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)

Alterations in protein phosphorylation may be important in the pathogenesis of Alzheimer's disease and recent observations suggest that a subset of protein kinase pathways may be selectively altered. Calcium/calmodulin-dependent protein kinase II CaM kinase II) is the most abundant protein kinase in the brain and is believed to play an important role in the regulation of synaptic transmission, long-term potentiation and other forms of neuronal plasticity. We have now evaluated brains of individuals with Alzheimer's disease for changes in the distribution and density of immunoreactivity for the alpha subunit of CaM kinase II. CaM kinase II immunoreactivity was found in cytoarchitectural areas and neurons vulnerable to the formation of neurofibrillary angles and senile plaques. Over 80% of neurons bearing neurofibrillary tangles expressed CaM kinase II. Loss of CaM kinase II immunoreactivity was found in CA1, commensurate with neuronal loss in this area. Remaining CA1 neurons, however, had preserved CaM kinase II immunoreactivity. Preservation in the distribution and density of CaM kinase II immunoreactivity was observed in other hippocampal regions and in a multimodal association area, area 20. These results suggest CaM kinase II expression in the Alzheimer's disease brain is unaltered despite marked neuropathological changes.
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PMID:Calcium/calmodulin-dependent protein kinase II immunostaining is preserved in Alzheimer's disease hippocampal neurons. 782 Jun 30

We previously reported that the level of Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) alpha and beta proteins increases with postnatal age. In the present study, we investigated the developmental changes in whole protein substrates of CaM kinase II as compared with those of cAMP-dependent protein kinase (A-kinase) in the rat forebrain. Protein substrates were phosphorylated with [gamma-33P]ATP, and analysed by two-dimensional gel electrophoresis. More than 50 substrates for CaM kinase II were found in the soluble and particulate fractions. The phosphorylation level of more than 15 substrates increased in the particulate fraction during development. Similarly, that of more than 3 substrates increased in the soluble fraction. Some substrates for A-kinase also increased during development, although some decreased. These findings suggest that the expression of some substrates is regulated during development and that the phosphorylation reaction involves the regulation of neuronal development.
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PMID:Developmental changes of protein substrates of Ca2+/calmodulin-dependent protein kinase II in the rat forebrain. 782 Jun 80

The phosphorylation of bovine tau, either by GSK-3 alone or by a combination of GSK-3 and several non-proline-dependent protein kinases (non-PDPKs), was studied. GSK-3 alone catalyzed the incorporation of approximately 3 mol 32P/mol tau at a relatively slow rate. Prephosphorylation of tau by A-kinase, C-kinase, or CK-2 (but not by CK-1, CaM kinase II or Gr kinase) increased both the rate and extent of a subsequent phosphorylation catalyzed by GSK-3 by several-fold. These results suggest that the phosphorylation of tau by PDPKs such as GSK-3 (and possibly MAP kinase, cdk5) may be positively modulated at the substrate level by non-PDPK-catalyzed phosphorylations.
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PMID:Modulation of GSK-3-catalyzed phosphorylation of microtubule-associated protein tau by non-proline-dependent protein kinases. 782 26

The active 30-kDa chymotryptic fragment of calmodulin-dependent protein kinase II (CaM kinase II), devoid of the autoinhibitory domain, and the enzyme, autothiophosphorylated at Thr286/Thr287, were much more labile than was the original native enzyme. They were markedly stabilized by synthetic peptides, designed after the sequence around the autophosphorylation site in the autoinhibitory domain, such as autocamtide-2 and CaMK-(281-309), but such marked stabilizations were not observed with the ordinary exogenous substrates, such as syntide-2. These results suggest that the autoinhibitory domain of CaM kinase II plays a crucial role in stabilizing the enzyme. A nonphosphorylatable analog of autocamtide-2, AIP, strongly inhibited the activity of the 30-kDa fragment. Kinetic analysis revealed that the inhibition by AIP was competitive with respect to autocamtide-2 and CaMK-(281-289) and noncompetitive with respect to syntide-2 and ATP/Mg2+, suggesting that CaM kinase II possesses at least two distinct substrate-binding sites; one for ordinary exogenous substrates such as syntide-2 and the other for an endogenous substrate, the autophosphorylation site (Thr286/Thr287) in the autoinhibitory domain. Fluorescence analysis of the binding of 7-nitrobenz-2-oxa-1,3-diazole-4-yl labeled AIP to the 30-kDa fragment also supported this contention. Thus, the autoinhibitory domain appears to play a crucial role in keeping the enzyme stable by binding to the substrate-binding site for the autophosphorylation site.
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PMID:Stabilization of calmodulin-dependent protein kinase II through the autoinhibitory domain. 783 45

