Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent molecular genetic investigations of primary cardiac tumors (myxomas, lipomas, rhabdomyomas, and fibromas) have provided insight into fundamental mechanisms of cardiac cell growth. Myxomas are the most common adult cardiac tumor, and familial cardiac myxomas are now appreciated to be caused by mutations in the PRKAR1alpha gene that encodes a regulatory subunit of protein kinase A. Cytogenetic studies have targeted candidate chromosomal loci that may be perturbed during cardiac lipoma pathogenesis. Rhabdomyomas, the most common pediatric cardiac neoplasm, are frequently associated with tuberous sclerosis, caused by mutations in the TSC-1 and TSC-2 genes. The study of Gorlin syndrome has shed light on the etiology of cardiac fibromas. This disorder is caused by mutation of the PTC gene, which regulates cell growth, commitment and differentiation. In the future, manipulation of PRKAR1alpha-, TSC-, and PTC-dependent pathways may foster new strategies to regenerate myocardium in the ischemic or myopathic heart.
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PMID:Tumors and the heart: molecular genetic advances. 1135 16

Insulin-like growth factors elicit many responses through activation of phosphoinositide 3-OH kinase (PI3K). The tuberous sclerosis complex (TSC1-2) suppresses cell growth by negatively regulating a protein kinase, p70S6K (S6K1), which generally requires PI3K signals for its activation. Here, we show that TSC1-2 is required for insulin signaling to PI3K. TSC1-2 maintains insulin signaling to PI3K by restraining the activity of S6K, which when activated inactivates insulin receptor substrate (IRS) function, via repression of IRS-1 gene expression and via direct phosphorylation of IRS-1. Our results argue that the low malignant potential of tumors arising from TSC1-2 dysfunction may be explained by the failure of TSC mutant cells to activate PI3K and its downstream effectors.
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PMID:The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. 1524 83

The mammalian target of rapamycin (mTOR) coordinates cell growth with the growth factor and nutrient/energy status of the cell. The phosphatidylinositol 3-kinase-AKT pathway is centrally involved in the transmission of mitogenic signals to mTOR. Previous studies have shown that mTOR is a direct substrate for the AKT kinase and identified Ser-2448 as the AKT target site in mTOR. In this study, we demonstrate that rapamycin, a specific inhibitor of mTOR function, blocks serum-stimulated Ser-2448 phosphorylation and that this drug effect is not explained by the inhibition of AKT. Furthermore, the phosphorylation of Ser-2448 was dependent on mTOR kinase activity, suggesting that mTOR itself or a protein kinase downstream from mTOR was responsible for the modification of Ser-2448. Here we show that p70S6 kinase phosphorylates mTOR at Ser-2448 in vitro and that ectopic expression of rapamycin-resistant p70S6 kinase restores Ser-2448 phosphorylation in rapamycin-treated cells. In addition, we show that cellular amino acid status, which modulates p70S6 kinase (S6K1) activity via the TSC/Rheb pathway, regulates Ser-2448 phosphorylation. Finally, small interfering RNA-mediated depletion of p70S6 kinase reduces Ser-2448 phosphorylation in cells. Taken together, these results suggest that p70S6 kinase is a major effector of mTOR phosphorylation at Ser-2448 in response to both mitogen- and nutrient-derived stimuli.
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PMID:Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase. 1589 89

Target of Rapamycin (TOR), a giant protein kinase expressed by all eucaryotic cells, controls cell size in response to nutrient signals. In metazoans, cell and organismal growth is controlled by nutrients and the insulin/insulin-like growth factor (IGF) system, and the understanding of how these inputs coordinately regulate TOR signaling has advanced greatly in the past 5 years. In single-cell eucaryotes and Caenorhabditis elegans, TOR is a dominant regulator of overall mRNA translation, whereas in higher metazoans, TOR controls the expression of a smaller fraction of mRNAs that is especially important to cell growth. TOR signals through two physically distinct multiprotein complexes, and the control of cell growth is mediated primarily by TOR complex 1 (TORC1), which contains the polypeptides raptor and LST8. Raptor is the substrate binding element of TORC1, and the ability of raptor to properly present substrates, such as the translational regulators 4E-BP and p70 S6 kinase, to the TOR catalytic domain is essential for their TOR-catalysed phosphorylation, and is inhibited by the Rapamycin/FKBP-12 complex. The dominant proximal regulator of TORC1 signaling and kinase activity is the ras-like small GTPase Rheb. Rheb binds directly to the mTOR catalytic domain, and Rheb-GTP enables TORC1 to attain an active configuration. Insulin/IGF enhances Rheb GTP charging through the ability of activated Akt to inhibit the Rheb-GTPase-activating function of the tuberous sclerosis heterodimer (TSC1/TSC2). Conversely, energy depletion reduces Rheb-GTP charging through the ability of the adenosine monophosphate-activated protein kinase to phosphorylate TSC2 and stimulate its Rheb-GTPase activating function, as well as by HIFalpha-mediated transcriptional responses that act upstream of the TSC1/2 complex. Amino-acid depletion inhibits TORC1 acting predominantly downstream of the TSC complex, by interfering with the ability of Rheb to bind to mTOR. The components of the insulin/IGF pathway to TORC1 are now well established, whereas the elements mediating the more ancient and functionally dominant input of amino acids remain largely unknown.
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PMID:Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase. 1704 22

