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)

Cyclic AMP has been implicated to a greater or lesser extent in the regulation of four key enzymes which interact to regulate intracellular cholesterol metabolism; HMG CoA reductase; ACAT; cholesteryl ester hydrolase; and cholesterol 7 alpha hydroxylase. The relationship between these enzymes and the sites where current evidence suggests that cyclic AMP may be involved are summarized in Fig. 3. Cholesterol 7 alpha hydroxylase controls the catabolism of cholesterol to bile acids in the liver, and thus its removal from the body via the bile, but does not have a major role in cholesterol metabolism in extrahepatic tissues. It is clear that cyclic AMP is able to influence the activity of this enzyme in liver sub-cellular fractions and isolated hepatocytes in vitro, and studies in our laboratory have shown that changes in Ca2+ fluxes within the cell may be important in its mechanism of action. Whether or not the cyclic nucleotide has a role regulating cholesterol 7 alpha hydroxylase activity in vivo, however, is not known. HMG CoA reductase is inactivated by phosphorylation both in vitro and in vivo, but although cyclic AMP and glucagon have been shown to inhibit the enzyme, cyclic AMP-dependent protein kinase is not directly involved. The exact mechanism by which the cyclic nucleotide influences the system remains unclear, but it may be related to activation of microsomal phosphatases. The activity of ACAT has been shown to be modulated by phosphorylation in a number of tissues in vitro, but the involvement of cyclic AMP has not been unequivocally demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclic AMP and the regulation of cholesterol metabolism. 132 21

Parietal cell secretion can be stimulated by both histaminergic and cholinergic agonists. We have recently found that inhibition of calmodulin-dependent protein kinase II (CaMK II) activity can abolish cholinergic but not histaminergic stimulation of parietal cell secretion (Am. J. Physiol. 262:G118-122). We have investigated the presence of calmodulin-binding proteins and CaMK II in isolated rabbit parietal cells. Calmodulin-binding proteins with apparent molecular masses of 50, 60, 85, 100, and 240 kDa were observed. The major calmodulin-binding species was a 50 kDa band which was enriched in 50,000 g. microsomal membranes. The 50 kDa calmodulin binding comigrated with immunoreactivity for CaMK II. Partial purification of the microsomal CaMK II demonstrated a 250 kDa oligomer. The results demonstrate that CaMK II is the major calmodulin-binding protein in parietal cells and is associated primarily with light microsomal membranes.
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PMID:The major calmodulin-binding protein in rabbit parietal cells is Ca2+/calmodulin-dependent protein kinase II. 133 20

Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), which lead to defective Cl- conductance in epithelial cells. While the CFTR gene product has been detected in the plasma membrane, its presence and functional role in the membranes of intracellular compartments remain to be established. The purpose of the present experiments was to functionally localize CFTR in the endosomal membrane and to test the role of the associated Cl- conductance in the regulation of endosomal pH (pH(en)). When using conductive protonophores, the net H+ flux across the endosomal membrane of Chinese hamster ovary (CHO) cells is limited by the movement of counterions. Thus, ionic permeability could be estimated indirectly, from the changes in pH(en) determined fluorimetrically. Measurements in situ and in a cell-free microsomal preparation indicate the presence of a protein kinase A (PKA)-activated anion conductance in endosomes from CHO cells transfected with CFTR, but not in endosomes from wild-type or mock-transfected cells. In endosomes isolated from CFTR-expressing cells, the stimulatory effect of PKA was diminished by a specific peptide inhibitor of PKA, by alkaline phosphatase treatment or by a monoclonal antibody against the second nucleotide binding fold of CFTR. Increasing counterion permeability by phosphorylation of CFTR or by addition of valinomycin failed to alter the rate or extent of endosomal acidification in situ. Our observations indicate that functional CFTR, susceptible to activation by PKA, is present in endosomes of transfected CHO cells. More importantly, the data suggest that factors other than counterion permeability are the major determinants of pH(en).
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PMID:The cystic fibrosis transmembrane regulator is present and functional in endosomes. Role as a determinant of endosomal pH. 137 35

