylation events including that of p125FAK and other proteins associated with focal adhesions.
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PMID:Intracellular signaling mechanisms activated by cholecystokinin-regulating synthesis and secretion of digestive enzymes in pancreatic acinar cells. 1118 49

FKBP12-rapamycin associated protein (FRAP, also known as mTOR or RAFT) is the founding member of the phosphatidylinositol kinase-related kinase family and functions as a sensor of physiological signals that regulate cell growth. Signals integrated by FRAP include nutrients, cAMP levels, and osmotic stress, and cellular processes affected by FRAP include transcription, translation, and autophagy. The mechanisms underlying the integration of such diverse signals by FRAP are largely unknown. Recently, FRAP has been reported to be regulated by mitochondrial dysfunction and depletion of ATP levels. Here we show that exposure of cells to hyperosmotic conditions (and to glucose-deficient growth medium) results in rapid and reversible dissipation of the mitochondrial proton gradient. These results suggest that the ability of FRAP to mediate osmotic stress response (and glucose deprivation response) is by means of an intermediate mitochondrial dysfunction. We also show that in addition to cytosolic FRAP a large portion of FRAP associates with the mitochondrial outer membrane. The results support the existence of a stress-sensing module consisting of mitochondria and mitochondrial outer membrane-associated FRAP. This module allows the cell to integrate a variety of stress signals that affect mitochondrial function and regulate a growth checkpoint involving p70 S6 kinase.
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PMID:FKBP12-rapamycin-associated protein associates with mitochondria and senses osmotic stress via mitochondrial dysfunction. 1193

Glucose can activate the mitogen-activated kinases, Erk-1/2, and the ribosomal-S6 kinase, p70(S6K), in beta-cells, contributing to an increase in mitogenesis. However, the signaling mechanism by which glucose induces Erk-1/2 and p70(S6K) phosphorylation activation is undefined. Increased glucose metabolism increases [Ca(2+)](i) and [cAMP], and it was investigated if these secondary signals were linked to glucose-induced Erk-1/2 and p70(S6K) activation in pancreatic beta-cells. Blocking Ca(2+) influx with verapamil, or inhibiting protein kinase A (PKA) with H89, prevented glucose-induced Erk-1/2 phosphorylation. Increasing cAMP levels by GLP-1 potentiated glucose-induced Erk-1/2 phosphorylation via PKA activation. Elevation of [Ca(2+)](i) by glyburide potentiated Erk-1/2 phosphorylation, which was also inhibited by H89, suggesting increased [Ca(2+)](i) preceded PKA for glucose-induced Erk-1/2 activation. Adenoviral-mediated expression of dominant negative Ras in INS-1 cells decreased IGF-1-induced Erk-1/2 phosphorylation but had no effect on that by glucose. Collectively, our study indicates that a glucose-induced rise in [Ca(2+)](i) leads to cAMP-induced activation of PKA that acts downstream of Ras and upstream of the MAP/Erk kinase, MEK, to mediate Erk-1/2 phosphorylation via phosphorylation activation of Raf-1. In contrast, glucose-induced p70(S6K) activation, in the same beta-cells, was mediated by a distinct signaling pathway independent of Ca(2+)/cAMP, most likely via mTOR-kinase acting as an "ATP-sensor."
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PMID:Differential activation mechanisms of Erk-1/2 and p70(S6K) by glucose in pancreatic beta-cells. 1266 69

Thyroid-stimulating hormone (TSH) regulates the growth and differentiation of thyrocytes by activating the TSH receptor (TSHR). This study investigated the roles of the phosphatidylinositol 3-kinase (PI3K), PDK1, FRAP/mammalian target of rapamycin, and ribosomal S6 kinase 1 (S6K1) signaling mechanism by which TSH and the stimulating type TSHR antibodies regulate thyrocyte proliferation and the follicle activities in vitro and in vivo. The TSHR immunoprecipitates exhibited PI3K activity, which was higher in the cells treated with either TSH or 8-bromo-cAMP. TSH and cAMP increased the tyrosine phosphorylation of TSHR and the association between TSHR and the p85alpha regulatory subunit of PI3K. TSH induced a redistribution of PDK1 from the cytoplasm to the plasma membrane in the cells in a PI3K- and protein kinase A-dependent manner. TSH induced the PDK1-dependent phosphorylation of S6K1 but did not induce Akt/protein kinase B phosphorylation. The TSH-induced S6K1 phosphorylation was inhibited by a dominant negative p85alpha regulatory subunit or by the PI3K inhibitors wortmannin and LY294002. Rapamycin inhibited the phosphorylation of S6K1 in the cells treated with either TSH or 8-bromo-cAMP. The stimulating type TSHR antibodies from patients with Graves disease also induced S6K1 activation, whereas the blocking type TSHR antibodies from patients with primary myxedema inhibited TSH- but not the insulin-induced phosphorylation of S6K1. In addition, rapamycin treatment in vivo inhibited the TSH-stimulated thyroid follicle hyperplasia and follicle activity. These findings suggest an interaction between TSHR and PI3K, which is stimulated by TSH and cAMP and might involve the downstream S6K1 but not Akt/protein kinase B. This pathway may play a role in the TSH/stimulating type TSH receptor antibody-mediated thyrocyte proliferation in vitro and in the response to TSH in vivo.
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PMID:Regulation of the phosphatidylinositol 3-kinase, Akt/protein kinase B, FRAP/mammalian target of rapamycin, and ribosomal S6 kinase 1 signaling pathways by thyroid-stimulating hormone (TSH) and stimulating type TSH receptor antibodies in the thyroid gland. 1266 83

