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)

In this review we summarize the structural and functional characteristics of the VPS (vacuolar protein sorting) gene products that have provided insight into the regulatory interactions and molecular mechanisms underlying protein sorting pathways in eukaryotic cells. Genetic selections in yeast have resulted in the identification of more than 40 genes required for the vesicle-mediated sorting of proteins to the lysosome-like vacuole. Molecular characterization of these VPS gene products has revealed a number of biochemical activities involved in this process. Analogous to the mannose-6-phosphate receptors in mammalian cells, the VPS10 gene encodes a transmembrane sorting receptor for the yeast vacuolar hydrolase carboxypeptidase Y. The VPS15 and VPS34 genes encode components of a novel signal transduction complex essential for the delivery of soluble vacuolar hydrolases. VPS15 and VPS34 encode a serine/ threonine protein kinase and a phosphatidylinositol 3-kinase, respectively, that interact at the cytoplasmic face of an intracellular membrane compartment, most likely corresponding to the late Golgi. Other VPS gene products have homologues that are involved in membrane trafficking pathways: The VPSI and VPS21 genes encode GTPases of the dynamin and rab families, respectively, and the products of the VPS33, VPS45, and PEP12/VPS6 genes are homologues of proteins involved in regulated synaptic vesicle exocytosis. The VPS gene products constitute components of a molecular apparatus responsible for the recognition, packaging, and vesicular transport of proteins to the vacuole in yeast.
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PMID:Receptor-mediated protein sorting to the vacuole in yeast: roles for a protein kinase, a lipid kinase and GTP-binding proteins. 868 53

Receptor-associated protein (RAP) is an endoplasmic reticulum/Golgi protein involved in the processing of receptors of the low density lipoprotein receptor family. A approximately 95-kDa membrane glycoprotein, designated gp95/sortilin, was purified from human brain extracts by RAP affinity chromatography and cloned in a human cDNA library. The gene maps to chromosome 1p and encodes an 833-amino acid type I receptor containing an N-terminal furin cleavage site immediately preceding the N terminus determined in the purified protein. Gp95/sortilin is expressed in several tissues including brain, spinal cord, and testis. Gp95/sortilin is not related to the low density lipoprotein receptor family but shows intriguing homologies to established sorting receptors: a 140-amino acid lumenal segment of sortilin representing a hitherto unrecognized type of extracellular module shows extensive homology to corresponding segments in each of the two lumenal domains of yeast Vps10p, and the extreme C terminus of the cytoplasmic tail of sortilin contains the casein kinase phosphorylation consensus site and an adjacent dileucine sorting motif that mediate assembly protein-1 binding and lysosomal sorting of the mannose-6-phosphate receptors. Expression of a chimeric receptor containing the cytoplasmic tail of gp95/sortilin demonstrates evidence that the tail conveys colocalization with the cation-independent mannose6-phosphate receptor in endosomes and the Golgi compartment.
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PMID:Molecular identification of a novel candidate sorting receptor purified from human brain by receptor-associated protein affinity chromatography. 901 11

Numerous hepatic and adipocytic genes are transcriptionally controlled by glucose and insulin. It is the case, for example, of the pyruvate kinase L (L-PK) gene in the liver and of the spot 14 gene in adipocytes, coding for proteic factors of glycolysis and lipogenesis, respectively. At the hepatic level, the role of insulin is mainly to stimulate the synthesis of glucokinase, needed for phosphorylation of glucose to glucose 6-phosphate. An efficient regulation of the L-PK gene by glucose also needs the synthesis of the glucose transporter (Glut2): in its absence, transcription of the gene is independent of the presence of glucose in the medium. The role of Glut2 can be to enhance the depletion of gluconeogenic cells into glucose-6-phosphate (G6-P) when cultivated without glucose. G6-P seems to act by one of its metabolites in the pentose phosphate pathway, probably a pentose phosphate, maybe xylulose 5-phosphate. The active metabolites of this pathway could control the activity of protein kinase and protein phosphatase cascades, leading to a modification of the phosphorylation state of the glucose response complex. This complex is assembled by so-called glucose/carbohydrate response elements (GIRE, ChoRE) that are composed of E boxes of the CACGTG type, more or less modified, forming a palindrome whose both parts are separated by five bases. These sequences are able to bind USF1 and USF2 proteins, which seem to be necessary to the glucose response. However, the binding of USF proteins to the GIRE of the L-PK gene, appreciated by in vivo footprints, is not modulated by nutritional conditions. Therefore, these USF proteins could interact with different partners which are targets of regulating cues: transcription factors bound in the immediate vicinity of the glucose response complex, notably the HNF4 factor, and, maybe, other proteins interacting with the USF factors assembled to the GIRE. The actually ongoing experiments try to appreciate the nature and the role of these partners, and to evaluate the metabolic response of mice whose USF genes were disabled by homologous recombination.
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PMID:Transcriptional regulation by glucose in the liver. 920 6

