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)

A sequence homology has been noted between the carboxyl quarter of the catalytic gamma subunit of phosphorylase kinase and the region of troponin I coded by exon VII. Because this portion of troponin I contains the inhibitory region that interacts with actin and troponin C, we have examined whether the gamma subunit of phosphorylase kinase can functionally mimic troponin I by also interacting with actin and troponin C. We have found that troponin C not only activates the isolated gamma subunit of phosphorylase kinase but also binds with approximately the same affinity as calmodulin. Although actin had no effect on the activity of the gamma subunit alone, it did inhibit the activity of gamma-calmodulin and gamma-troponin C complexes. Conversely, the gamma subunit was able to inhibit actomyosin ATPase in a process that could be overcome by calmodulin. These results suggest that actin and calmodulin (or troponin C) compete for binding to the gamma subunit. Moreover, the structural and functional similarities between the gamma subunit and troponin I suggest that the gamma subunit of phosphorylase kinase may have evolved from the fusion of a protein kinase protogene with a progenitor of exon VII of troponin I.
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PMID:Functional and structural similarities between the inhibitory region of troponin I coded by exon VII and the calmodulin-binding regulatory region of the catalytic subunit of phosphorylase kinase. 240 8

A cyclic AMP and calcium-independent protein kinase has been identified and purified from pig brain to near homogeneity. This independent protein kinase was isolated in an inactive form, and activation required ATP and Mg2+. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the purified enzyme contains 1 subunit with a molecular mass of about 36 kDa. Although there was no significant phosphorylation of phosphorylase, phosphorylase b kinase, casein, phosvitin, and protamine, this kinase was found to be very active toward myelin basic protein and histones H1, 2A, and 2B. Trypsinolysis completely destroyed the kinase activity, indicating that this is not a protease-activated protein kinase. More interesting, this cAMP and calcium-independent protein kinase can be regulated by its state of phosphorylation. In its non-phosphorylated state, the kinase was essentially inactive but could be fully activated when the enzyme was phosphorylated up to a 1:1 molar ratio. Conversely, partial dephosphorylation of the phosphorylated enzyme was associated with a time-dependent decrease in the kinase activity and a loss of 32P. All the results taken together point out that this kinase is distinguished from all the reported protein kinases and may represent a previously undiscovered protein kinase. The results also provide initial evidence that a cascade activation mechanism may possibly be involved in the regulation of a protein kinase activity which is independent of cAMP and calcium.
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PMID:Identification and characterization of a phosphorylation-activated, cyclic AMP and Ca2+-independent protein kinase in the brain. 243 73

Monoclonal antibodies against human erythrocyte membrane Ca2+-ATPase were obtained. The binding of monoclonal antibodies to the enzyme resulted in a decrease in the enzyme sensitivity to calmodulin (CaM). The effects of monoclonal antibodies on other CaM-dependent enzymes, namely, on the phosphodiesterase of cAMP, phosphorylase kinase, and Ca2+-CaM-dependent protein kinase II (PK II), were studied. It was found that all four enzymes contain a common antigenic site. However, the inhibitory effect of antibodies was observed only with respect to Ca2+-ATPase and PK II. The kinetics of the binding of monoclonal antibodies and their inhibitory action were investigated. It was shown that the antigenic site is confined to the calmodulin-binding portion of Ca2+-ATPase and PK II.
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PMID:Elucidation of conservative elements of calmodulin-dependent enzymes with the use of monoclonal antibodies. 246 54

Following incubation of HPV 1-induced warts in the presence of [32P] phosphate several of the E4-encoded proteins were found to be radiolabeled. Two-dimensional isoelectric focusing sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicated that the 17K E4 polypeptides had incorporated [32P]phosphate whereas those of 16K were unlabeled. Purified E4 gene products were separated by ion exchange chromatography into a large number of different species, which were of similar size but of different charge due to varying extents of phosphorylated peptides have been isolated and identified. Phosphoserine and phosphothreonine were identified in all 16/17K E4 fractions but not phosphotyrosine. Both HPV 1 E4 16K and 17K fractions were phosphorylated in vitro by cAMP-dependent protein kinase but not by myosin light chain kinase or by phosphorylase kinase. Incubation with cAMP PK gave incorporation of approx. 0.5 mole phosphate/mol of protein indicating that the cAMP-dependent protein kinase site(s) was partially phosphorylated in vivo. This view was supported by the fact that species which were more heavily phosphorylated in vivo incorporated less phosphate after cAMP-dependent protein kinase phosphorylation. HPV 1 E4 was also phosphorylated at serine and threonine residues by a crude cytoplasmic extract prepared from cultured human keratinocytes and cultured human retinoblasts. These results are discussed in the light of the known effects of phosphorylation on the interactions of other keratinocyte-specific proteins.
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PMID:Phosphorylation of the human papillomavirus type 1 E4 proteins in vivo and in vitro. 247 Jan 93