Transforming growth factor-beta1-stimulated clone 22 (TSC-22) encodes a leucine zipper-containing protein that is highly conserved among various species. Mammalian TSC-22 is a potential tumor suppressor gene. It translocates into nuclei and suppresses cell division upon antiproliferative stimuli. In human colon carcinoma cells, TSC-22 inhibits cell growth by upregulating expression of the p21 gene, a cyclin-dependent kinase (Cdk) inhibitor. We previously showed that the Xenopus laevis homologue of the TSC-22 gene (XTSC-22) is required for cell movement during gastrulation through cell cycle regulation. In this report, we investigated the molecular mechanism of the antiproliferative effect of XTSC-22. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis suggested that XTSC-22 did not affect the expression levels of the p21 family of Cdk inhibitors or other cell cycle regulators. Analysis of deletion mutants of XTSC-22 revealed that nuclear localization of the N-terminal TSC-box is necessary for cell cycle inhibition by XTSC-22. Further experiments suggested that p27Xic1, a key Cdk inhibitor in Xenopus, interacts with XTSC-22. Because p27Xic1 is a cell cycle inhibitor with a nuclear localization signal, it is possible that XTSC-22 suppresses cell division by translocating into the nucleus with p27Xic1, where it may potentiate the intranuclear action of p27Xic1.
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PMID:TSC-box is essential for the nuclear localization and antiproliferative effect of XTSC-22. 1739 98

The TSC/Rheb/TOR signaling pathway plays important roles in growth and cell cycle regulation. The main player TOR belongs to the PI3K-related protein kinase family. Recent studies utilizing fission yeast Tor2 have led to the identification of a number of amino acid changes that lead to inactivation as well as activation of TOR kinase. Also, constitutive active mutations in its upstream regulator, Rheb, have been identified. Isolation and characterization of temperature sensitive Tor2 mutants have established that this kinase functions as a key switch that determines cell fate between growth and sexual development. Introduction of Tor2 activating mutations into mTOR conferred nutrient independent activation of mTOR. Interestingly, these studies point to regions of TOR kinase important for its function.
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PMID:The TSC/Rheb/TOR signaling pathway in fission yeast and mammalian cells: temperature sensitive and constitutive active mutants of TOR. 1763 64

Glucose transport is a highly regulated process and is dependent on a variety of signaling events. Glycogen synthase kinase-3 (GSK-3) has been implicated in various aspects of the regulation of glucose transport, but the mechanisms by which GSK-3 activity affects glucose uptake have not been well defined. We report that basal glycogen synthase kinase-3 (GSK-3) activity regulates glucose transport in several cell types. Chronic inhibition of basal GSK-3 activity (8-24 h) in several cell types, including vascular smooth muscle cells, resulted in an approximately twofold increase in glucose uptake due to a similar increase in protein expression of the facilitative glucose transporter 1 (GLUT1). Conversely, expression of a constitutively active form of GSK-3beta resulted in at least a twofold decrease in GLUT1 expression and glucose uptake. Since GSK-3 can inhibit mammalian target of rapamycin (mTOR) signaling via phosphorylation of the tuberous sclerosis complex subunit 2 (TSC2) tumor suppressor, we investigated whether chronic GSK-3 effects on glucose uptake and GLUT1 expression depended on TSC2 phosphorylation and TSC inhibition of mTOR. We found that absence of functional TSC2 resulted in a 1.5-to 3-fold increase in glucose uptake and GLUT1 expression in multiple cell types. These increases in glucose uptake and GLUT1 levels were prevented by inhibition of mTOR with rapamycin. GSK-3 inhibition had no effect on glucose uptake or GLUT1 expression in TSC2 mutant cells, indicating that GSK-3 effects on GLUT1 and glucose uptake were mediated by a TSC2/mTOR-dependent pathway. The effect of GSK-3 inhibition on GLUT1 expression and glucose uptake was restored in TSC2 mutant cells by transfection of a wild-type TSC2 vector, but not by a TSC2 construct with mutated GSK-3 phosphorylation sites. Thus, TSC2 and rapamycin-sensitive mTOR function downstream of GSK-3 to modulate effects of GSK-3 on glucose uptake and GLUT1 expression. GSK-3 therefore suppresses glucose uptake via TSC2 and mTOR and may serve to match energy substrate utilization to cellular growth.
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PMID:A GSK-3/TSC2/mTOR pathway regulates glucose uptake and GLUT1 glucose transporter expression. 1865 Feb 61

