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 phosphorylation sites in liver synthase were studied using gel filtration and high performance liquid chromatography of 32P-labeled tryptic peptides. Phosphorylase b kinase, calmodulin-dependent glycogen synthase kinase and glycogen synthase kinase 4 from liver phosphorylated the same low Mr tryptic peptide. cAMP-dependent protein kinase mainly phosphorylated the low Mr tryptic peptide, but also incorporated phosphate into two other peptides. Glycogen synthase kinase 5 phosphorylated a single tryptic peptide, whereas glycogen synthase kinase 3 phosphorylated several tryptic peptides. Calcium-phospholipid-dependent protein kinase phosphorylated two tryptic peptides, the major one of which had the same chromatographic properties as the low Mr peptide described above. These findings confirm that liver glycogen synthase undergoes multi-site phosphorylation and suggest that the topography of the sites is generally similar to that in muscle glycogen synthase.
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PMID:Multiple phosphorylation of rat-liver glycogen synthase by protein kinases. 608 94

We have previously reported that rabbit skeletal muscle phosphorylase kinase is phosphorylated by glycogen synthase (casein) kinase-1 (CK-1) primarily on the beta subunit (beta = 1 mol of PO4; alpha = 0.2 mol of PO4) when the reaction was carried out in beta-glycerophosphate. The resultant enzyme activation was 16-fold (Singh, T. J., Akatsuka, A., and Huang, K.-P. (1982) J. Biol. Chem. 257, 13379-13384). In the present study we found that in Tris-Cl buffer CK-1 catalyzes the incorporation of greater than 2 mol of PO4/monomer into each of the alpha and beta subunits. Phosphorylase kinase activation resulting from the higher level of phosphorylation remained 16-fold. 32P-Labeled tryptic peptides from the alpha and beta subunits were analyzed by isoelectric focusing. Cyclic AMP-dependent protein kinase (A-kinase) phosphorylates a single major site in each of the alpha and beta subunits at 1.5 mM Mg2+. In addition to these two sites, A-kinase phosphorylates at least three other sites in the alpha subunit at 10 mM Mg2+. CK-1 also catalyzes the phosphorylation of multiple sites in both the alpha and beta subunits. Of the two major sites phosphorylated by CK-1 in the beta subunit, one of these sites is also recognized by A-kinase. At least three sites are phosphorylated by CK-1 in the alpha subunit. One of these sites is recognized by CK-1 only after a prior phosphorylation of phosphorylase kinase by A-kinase at a single site in each of the alpha and beta subunits at 1.5 mM Mg2+. The roles of the different phosphorylation sites in phosphorylase kinase activation are discussed.
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PMID:Comparison of the phosphorylation of rabbit skeletal muscle phosphorylase kinase by cAMP-dependent protein kinase and cAMP-independent glycogen synthase (casein) kinase-1. 609 48

