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 fission yeast cdr1/nim1 protein kinase phosphorylates and inactivates the weel cdc2-inhibitory kinase. We have investigated the role played by cdr1/nim1 in the connection between nutritional signals and the cell cycle machinery. We show that loss of nim1 activity impairs the appropriate cellular adaptation to nutritional changes. However, the reduction in cell size at division in response to nitrogen starvation is independent of nim1. Moreover, we report that nim1 is an unstable protein that is rapidly degraded upon starvation, through a mechanism that is dependent upon protein synthesis. We propose that nim1, as a constitutive indirect activator of cdc2 at mitosis, favors the cellular response to starvation but does not actively participate in it. On the contrary, upon nitrogen starvation nim1 must be actively destroyed to protect the cells from a commitment into the cell cycle under unfavourable growth conditions.
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PMID:Role of the fission yeast nim 1 protein kinase in the cell cycle response to nutritional signals. 912 32

A new route to N-1-substituted pyrazolo- and pyrroloquinazolines has been developed from the known quinazolones 19 and 23, via conversion to the corresponding thiones, S-methylation to the thioethers, N-1-alkylation, and coupling with 3-bromoaniline. C-3-Substituted pyrroloquinazolines were prepared by Mannich base chemistry. A series of compounds bearing solubilizing side chains at these positions has been prepared and evaluated for inhibition of the tyrosine kinase activity of the isolated epidermal growth factor receptor (EGFR) and of its autophosphorylation in EGF-stimulated A431 cells. Several analogues, particularly C-3-substituted pyrroloquinazolines, retained high potency in both assays. A model for the binding of the general class of 4-anilinoquinazolines to the EGFR was constructed from structural information (particularly for the catalytic subunit of the cAMP-dependent protein kinase) and structure-activity relationships (SAR) in the series. In this model, the pyrrole ring in pyrroloquinazolines (and the 6- and 7-positions of quinazoline and related pyridopyrimidine inhibitors) occupies the entrance of the ATP binding pocket of the enzyme, with the pyrrole nitrogen located at the bottom of the cleft and the pyrrole C-3 position pointing toward a pocket corresponding to the ribose binding site of ATP. This allows considerable bulk tolerance for C-3 substituents and lesser but still significant bulk tolerance for N-1 substituents. The observed high selectivity of these compounds for binding to EGFR over other similar tyrosine kinases is attributed to the 4-anilino ring binding in an adjacent hydrophobic pocket which has an amino acid composition unique to the EGFR. The SAR seen for inhibition of the isolated enzyme by the pyrazolo- and pyrroloquinazolines discussed here is fully consistent with this binding model. For the N-1-substituted compounds, inhibition of autophosphorylation in A431 cells correlates well with inhibition of the isolated enzyme, as seen previously for related pyridopyrimidines. However, the C-3-substituted pyrroloquinazolines show unexpectedly high potencies in the autophosphorylation assay, making them of particular interest.
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PMID:Tyrosine kinase inhibitors. 11. Soluble analogues of pyrrolo- and pyrazoloquinazolines as epidermal growth factor receptor inhibitors: synthesis, biological evaluation, and modeling of the mode of binding. 915 73

The aim of the present work is to study the participation of RAS2/PKA signal pathway in the nitrogen regulation of L-leucine transport in yeast cells. The study was performed on Saccharomyces cerevisiae isogenic strains with the normal RAS2 gene, the RAS2val19 mutant and the disrupted ras2::LEU2. These strains bring about different activities of the RAS2/PKA signal pathway, L-(14C)-Amino acid uptake measurements were determined in cells grown in a rich YPD medium with a mixed nitrogen source or in minimal media containing NH4+ or L-proline as the sole nitrogen source. We report herein that in all strains used, even in those grown in a minimal proline medium, the activity of the general amino acid permease (GAP1) was not detected. L-Leucine uptake in these strains is mediated by two kinetically characterized transport systems. Their KT values are of the same order as those of S1 and S2 L-leucine permeases. Mutation in the RAS2 gene alters initial velocities and Jmax values in both high and low affinity L-leucine transport systems. Activation of the RAS2/PKA signalling pathway by the RAS2val19 mutation, blocks the response to a poor nitrogen source whereas inactivation of RAS2 by gene disruption, results in an increase of the same response.
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PMID:RAS2/PKA pathway activity is involved in the nitrogen regulation of L-leucine uptake in Saccharomyces cerevisiae. 920 29