Several forms of protein kinase C with molecular masses of 74-, 77-, and 80-kDa were detected in subcellular fractions of human breast cancer MDA-MB-231 cells which express the alpha-type protein kinase C. Several lines of evidence indicated that the 74-kDa is the precursor of the 77- and 80-kDa protein kinase C forms. (i) Pulse-labeling experiments revealed that protein kinase C is synthesized on membranes as a 74-kDa protein that can be chased into the 77- and the 80-kDa protein kinase C forms. (ii) The primary translation product of protein kinase C displayed an apparent molecular size of 74-kDa as determined by in vitro translation of poly(A)+ RNA from MDA-MB-231 cells. (iii) Incubation with serine/threonine-specific protein phosphatases (potato acid phosphatase and phosphatase 1 or 2A) resulted in the complete dephosphorylation of the 77-kDa to the 74-kDa protein kinase C form. Protein kinase C appears to be synthesized in membranes as an unphosphorylated and presumably inactive 74-kDa form that is converted into the active 77- and 80-kDa protein kinase C by post-translational modification involving at least two phosphorylation steps. The first phosphorylation is probably achieved by a specific, yet unidentified, "protein kinase C kinase" since the 74-kDa protein kinase C species did not undergo autophosphorylation and was neither a substrate for the purified protein kinase C, S6 kinase, phosphorylase kinase, casein kinase II, nor for the catalytic subunit of cAMP-dependent protein kinase. Except for phosphorylase kinase and the catalytic subunit of the cAMP-dependent protein kinase, phosphorylation of the 77-kDa protein kinase C form with purified protein kinase C (autophosphorylation), S6 kinase or casein kinase II shifted the molecular mass of the 77-kDa protein kinase C to 80-kDa. Prolonged exposure of MDA-MB-231 cells to phorbol 12-myristate 13-acetate not only leads to a complete down-regulation of protein kinase C activity but also to an accumulation of 74-kDa protein kinase C due to a retarded conversion of the 74-kDa into the 77- and 80-kDa protein kinase C forms in these cells. Our data indicate that tumor promoters additionally interfere with the posttranslational processing that converts the 74-kDa protein kinase C precursor into the 77- and 80-kDa forms of the enzyme.
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PMID:Biosynthesis and posttranslational modifications of protein kinase C in human breast cancer cells. 247 38

Mouse BC3H1 myocytes were incubated with 32Pi before acetylcholine receptors were solubilized, immunoprecipitated, and subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis. More than 90% of the 32P found in the receptor was bound to the delta subunit. Two phosphorylation sites in this subunit were resolved by reverse phase high performance liquid chromatography after exhaustive proteolysis of the protein with trypsin. Sites 1 and 2 were phosphorylated to approximately the same level in control cells. The divalent cation ionophore, A23187, increased 32P in site 1 by 40%, but did not affect the 32P content of site 2. In contrast, isoproterenol increased 32P in site 2 by more than 60%, while increasing 32P in site 1 by only 20%. When dephosphorylated receptor was incubated with [gamma-32P]ATP and the catalytic subunit of cAMP-dependent protein kinase, the delta subunit was phosphorylated to a maximal level of 1.6 phosphates/subunit. Approximately half of the phosphate went into site 2, with the remainder going into a site not phosphorylated in cells. The alpha subunit was phosphorylated more slowly, but phosphorylation of both alpha and delta subunits was blocked by the heat-stable protein inhibitor of cAMP-dependent protein kinase. Phosphorylation of the receptor was also observed with preparations of phosphorylase kinase. In this case phosphorylation occurred in the beta subunit and site 1 of the delta subunit, neither of which were phosphorylated by cAMP-dependent protein kinase. The rate of receptor phosphorylation by phosphorylase kinase was slow relative to that catalyzed by cAMP-dependent protein kinase. Therefore, it can not yet be concluded that phosphorylase kinase phosphorylates the beta subunit and the delta subunit site 1 in cells. However, the results strongly support the hypothesis that phosphorylation by cAMP-dependent protein kinase accounts for phosphorylation of the alpha subunit and the delta subunit site 2 in response to elevations in cAMP.
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PMID:Ca2+-dependent and cAMP-dependent control of nicotinic acetylcholine receptor phosphorylation in muscle cells. 254 36

The first example of an enzyme that undergoes phosphorylation and dephosphorylation was phosphorylase, which catalyzes the initial step in the breakdown of tissue glycogen, a process that occurs when cells are stimulated by certain hormones. The phosphorylation reaction that activates phosphorylase is catalyzed by an enzyme designated "phosphorylase kinase," whereas the dephosphorylation reaction is catalyzed by an enzyme called "phosphorylase phosphatase." Phosphorylase kinase, like phosphorylase itself, is regulated by phosphorylation-dephosphorylation. In this instance the enzyme is phosphorylated and activated by a protein kinase that is the intracellular target of adenosine 3',5'-cyclic phosphate, the second messenger of hormone action that was discovered by the late Earl Sutherland. Knowledge of these steps led to the establishment of the glycogenolytic cascade in which adenosine 3',5'-cyclic phosphate, formed as a result of hormone action, first activates the adenosine 3',5'-cyclic phosphate-dependent protein kinase, which in turn activates phosphorylase kinase, which then converts inactive phosphorylase to its active form. This is followed by the breakdown of glycogen.
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PMID:The Albert Lasker Medical Awards. Role of the cyclic AMP-dependent protein kinase in signal transduction. 255 Jun 80

