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)

The phosphatidylinositol 3'-kinase (PI3K)/Akt pathway is often constitutively activated in malignant glioma cells, in many cases as a result of mutation of phosphatase and tensin homologue deleted on chromosome ten (PTEN), an endogenous inhibitor of Akt, which renders tumor cells resistant to cytotoxic insults, including those related to anticancer drugs. Pharmacological inhibition of this pathway may potentially restore or augment the effectiveness of conventional chemotherapy or other signaling-targeted agents. Because the heat shock protein (HSP) is involved in the conformational maturation of a number of signaling proteins critical to the proliferation of malignant glioma cells, we hypothesized that the combination of the PI3K inhibitor LY294002 and the HSP90 inhibitor 17-allyl-aminogeldanamycin (17-AAG) would promote glioma cytotoxicity by decreasing both the activation status and levels of Akt, as well as downregulating the levels of other relevant signaling effectors. We, therefore, examined the effects of LY294002 and 17-AAG, alone and in combination, on signal transduction and apoptosis in a series of malignant glioma cell lines. Simultaneous exposure to these inhibitors significantly induced cell death, and irreversibly inhibited proliferative activity and colony forming ability of the glioma cell lines. Quantitative analysis revealed that enhancement by LY294002 of 17-AAG-induced cytotoxicity was synergistic, leading to a pronounced increase in active caspase-3 and poly (adenosine diphosphate-ribose) polymerase (PARP) cleavage together with the release of cytochrome c and apoptosis inducing factor (AIF). No significant growth inhibition or caspase activation was seen in control cells. The enhanced cytotoxicity of this combination was associated with diminished Akt activation and a significant downregulation of epidermal growth factor receptor (EGFR), Raf-1, and mitogen activated protein kinase. Combination of 17-AAG and LY294002 did not modify phospho-JNK/SPK and phospho-p38. Cells exposed to 17-AAG and LY294002 displayed a significant reduction in cell-cycle regulatory proteins, such as retinoblastoma (Rb), cyclin dependent kinase (CDK)4, CDK6, cyclin D1, and cyclin D3. Taken together, these findings suggest that the PI3K/Akt pathway plays a critical role in regulating the apoptotic response to 17-AAG and that targeting this pathway could provide a potent strategy to treat patients with malignant gliomas.
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PMID:Synergistic interaction between 17-AAG and phosphatidylinositol 3-kinase inhibition in human malignant glioma cells. 1626 32

Prostate cancer (PrCa) is characterized by progression from an androgen-dependent phenotype to one that is inevitably androgen independent (AI) and lethal. Recent evidence strongly suggests that the phosphatidylinositol-3-kinase/Akt (PI3K/Akt) and androgen receptor (AR) signalling pathways provide prostatic epithelium with the necessary signalling events to escape the apoptotic response associated with androgen withdrawal therapy. Silencing of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and glycogen synthase kinase beta (GSK3beta) are frequently associated with advanced PrCa systems and likely serve critical roles in promoting AR and PI3K/Akt gain-of-function. That PTEN negatively regulates AR and is sufficient to promote metastatic PrCa in murine models strongly implies its role as a gatekeeper of progressive PrCa. In human PrCa, PTEN loss is correlated with substantial increases in Akt(Ser473) and integrin-linked kinase expression, both of which promote Ser(9) phospho-inhibition of GSK3beta and inactivation of apoptotic factors. Sufficient evidence also suggests that GSK3beta is not only a critical regulator of proproliferative signalling but also a promiscuous one as PI3K/Akt pools of GSK3beta are, at least in part, functionally interchangeable with those of the Wnt/beta-catenin pathway. Thus, GSK3beta may serve not only as a mediator of PI3K/Akt activation but may also regulate the potent transactivation and proproliferative effects that Wnt3a and beta-catenin confer upon AR. These data suggest that prostate-specific activation of GSK3beta may serve as a viable pharmacological option. Thus, in this review, we emphasize that temporal changes in GSK3beta and PTEN expression during progression to AI PrCa are important factors when considering the potential for therapies targeting the oncogenic contributions of PI3K/Akt and AR signalling pathways.
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PMID:PTEN and GSK3beta: key regulators of progression to androgen-independent prostate cancer. 1642 4