This study shows the presence of seven different low-molecular-weight GTP binding proteins (smg proteins) with molecular masses between 18 and 27 kDa in subfractions of rat pancreatic acinar cells. After stimulation of isolated intact and permeabilized pancreatic acinar cells with cholecystokinin octapeptide (CCK-OP), the diacylglycerol (DG) analogue 12-O-tetradecanoylphorbol 13-acetate (TPA), vasoactive intestinal peptide (VIP), adenosine 3',5'-cyclic monophosphate (cAMP), or guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S), [alpha-32P]GTP binding to 21- to 22-kDa smg protein(s) in microsomal membranes (MM) was reduced, whereas the [alpha-32P]GTP binding to 23-kDa protein(s) was enhanced. In addition, prestimulation of permeabilized cells with GTP gamma S caused enhancement of [alpha-32P]GTP binding to a 19-kDa protein in MM [immunologically identified as the ADP-ribosylation factor (arf)]. In the presence of cytosol, direct addition of GTP gamma S to isolated MM resulted in an apparent translocation of the 19-kDa protein (arf) from the cytosol to membranes. This indicates increased association of arf with the membrane in its GTP-bound state. In CCK-OP-prestimulated acinar cells, [alpha-32P]GTP binding to plasma membrane-located 21- to 22-kDa proteins (immunologically identified as p21ras proteins) was enhanced, suggesting that there is an interrelationship between p21ras proteins and CCK receptors. Our results give evidence for a role of 19-kDa, 21- to 22-kDa, and 23-kDa smg proteins in cAMP-protein kinase A- and DG-protein kinase C-mediated stimulation of intracellular pathways in pancreatic acinar cells.
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PMID:Effects of agonists on p21ras and ras-related proteins in rat pancreatic acinar cells. 141 52

1. Guinea-pig liver contained more phosphorylase in the active (phosphorylated) form and less synthase in the active (dephosphorylated) form when compared with rat liver. 2. Activities of cyclic AMP-dependent protein kinase and Ca(2+)-dependent phosphorylase kinase were the same in rat and guinea-pig livers. 3. Activities of phosphorylase phosphatase and synthase phosphatase in the extract and glycogen plus microsomal fraction of guinea-pig liver were significantly lower than those of rat liver. 4. The existence of inhibitor-1 in the liver of guinea-pig can maintain a lower activity of type-1 protein phosphatase, especially when inhibitor-1 is phosphorylated by cyclic AMP-dependent protein kinase.
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PMID:Comparative characterization of liver glycogen metabolism in rat and guinea-pig. 145 30

Rat submandibular and parotid gland exocytosis is primarily controlled by beta-adrenergic receptor stimulation. Although its precise role in the regulation of salivary gland exocytosis is not fully understood, protein phosphorylation, mediated by the activation of cAMP-dependent protein kinase, may be directly involved. Previous studies suggest that analogous 26-kDa integral membrane phosphoproteins may play a direct role in regulating exocytosis. Studies were here undertaken to purify and partially characterize both phosphoproteins. After endogenous phosphorylation with 32P, subcellular fraction and solubilization of the microsomal fraction in n-octyl beta-glucopyranoside, the 26-kDa integral membrane phosphoproteins were purified by high performance liquid chromatography (HPLC), followed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and electroelution of the proteins. Amino acid analysis indicated a significant number of serine amino acids: N-terminal sequence data demonstrated a high level of homology; and trypsin digestion followed by reversed-phase HPLC indicated the possibility of multiple phosphorylation sites.
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PMID:Purification and partial characterization of analogous 26-kDa rat submandibular and parotid gland integral membrane phosphoproteins that may have a role in exocytosis. 152 94

Soybean nodulin-26, a homologue of bovine eye lens major intrinsic protein (MIP-26), is an integral protein of the peribacteroid membrane in symbiotic root nodules. It comprises 271 amino acids with six potential transmembrane domains and lacks an amino-terminal signal sequence. A full-length nodulin-26 cDNA and its various deletion derivatives were transcribed in vitro after linking them to bacteriophage T3 promoter. In vitro translation of these transcripts in a rabbit reticulocyte lysate, in the presence or absence of canine pancreatic microsomal membranes, suggested that nodulin-26 is cotranslationally inserted into the microsomes without a cleavable signal peptide. The first two transmembrane domains (103 amino acids) of the protein are sufficient for microsomal membrane insertion. Membrane-translocated nodulin-26 binds to Con-A and is sensitive to endoglycosidase-H treatment, suggesting that it is glycosylated. Native nodulin-26 from root nodules retains its sugar moiety as it, too, binds to Con-A. Chemical cleavage mapping at cysteine residues, a trypsin protection assay, and the Con-A binding affinity of nodulin-26 suggested that both the NH2 and COOH termini of this protein are on the cytoplasmic surface of the peribacteroid membrane, while the glycosidic residue is on the surface of the membrane facing the bacteroids. In vitro phosphorylation experiments showed that nodulin-26 is a major phosphorylated protein in the peribacteroid membrane. This phosphorylation is mediated by a Ca(2+)-dependent, calmodulin-independent protein kinase located in the peribacteriod membrane. Externally supplied acid phosphatase dephosphorylates this protein, but alkaline phosphatase does not. Based on its homology with several eukaryotic and prokaryotic channel-type membrane proteins, nodulin-26 may form a channel translocating specific molecules to the bacteroids during endosymbiosis in legume plants.
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PMID:Topology and phosphorylation of soybean nodulin-26, an intrinsic protein of the peribacteroid membrane. 162 42