The activity of adenosine kinase (AK) was significantly impaired in splenocytes isolated from diabetic rats. Administration of insulin to diabetic animals restored AK activity, protein, and mRNA levels in diabetic splenocytes. Experiments performed on cultured rat lymphocytes demonstrated that insulin did not change the stability of AK mRNA. Insulin induced AK gene expression in a dose- and time-dependent manner. Maximal increases in AK mRNA (3.9-fold) and activity level (3.7-fold) were observed at the fourth and fifth hours of cell incubation with 10 nM insulin, respectively. The insulin effect on AK expression was not influenced by dibutyryl cAMP (dcAMP). On the other hand dcAMP weakly increased (1.7-fold) basal expression of AK. Exposure of rat lymphocytes to wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K), or rapamycin, an inhibitor of mTOR, did not affect the ability of insulin to stimulate expression of AK. Prior treatment of the cells with 10 microM PD98059, an inhibitor of mitogen-activated protein kinase (MAPK) kinase (MEK) completely blocked insulin-stimulated expression of AK gene. Insulin produced a significant transient increase in the tyrosine phosphorylation of ERK1/2, and PD98059 inhibited this phosphorylation. Furthermore exposure of cells to insulin has resulted in transient phosphorylation of Elk-1 on Ser-383 and sustained elevation of c-Jun and c-Fos protein. The maximal phosphorylation of Elk-1 was observed at 15 min, and was blocked by PD98059. We concluded that insulin stimulates AK gene expression through a series of events occurring sequentially. This includes activation of the MAPK cascade and subsequent phosphorylation of Elk-1 followed by increased expression of c-fos and c-jun genes.
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PMID:Insulin induces expression of adenosine kinase gene in rat lymphocytes by signaling through the mitogen-activated protein kinase pathway. 1272 3

The cAMP pathway activates p38-MAPKs in the FRTL-5 rat thyroid cell line, contributing to the increased expression of the Na+/I- symporter (NIS) mRNA. This study investigates the cAMP-dependent expression and transcriptional activity of the p38-MAPK substrate CCAAT/enhancer-binding protein-homologous protein (CHOP). CHOP is expressed in the rat thyroid gland and in confluent PCCL3 and FRTL-5 cells. In FRTL-5 cells, TSH withdrawal induced a rapid down-regulation of CHOP that could be prevented by forskolin (Fk). Moreover, TSH and Fk were able to reinduce CHOP expression. The use of pharmacological inhibitors indicated that cAMP-induced CHOP expression was dependent on protein kinase A (PKA), mammalian target of rapamycin pathway, and reactive oxygen species. Transfection of a CHOP trans- reporting system revealed strong stimulation of the transcriptional activity of CHOP by Fk, by chlorophenylthio-cAMP, and by the catalytic subunit of PKA. CHOP transcriptional activity was significantly reduced by the p38-MAPK inhibitor SB203580, by transfection of a dominant-negative variant of p38alpha-MAPK, or by mutation of two serine residues in CHOP targeted by p38-MAPKs. Finally, cAMP-induced NIS mRNA expression was higher in FRTL-5 cells stably transfected with CHOP cDNA than in control cells. Likewise, the activity of the NIS promoter was higher in cells overexpressing CHOP than in control cells. These findings suggest that the stimulation of CHOP expression and transcriptional activity by the cAMP pathway may contribute to the regulation of genes involved in thyroid cell differentiation.
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PMID:CCAAT/enhancer-binding protein-homologous protein expression and transcriptional activity are regulated by 3',5'-cyclic adenosine monophosphate in thyroid cells. 1290 53

The genes encoding microtubule-associated protein 2 (MAP2), and the alpha subunit of calcium/calmodulin-dependent protein kinase II (alphaCaMKII), are members of a small number of genes whose expression is increased in hippocampal neurones during the intermediate phase of long-term potentiation (LTP)-a phase dependent on mRNA translation but not on gene transcription. However, the intracellular signalling pathways which mediate these increases in expression are largely unknown. Organotypic slice cultures of rat hippocampus were exposed to either forskolin (to elevate cAMP levels), A23187 (to increase intracellular Ca(2+) levels) or the corresponding vehicle. The levels of immunoreactive (ir-) MAP2 were increased 4 h after forskolin treatment, but were unaffected by A23187 treatment. Conversely, the levels of ir-alphaCaMKII were increased 4 h after A23187 treatment, but were unaffected by forskolin. The regulation of the expression of these proteins was the same in the CA3 region as in the CA1 and dentate gyrus of the hippocampus. While rapamycin reduced the basal levels of ir-MAP2, it did not affect the ability of either forskolin or A23187 to enhance ir-MAP2 or ir-alphaCaMKII levels. These results suggest that cAMP and Ca(2+) differentially modulate the expression of these two plasticity-related genes, and that translational enhancement via the mammalian target of rapamycin kinase is not involved in these effects.
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PMID:Differential regulation of MAP2 and alphaCamKII expression in hippocampal neurones by forskolin and calcium ionophore treatment. 1499 11

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