We have demonstrated recently that in cardiac sarcoplasmic reticulum (SR), a membrane-associated Ca2+/calmodulin-dependent protein kinase (CaM kinase) phosphorylates and activates the Ca(2+)-pumping ATPase (Ca(2+)-ATPase) in addition to phosphorylating the previously characterized substrates, phospholamban, and Ca2+ release channel (ryanodine receptor) (Xu, A., Hawkins, C., and Narayanan, N. (1993) J. Biol. Chem. 268, 8394-8397). The present study shows that a CaM kinase regulatory system capable of modulating SR Ca2+ pump activity through direct phosphorylation of the Ca(2+)-ATPase is functional in slow twitch but not fast twitch skeletal muscle. Incubation of SR vesicles isolated from rabbit slow twitch (soleus) and fast twitch (adductor magnus) skeletal muscles in the presence of Ca2+ and calmodulin resulted in phosphorylation of the Ca(2+)-ATPase in slow twitch muscle SR but not in fast twitch muscle SR. Exogenous CaM kinase II, which stimulated phosphorylation of the cardiac and slow twitch muscle SR Ca(2+)-ATPase, failed to phosphorylate fast twitch muscle SR Ca(2+)-ATPase. These observations demonstrate that CaM kinase-catalyzed phosphorylation of the Ca2+ pump is isoform-specific since heart and slow twitch muscle express the same Ca(2+)-ATPase isoform (SERCA2a), which is distinct from that of fast twitch muscle (SERCA1). As in the case of cardiac SR Ca(2+)-ATPase, phosphorylation of the slow twitch muscle SR Ca(2+)-ATPase (occurring at a serine residue) resulted in a 2-fold increase in catalytic activity of the enzyme without alteration in its Ca2+ sensitivity. In addition, Ca2+/calmodulin-dependent prephosphorylation of slow twitch muscle SR resulted in a greater than 2-fold increase in its Ca2+ transport activity. In both cardiac and slow twitch muscle SR, phosphorylation of the Ca(2+)-ATPase by the endogenous CaM kinase occurred rapidly (maximum within 2 min at 37 degrees C), had similar pH optimum (8.5-9.0), temperature optimum (30 degrees C), and calmodulin concentration-dependence (k0.5 50-60 nM). cAMP-dependent protein kinase did not phosphorylate the Ca(2+)-ATPase appreciably in either cardiac or slow twitch muscle SR. These findings suggest a muscle-specific role for the membrane-associated CaM kinase in the modulation of Ca2+ uptake and release functions of the SR. In cardiac and slow twitch muscle, phosphorylation of the SR Ca(2+)-ATPase by CaM kinase might provide a novel mechanism for the modulation of the enzymatic and Ca2+ transport functions of this enzyme.
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PMID:Sarcoplasmic reticulum calcium pump in cardiac and slow twitch skeletal muscle but not fast twitch skeletal muscle undergoes phosphorylation by endogenous and exogenous Ca2+/calmodulin-dependent protein kinase. Characterization of optimal conditions for calcium pump phosphorylation. 798 62

Male Sprague-Dawley rats were administered a daily i.p. dose of 0.70 mmol/kg body weight of acrylamide, propionamide (a non-neurotoxic structural analog of acrylamide) or deionized water. Animals were sacrificed when signs of severe neurotoxicity were apparent. Neurofilaments (NFs) and endogenous kinase were isolated from the brain and spinal cord by axonal floatation. Increased in vitro Ca2+/calmodulin-dependent phosphorylation of endogenous and exogenous NF proteins and autophosphorylation of Ca2+/calmodulin protein kinase II (CaM kinase II, EC 2-7-1-37) were observed in samples from both brain and spinal cord of acrylamide-treated animals compared with controls. There was no significant difference between samples isolated from propionamide-treated animals and controls. Increased calmodulin binding to brain supernatant CaM kinase II was also observed as a result of acrylamide treatment. There was no significant difference observed in the amount of antibody binding to the alpha-subunit of brain supernatant CaM kinase II between treated or control animals. These results suggest that increased CaM kinase II-dependent phosphorylation of cytoskeletal proteins may be involved in the mechanisms of acrylamide-induced neurotoxicity.
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PMID:Acrylamide increases in vitro calcium and calmodulin-dependent kinase-mediated phosphorylation of rat brain and spinal cord neurofilament proteins. 799 94

The influence of the insulin secretagogues, glucose and K+, to activate the multifunctional, Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) in isolated rat pancreatic islets has been examined. Glucose (28 mM) and K+ (40 mM) were demonstrated to induce a 1.89 +/- 0.19- and 1.75 +/- 0.15-fold increase, respectively, in phosphorylation of a subunit of CaM kinase II immunoprecipitated by an anti-CaM kinase II alpha antibody. In intact islets, glucose and K+ also induced the generation of an autonomous, Ca2+/calmodulin-independent protein kinase II activity characteristic of autophosphorylated enzyme. Maximal activation, 2.9 +/- 0.2- and 3.0 +/- 0.5-fold for glucose and K+, respectively, relative to basal glucose control, was achieved at 2.5-5 min followed by a decline to near basal levels by 20 min. Glucose induced the production of autonomous CaM kinase II activity that, in terms of -fold stimulation, correlated closely with the extent of insulin release over a glucose concentration range of 3-28 mM. This stimulated activity was completely prevented by an inhibitor of glucose metabolism, mannoheptulose. These data demonstrate that the exposure of islets to stimulatory glucose concentrations activates CaM kinase II. The close correlation of enzyme activation with insulin secretion is consistent with the hypothesis that CaM kinase II plays an important role in the regulation of insulin secretion or related beta-cell processes.
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PMID:Glucose activates the multifunctional Ca2+/calmodulin-dependent protein kinase II in isolated rat pancreatic islets. 810 69

