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)

All proteins of this world are constructed in compliance with the same rule. Accordingly, two totally unrelated proteins, on the average, share 30 identical tripeptides, two tetrapeptides, and one pentapeptide per 500 residues. With this in mind, the 221-residue-long influenza virus hemagglutinin II (IVHA-II), as a representative of alien antigens, was compared with three diverse proteins representing the host: 533-residue-long chicken c-src protein kinase (c-src product of the cellular oncogene of Rous sarcoma virus), 595-residue-long human estrogen receptor, and 585-residue-long human serum albumin. Forty-three tripeptides, two tetrapeptides, and one pentapeptide of IVHA-II were also found in one or the other of the three host proteins. Six regions of IVHA-II (9-22 residues long) in which oligopeptides were clustered that were identical to their host oligopeptides were defined as "host-homologous" regions, and the remaining regions were called "nonself" or "pathogen-specific" regions. Because the total number of host proteins is vastly more than three, host-homologous regions were no doubt underestimated, while only one or two regions of IVHA-II must remain as truly pathogen-specific. Nevertheless, oligopeptide analysis of two known T-cell response-eliciting peptide fragments and one known inert peptide fragment of a virus and a malarial protozoan readily revealed the latter to be a host-homologous region. Of the two known T-cell response-eliciting peptide fragments, one was more nonself than the other. Not surprisingly, the more nonself fragment elicited helper T-cell response from individuals of diverse major histocompatibility complex haplotypes, whereas the less nonself fragment elicited cytotoxic T-cell response only from HLA-A2 human individuals.
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PMID:Many peptide fragments of alien antigens are homologous with host proteins, thus canalizing T-cell responses. 170 30

Partially permeabilized rat adipocytes with a high responsiveness to insulin were prepared by electroporation and used to study the effect of 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) on insulin actions in adipocytes. H-7 is a well-documented inhibitor of several protein kinases, including protein kinase C; however, it does not rapidly enter adipocytes protected with the intact plasma membrane. The cells were suspended in Buffer X [4.74 mM NaCl, 118.0 mM KCl, 0.38 mM CaCl2, 1.00 mM EGTA, 1.19 mM Mg2SO4, 1.19 mM KH2PO4, 25.0 mM Hepes/K, 20 mg/ml bovine serum albumin, and 3 mM pyruvate/Na, pH 7.4] and electroporated six times with a Gene-Pulser (from Bio-Rad) set at 25 microF and 2 kV/cm. In cells electroporated as above, insulin stimulated (a) membrane-bound, cAMP phosphodiesterase approximately 2.6-fold when the hormone concentration was 10 nM and (b) glucose transport activity approximately 4.5-fold when the hormone concentration was raised to 100 nM. H-7 strongly inhibited the actions of insulin on both glucose transport (apparent Ki = 0.3 mM) and cAMP phosphodiesterase (apparent Ki = 1.2 mM) in electroporated adipocytes. H-7 also inhibited lipolysis in adipocytes; the apparent Ki value for the reaction in intact cells was 0.45 mM, and that in electroporated cells was 0.075 mM. It is suggested that a certain protein kinase or kinases that are significantly sensitive to H-7 may be involved in the insulin-dependent stimulation of glucose transport and that of phosphodiesterase. However, protein kinase C (or Ca2+/phospholipid-dependent protein kinase) may not be involved, at least, in the hormonal action on phosphodiesterase since the apparent Ki value of H-7 for the reaction is too high.
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PMID:Evidence that protein kinase C may not be involved in the insulin action on cAMP phosphodiesterase: studies with electroporated rat adipocytes that were highly responsive to insulin. 184 37