The signal transduction pathway of cAMP, mediated by the cAMP-dependent protein kinase (PKA), is involved in the regulation of metabolisms, cell growth and differentiation and gene expression. Isolated PKA mutants from Chinese hamster ovary (CHO) cells were used in our laboratory to study the role of cAMP in the development of drug resistance in cancer. We have found that PKA mutants harboring a defective regulatory (RI alpha) subunit, but not the catalytic (C) subunit, are more resistant to the chemotherapeutic drug cisplatin. To clarify the role of PKA in cisplatin resistance, we have performed a step-wise selection with a CHO RI alpha subunit mutant cell line, 10248, for further resistance to cisplatin. A representative clone (10248/CDDP(R)-5) was used for further characterization. These cisplatin-resistant PKA mutant cells remained refractory to cAMP-induced growth inhibition and had decreased PKA activity comparable to the parental 10248 mutant cells. Furthermore, 10248/CDDP(R)-5 also exhibited cross-resistance to the nitrogen mustard melphalan but maintained the same sensitivity as wild-type cells to non-DNA-damaging agents such as methotrexate. The mechanism of resistance may be due to increased DNA repair as assessed by the host cell reactivation assay. We speculate that mutation and functional inactivation of PKA may result in deregulated growth response to cAMP, as well as the acquisition of resistance to cisplatin and other DNA-damaging agents in cancer.
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PMID:Characterization of a cAMP-dependent protein kinase mutant resistant to cisplatin. 921 44

Trehalase activity is markedly enhanced upon addition of glucose and a nitrogen source to cells of the fission yeast Schizosaccharomyces pombe. This increase corresponds to a post-translational activation of the enzyme, which is controlled by cAMP-dependent and cAMP-independent pathways. Recent work has shown that overexpression of SCK1 in Schiz. pombe is able to suppress mutations that result in reduced Pka1 (cAMP-dependent protein kinase A activity, suggesting that Sck1 (suppressor of loss of cAMP-dependent protein kinase) might be a functional analogue of Pka1 in the fission yeast. Here, an analysis of the possible role of Sck1 in the activation of trehalase triggered by glucose and a nitrogen source is reported in cells that were deficient in either Pka1, Sck1 or both protein kinases. The results showed that, except in repressed cells, Sck1 probably mediates a cAMP-independent activation of trehalase following the signal(s) triggered by glucose and the nitrogen source. The absence of functional Sck1 in depressed cells renders trehalase insensitive to activation by glucose and the nitrogen source even in the presence of Pka1, indicating that the Sck1-dependent, cAMP-independent pathway is the main signalling pathway controlling trehalase activation under derepression conditions. It is proposed that, during the activation of trehalase induced by glucose or a nitrogen source, the cAMP-Pka1 activation pathway previously characterized is to some extent parallel to this newly described one which includes Sck1 as phosphorylating enzyme. Neither of these two pathways, however, plays a key role in the heat-induced increase in trehalase activity.
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PMID:Protein kinase Sck1 is involved in trehalase activation by glucose and nitrogen source in the fission yeast Schizosaccharomyces pombe. 924 26

In cells of the yeast Saccharomyces cerevisiae, trehalase activation, repression of CTT1 (catalase), SSA3 (Hsp70) and other STRE-controlled genes, feedback inhibition of cAMP synthesis and to some extent induction of ribosomal protein genes is controlled by the Ras-adenylate cyclase pathway and by the fermentable-growth-medium-induced pathway (FGM pathway). When derepressed cells are shifted from a non-fermentable carbon source to glucose, the Ras-adenylate cyclase pathway is transiently activated while the FGM pathway triggers a more lasting activation of the same targets when the cells become glucose-repressed. Activation of the FGM pathway is not mediated by cAMP but requires catalytic activity of cAMP-dependent protein kinase (cAPK; Tpk1, 2 or 3). This study shows that elimination of Sch9, a protein kinase with homology to the catalytic subunits of cAPK, affects all target systems in derepressed cells in a way consistent with higher activity of cAPK in vivo. In vitro measurements with trehalase and kemptide as substrates confirmed that elimination of sch9 enhances cAPK activity about two- to threefold, in both the absence and presence of cAMP. In vivo it similarly affected the basal and final level but not the extent of the glucose-induced responses in derepressed cells. The reduction in growth rate caused by deletion of SCH9 is unlikely to be responsible for the increase in cAPK activity since reduction of growth rate generally leads to lower cAPK activity in yeast. On the other hand, deletion of SCH9 abolished the responses of the protein kinase A targets in glucose-repressed cells. Re-addition of nitrogen to cells starved for nitrogen in the presence of glucose failed to trigger activation of trehalase, caused strongly reduced and aberrant repression of CTT1 and SSA3, and failed to induce the upshift in RPL25 expression. From these results three conclusions can be drawn: (1) Sch9 either directly or indirectly reduces the activity of protein kinase A; (2) Sch9 is not required for glucose-induced activation of the Ras-adenylate cyclase pathway; and (3) Sch9 is required for nitrogen-induced activation of the FGM pathway. The latter indicates that Sch9 might be the target of the FGM pathway rather than cAPK itself.
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PMID:The Sch9 protein kinase in the yeast Saccharomyces cerevisiae controls cAPK activity and is required for nitrogen activation of the fermentable-growth-medium-induced (FGM) pathway. 927 16

