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 cellular actions of nerve growth factor (NGF) and epidermal growth factor (EGF) may be mediated by changes in protein phosphorylation. The tyrosine phosphorylation of two predominant proteins of molecular mass 40 and 42 kDa is seen in PC-12 cells treated with NGF or EGF, correlating with activation of a previously identified serine/threonine protein kinase that phosphorylates microtubule-associated protein (MAP). Stimulation of phosphoprotein (pp) 40 and 42 phosphorylation and MAP kinase activity by NGF but not EGF is selectively attenuated by staurosporine and K-252A. Moreover, the time courses of pp40/42 phosphorylation and MAP kinase activation produced by NGF or EGF are identical. Chromatography of lysates from growth factor-treated cells on ion-exchange or hydrophobic-interaction HPLC resolves MAP kinase into two peaks, neither of which precisely coelutes with pp40 or pp42. One of these peaks (II) exhibits no detectable phosphotyrosine. The other peak (I) has some overlap with pp40. However, the activity residing in both peaks is almost completely inhibited after treatment with alkaline phosphatase, suggesting that, at least, serine/threonine phosphorylation is required for the activity of these enzymes. These data indicate that while tyrosine phosphorylation appears to be a critical early event in NGF action, the role of this modification in activation of MAP kinases remains unclear.
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PMID:Nerve growth factor stimulates protein tyrosine phosphorylation in PC-12 pheochromocytoma cells. 184 70

Poly[15(IPGVG),(RGYSLG)], where RGYSLG is a protein kinase site, was synthesized. On raising the temperature of a 5 mg/ml solution, this polypeptide undergoes an inverse temperature transition at 18 degrees C in which it folds into a contracted state by optimizing intramolecular hydrophobic interactions. Averaging the data of five experiments, phosphorylation by means of a 3':5' cyclic AMP dependent protein kinase to the extent of one phosphate in 360 residues raises the temperature of the folding transition to 32 degrees C. The shift is completely reversed on dephosphorylation by alkaline phosphatase. Phosphorylation is hereby shown to be the most potent chemical perturbation known for shifting the temperature of an inverse temperature transition, which has been shown to be an efficient mechanism for achieving chemomechanical transduction (mechanochemical coupling).
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PMID:Phosphorylation and dephosphorylation modulation of an inverse temperature transition. 185 15

The activity of the eukaryotic elongation factor 2 (eEF-2)-specific Ca(2+)- and calmodulin-dependent protein kinase III (CaM PK III) is regulated by phosphorylation. The kinase can be inactivated by treatment with alkaline phosphatase and subsequently reactivated by endogenous protein kinase. This kinase can be substituted for by the catalytic subunit of cAMP-dependent protein kinase but not by casein kinase II. The purified kinase preparation contains only one protein as judged by gel electrophoresis. This protein has a molecular mass of approximately 90 kDa and an isoelectric point of 5.2. Reactivation of the eEF-2 kinase is associated with the phosphorylation of this protein. The amino acid sequence obtained from the 90-kDa protein reveals substantial homology with that of murine heat shock protein 86 (HSP 86) a member of the HSP 90-family. Conventional preparations of HSP 90 contain an inactive eEF-2 kinase that could be activated after dephosphorylation and phosphorylation by the catalytic subunit of cAMP-dependent protein kinase.
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PMID:Phosphorylation regulates the activity of the eEF-2-specific Ca(2+)- and calmodulin-dependent protein kinase III. 188 75

Protein kinase C from human brain was isolated and characterized. A protein kinase M like kinase of molecular weight 63 kDa was also partially purified and identified by its immunological properties similar to those of kinase C. The kinase M like kinase activity, devoid of Ca2+ and phospholipids dependency, was also characterized by its inhibition profile by several ligands. Since this kinase phosphorylates a G protein (M.W. 36 kDa) and decreases its GTPase activity which could be restored by alkaline phosphatase, it is concluded that this kinase M like kinase could interact with G protein mediated events of neuronal responses.
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PMID:Isolation of human brain protein kinase C: evidence for kinase C catalytic fragment modulating G protein-GTPase activity. 189 69