The isoquinolinesulfonamide derivative, KN-62, is a potent and specific inhibitor of Ca2+/calmodulin dependent protein kinase II (CaM kinase II) (Tokumitsu, H., Chijiwa, T., Hagiwara, M., Mizutani, A., Terasawa, M., and Hidaka, H.(1990) J. Biol. Chem. 265, 4315-4320). KN-62 inhibits growth of K562 cells, in a dose-dependent manner. Flow cytometric analysis demonstrates that the treatment of K562 cells with 10 microM KN-62 causes an accumulation of cells in S phase. Immunoblotting studies showed that specific antibodies against CaM kinase II recognized the 65 kDa of protein in K562 cells. This protein showed protein kinase activity as examined by the activity gel method. The inhibition of this enzyme activity by KN-62 was dose-dependent. The immunoprecipitates with the antibodies from K562 cells phosphorylates the synthetic peptide substrates, syntide-2. These results suggest that CaM kinase II plays an important role in the mechanisms for the cell growth in K562 cells.
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PMID:The effect of KN-62, Ca2+/calmodulin dependent protein kinase II inhibitor on cell cycle. 812 19

Two size forms of the class B N-type calcium channel alpha 1 subunit were recently identified with CNB1, an antipeptide antibody directed against an intracellular loop of this channel (Westenbroek, R.E., Hell, J.W., Warner, C., Dubel, S.J., Snutch, T.P., and Catterall, W.A. (1992) Neuron 9, 1099-1115). To investigate the biochemical differences between these two size forms, the antibodies CNB3 and CNB4 were raised against peptides with sequences corresponding to the COOH-terminal end of the full-length form. Immunoblot experiments demonstrated that both antibodies specifically recognize the longer form of 250 kDa, indicating that the COOH-terminal regions of the two size forms of the class B N-type channel alpha 1 subunit are different. Phosphorylation experiments with immunopurified calcium channels and different second messenger-activated protein kinases revealed that both the 220- and 250-kDa forms of the class B N-type calcium channel alpha 1 subunit are substrates for cAMP-dependent protein kinase, cGMP-dependent protein kinase, and protein kinase C. These three kinases incorporated approximately 1 mol of phosphate/mol of binding sites for omega-conotoxin (omega-CgTx) GVIA, a ligand specific for the N-type calcium channel, and may regulate the activity of both forms in vivo. In contrast, calcium- and calmodulin-dependent protein kinase II (CaM kinase II) phosphorylated only the long form of the class B N-type calcium channel alpha 1 subunit, with a stoichiometry of 0.5 mol of phosphate/mol of total omega-CgTx GVIA binding sites. Specific phosphorylation of the long form of the class B alpha 1 subunit by CaM kinase II may differentially regulate the function of N-type calcium channels containing different size forms of their alpha 1 subunits in vivo.
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PMID:Differential phosphorylation of two size forms of the N-type calcium channel alpha 1 subunit which have different COOH termini. 812 57

Purified dystrophin glycoprotein complex (DGC) contains an endogenous protein kinase activity which phosphorylates dystrophin. Mg2+ (or Mn2+) and ATP are required for this phosphorylation. Ca(2+)-calmodulin increases the rate of phosphorylation of dystrophin 12-fold relative to the EGTA control, while other protein kinase activators, cAMP and cGMP, have no effect. Phosphorylation of other proteins in the DGC preparation was observed, with a 59-kDa protein also being phosphorylated in a calmodulin-dependent manner. These phosphorylations were all on serine residues. The DGC protein kinase activity also phosphorylates syntide-2, a peptide substrate for CaM kinase II, and antibodies raised against CaM kinase II cross-react with DGC blotted onto nitrocellulose. Further, purified, baculovirus-expressed CaM kinase II phosphorylates dystrophin and also phosphorylates at least one of the peptides of dystrophin which is phosphorylated by the DGC protein kinase activity, as shown by tryptic peptide maps. CaM kinase II also phosphorylates other proteins present in the DGC preparation that are phosphorylated by the endogenous protein kinase. Finally, dystrophin sequence 2618-3074, produced by recombinant techniques, is phosphorylated by both the DGC protein kinase and purified CaM kinase II. Since dystrophin and two other DGC components have also been shown to bind calmodulin, two important components of signal transduction--calmodulin binding and protein phosphorylation--operate in the DGC.
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PMID:Calmodulin-activated phosphorylation of dystrophin. 818 Feb 8


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