Mitogen-activated protein kinase (MAPK) cascades are conserved signalling modules that regulate responses to diverse extracellular stimuli, developmental cues and environmental stresses. A MAPK is phosphorylated and activated by a MAPK kinase (MAPKK), which is activated by an upstream protein kinase, such as Raf, Mos or a MAPKK kinase. Ste7, a MAPKK in the yeast Saccharomyces cerevisiae, is required for two developmental pathways: mating and invasive (filamentous) growth. Kss1 and Fus3, the MAPK targets of Ste7, are required for mating, but their role in invasive growth has been unclear. Because no other S. cerevisiae MAPK has been shown to function in invasive growth, it was proposed that Ste7 may have non-MAPK targets. We show instead that Kss1 is the principal target of Ste7 in the invasive-growth response in both haploids and diploids. We demonstrate further that Kss1 in its inactive form is a potent negative regulator of invasive growth. Ste7 acts to relieve this negative regulation by switching Kss1 from an inhibitor to an activator. These results indicate that this MAPK has a physiologically important function in its unactivated state. Comparison of normal and MAPK-deficient cells indicates that nitrogen starvation and activated Ras stimulate filamentous growth through both MAPK-independent and MAPK-dependent means.
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PMID:Inhibitory and activating functions for MAPK Kss1 in the S. cerevisiae filamentous-growth signalling pathway. 936 95

Little is known about the mechanisms by which nutrient limitation leads to G1 arrest in Saccharomyces cerevisiae. We have shown that mutant cells deleted in the trehalose-6-phosphate synthase gene able to grow on glucose, when starved for nitrogen, did not arrest in the G1 phase of the cell cycle. We attribute this effect to an increase in the activity of cAMP-dependent protein kinase. When grown on maltose without nitrogen they arrested properly in G1. Tests with a mutant cell deleted in the specific trehalose phosphatase proved that the presence of the trehalose precursor, trehalose-6-phosphate, was sufficient to trigger the negative sign during nitrogen starvation, leading the cells to arrest in the G1 phase of the cell cycle.
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PMID:Nitrogen starvation in a Saccharomyces cerevisiae strain deleted in the trehalose-6-phosphate synthase complex. 938 50

In the yeast Saccharomyces cerevisiae several phenotypic properties controlled by cAMP-dependent protein kinase (cAPK) are indicative of high cAPK activity during growth on glucose and low activity during growth on non-fermentable carbon sources and in stationary phase. It has been a matter of debate whether the apparently higher activity of cAPK in cells growing on glucose is due to a higher cAMP level or to an alternative mechanism activating cAPK. The cAMP level during diauxic growth of yeast cells in cultures with different initial glucose levels and different initial cell densities has been reinvestigated and the previously reported twofold increase in cAMP during growth initiation has been confirmed. However, this increase was transient and entirely associated with the lag phase of growth. The initiation of exponential growth on glucose was associated with a decrease in the cAMP level and there was no correlation between this decrease in cAMP and the depletion of glucose in the medium. In mutants defective in feedback inhibition of cAMP synthesis, resuspension of exponential-phase glucose-grown cells in glucose medium caused an extended lag phase during which a huge, transient accumulation of cAMP occurred. The latter required the presence of glucose and nitrogen, but not phosphate or sulfate, and was not due to intracellular acidification, as shown by in vivo 31P-NMR spectroscopy. The initiation of exponential growth on glucose was also associated in this case with a decrease in cAMP rather than an increase. This behaviour was also observed in strains with attenuated catalytic subunit activity and lacking the regulatory subunit and even in strains without catalytic subunits of cAPK. This might indicate that other mechanisms are able to cause down-regulation of cAMP synthesis in a way mimicking feedback inhibition. Transfer of glucose-growing cells of wild-type or cAPK-attenuated strains to a nitrogen starvation medium resulted in an increase in the cAMP level rather than a decrease. The results indicate that the apparent changes in cAPK activity in vivo during diauxic growth on glucose and during nitrogen starvation cannot be explained on the basis of changes in the cAMP level.
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PMID:The lag phase rather than the exponential-growth phase on glucose is associated with a higher cAMP level in wild-type and cAPK-attenuated strains of the yeast Saccharomyces cerevisiae. 938 23

Many fungi undergo a morphological transition to filamentous growth in response to limiting nutrient conditions. Constitutively elongated Saccharomyces cerevisiae mutants (elm) have been isolated; the ELM1 gene encodes a putative serine/threonine protein kinase. A novel allele, elm1-15, has been isolated in an S288C-derived strain, which causes a pleiotropic phenotype, including media-specific growth effects, abnormal morphology and altered stress response, in cells that are auxotrophic for tryptophan. elm1-15 trp1 cells cannot use many nitrogen sources, are sensitive to amino acid analogues, have very low general amino acid permease activity and do not accumulate trehalose. In contrast, haploid elm1-15 TRP1 cells grow well in budding form on all media, are stress resistant and overaccumulate trehalose. Several lines of evidence suggest that Elm1 acts on functions related to the RAS/cAMP pathway. Overexpression of Elm1 partially rescues the ts phenotype of cdc25 and cyr1 mutants. Deletion of ELM1 in low PKA activity mutants increased the severity of their phenotypes, and activation of Ras2 decreases the cell elongation phenotype of elm1 mutants. A 'signal integration' model for the complex relationship of Elm1 and the RAS/cAMP pathway in controlling morphogenesis in response to nutrients is proposed.
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PMID:The control of morphogenesis in Saccharomyces cerevisiae by Elm1 kinase is responsive to RAS/cAMP pathway activity and tryptophan availability. 942 10


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