LKB1 plays the role of tumor suppressor, opposite to Akt, by negatively regulating mammalian target of rapamycin through the activation of AMP-activated protein kinase and TSC signaling. We have discovered a novel, potentially oncogenic role for LKB1 as a supporter of Akt-mediated phosphorylation of proapoptotic proteins. We found that Akt activation led to increased phosphorylation of FoxO3a at Thr(32) in LKB1 wild-type cells but not in LKB1-null cells. Depletion of LKB1 in the cells with wild-type LKB1 resulted in attenuation of that phosphorylation of FoxO3a by activated Akt, whereas the restoration of LKB1 function in LKB1-null cells reestablished Akt-mediated FoxO3a phosphorylation. On expanding our analysis to other Akt targets, using isogenic LKB1 knockdown cell line pairs and a phospho-specific antibody microarray, we observed that there was a requirement for LKB1 in the phosphorylation of other Akt downstream targets, including Ask1 (Ser(83)), Bad (Ser(136)), FoxO1 (Ser(319)), FoxO4 (Ser(197)), and glycogen synthase kinase 3beta (GSK3beta; Ser(9)). Because the phosphorylation of these sites by Akt suppresses apoptosis, the requirement of LKB1 suggests that LKB1 may have an antiapoptotic role in tumor cells with constitutively active Akt. Indeed, we found that the suppression of LKB1 expression led to apoptosis in three cell lines in which Akt is constitutively active but not in two cell lines without Akt activation. This observation may explain the lack of LKB1 somatic mutations in brain, breast, and colon cancers, where Akt is frequently activated due to mutations in phosphatidylinositol 3-kinase, PTEN, or Akt itself.
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PMID:LKB1 is necessary for Akt-mediated phosphorylation of proapoptotic proteins. 1879 13

Mammalian target of rapamycin (mTOR) is a key protein kinase controlling signal transduction from various growth factors and upstream proteins to the level of mRNA and ribosome with a regulatory effect on cell cycle progression, cellular proliferation and growth. TOR genes were discovered rather serendipitously while investigating the cause of resistance to immunosuppressant rapamycin in yeast. In normal cells, mTOR controls brilliantly the load of signals from its effectors resulting in a normal cell function. On the contrary, in various diseases and mainly in cancer this balance is lost due to mutations or overactivation of upstream pathways leading to a persistent proliferation and tumor growth. What makes mTOR attractive to researchers seems to be its key position which is on the crossroad of various signal pathways (Ras, PI3K/Akt, TSC, NF-kappaB) towards mRNA, ribosome, protein synthesis and translation of significant molecules, the uncontrolled production of which may lead to tumor proliferation and growth. Inhibition of mTOR by rapamycin (a natural product) or its analogs aims to prevent the deleterious effects of the abnormal signaling, regardless at which point of the signal pathway has the abnormality launched. Here, we will review the physiological functions of mTOR, its association to carcinogenesis and the latest evidence regarding the use of mTOR inhibitors in cancer treatment as well as future trends and aims of research.
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PMID:The role of mTOR in the management of solid tumors: an overview. 1901 21

Rapamycin and its derivatives represent a unique set of pharmaceutical agents being employed across a broad range of therapeutic indications including organ transplantation, cardiovascular disease, the treatment of harmartomas, and cancer. In cancer this family of drugs is unique as it exploits tumor-associated changes in cell metabolism. mTOR complex 1 (mTORC1), a protein kinase complex, is the major target of rapamycin, and is a key element of evolutionarily conserved pathways that regulate cellular metabolism in response to environmental nutrients and intracellular energy status. Upstream mTOR regulatory proteins -- the TSC tumor suppressor, the Rheb proto-oncogene, the hVps34 phophatidylinositol kinase, and the Rag GTPases -- determine tumor growth, metabolism, and apoptosis susceptibility. Novel compounds that target mTOR and PI3K enzymes may further enhance the efficacy in inhibiting this pathway in a number of human pathologies, particularly cancer.
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PMID:Tubers and tumors: rapamycin therapy for benign and malignant tumors. 1923 73


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