To investigate the possible involvement of some intracellular metabolic signaling other than the ATP derived from glucose metabolism under protein kinase A (PKA) activation, we measured the insulin secretory capacity stimulated by glucose and other fuel secretagogues using diazoxide-treated pancreatic islets. Under these conditions, we found a signal from a site proximal to glyceraldehyde-3-phosphate (GA-3-P) in the glycolysis to be necessary for glucose-induced insulin secretion. By using several different glycolytic enzyme inhibitors, we found that this proximal signal is derived from glucose-6-phosphate (G-6-P), and that metabolic signaling distal to GA-3-P also is necessary. Mycophenolic acid completely inhibited the augmented glucose-induced insulin secretion, which guanosine could reverse, indicating that the proximal signaling is coupling with endogenous GTP production. In this novel system of metabolic signaling, endogenous GTP derived from G-6-P in the glycolysis elicits the augmentation of glucose-induced insulin secretion under PKA activation in diazoxide-treated pancreatic islets.
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PMID:Necessity of endogenous GTP derived from glucose-6-phosphate for insulin secretion augmented by glucose under protein kinase A activation. 947 13

Escherichia coli strains devoid of one or both of the two pyruvate kinase isoenzymes (PKA and PKF), were grown on minimal media in batch fermentations. The strain lacking both PKs showed a 28% decrease on its specific growth rate when compared to the wild type. However, protein and CO2 yields did not change. Using radioactive 1-C14 glucose and collecting the CO2 produced by the cultures, it was found that the mutant lacking both pyruvate kinases, metabolized glucose mainly through the pentose pathway (PP). The increased participation of the PP in glucose metabolism in this strain, was also reflected on the levels of the glucose-6-phosphate and 6-phosphogluconate dehydrogenases.
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PMID:Stimulation of glucose catabolism through the pentose pathway by the absence of the two pyruvate kinase isoenzymes in Escherichia coli. 1019 3

In neuroendocrine cells sorting of proteins from immature secretory granules (ISGs) occurs during maturation and is achieved by clathrin-coated vesicles containing the adaptor protein (AP)-1. We have investigated the role of the mannose-6-phosphate receptors (M6PRs) in the recruitment of AP-1 to ISGs. M6PRs were detected in ISGs isolated from PC12 cells by subcellular fractionation, and by immuno-EM labelling on cryosections. In light of our previous results, where greater than 80% of the ISGs were found to contain furin, we examined the relationship between furin and M6PR on ISGs. By immunoisolation techniques we find that 50% at most of the ISGs contain the cation-independent (CI)-M6PR. Using sequential immunoisolation we could demonstrate that there are two populations of ISGs: those that have both M6PR and furin, and those which contain only furin. Furthermore, using immobilized GST-fusion proteins containing the cytoplasmic domain of the CI-M6PR we have shown binding of AP-1 requires casein kinase II phosphorylation of the CI-M6PR fusion protein, and in particular phosphorylation of Ser(2474). Addition of these phosphorylated GST-CI-M6PR fusion proteins to a cell-free assay reconstituting AP-1 binding to ISGs inhibits AP-1 recruitment to ISGs.
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PMID:Differential distribution of mannose-6-phosphate receptors and furin in immature secretory granules. 1054 56

Fatty acid synthase (EC 2.3.1.85) is an enzyme involved in the lipogenic pathway allowing fatty acid synthesis from glucose. Glucose up-regulates the transcription of the fatty acid synthase gene in both adipocytes and hepatocytes, with insulin having only an indirect role. The signal metabolite could be glucose-6-phosphate rather than glucose itself. The glucose response element of the fatty acid synthase gene has not yet been precisely identified, although a -2 kb region of the fatty acid synthase promoter is sufficient to confer nutritional responsiveness to a reporter gene. ADD1/SREBP1, a b-HLH-LZ transcription factor belonging to the sterol regulatory element-binding protein family might be involved in the transduction of the glucose effect. Finally, the stimulatory effect of glucose on the expression of the fatty acid synthase gene is inhibited by the activation of AMP-activated protein kinase. Interestingly enough, AMP-activated protein kinase is structurally and functionally related to the yeast SNF1 protein kinase complex which is essential for the transcriptional activation of glucose-repressed genes in Saccharomyces cerevisiae.
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PMID:Regulation of gene expression by glucose. 1060 95