Glycogen synthase I from human polymorphonuclear leukocytes was phosphorylated with cAMP dependent protein kinase, synthase kinase or phosvitin kinase prepared from these cells. Limited tryptic hydrolysis released four phosphopeptides (t-A, t-B, t-C, t-D). Subsequent alpha-chymotryptic hydrolysis of the trypsin resistant core released three phosphopeptides (c-A, c-B, c-C). The kinetic changes of glycogen synthase were compared with the phosphorylation of the peptides. Equivalent kinetic changes (Kc equals 0.2-0.3 mM Glc-6-P) were obtained when 1 Pi/subunit was introduced by cAMP dependent protein kinase, 0.5 Pi/subunit by synthase kinase and 0.8 Pi/subunit by both kinases. Initially, cAMP dependent protein kinase phosphorylated peptides c-A and t-C in parallel and somewhat later also t-B, whereas synthase kinase initially phosphorylated only c-A. The ultimate effect of the two kinases on c-A was additive. It was concluded that the initial kinetic changes were dependent on phosphorylation of c-A, which contained two sites, one for each kinase. The same kinetic changes were induced by phosphorylation on each of the sites. In the subsequent phosphorylation the kinases, separately or together, phosphorylated peptide c-C indicating one non-specific phosphorylatable site in this peptide. The cAMP dependent protein kinase alone phosphorylated t-C maximally, whereas both kinases were required for an equal phosphorylation of t-A and t-B. It is suggested that the cAMP dependent protein kinase phosphorylated t-A and t-C, whereas the data did not allow a similar suggestion for t-B. The kinetic changes occurring during the later stages of phosphorylation were an increase in Kc for Glc. 6-P to 4-5 mM at 1.85 Pi/subunit and to 20 mM at 3.3 Pi/subunit, but the changes could not be assigned to phosphorylation of any specific peptide. Phosphorylation of the peptides t-D and c-B were insignificant, but c-B may be phosphorylated under other experimental conditions (25). The phosvitin kinase phosphorylated glycogen synthase extremely slowly to an extent of 0.8 Pi/subunit, mainly in peptide c-C. Glycogen synthase would appear without physiological importance as substrate for this kinase. Phosphorylase kinase from rabbit skeletal muscle incorporated 0.7 Pi/subunit, mainly in peptide c-A causing a decrease in RI to 0.3, which upon further incubation remained constant. The rate of decrease in RI in 0.5 was unaffected by several synthase modifiers, including Glc-6-P, but was inhibited by ADP and Pi. The rate of phosphorylation by cAMP dependent protein kinase and synthase kinase was diversely affected in different buffers, however, without affecting the ultimate phosphorylation pattern.
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PMID:Phosphorylation of glycogen synthase I from human polymorphonuclear leukocytes. 626 29

We have examined the mechanism whereby glucagon stimulates the phosphorylation of ATP-citrate lyase in intact rat hepatocytes. Purified ATP-citrate lyase is phosphorylated in vitro by the catalytic subunit of the cyclic AMP-dependent protein kinase, in a reaction wherein 2-3 mol phosphate/mol lyase are incorporated, at an initial rate that approaches that observed for mixed histone. This reaction is completely abolished by the protein kinase inhibitor protein. Limited tryptic digestion of ATP-citrate lyase phosphorylated in vitro by the cyclic AMP-dependent protein kinase yields a pattern of 32P-labeled peptides, indistinguishable from those observed in parallel digests of lyase isolated from 32P-labeled, glucagon-stimulated hepatocytes. Phosphorylase b kinase catalyzes the incorporation of 1 mol phosphate/mol lyase, albeit at less than 1/160 the rate observed for phosphorylase b. The phosphorylation of purified ATP-citrate lyase is also catalyzed by homogenates of hepatocytes. This reaction is stimulated by cyclic AMP. At 30 degrees C, in the presence of maximally stimulating concentrations of cyclic AMP, the addition of excess protein kinase inhibitor protein inhibits the phosphorylation of ATP-citrate lyase by 67%. Thus, hepatocytes contain both cyclic AMP-dependent and cyclic AMP-independent ATP-citrate lyase kinase activities. Pretreatment of hepatocytes with glucagon (10(-8) M for 2 min) prior to homogenization results in activation of an endogenous hepatocyte ATP-citrate lyase kinase, as well as histone kinase and phosphorylase b kinase; the glucagon-stimulated increment in lyase kinase (and histone kinase) is observed only when homogenates are assayed in the absence of added cyclic AMP, and is completely abolished by an excess of the protein kinase inhibitor protein. We conclude that the glucagon-stimulated phosphorylation of ATP-citrate lyase in intact hepatocytes is catalyzed directly by the cyclic AMP-dependent protein kinase.
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PMID:The role of the cyclic AMP-dependent protein kinase in the glucagon-stimulated phosphorylation of ATP-citrate lyase. 626 46