Incubation of stripped rough microsomes (SRM) with the catalytic subunit of protein kinase A (PKA) permitted specific phosphorylation of seven proteins having relative molecular mass values of 55, 35, 23, 22.5, 22, 18.5 and 16.5 kDa (P55, P35 etc.). By two dimensional gel analysis, we compared these phosphoproteins with low-molecular-weight GTP-binding proteins and revealed that P23 and P22.5 co-migrated with known GTP-binding proteins. Next we examined the effect of cAMP-dependent phosphorylation on a GTP-dependent membrane function, membrane fusion. Quantitative analysis indicated no difference in the amount of membrane fusion obtained whether SRM were incubated in the absence or in the presence of PKA. Thus several rough microsomal proteins underwent cAMP-dependent phosphorylation and this post-translational modification did not affect GTP-dependent membrane fusion in a cell free system.
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PMID:cAMP-dependent phosphorylation of RER proteins from rat liver: relationship with GTP-dependent membrane fusion. 165 58

Rat liver microsomes contain type-1 S6 phosphatase (acting on the serine residues phosphorylated by protein kinase A) and type-1 phosphorylase phosphatase activities. The main aim of this study has been to characterize the microsomal S6 phosphatase activity and to compare its properties with those of the phosphorylase phosphatase activity in the same microsomal preparation. The specific activities of both microsomal S6 phosphatase and phosphorylase phosphatase were 1.6- to 1.7-fold higher in the smooth endoplasmic reticulum than in the rough sarcoplasmic reticulum. Both phosphatase activities were inhibited to a similar extent by MgCl2 (10 mM) and NaF (22 mM), were completely suppressed by glycerophosphate (80 mM) and ZnCl2(10 mM), and were stimulated by MnCl2(1 mM). When analyzed by gel filtration on Sephadex G-100 superfine, both phosphatase activities eluted as broad peaks, stretching from the void volume to 45-60 kDa. The microsomal S6 phosphatase and phosphorylase phosphatase activities also displayed the following distinct characteristics: (a) Mn2+ stimulated the S6 phosphatase activity 2.9-fold more than the phosphorylase phosphatase activity, (b) limited trypsin digestion of microsomal preparations increased the phosphorylase phosphatase activity by 1.5- to 2-fold, but decreased the S6 phosphatase activity by 50%, (c) a synthetic peptide analog of S6 (S6229-239) (200 microM), which did not act as a substrate for the microsomal S6 phosphatase and did not affect its activity, inhibited the microsomal phosphorylase phosphatase activity by about 50%, and (d) the elution profile of the phosphorylase phosphatase activity was markedly broader than that of the S6 phosphatase activity. A series of in vivo studies showed that streptozotocin-diabetes and insulin replacement therapy as well as ip injection of insulin or vanadate, which modified the microsomal S6 phosphatase activity, had no statistically significant effects on the microsomal phosphorylase phosphatase activity. Taken together, these results suggest that the microsomal S6 phosphatase and phosphorylase phosphatase activities are due to two distinct enzyme populations.
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PMID:A comparative study of the microsomal S6 phosphatase and phosphorylase phosphatase activities in rat liver. 165 55

Protein phosphatase-1 (PP-1) and -2A (PP-2A), two regulatory subunits of PP-1, the glycogen-binding subunit G and inhibitor-2 (I-2), kinase FA, and casein kinase II (CK-II) were investigated in skeletal muscle of diabetic rats 2 days after streptozotocin injection. FA and CK-II activate PP-1 in vitro and might be involved in the activation of PP-1 by insulin. Following muscle fractionation we found that (1) diabetes decreased both basal and trypsin-stimulated PP-1 activities; the decrease was more significant in the glycogen-bound and microsomal fractions than in the cytosol (cytosolic PP-1 decreased as specific activity but not as activity/g of muscle); also PP-2A was lower in diabetic cytosols; (2) less G was immunoprecipitated from diabetic glycogen-bound fractions compared to controls, while I-2 was not significantly changed; (3) diabetes decreased also FA (assayed as PP-1 activator) and CK-II (assayed using a synthetic peptide as substrate); (4) diabetes did not have any effect on phosphorylase (a + b) activity in the glycogen-bound fraction. Altogether the data show that acute diabetes decreased PP-1, one of its regulatory subunits and two potentially physiological regulators of PP-1, in addition to PP-2A. This may indicate that insulin is responsible for the long-term regulation of the same enzymes that are also under acute insulin control.
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PMID:Protein phosphatase-1 and -2A, kinase FA, and casein kinase II in skeletal muscle of streptozotocin diabetic rats. 165 59


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