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)

Glutamate transporters play a crucial role in physiological glutamate homeostasis, neurotoxicity, and glutamatergic regulation of opioid tolerance. However, how the glutamate transporter turnover is regulated remains poorly understood. Here we show that chronic morphine exposure induced posttranscriptional down-regulation of the glutamate transporter EAAC1 in C6 glioma cells with a concurrent decrease in glutamate uptake and increase in proteasome activity, which were blocked by the selective proteasome inhibitor MG-132 or lactacystin but not the lysosomal inhibitor chloroquin. At the cellular level, chronic morphine induced the PTEN (phosphatase and tensin homolog deleted on chromosome Ten)-mediated up-regulation of the ubiquitin E3 ligase Nedd4 via cAMP/protein kinase A signaling, leading to EAAC1 ubiquitination and proteasomal degradation. Either Nedd4 or PTEN knockdown with small interfering RNA prevented the morphine-induced EAAC1 degradation and decreased glutamate uptake. These data indicate that cAMP/protein kinase A signaling serves as an intracellular regulator upstream to the activation of the PTEN/Nedd4-mediated ubiquitin-proteasome system activity that is critical for glutamate transporter turnover. Under an in vivo condition, chronic morphine exposure also induced posttranscriptional down-regulation of the glutamate transporter EAAC1, which was prevented by MG-132, and transcriptional up-regulation of PTEN and Nedd4 within the spinal cord dorsal horn. Thus, inhibition of the ubiquitin-proteasome-mediated glutamate transporter degradation may be an important mechanism for preventing glutamate overexcitation and may offer a new strategy for treating certain neurological disorders and improving opioid therapy in chronic pain management.
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PMID:Morphine induces ubiquitin-proteasome activity and glutamate transporter degradation. 1853 96

The signalling components upstream and downstream of the protein kinase mammalian target of rapamycin (mTOR) are frequently altered in a wide variety of human diseases. Upstream of mTOR key signalling molecules are the small GTPase Ras, the lipid kinase PI3K, the Akt kinase, and the GTPase Rheb, which are known to be deregulated in many human cancers. Mutations in the mTOR pathway component genes TSC1, TSC2, LKB1, PTEN, VHL, NF1 and PKD1 trigger the development of the syndromes tuberous sclerosis, Peutz-Jeghers syndrome, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Lhermitte-Duclos disease, Proteus syndrome, von Hippel-Lindau disease, Neurofibromatosis type 1, and Polycystic kidney disease, respectively. In addition, the tuberous sclerosis proteins have been implicated in the development of several sporadic tumors and in the control of the cyclin-dependent kinase inhibitor p27, known to be of relevance for several cancers. Recently, it has been recognized that mTOR is regulated by TNF-alpha and Wnt, both of which have been shown to play critical roles in the development of many human neoplasias. In addition to all these human diseases, the role of mTOR in Alzheimer's disease, cardiac hypertrophy, obesity and type 2 diabetes is discussed.
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PMID:The mTOR pathway and its role in human genetic diseases. 1859 80

Glucose induces many changes in the transcriptional pattern of beta-cells derived from the endocrine pancreas. The zinc finger protein Egr-1 belongs to the transcription factors that are activated in glucose-treated beta-cells. Egr-1 expression is additionally induced by treatment of MIN6 pancreatic beta-cells with tolbutamide, a compound that triggers a closure of ATP-dependent potassium channels, K(ATP), in the plasma membrane or by KCl that depolarizes the cell membrane. Stimulation with glucose, tolbutamide or KCl induces a Ca2+ influx into the beta-cells via L-type Ca2+ channels. Accordingly, incubation of the cells with the L-type Ca2+ channel blocker nifedipine or the acetoxymethylester of the cytosolic Ca2+ chelator BAPTA prevented Egr-1 expression. Moreover, diacylgycerol-dependent protein kinase C isoenzymes and activation of extracellular signal-regulated protein kinase (ERK) are required for glucose-, tolbutamide- and KCl-induced Egr-1 expression. The signaling cascade was blocked by MAP kinase phosphatase-1 (MKP-1) overexpression that dephosphorylated ERK in the nucleus. Stimulation of beta-cells by glucose, tolbutamide and KCl induced the phosphorylation of the transcription factors Elk-1 and CREB. ChIP experiments revealed that phosphorylated Elk-1 and CREB bound under physiological conditions to the Egr-1 gene. Lentiviral-mediated expression of dominant-negative mutants of Elk-1 or CREB interfered with glucose-, tolbutamide- and KCl-induced upregulation of Egr-1 biosynthesis. Together, these data indicate that stimulus-induced transcription of the Egr-1 gene in beta-cells requires combinatorial regulation by Elk-1 and CREB following activation of ERK. The newly synthesized Egr-1 is biologically active and binds under physiological conditions to the genes encoding basic fibroblast growth factor, tumor necrosis factor alpha, transforming growth factor beta and PTEN.
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PMID:Calcium influx into MIN6 insulinoma cells induces expression of Egr-1 involving extracellular signal-regulated protein kinase and the transcription factors Elk-1 and CREB. 1878 46