The influence of phosphorylation on the binding of microtubule-associated protein 2 (MAP2) to cellular microtubules was studied by microinjecting MAP2 in various phosphorylation states into rat-1 fibroblasts, which lack endogenous MAP2. Conventionally prepared brain MAP2, containing 10 mol of endogenous phosphate per mol (MAP2-P10), was completely bound to cellular microtubules within 2-3 min after injection. MAP2 prepared in the presence of phosphatase inhibitors, containing 25 mol/mol of phosphate (MAP2-P25), also bound completely. However, MAP2 whose phosphate content had been reduced to 2 mol phosphate per mol by treatment with alkaline phosphatase in vitro (MAP2-P2) did not initially bind to microtubules, suggesting that phosphorylation of certain sites in MAP2 is essential for binding to microtubules. MAP2-P10 was further phosphorylated in vitro via an endogenously bound protein kinase activity, adding 12 more phosphates, giving a total of 22 mol/mol. This preparation (MAP2-P10+12) also did not bind to microtubules. Assay of the binding of these preparations to taxol-stabilized tubulin polymers in vitro confirmed that their binding to tubulin depended on the state of phosphorylation, but the results obtained in microinjection experiments differed in some cases from in vitro binding. The results suggest that the site of phosphate incorporation rather than the amount is the critical factor in determining microtubule binding activity of MAP2. Furthermore, the interaction of MAP2 with cellular microtubules may be influenced by additional factors that are not evident in vitro.
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PMID:Phosphorylation determines the binding of microtubule-associated protein 2 (MAP2) to microtubules in living cells. 190 76

Insulin resistance, which may precede the development of non-insulin-dependent diabetes mellitus in Pima Indians, appears to result from a postreceptor defect in signal transduction in skeletal muscle. To identify the putative postreceptor lesion responsible for insulin resistance in Pima Indians, we investigated the influence of insulin on the activity of casein kinase II (CKII) in skeletal muscle of seven insulin-sensitive, four insulin-resistant, nondiabetic, and five insulin-resistant diabetic Pima Indians during a 2 h hyperinsulinemic, euglycemic clamp. In sensitive subjects, CKII was transiently activated reaching a maximum over basal activity (42%) at 45 min before declining. CKII was also stimulated in resistant (19%) and diabetic (34%) subjects. Basal CKII activity in resistant subjects was 40% higher than in either sensitive or diabetic subjects, although the concentration of CKII protein, as determined by Western blotting, was equal among the three groups. Basal CKII activity was correlated with fasting plasma insulin concentrations, suggesting that the higher activity in resistant subjects resulted from insulin action. Extracts of muscle obtained from all three groups either before or after insulin administration were treated with immobilized alkaline phosphatase, which reduced and equalized CKII activity. These results suggest that insulin stimulates CKII activity in human skeletal muscle by a mechanism involving phosphorylation of either CKII or of an effector molecule, and support the idea that elevated basal activity in resistant subjects results from insulin action. It appears that the ability of insulin to activate CKII in skeletal muscle is not impaired in insulin-resistant Pima Indians, and that the biochemical lesion responsible for insulin resistance occurs either downstream from CKII or in a different pathway of insulin action.
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PMID:Activation of skeletal muscle casein kinase II by insulin is not diminished in subjects with insulin resistance. 199 82

We have previously described the purification of a myelin basis protein (MBP) kinase from maturing sea star oocytes (Sanghera, J. S., Paddon, H. B., Bader, S. A., and Pelech, S. L. (1990) J. Biol. Chem. 265, 52-57). The ability of the purified 44-kDa protein to bind azido-ATP and undergo autophosphorylation on the serine residue implied that it is a protein kinase. Furthermore, partial amino acid sequence data has revealed that it is a novel protein kinase, which we have provisionally designated p44mpk. Autophosphorylation of p44mpk to 0.7 mol of phosphate/mol of enzyme was correlated with a modest (approximately 17%) increase in the MBP-phosphorylating activity of the kinase. Rabbit polyclonal antibody raised against purified p44mpk recognized on immunoblots the protein in highly purified preparations as well as crude oocyte extracts. The affinity-purified anti-p44mpk antibody could immunoprecipitate active kinase, but a subpopulation of the antibody also appeared to be inhibitory. Using this antibody, we have demonstrated that the up to 12-fold stimulation of the cytosolic MBP-phosphorylating activity of this kinase that occurs during sea star oocyte maturation is not due to an increase in the amount of enzyme protein, either from a redistribution within the oocyte or protein synthesis. A slight retardation of the migration of the activated p44mpk on sodium dodecyl sulfate-polyacrylamide gels and its tighter interaction with a MonoQ column is consistent with phosphorylation of the kinase during maturation. p44mpk underwent enhanced phosphorylation when oocytes prelabeled with [32P]orthophosphate were induced to mature with 1-methyladenine. The stimulated MBP-phosphorylating activity of p44mpk in cytosols from maturing oocytes was partly stabilized by the presence of the phosphatase inhibitor beta-glycerol phosphate. Furthermore, treatment of purified p44mpk with protein phosphatase 2A and alkaline phosphatase resulted in 56 and 86% decreases, respectively, in the activity of the kinase. Together, these findings strongly implicate a role for phosphorylation of p44mpk in its activation during sea star oocyte maturation.
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PMID:Role of protein phosphorylation in the maturation-induced activation of a myelin basic protein kinase from sea star oocytes. 201 85