CKS-17, an immunosuppressive peptide homologous to certain retroviral transmembrane envelope protein, has been shown to inhibit lymphocyte proliferation in response to mitogens or alloantigens when covalently attached to bovine serum albumin (CKS-17-BSA). To define its site of action, we determined if CKS-17 conjugated to human serum albumin (CKS-17-HSA) could block the direct activation of lymphocytes by phorbol-12-myristate-13-acetate (PMA) or by a synthetic diacylglycerol, dioctanoylglycerol (DiC8). CKS-17-HSA inhibited lymphocyte proliferation in response to PMA and ionomycin in a dose-dependent manner with up to 88% inhibition occurring with 15 microM CKS-17-HSA. The conjugated peptide also inhibited the proliferation of lymphocytes in response to DiC8 and ionomycin by up to 57% at 15 microM CKS-17-HSA. Based on these findings we investigated the effect of CKS-17-HSA on the activity of protein kinase C (PKC), an enzyme directly activated by PMA and DiC8. PKC was isolated chromatographically from the cytosol of human neutrophils or the human lymphoblastoid cell line Jurkat. CKS-17-HSA caused a dose-dependent enzyme inhibition with a concentration giving half-maximal inhibition (IC50) of ca.3 microM and greater than 95% inhibition at 15 microM CKS-17-HSA. Inhibition of PKC by the conjugated peptide was not reversed by increasing concentrations of Ca2+, Mg2+, phosphatidylserine, diolein, or adenosine triphosphate (ATP), indicating that the conjugated peptide did not function as a chelator or competitive inhibitor. In contrast to its effects on PKC, CKS-17-HSA did not inhibit the activity of adenosine 3':5'-cyclic monophosphate (cyclic AMP)-dependent protein kinase (PK-A) nor the calcium and phospholipid-independent form of PKC (PK-M). Moreover the peptide inhibited in vivo PKC activity in cytosol of intact cells and in membrane of PMA-stimulated cells. These results suggest that the inhibition of lymphocyte proliferation by CKS-17-HSA may be due to the direct inactivation of PKC.
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PMID:A synthetic peptide homologous to retroviral transmembrane envelope proteins depresses protein kinase C mediated lymphocyte proliferation and directly inactivated protein kinase C: a potential mechanism for immunosuppression. 192 61

An inhibitor of protein kinases, staurosporine (ssp), was found to affect the endocytic pathway of asialoglycoproteins subsequent to endocytosis in monolayer cultures of rat hepatocytes. The effect of 5 or 10 microM staurosporine on the internalization of a synthetic ligand (galBSA-HRP: bovine serum albumin exposing galactose, horseradish peroxidase conjugates) prebound to the cell surface was minimal. The presence of 5, 7, or 10 microM ssp during a 1-h chase period resulted in the ligand remaining in a low density (1.04-1.05 g/ml), nonlysosomal subcellular fraction in a Percoll gradient. The ligand, arrested by 7 microM ssp, was further processed to the lysosome during subsequent incubation in the absence of ssp. Cells maintained the ability to internalize ligand at 37 degrees C for 1 h in the presence of these concentrations of ssp. During a 1-h continuous uptake of 0-50 micrograms/ml nonlabeled ligand, the presence of 7 microM ssp did not cause any decrease in the amount of asialoglycoprotein receptor at the cell surface, which indicates receptor recycling occurred normally. These results suggest a possible involvement of protein kinase(s), which can be inhibited by ssp, in the delivery of endocytosed ligand to the lysosome, but not in ligand endocytosis and receptor recycling.
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PMID:An inhibitory effect of a protein kinase inhibitor, staurosporine, on delivery of endocytosed asialoglycoprotein to lysosome in monolayer culture of rat hepatocytes. 195 54

Treatment of PC12 cells with nerve growth factor (NGF) resulted in the rapid, but transient, activation of a protein kinase which specifically phosphorylated an endogenous 250-kDa cytoskeletal protein (pp250). We report that the microtubule-associated protein, MAP2, is an alternative substrate for the NGF-activated kinase. NGF treatment maximally activated the kinase within 5 min; however, the activity declined with longer exposure to NGF. The enzyme was localized predominantly in microsomal and soluble fractions and phosphorylated MAP2 on serine and threonine residues. The soluble enzyme was fractionated by DEAE chromatography and gel filtration and had an apparent Mr of 45,000. The enzyme was purified to near homogeneity by chromatofocussing and had a pI of 4.9. Kinetic analysis revealed that NGF treatment caused a sevenfold increase in Vmax for MAP2. The Km with respect to the MAP2 substrate was approximately 50 nM and was not altered by NGF treatment. A novel feature of the NGF-stimulated enzyme was its sharp dependence on Mn2+ concentration. The active enzyme is likely to be phosphorylated, because inclusion of phosphatase inhibitors was required for recovery of optimal activity and the activity was lost on treatment of the enzyme with alkaline phosphatase. Histones, tubulin, casein, bovine serum albumin, and the ribosomal subunit protein S-6 were not phosphorylated by this enzyme. The NGF-stimulated kinase was distinct from A kinase, C kinase, or other NGF-stimulated kinases. The rapid and transient activation of the protein kinase upon NGF treatment suggests that the enzyme may play a role in signal transduction in PC12 cells.
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PMID:Characterization of a nerve growth factor-stimulated protein kinase in PC12 cells which phosphorylates microtubule-associated protein 2 and pp250. 216 72