The glycogen-associated form of protein phosphatase-1 (PP-1G) is a heterodimer comprising a 37-kDa catalytic (C) subunit and a 161-kDa glycogen-binding (G) subunit, the latter being phosphorylated by cAMP-dependent protein kinase at two serine residues (site 1 and site 2). Here the amino acid sequence surrounding site 2 has been determined and this phosphoserine shown to lie 19 residues C-terminal to site 1 in the primary structure. The sequence in this region is: (sequence; see text) At physiological ionic strength, phosphorylation of glycogen-bound PP-1G was found to release all the phosphatase activity from glycogen. The released activity was free C subunit, and not PP-1G, while the phospho-G subunit remained bound to glycogen. Dissociation reflected a greater than or equal to 4000-fold decrease in affinity of C subunit for G subunit and was readily reversed by dephosphorylation. Phosphorylation and dephosphorylation of site 2 was rate-limiting for dissociation and reassociation of C subunit. Release of C subunit was also induced by the binding of anti-site-1 Fab fragments to glycogen-bound PP-1G. At near physiological ionic strength, PP-1G and glycogen concentration, site 2 was autodephosphorylated by PP-1G with a t0.5 of 2.6 min at 30 degrees C, approximately 100-fold slower than the t0.5 for dephosphorylation of glycogen phosphorylase under the same conditions. Site 2 was a good substrate for all three type-2 phosphatases (2A, 2B and 2C) with t0.5 values less than those toward the alpha subunit of phosphorylase kinase. At the levels present in skeletal muscle, the type-2A and type-2B phosphatases are potentially capable of dephosphorylating site 2 in vivo within seconds. Site 1 was at least 10-fold less effective than site 2 as a substrate for all four phosphatases. In conjunction with information presented in the following paper in this issue of this journal, the results substantiate the hypothesis that PP-1 activity towards the glycogen-metabolising enzymes is regulated in vivo by reversible phosphorylation of a targetting subunit (G) that directs the C subunit to glycogen--protein particles. The efficient dephosphorylation of site 2 by the Ca2+/calmodulin-stimulated protein phosphatase (2B) provides a potential mechanism for regulating PP-1 activity in response to Ca2+, and represents an example of a protein phosphatase cascade.
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PMID:Regulation of protein phosphatase-1G from rabbit skeletal muscle. 1. Phosphorylation by cAMP-dependent protein kinase at site 2 releases catalytic subunit from the glycogen-bound holoenzyme. 255 13

In addition to acetyl-CoA carboxylase and HMG-CoA reductase, the AMP-activated protein kinase phosphorylates glycogen synthase, phosphorylase kinase, hormone-sensitive lipase and casein. A number of other substrates for the cyclic AMP-dependent protein kinase, e.g., L-pyruvate kinase and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, are not phosphorylated at significant rates. Examination of the sites phosphorylated on acetyl-CoA carboxylase, hormone-sensitive lipase, glycogen synthase and phosphorylase kinase suggests a consensus recognition sequence in which the serine residue phosphorylated by the AMP-activated protein kinase has a hydrophobic residue on the N-terminal side (i.e., at -1) and at least one arginine residue at -2, -3 or -4. Substrates for cyclic AMP-dependent protein kinase which lack the hydrophobic residue at -1 are not substrates for the AMP-activated protein kinase.
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PMID:The substrate and sequence specificity of the AMP-activated protein kinase. Phosphorylation of glycogen synthase and phosphorylase kinase. 256 85

The synthetic peptide, Asp-Asp-Asp-Glu-Glu-Ser-Ile-Thr-Arg-Arg, derived from the phosphorylation site of casein kinase-1 (CK-1) in beta-casein A(2), is readily phosphorylated by CK-1, but not by casein kinase-2(CK-2), cyclic AMP-dependent protein kinase, protein kinase C, phosphorylase kinase and protein kinase FA. Phosphorylation by CK-1 occurs only at Ser-6, Thr-8 being unaffected. The Km for the peptide is higher (1 mM) than for beta-casein A(2) (40 microM), while the Vmax is quite comparable. This is the first synthetic peptide substrate for CK-1 described so far, and can be used for the rapid and specific estimation of CK-1 activity in crude extracts.
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PMID:A synthetic peptide substrate specific for casein kinase I. 259 14


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