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

Signal transduction of many growth factors and oncogenes is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1), a master regulator of a number of downstream signal protein kinase cascades. Hence, PDK1 represents a convergence point for receptor tyrosine kinase and cytokine-mediated pathways for the regulation of vital cell processes such as cell survival and proliferation. Pathological upregulation of PDK1 signalling due to constitutive growth factor receptor activation and/or PTEN (phosphatase and tensin homologue) mutations significantly triggers downstream signalling, e.g. PKB/Akt, which subsequently promote proliferative events such as tumour invasiveness, angiogenesis, and progression. Consistent with this, a mouse model expressing low levels of PDK1 is protected from tumourigenesis resulting from loss of PTEN. Because more than 50 % of all human cancers possess significant overstimulation of the PDK1 signalling pathway, inhibition of this protein kinase by small molecules is predicted to result in effective inhibition of cancer cell proliferation and thus be therapeutically beneficial. Various classes of small-molecule PDK1 inhibitors have been published in patents and papers. Herein we present for the first time a comprehensive collection of small molecules reported to interact with PDK1, and we refer to their biological characterisation in terms of activity and selectivity for PDK1.
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PMID:Small-molecule inhibitors of PDK1. 1897 68

Although Ras is a potent oncogene, its tumorigenicity depends on cellular context and cooperative events. Tumor suppressor PTEN is the most important negative regulator of the cell-survival signaling pathway initiated by phosphoinositide 3-OH kinase. Previously, we established various NIH/3T3 cells expressing H-Ras mutant proteins. This report shows that expression of PTEN is suppressed by the oncogenic H-Ras at its protein and transcript levels as well as by oncogenic K- and N-Ras. This activity of oncogenic Ras is mediated by Raf-1/Erk/MEK signaling pathway. In our previous reports, FAK Y(861) phosphorylation is higher in H-Ras transformed NIH/3T3 cells. In this report, level of FAK pY(861) was examined in Ras mutant cell lines. By generating wild-type PTEN, lipid phosphatase-deficient PTEN and activity-inert PTEN-inducible cell lines in the background of oncogenic H-Ras stable expression in NIH/3T3 cells, we show level of FAK pY(861) is decreased by protein phosphatase activity of PTEN.
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PMID:A cross-talk between oncogenic Ras and tumor suppressor PTEN through FAK Tyr861 phosphorylation in NIH/3T3 mouse embryonic fibroblasts. 1900 Jun 54

Intra-type genome variations of high risk Human papillomavirus (HPV) have been associated with a differential threat for cervical cancer development. In this work, the effect of HPV18 E6 isolates in Akt/PKB and Mitogen-associated protein kinase (MAPKs) signaling pathways and its implication in cell proliferation were analyzed. E6 from HPV types 16 and 18 are able to bind and promote degradation of Human disc large (hDlg). Our results show that E6 variants differentially modulate hDlg degradation, rebounding in levels of activated PTEN and PKB. HPV18 E6 variants are also able to upregulate phospho-PI3K protein, strongly correlating with activated MAPKs and cell proliferation. Data was supported by the effect of E6 silencing in HPV18-containing HeLa cells, as well as hDlg silencing in the tested cells. Results suggest that HPV18 intra-type variations may derive in differential abilities to activate cell-signaling pathways such as Akt/PKB and MAPKs, directly involved in cell survival and proliferation.
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PMID:E6 variants of human papillomavirus 18 differentially modulate the protein kinase B/phosphatidylinositol 3-kinase (akt/PI3K) signaling pathway. 1900 61