A DNA-activated protein kinase (DNA-PK) was purified from nuclei of HeLa cells. Activity was associated with a single high-molecular-mass (approximately-300,000 Da) polypeptide when analyzed by gel filtration, denaturing polyacrylamide gel electrophoresis, and Western immunoblotting using a monoclonal antibody that also inhibits enzyme activity. Nuclear localization was indicated by subcellular fractionation and confirmed by immunofluorescence on whole cells. Double-stranded DNA stimulated phosphorylation of the 300-kDa polypeptide in purified preparations as well as phosphorylation of the exogenous substrates alpha-casein, simian virus 40 large T antigen, and the human heat shock protein hsp90. Autophosphorylation led to inactivation of the enzyme. The phosphorylation of casein was stimulated over 30-fold by DNA and was specific for serine and threonine residues. Bovine serum albumin and histone H1 were poor substrates for DNA-PK, and no phosphorylation of immunoglobulin G or histones other than H1 was observed. Supercoiled or heat-denatured DNA and synthetic double-stranded RNA or RNA-DNA copolymers did not stimulate casein phosphorylation by DNA-PK. Interaction of the enzyme with DNA in the absence of exogenous substrates was demonstrated by thermal inactivation and gel mobility shifts. These characteristics identify DNA-PK as distinct from other protein kinases described in the literature and suggest that activation by DNA is an important feature of the enzyme's in vivo function.
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PMID:A DNA-activated protein kinase from HeLa cell nuclei. 224 66

ADvF11 cells are a CHO adhesion variant which, unlike wild type (WT) cells, are not able to adhere to fibronectin (Fn) coated substrata or to be aggregated by Fn-beads. However, ADvF11 cells bind Fn-beads to the same extent as WT cells, thus suggesting that the defect(s) associated with ADvF11 cells are distal to the initial receptor-ligand binding event (Cheung and Juliano, Exp. Cell Res. 152:127, 1984). In this communication we report that cAMP analogs such as dibutyryl-cAMP (dbcAMP) and 8-bromo-cAMP are able to correct defect(s) associated with ADvF11 cells enabling them to adhere to Fn-coated dishes and to aggregate in the presence of Fn-beads. However, only approximately 40% of ADvF11 cells were found to be responsive to dbcAMP suggesting heterogeneity in the cell population with respect to dbcAMP sensitivity. Further analysis of this partial response led us to isolate a subclone of ADvF11 cells, F11CA11, which is highly responsive to dbcAMP treatment. Induction of Fn-mediated cell adhesion and aggregation in F11CA11 by dbcAMP is both time and dose dependent. Optimal responses were obtained after overnight incubation in alpha-MEM containing, 1% fetal calf serum, 4% bovine serum albumin, 0.5 mM dbcAMP and 0.2 mM methyl-isobutyl-xanthine (MIX), a phosphodiesterase inhibitor. Under these conditions, 70-80% of F11CA11 cells were found to be adherent, compared to 5-7% of untreated F11CA11 cells and 95-100% of WT cells. Aggregation of dbcAMP-MIX treated F11CA11 cells induced by Fn-beads also approached that of WT cells. In addition, treatment with dbcAMP-MIX markedly increased the ability of F11CA11 cells to internalize Fn-beads. The maintenance of the adherent phenotype required the constant presence of dbcAMP-MIX. Removal of dbcAMP-MIX from the incubation medium resulted in return to the original nonadhesive phenotype. Thus, elevation of cAMP levels can dramatically modify the behavior of F11CA11 cells with respect to fibronectin mediated adhesion, aggregation and endocytosis, in effect causing a phenotypic reversion of all three parameters to wild type status. This suggests that the mechanisms for adhesion, aggregation and endocytosis may each involve regulation by cyclic AMP-protein kinase systems.
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PMID:cAMP-induced phenotypic reversion of adhesion, aggregation, and endocytosis in adhesion-defective CHO cell variants. 241 52