Phosphorylase kinase from rabbit skeletal muscle inhibited the dephosphorylation of phosphorylase a by phosphoprotein phosphatase. Phosphorylation (activation) of phosphorylase kinase by cyclic AMP-dependent protein kinase greatly increased this inhibitory effect. Thus, phosphoprotein phosphatase is inhibited by phosphorylase kinase in a reversible manner (Gergely et al. (1976) Biochim. Biophys. Acta 429 809-816). In this paper the regulation by phosphorylase kinase at phosphoprotein phosphatase activity in different fractions of muscle extract and in the presence of various ligands has been investigated. The presence of phosphorylase kinase also affected the ligand control of phosphatase activity. Phosphorylase kinase almost cancelled the inhibitory effect of AMP but hardly influenced the activating effect of glucose, glucose 6-phosphate and caffeine. Calmodulin, glycogen and phosphorylase b (effectors of phosphorylase kinase) did not influence the inhibitory effect of phosphorylase kinase. Fractions of muscle extract also demonstrated the regulatory role of phosphorylase kinase. These fractions contained considerable amounts of phosphorylase kinase and phosphatase. Phosphatase activity was inhibited by phosphorylation reactions triggered by Mg++ and ATP. Heat-stable inhibitors were absent from these fractions, therefore the transient inhibition of phosphatase could be attributed to the phosphorylation of endogenous phosphorylase kinase. The introduction between phosphorylase kinase and phosphatase resulted in a loss of AMP sensitivity, i.e. AMP did not inhibit the activity of phosphatase in those fractions. Our results imply that the phosphorylation of phosphorylase kinase is equally important both in the formation of enzymatically active phosphorylase a and in the inhibition of dephosphorylation of phosphorylase a. The consequence of these two effects is the elevated level of phosphorylase a.
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PMID:Regulation by phosphorylase kinase of phosphoprotein phosphatase activity: simultaneous control of protein phosphorylation and dephosphorylation in skeletal muscle. 629 2

Phosphorylase kinase from rabbit skeletal muscle can be phosphorylated and activated by a cyclic nucleotide- and Ca2+-independent protein kinase previously identified as a glycogen synthase kinase (Itarte, E., and Huang, K.-P. (1979) J. Biol. Chem. 254, 4052-4057). This independent kinase phosphorylates the beta subunit of phosphorylase kinase approximately 15 times faster than it does the alpha subunit. The cAMP-dependent and -independent kinases separately catalyze the incorporation of 1 mol of phosphate into the beta subunit. Analyses of the tryptic peptides from the beta subunit phosphorylated with either kinase by isoelectric focusing and peptide mapping indicate that both kinases phosphorylate the same site on the beta subunit. Activation of phosphorylase kinase catalyzed by the independent kinase is only 60% of that observed with cAMP-dependent kinase. If phosphorylase kinase is first incubated with the independent kinase to phosphorylate the beta subunit, subsequent addition of cAMP-dependent kinase results in a predominant phosphorylation of the alpha subunit. This additional phosphorylation of the alpha subunit is accompanied by a further activation of the alpha subunit is accompanied by a further activation of phosphorylase kinase to the same extent as that achieved by cAMP-dependent kinase alone. Hence, the phosphorylation of the alpha subunit is clearly required for full activation of phosphorylase kinase, even at low [Mg2+].
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PMID:Phosphorylation and activation of rabbit skeletal muscle phosphorylase kinase by a cyclic nucleotide- and Ca2+-independent protein kinase. 629 88

Two phosphorylase kinase activities were resolved by DEAE-cellulose chromatography. The main activity peak was enriched 2800-fold, the minor appeared to be an aggregate of the enzyme. Phosphorylase kinase also phosphorylated histone and casein with no changes in phosphorylation ratios throughout the preparation steps but was most active on yeast phosphorylase. The molecular weight was 29000 +/- 2000. ATP, UTP, GTP served as substrates while CTP was inactive. Mg-ions activated the kinase without inhibition at high concentrations (30 mM). In addition to this cAMP-independent kinase, cAMP-dependent protein kinase also phosphorylated phosphorylase. The catalytic subunit and phosphorylase kinase were not identical since the latter was not inhibited by yeast cAMP binding protein.
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PMID:Characterization of phosphorylase kinase activities in yeast. 630 69