The diverse effects mediated by PI3K/PTEN (phosphoinositide 3-kinase/phosphatase and tensin homologue deleted on chromosome 10) signalling in the heart clearly support an important biological and pathophysiological role for this signalling cascade. PI3Ks are a family of evolutionarily conserved lipid kinases that mediate many cellular responses to physiological and pathophysiological stimuli. Class I PI3K can be activated by either receptor tyrosine kinase/cytokine receptor activation (class IA) or G-protein-coupled receptors (class IB), leading to the generation of phosphatidyl inositol (3,4,5)P3 and recruitment and activation of Akt/protein kinase B, 3'-phosphoinositide-dependent kinase-1 (PDK1), or monomeric G-proteins, and phosphorylation of a wide range of downstream targets including glycogen synthase kinase 3beta (GSK3beta), mTOR (mammalian target of rapamycin), p70S6 kinase, endothelial nitric oxide synthase, and several anti-apoptotic effectors. Class IA (PI3Kalpha, beta, and delta) and class IB (PI3Kgamma) PI3Ks mediate distinct phenotypes in the heart under negative control by the 3'-lipid phosphatase PTEN, which dephosphorylates PtdIns(3,4,5)P3 to generate PtdIns(4,5)P2. PI3Kalpha, PI3Kgamma, and PTEN are expressed in cardiomyocytes, fibroblasts, endothelial cells, and vascular smooth muscle cells, where they modulate cell survival, hypertrophy, contractility, metabolism, and mechanotransduction. The PI3K/PTEN signalling pathways are involved in a wide variety of diseases including myocardial hypertrophy and contractility, heart failure, and preconditioning. In this review, we discuss the signalling pathways mediated by PI3K class I isoforms and PTEN and their roles in cardiac structure and function.
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PMID:Cardiac regulation by phosphoinositide 3-kinases and PTEN. 1914 53

The protein kinase Akt plays an important role in cell proliferation and survival in many cancers, including prostate cancer. Due to its kinase activity, it serves as a molecular conduit for inhibiting apoptosis and promoting angiogenesis in most cell types. In most of the prostate tumors, Akt signaling is constitutively activated due to the deletion or mutation of the tumor suppressor PTEN, which negatively regulates phosphatidylinositol 3-kinase through lipid phosphatase activity. Recently, we identified a natural compound, psoralidin, which inhibits Akt phosphorylation, and its consequent activation in androgen-independent prostate cancer (AIPC) cells. Furthermore, ectopic expression of Akt renders AIPC cells resistant to chemotherapy; however, psoralidin overcomes Akt-mediated resistance and induces apoptosis in AIPC cells. While dissecting the molecular events, both upstream and downstream of Akt, we found that psoralidin inhibits phosphatidylinositol 3-kinase activation and transcriptionally represses the activation of nuclear factor-kappaB and its target genes (Bcl-2, Survivin, and Bcl-xL, etc.), which results in the inhibition of cell viability and induction of apoptosis in PC-3 and DU-145 cells. Interestingly, psoralidin selectively targets cancer cells without causing any toxicity to normal prostate epithelial cells. In vivo xenograft assays substantiate these in vitro findings and show that psoralidin inhibits prostate tumor growth in nude mice. Our findings are of therapeutic significance in the management of prostate cancer patients with advanced or metastatic disease, as they provide new directions for the development of a phytochemical-based platform for prevention and treatment strategies for AIPC.
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PMID:Psoralidin, an herbal molecule, inhibits phosphatidylinositol 3-kinase-mediated Akt signaling in androgen-independent prostate cancer cells. 2202 47

Epidemiological and clinical data suggest that selenium may prevent prostate cancer; however, the cellular effects of selenium in malignant prostate cells are not well understood. We previously reported that the activity of the tumor suppressor PTEN is modulated by thioredoxin (Trx) in a RedOx-dependent manner. In this study, we demonstrated that the activity of Trx reductase (TR) is increased by sevenfold in the human prostate cancer cell line, DU-145, after 5 days of sodium selenite (Se) treatment. The treatment of DU-145 cells with increasing concentrations of Se induced an increase in PTEN lipid phosphatase activity by twofold, which correlated with a decrease in phospho-ser(473)-Akt, and an increase in phospho-Ser(370)-PTEN levels. Se also increased casein kinase-2 (CK2) activity; and the use of apigenin, an inhibitor of CK2, revealed that the regulation of the tumor suppressor PTEN by Se may be achieved via both the Trx-TR system and the RedOx control of the kinase involved in the regulation of PTEN activity.
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PMID:Sodium selenite increases the activity of the tumor suppressor protein, PTEN, in DU-145 prostate cancer cells. 1937 5


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