A protamine kinase has been purified to apparent homogeneity from extracts of the cytosol of bovine kidney cortex. This protamine kinase exhibited an apparent Mr = 43,000 as estimated by gel permeation chromatography on Sephacryl S-200 and an apparent Mr = 45,000 as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The purified protamine kinase exhibited about 5% activity with casein, 8% with histone H2B, and less than 0.1% with histone H1, histone H4, glycogen synthase a from rabbit skeletal muscle, ovalbumin, bovine serum albumin, and phosvitin. The activity of the highly purified protamine kinase was unaffected by cyclic AMP (up to 0.1 mM), cyclic GMP (up to 0.1 mM), the heat-stable protein inhibitor of cyclic AMP-dependent protein kinase (up to 100 micrograms/ml), heparin (up to 100 micrograms/ml), EGTA (up to 1 mM), Ca2+ (up to 1 mM), calmodulin (up to 0.5 microM) in the absence or presence of Ca2+ (0.05 mM), and phosphatidylserine (up to 40 micrograms/ml) and/or diolein (up to 1 microgram/ml) in the absence or presence of Ca2+ (up to 0.5 mM). Experiments in which extracts of kidney cytosol were incubated with [gamma-32P]ATP and MgCl2 revealed that the phosphorylation of numerous polypeptides was markedly increased in the presence of the purified protamine kinase. The results indicate that this protamine kinase of kidney cytosol is a novel protein kinase.
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PMID:Purification and properties of a distinct protamine kinase from the cytosol of bovine kidney cortex. 253 82

The intracellular concentrations of cyclic AMP, polyphosphoinosides and free Ca2+ were unaffected during receptor-mediated endocytosis of the neoglycoprotein beta-D-galactosyl-bovine serum albumin (D-Gal-BSA) by isolated hepatocytes. Elevation of either intracellular cyclic AMP by glucagon or inositol phosphates and Ca2+ by vasopressin were without effect on the binding and internalization of D-Gal-BSA. The normal response of this cell to glucagon- and vasopressin-mediated mobilization of these second messengers was not modified in the presence of saturating concentrations of D-Gal-BSA. Receptor-mediated endocytosis of diferric transferrin (Fe3+-TRF) by both hepatocytes and HL60 cells was also shown to be independent of second messengers, although the unequivocal expression of the transferrin receptor by hepatocytes could not be satisfactorily demonstrated. The results of the present study are at variance with a suggested regulatory role for second messengers in receptor-mediated endocytosis of serum-derived ligands such as asialoglycoproteins and Fe3+-TRF. Receptor phosphorylation by protein kinase C in particular has been proposed to regulate the distribution and recycling of these receptors in actively endocytosing cells. We would suggest that if receptor phosphorylation has a regulatory role during endocytosis, it is likely to be mediated by a second-messenger-independent protein kinase analogous to casein kinase II. An alternative interpretation is that phosphorylation has no physiological significance and receptor-mediated endocytosis is a constitutive event coupled to membrane turnover.
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PMID:Receptor-mediated endocytosis of asialoglycoproteins and diferric transferrin is independent of second messengers. 254 88

Inhibitor-1 is a potent and specific inhibitor of protein phosphatase 1. Phosphorylation by cAMP-dependent protein kinase is required for expression of its inhibitor activity. In the present study, we have used immobilized inhibitor-1 preparations to study the mechanism underlying protein phosphatase 1 inhibition. Protein phosphatase 1 bound to phosphorylated inhibitor-1 covalently coupled to Sepharose or Affi-Gel beads but did not bind to immobilized preparations of dephosphorylated inhibitor-1 or bovine serum albumin. Phosphorylated inhibitor-1 coupled to Sepharose or Affi-Gel beads retained its ability to inhibit protein phosphatase 1, although the apparent IC50 was decreased about 500-fold. The extent of protein phosphatase 1 binding to immobilized phosphorylated inhibitor-1 was comparable to the degree of protein phosphatase inhibition when the inhibitor protein was present at a concentration near the IC50. The efficiency of protein phosphatase 1 binding to immobilized phosphorylated inhibitor-1 was dependent on the inhibitor concentration on the matrix. Taken together these data indicate that the inhibition of protein phosphatase 1 by phosphorylated inhibitor-1 is a consequence of the binding of the inhibitor protein to one or more sites on protein phosphatase 1.
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PMID:Immobilized inhibitor-1 binds and inhibits protein phosphatase 1. 254 51


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