Purified rabbit liver glycogen synthase was found to be a substrate for six different protein kinases: (i) cyclic AMP-dependent protein kinase, (ii) two Ca2+-stimulated protein kinases, phosphorylase kinase (from muscle) and a calmodulin-dependent glycogen synthase kinase, and (iii) three members of a Ca2+ and cyclic nucleotide independent class, PC0.7, FA/GSK-3, and casein kinase-1. Greatest inactivation accompanied phosphorylation by cyclic AMP-dependent protein kinase (to 0.5-0.7 phosphate/subunit, +/- glucose-6-P activity ratio reduced from approximately 1 to 0.6) or FA/GSK-3 (to approximately 1 phosphate/subunit, activity ratio, 0.46). Phosphorylation by the combination FA/GSK-3 plus PC0.7 was synergistic, and more extensive inactivation was achieved. The phosphorylation reactions just described caused significant reductions in the Vmax of the glycogen synthase with little effect on the S0.5 (substrate concentration corresponding to Vmax/2). Phosphorylase kinase achieved a lesser inactivation, to an activity ratio of 0.75 at 0.6 phosphate/subunit. PC0.7 acting alone, casein kinase-1, and the calmodulin-dependent protein kinase did not cause inactivation of liver glycogen synthase with the conditions used. Analysis of CNBr fragments of phosphorylated glycogen synthase indicated that the phosphate was distributed primarily between two polypeptides, with apparent Mr = 12,300 (CB-I) and 16,000-17,000 (CB-II). PC0.7 and casein kinase-1 displayed a decided specificity for CB-II, and the calmodulin-dependent protein kinase was specific for CB-I. The other protein kinases were able, to some extent, to introduce phosphate into both CB-I and CB-II. Studies using limited proteolysis indicated that CB-II was located at a terminal region of the subunit. CB-I contains a minimum of one phosphorylation site and CB-II at least three sites. Liver glycogen synthase is therefore potentially subject to the same type of multisite regulation as skeletal muscle glycogen synthase although the muscle and liver enzymes display significant differences in both structural and kinetic properties.
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PMID:Phosphorylation of rabbit liver glycogen synthase by multiple protein kinases. 632 70

Yeast phosphorylase is phosphorylated and activated by a cyclic AMP-independent protein kinase (called phosphorylase kinase) and a cyclic AMP-dependent protein kinase. Only in the presence of both kinases is phosphorylase fully activated and phosphorylated. No evidence was found for the presence of two phosphorylation sites as an identical phosphopeptide pattern of phosphorylase is obtained after phosphorylation by either one or both kinases. The kinases probably phosphorylate identical sites but recognize different subunits of phosphorylase. Phosphorylase kinase phosphorylates the high-Mr subunit while cAMP-dependent protein kinase phosphorylates the low-Mr subunit.
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PMID:Regulation of yeast phosphorylase by phosphorylase kinase and cAMP-dependent protein kinase. 635 52

Phosphorylase kinase is a multimeric protein kinase (alpha 4 beta 4 gamma 4 delta 4) whose enzymatic activity is conferred by its gamma-subunit. A library of 18 overlapping synthetic peptides spanning residues 277-386 of the gamma-subunit has been prepared to use in identifying important regulatory structures in the protein. In the present study, the library was screened to identify regions that might function as autoinhibitory domains. Peptides from two distinct regions were found to inhibit the Ca2(+)-activated holoenzyme. The same regions were previously found to bind calmodulin (i.e. the delta-subunit; Dasgupta, M. Honeycutt, T., and Blumenthal, D. K. (1989) J. Biol. Chem. 264, 17156-17163). The most potent substrate antagonist peptides were PhK13 (residues 302-326; Ki = 300 nM) and PhK5 (residues 342-366; Ki = 20 microM). Both peptides inhibited the holoenzyme competitively with respect to phosphorylase b and noncompetitively with respect to Mg.ATP. When the pattern of inhibition with both peptides present was analyzed, inhibition was observed to be synergistic and modestly cooperative indicating that the two peptides can simultaneously occupy the protein substrate-binding site(s). These data are consistent with a model in which the regions of the gamma-subunit represented by PhK5 and PhK13 work in concert as regulatory subdomains that transduce Ca2(+)-induced conformational changes in the delta-subunit to the catalytic gamma-subunit through a pseudosubstrate autoinhibitory mechanism.
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PMID:Characterization of the regulatory domain of the gamma-subunit of phosphorylase kinase. The two noncontiguous calmodulin-binding subdomains are also autoinhibitory. 767 9


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