Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.26 (GSK)
 6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A form of glycogen synthase kinase designated GSK-M3 was purified 4000-fold from rat skeletal muscle by phosphocellulose, Affi-Gel blue, Sephacryl S-300 and carboxymethyl-Sephadex column chromatography. Separation of GSK-M from the catalytic subunit of the cAMP-dependent protein kinase was facilitated by converting the catalytic subunit to the holoenzyme form by addition of the regulatory subunit prior to the gel filtration step. GSK-M had an apparent Mr 62,000 (based on gel filtration), an apparent Km of 11 microM for ATP, and an apparent Km of 4 microM for rat skeletal muscle glycogen synthase. The kinase had very little activity with 0.2 mM GTP as the phosphate donor. Kinase activity was not affected by the addition of cyclic nucleotides, EGTA, heparin, glucose 6-P, glycogen, or the heat-stable inhibitor of cAMP-dependent protein kinase. Phosphorylation of glycogen synthase from rat skeletal muscle by GSK-M reduced the activity ratio (activity in the absence of Glc-6-P/activity in the presence of Glc-6-P X 100) from 90 to 25% when approximately 1.2 mol of phosphate was incorporated per mole of glycogen synthase subunit. Phosphopeptide maps of glycogen synthase obtained after digestion with CNBr or trypsin showed that this kinase phosphorylated glycogen synthase in serine residues found in the peptides containing the sites known as site 2, which is located in the N-terminal CNBr peptide, and site 3, which is located in the C-terminal CNBr peptide of glycogen synthase. In addition to phosphorylating glycogen synthase, GSK-M phosphorylated inhibitor 2 and activated ATP-Mg-dependent protein phosphatase. Activation of the protein phosphatase by GSK-M was dependent on ATP and was virtually absent when ATP was replaced with GTP. GSK-M had minimal activity toward phosphorylase b, casein, phosvitin, and mixed histones. These data indicate that GSK-M, a major form of glycogen synthase kinase from rat skeletal muscle, differs from the known glycogen synthase kinases isolated from rabbit skeletal muscle.
 ...
PMID:Characterization of GSK-M, a glycogen synthase kinase from rat skeletal muscle. 282 16

The ATP.Mg-dependent protein phosphatase activating factor (FA) has been identified as a microtubule protein kinase and as a microtubule protein phosphatase activator. FA could phosphorylate microtubule-associated tau protein up to 4 moles of phosphates per mole of protein. However, more than 80% of the phosphates in 32P-tau phosphorylated by FA could be removed by ATP.Mg-dependent protein phosphatase and the tau phosphatase activity was FA-dependent. Functional study further revealed that as a tau kinase, FA could phosphorylate tau and thereby inhibits cross-linking copolymerization of tau with tubulin and actin filaments whereas as a tau phosphatase activating factor, FA could promote copolymerization of tau with tubulin and actin filaments. Taken together, the results provide evidence that a cyclic modulation of cytoskeleton assembly-disassembly can be controlled by FA, representing an efficient cyclic cascade mechanism for rapid structural and functional regulation of cytoskeletal system in the central nervous system.
 ...
PMID:Cyclic modulation of cytoskeleton assembly-disassembly by the ATP.Mg-dependent protein phosphatase activator (kinase FA). 839 3

The microtubule-associated protein tau, in a hyperphosphorylated form, aggregates into insoluble paired-helical filaments (PHFs) in Alzheimer's disease (AD) and other tauopathies. In AD, there is approximately 8 mol of phosphate per mole of tau distributed among approximately 30 PHF phosphorylation sites as compared to 2-3 mol of phosphate per mole in normal brain. In AD, kinases such as glycogen synthase kinase-3beta (GSK-3beta) are believed to be involved in the generation of hyperphosphorylated tau. However, the functional consequences of hyperphosphorylation on the microtubule binding and polymerization of tau are not well understood. To address this question, we have generated pseudohyperphosphorylation mutants consisting of six and seven sites in the proline-rich region and carboxy terminus of tau by amino acid substitution. In addition, several single, double, and triple pseudophosphorylation mutants were also generated. Pseudophosphorylation of tau decreases its affinity for microtubules, and pseudohyperphosphorylated forms of tau do not have significantly decreased levels of microtubule binding as compared to single and double sites. Three pseudohyperphosphorylated forms of tau with altered sodium dodecyl sulfate-polyacrylamide gel electrophoresis migration have a greater effect on its inducer-mediated polymerization, slowing the rate of nucleation and elongation. On the basis of the observations that pseudohyperphosphorylated tau has decreased affinity for microtubules and reduced inducer-initiated rates of nucleation and polymerization, we propose that this combination could be the cause of the increased cytotoxicity of hyperphosphorylated tau in Alzheimer's disease and also explain the potentially beneficial role of tau polymerization and NFT formation.
 ...
PMID:Pseudohyperphosphorylation causing AD-like changes in tau has significant effects on its polymerization. 1945 90