In skeletal muscle, insulin activates glycogen synthase by reducing phosphorylation at both NH2- and COOH-terminal sites of the enzyme and by elevating the levels of glucose-6-phosphate, an allosteric activator of glycogen synthase. To study the mechanism of regulation of glycogen synthase by insulin and glucose-6-phosphate, we generated stable Rat-1 fibroblast clones expressing rabbit muscle glycogen synthase with Ser-->Ala substitutions at key phosphorylation sites. We found that 1) elimination of the phosphorylation of either NH2- or COOH-terminal sites did not abolish insulin stimulation of glycogen synthase; 2) mutations at both Ser-7 and Ser-640 were necessary to bypass insulin activation; 3) mutation at Ser-7, coupled with the disruption of the motif for recognition by glycogen synthase kinase-3 (GSK-3), did not eliminate the insulin effect; and 4) mutation of either Ser-7 or Ser-640 increased the sensitivity of glycogen synthase to glucose 6-phosphate >10-fold. We conclude that Ser-7 and Ser-640 are both involved in mediating the response of glycogen synthase to insulin and activation by glucose 6-phosphate. In Rat-1 fibroblasts, GSK-3 action is not essential for glycogen synthase activation by insulin, and GSK-3-independent mechanisms also operate.
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PMID:Glycogen synthase sensitivity to insulin and glucose-6-phosphate is mediated by both NH2- and COOH-terminal phosphorylation sites. 1090 64

Ineffectual wound healing in hyperglycaemic patients suffering from diabetes mellitus is characterised by a reduction in capillary reformation (angiogenesis). Basic fibroblast growth factor (FGF-2) is secreted by fibroblasts, macrophages and in particular endothelial cells (EC) in response to tissue injury and is important in promotion of neovascularisation. Recently, glycation of FGF-2 has been shown to significantly reduce its activity in vitro. We have examined the kinetics of FGF-2 glycation and compared its ability with that of native FGF-2 to activate mitogenesis, capillary formation and associated signal transduction in bovine aortic EC (BAEC). FGF-2 was exposed to 0.25 M glucose-6-phosphate (G-6-P) for 24-72 h and the degree of glycation determined by matrix assisted laser desorption ionisation mass spectrometry. Native FGF-2 was heterogeneous with Mw in the range 15,153.6-17,903 Da. After 24 h incubation with G-6-P there was evidence of glycation, and the mass increase corresponded to addition of 2.7 mol of G-6-P residues; after 48 h, 4 mol sugar was added and this increased to 8.7 after 72 h. Dimerisation of FGF-2 was observed after 72 h of treatment. Induction of mitogenesis in BAEC was significantly reduced by 25%-40% after treatment for 48-96 h with glycated (24 h) FGF-2 (gFGF-2; 100 pg/ml-5 ng/ml; P < 0.05), whilst capillary tubule formation was significantly reduced by between 60% and 90% (100 pg/ml-1 ng/ml; P < 0.05) after 5 days compared to native FGF-2. Subsequent investigation of the signal transduction molecules associated with mitogenesis showed a reduction in FGF-2 induced tyrosine phosphorylated proteins of approximate Mw 20-150 kDa between 10 min and 24 h, in particular, mitogen activated protein kinase (MAPK)/early response kinase (ERK-1, ERK-2), after glycation. To determine the reason for reduced angiogenic activity of gFGF-2, we compared its binding characteristics to that of native FGF-2. Total binding of gFGF-2 to the cell surface was significantly reduced in BAEC analysed by FACS compared to native FGF-2 (P < 0.05). Further investigation using 125I-labelled differentially washed samples, demonstrated a significant reduction in gFGF-2 binding to the high affinity tyrosine kinase receptor (46%) compared to native FGF-2. In summary, glycation of FGF-2 in vitro occurs rapidly within 24 h in the presence of elevated levels of G-6-P. Glycation caused a significant reduction in the ability of FGF-2 to bind to the tyrosine kinase receptor and activate signal transduction pathways responsible for both mitogenesis and capillary formation in BAEC. These results could help to explain the mechanism behind impaired wound healing in patients with diabetes mellitus.
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PMID:Effect of glycation on basic fibroblast growth factor induced angiogenesis and activation of associated signal transduction pathways in vascular endothelial cells: possible relevance to wound healing in diabetes. 1219 73

Annual changes of activity of sucrose-phosphate synthase (SPS) from spruce (Picea abies [L.] Karst.) needles were studied with respect to three regulatory levels: metabolic fine control, covalent modification (phosphorylation), and protein amount. Glucose-6-phosphate served as an allosteric activator of spruce SPS by shifting the Michaelis constant for the substrate fructose-6-phosphate from 4.2 to 0.59 mM, whereas inorganic phosphate competitively inhibited this activation. The affinity for the other substrate, UDP-glucose, was unaffected. Incubation of the crude extract with ATP resulted in a time- and concentration-dependent decrease of the maximal velocity of SPS. This inactivation was sensitive to staurosporine, a potent protein kinase inhibitor, indicating the participation of a protein kinase. Probing SPS protein with heterologous antibodies showed that the subunit of spruce SPS is an approximately 139-kD protein and that changes in the extractable activity during the course of a year were correlated with the amount of SPS protein. High SPS activities in winter were paralleled by increased levels of the activator glucose-6-phosphate and the substrate fructose-6-phosphate, indicating a high capacity for sucrose synthesis that may be necessary to maintain photosynthetic CO2 fixation in cold-hardened spruce needles.
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PMID:Coarse and Fine Control and Annual Changes of Sucrose-Phosphate Synthase in Norway Spruce Needles. 1222 18


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