Axonal elongation and guidance are controlled by extracellular factors such as the neurotrophins. Indeed, nerve growth factor (NGF) seems to promote axon growth through binding to its p75NTR receptor and inactivating RhoA. Furthermore, the local inhibition of glycogen synthase kinase (GSK)-3beta by NGF also favors microtubule polymerization and axon extension. Inactivation of GSK-3beta may be due to the NGF/TrkA-mediated activation of phosphatidylinositol-3 kinase (PI-3 kinase), which increases the levels of phosphatydilinositol 3-phosphate [PI3P]. However, we show here that NGF may inactivate GSK-3beta through an alternative mechanism. In cultured hippocampal neurons, the capacity of NGF to promote axon elongation is mostly mediated by p75NTR, and the activation of this pathway leads to the inactivation of GSK-3beta. However, the signaling pathway triggered by NGF/p75NTR acts through casein kinase II (CK2). NGF/p75NTR-activated CK2 phosphorylates the phosphatase and tensin homologue deleted on chromosome 10 (PTEN), thus rendering this phosphatase inactive. Like activation of the PI-3 kinase, PTEN inactivation allows PI3P levels to increase, thus favoring GSK-3beta inactivation and axon outgrowth. This newly disclosed mechanism may help to extend the repertoire of pharmacological agents that activate CK2 or that inhibit PTEN to stimulate axon regeneration after trauma or disease.
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PMID:Activation of casein kinase II and inhibition of phosphatase and tensin homologue deleted on chromosome 10 phosphatase by nerve growth factor/p75NTR inhibit glycogen synthase kinase-3beta and stimulate axonal growth. 1672 2

Although PTEN (phosphatase and tensin homologue deleted on chromosome 10) is one of the most commonly mutated tumour suppressors in human cancers, loss of PTEN expression in the absence of mutation appears to occur in an even greater number of tumours. PTEN is phosphorylated in vitro on Thr366 and Ser370 by GSK3 (glycogen synthase kinase 3) and CK2 (casein kinase 2) respectively, and specific inhibitors of these kinases block these phosphorylation events in cultured cells. Although mutation of these phosphorylation sites did not alter the phosphatase activity of PTEN in vitro or in cells, blocking phosphorylation of Thr366 by either mutation or GSK3 inhibition in glioblastoma cell lines led to a stabilization of the PTEN protein. Our data support a model in which the phosphorylation of Thr366 plays a role in destabilizing the PTEN protein.
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PMID:PTEN is destabilized by phosphorylation on Thr366. 1744 18

One of the major problems in treating colon cancer is chemoresistance to cytotoxic chemotherapeutic agents. There is therefore a need to devise new strategies to inhibit colon cancer cell growth and survival. Here, we show that a combination of low doses of the adenylyl cyclase activator forskolin together with the specific cyclic AMP (cAMP) phosphodiesterase-4 (PDE4) inhibitor rolipram, but not the cAMP phosphodiesterase-3 (PDE3) inhibitor cilostamide, causes profound growth arrest of chemoresistant KM12C colon cancer cells. Low-dose forskolin causes KM12C cells to exit the cell cycle in G1 by inducing p27(Kip1) and primes cells for apoptosis on addition of rolipram. The effect of the low-dose forskolin/rolipram combination is mediated by displacement of the phosphatidylinositol 3,4,5-trisphosphate/phosphoinositide 3-kinase signaling module from the plasma membrane and suppression of the Akt/protein kinase-B oncogene pathway, to which KM12C cells are addicted for growth. The cAMP and phosphoinositide 3-kinase pathways form a critical intersection in this response, and reexpression of the tumor suppressor lipid phosphatase, phosphatase and tensin homologue, which is commonly lost or mutated in colon cancer, sensitizes KM12C cells to growth inhibition by challenge with low-dose forskolin. Certain chemoresistant colon cancer cells are therefore exquisitely sensitive to subtle elevation of cAMP by a synergistic low-dose adenylyl cyclase activator/PDE4 inhibitor combination. Indeed, these cells are addicted to maintenance of low cAMP concentrations in a compartment that is regulated by PDE4. Well-tolerated doses of PDE4 inhibitors that are already in clinical development for other therapeutic indications may provide an exciting new strategy for the treatment of colon cancer.
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PMID:Chemoresistant KM12C colon cancer cells are addicted to low cyclic AMP levels in a phosphodiesterase 4-regulated compartment via effects on phosphoinositide 3-kinase. 1754 4