The Mr = 38,300 polypeptide of the purified recombinant rat DNA polymerase beta served as an excellent substrate for protein kinase C (PKC) in vitro but not for the catalytic subunit of cAMP-dependent protein kinase. The phosphorylation by PKC resulted in inactivation of DNA polymerase beta activity, and recovery was achieved by dephosphorylation with alkaline phosphatase. Since the phosphorylated DNA polymerase beta was retained with use of a single-stranded DNA-cellulose column, inactivation might occur at a site different from that for the DNA binding. Amino acid sequence analysis of the phosphopeptides revealed that the phosphorylated sites were 2 serine residues at positions 44 and 55 from the NH2 terminus, either or both of which might be involved in the catalytic activity of DNA polymerase beta. Thus, the inactivation of the DNA repair enzyme, DNA polymerase beta, by PKC may be an important process in the modification of DNA metabolism in the nucleus through signal transduction processes.
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PMID:Inactivation of DNA polymerase beta by in vitro phosphorylation with protein kinase C. 204 Jun 2

As a first step in understanding the function of the 68-kDa Alz-50 antigen (A68) in the pathophysiology of Alzheimer's disease (AD), we have reexamined preliminary observations in our laboratory (Wolozin and Davies, 1986) of a protein kinase activity associated with crude preparations of the protein. This study was undertaken to determine whether the kinase activity is an inherent property of the Alz-50 antigen, or is a property of an associated protein. Phosphorylation was therefore examined by incubating A68-enriched preparations with radiolabelled ATP. This resulted in the appearance of a labelled 68-kDa phosphoprotein, comigrating with the Alz-50 reactive A68 protein. The labelling of this 68-kDa protein occurred in the presence of 2% SDS, suggesting that it is more likely to represent an autophosphorylation than a transfer of phosphate mediated by another kinase. Upon further inspection, it was found that the autophosphorylated 68-kDa protein was not localized to regions of AD brain where A68 was detectable, but displayed a more ubiquitous distribution. In addition, this phosphoprotein was also observed to be present in similar preparations from normal brain, which lacked the Alz-50 antigen (Wolozin et al, 1986). These findings indicate that the auto-kinase activity at 68 kDa is not closely associated with the A68 protein, but with a comigrating contaminant in the preparation. Other experiments in this study indicate that A68 is not a substrate for in vitro phosphorylation. Following incubation of A68 preparations with radiolabelled ATP, immunoprecipitation of the antigen did not reveal any phosphate transfer to the protein. These results were unaffected by a prior incubation with alkaline phosphatase, even when the subsequent phosphorylation reactions were conducted in the presence of protein kinase activators. Incubation with alkaline phosphatase did not produce any alterations in electrophoretic mobility of A68, nor did it affect the binding of antibodies directed against phosphatase-sensitive epitopes with A68. Thus, despite the suggestion that A68 is a modified form of tau, the antigen exhibits remarkable differences from tau with regard to its sensitivity to kinases and to alkaline phosphatase.
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PMID:Phosphorylation characteristics of the A68 protein in Alzheimer's disease. 212 70

Studies involving 32P labeling and wet ashing of isolated dynein reveal that isolated dynein contains approximately 6 mol of phosphate predominantly distributed over four polypeptides of molecular masses of 78, 76, 47, and 23 kDa. Dynein must, therefore, be phosphorylated to at least this extent in vivo. The catalytic subunit of cAMP-dependent protein kinase and an axonemal cAMP-dependent protein kinase contaminating the dynein preparation can further phosphorylate dynein in vitro. Each kinase can place up to 0.5 mol of phosphate on native dynein polypeptides of molecular masses of 78 and 34 kDa. Removal of two of the phosphates on isolated dynein by either acid or alkaline phosphatase results in a 28% decrease in the specific activity of dynein in the presence or absence of microtubules. Selective attenuation of the microtubule-activated ATPase, but not the uncoupled free dynein ATPase, would be indicative of a regulatory function of the phosphates. The in vivo regulation of the dynein ATPase by the two phosphates accessible to acid or alkaline phosphatase is therefore subject to question. Other phosphates on dynein must be examined for their effect on the microtubule-dynein cross-bridge cycle and motility before phosphorylation can definitively be established as a mode of dynein regulation.
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PMID:Phosphorylation of Tetrahymena 22 S dynein. 214 71


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