We previously reported that ischemic postconditioning with a series of mechanical interruptions of reperfusion reduced infarct volume 2 days after focal ischemia in rats. Here, we extend this data by examining long-term protection and exploring underlying mechanisms involving the Akt, mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) signaling pathways. Post-conditioning reduced infarct and improved behavioral function assessed 30 days after stroke. Additionally, postconditioning increased levels of phosphorylated Akt (Ser473) as measured by western blot and Akt activity as measured by an in vitro kinase assay. Inhibiting Akt activity by a phosphoinositide 3-kinase inhibitor, LY294002, enlarged infarct in postconditioned rats. Postconditioning did not affect protein levels of phosphorylated-phosphatase and tensin homologue deleted on chromosome 10 or -phosphoinositide-dependent protein kinase-1 (molecules upstream of Akt) but did inhibit an increase in phosphorylated-glycogen synthase kinase 3beta, an Akt effector. In addition, postconditioning blocked beta-catenin phosphorylation subsequent to glycogen synthase kinase, but had no effect on total or non-phosphorylated active beta-catenin protein levels. Furthermore, postconditioning inhibited increases in the amount of phosphorylated-c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2 in the MAPK pathway. Finally, postconditioning blocked death-promoting deltaPKC cleavage and attenuated reduction in phosphorylation of survival-promoting epsilonPKC. In conclusion, our data suggest that postconditioning provides long-term protection against stroke in rats. Additionally, we found that Akt activity contributes to postconditioning's protection; furthermore, increases in epsilonPKC activity, a survival-promoting pathway, and reductions in MAPK and deltaPKC activity; two putative death-promoting pathways correlate with postconditioning's protection.
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PMID:The Akt signaling pathway contributes to postconditioning's protection against stroke; the protection is associated with the MAPK and PKC pathways. 1818 53

Several oncogenic proteins and tumour suppressors target the RNA polymerase I and interfere with rRNA synthesis. Here, we show that the glycogen synthase kinase (GSK) 3beta, which phosphorylates the tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10), is selectively enriched in nucleoli of RAS-transformed cells. Immunoprecipitation and chromatin immunoprecipitation assays performed on epithelial and endothelial cells transformed with oncogenic RAS show that GSK3beta and PTEN are part of the same complex and associate with promoter and coding region of the rDNA. An active GSK3beta mutant abolished nucleolar BrUTP incorporation and associated with the member of the selectivity factor 1 complex TAF(I)110. Finally, GSK3beta inhibition upregulated 45S, 18S and 28S rRNA synthesis in RAS-transformed epithelial cells as revealed by semiquantitative real-time PCR and promoted cellular proliferation. Our results underscore a repressive function for GSK3beta in rRNA biogenesis supporting its role as a tumour supressor.
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PMID:The glycogen synthase kinase (GSK) 3beta represses RNA polymerase I transcription. 1849 Sep 23

The ubiquitin-proteasome system plays an important role in many cellular processes through degradation of specific proteins. Low molecular mass polypeptide 2 (LMP-2 or beta(1i)) is one important subunit of the immunoproteasome. Ischemic preconditioning (IPC) activates cell signaling pathways and generates cardioprotection but has not been linked to LMP-2 function previously. LMP-2 knockout mice (C57BL6 background) and wild-type C57BL6 mice were subjected to 30 min of ischemia (I-30) and 120 min of reperfusion (R-120) with or without preceding IPC (10 min of infusion and 5 min of reperfusion). IPC significantly increased left ventricular developed pressure and decreased infarct size in wild-type mice, but this protective effect of IPC was lost in LMP-2 knockout mice. IPC-mediated degradation of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and activation of the downstream protein kinase Akt were impaired in LMP-2 knockout hearts. The impairment of PTEN degradation was associated with defective immunoproteasomes and decreased proteolytic activities. When LMP-2 knockout mice were pretreated with the PTEN inhibitor bpV(HOpic), cardiac function was significantly improved, and myocardial infarct size was significantly reduced after I-30/R-120. In conclusion, LMP-2 is required for normal proteasomal function and IPC induction in the heart. Its action may be related to PTEN protein degradation.
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PMID:Ischemic preconditioning-induced cardioprotection is lost in mice with immunoproteasome subunit low molecular mass polypeptide-2 deficiency. 1872 17

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

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


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