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)

In Th1 clones, TCR occupancy together with a costimulatory signal from APC results in IL-2 production. TCR occupancy alone results in unresponsiveness (anergy) to antigenic stimulation, a phenomenon that may be important for self-tolerance in vivo. Inasmuch as inositol phosphate production occurs during the induction of anergy other biochemical signals must be necessary for IL-2 production. Here we assess the role of tyrosine-specific protein kinases using the specific inhibitor, genistein. IL-2 secretion and responsiveness were very dependent on tyrosine-specific protein kinase activation and could be completely blocked under conditions where inositol phosphate generation occurred normally. Although anergy induction could also be blocked by inhibition of tyrosine-specific protein kinase activation this probably occurred indirectly via inhibition of inositol phospholipid hydrolysis. The differential susceptibility of IL-2 secretion and anergy induction to inhibition by genistein indicates that positive and negative outcomes of TCR occupancy may be mediated by distinct biochemical pathways.
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PMID:IL-2 secretion and T cell clonal anergy are induced by distinct biochemical pathways. 184 93

In Dictyostelium, cAMP functions as an extracellular regulatory molecule that controls aggregation, expression of a number of classes of genes, and cellular differentiation by binding to cell-surface receptors that activate intracellular signal transduction pathways. To investigate possible roles for intracellular cAMP, we have overexpressed the wild-type mouse type-I regulatory subunit (RI) of cAMP-dependent protein C (PKA) in Dictyostelium cells, as well as mutant forms of the subunit that are altered in their ability to bind cAMP. We show that overexpression of a mutated RI, which lacks both cAMP-binding sites and presumably forms a complex with the endogenous Dictyostelium catalytic subunit that cannot be activated by cAMP, results in cells that do not aggregate or express sets of genes that are normally induced in the multicellular stages. Transformations that express the mutant subunit at low levels show no observable phenotype. We show that these cells can respond to pulses of cAMP and activate cAMP receptor/G protein-mediated processes, including the activation of adenylate and guanylate cyclases and the induction of a class of genes known to be regulated through the receptor-mediated pathways; however, the cells do show an altered pattern of expression of other genes normally active during the preaggregation/interphase and aggregation stages. Of interest is a substantial overexpression of the developmentally regulated PDE mRNA. Cell lines carrying constructs encoding the wild-type subunit or mutant subunits lacking one of the two binding sites show no visual phenotype. The results suggest that PKA-mediated functions, presumably controlled by increases in intracellular cAMP, are essential for Dictyostelium aggregation.
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PMID:A role for cAMP-dependent protein kinase A in early Dictyostelium development. 196 13

Increased in vitro phosphorylation of the 47 kdalton, 4.5 pI protein F1 was observed in dorsal hippocampal tissue from animals exhibiting long term enhancement (LTE) three days after high frequency stimulation of the perforant pathway, as compared to tissue from low frequency stimulated controls or from unoperated animals. The increase in protein F1 phosphorylation was related to LTE rather than simple activation of perforant path-dentate gyrus synapses. This is the first report of a change in brain protein phosphorylation accompanying synaptic enhancement lasting days. The extent of growth of LTE over the three days following stimulation was directly related (r = +0.66, P less than 0.05) to protein F1 phosphorylation. Among the phosphoproteins studied this relationship between LTE and phosphorylation was selective for protein F1. This suggests that protein F1 may regulate growth of synaptic plasticity for at least a three day period. The mechanism for the LTE-related increase in protein F1 phosphorylation has not been established. However, recent evidence from this laboratory indicates: that protein F1 is phosphorylated by the calcium/phospholipid-dependent protein kinase C; and that kinase C is activated 1 h after LTE. Therefore, the increase in protein F1 phosphorylation following LTE may result from long term activation of protein C kinase.
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PMID:A selective increase in phosporylation of protein F1, a protein kinase C substrate, directly related to three day growth of long term synaptic enhancement. 299 27

The pharmacological manipulation of oocyte maturation in vitro offers an interesting tool for the study of the cell division cycle. The molecular mechanisms which are involved in this process are initiated at the oocyte plasma membrane and lead to a cascade of events, such as breakdown of the nuclear membrane (GVBD), chromosome condensation and cell division. Our pharmacological results point to an essential role for membrane in the communication between external information and intracellular signals mediating the physiological process. In Xenopus as well as in mouse oocytes, protein phosphorylation processes appear to be involved, either through the activation/inhibition of protein C kinase (calcium activated and phospholipid-dependent) and/or protein-A-kinase (cAMP dependent). Indeed in both systems, forskolin inhibits the first step of the process (GBVD) assessing the existence of an oocyte adenylate cyclase. Moreover, inhibitors of protein kinase C induce maturation in Xenopus oocyte whereas activators of this kinase prevent the process in denuded mouse oocytes. Interestingly, inhibitors of transmethylation reactions maintain the prophase block in both systems suggesting a role for membrane fluidity (phospholipid methylation) in the regulation of oocyte maturation.
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PMID:Pharmacological manipulation of meiotic maturation in vitro: a comparative study between the amphibian-(Xenopus) and the mammalian (mouse)-oocyte. 344 60

A putative explanation of the effect of sulindac on adenomatous colon and duodenal polyps from clinical observations and related in vitro experiments is presented. In cells with mutant APC genes, persistent high prostaglandin content of polyps leads to desensitization, downregulation of adenylate cyclase, uncoupling of cAMP synthesis from prostaglandin, and inactivation of protein kinase A (PKA). It is suggested that in normal cells, (APC) protein binds to catenins and microtubules to maintain structure and contribute to cell-cell communication, adherence, and the dephosphorylated state, a necessary condition for such functions. Cells with mutant APC product become isolated, deprived of communication and adhesion to other epithelial cells, overphosphorylated, and without corrective capability. The latter is largely due to downregulation of cAMP synthesis and protein kinase A activity secondary to high prostaglandin. Three main biochemical defects ensue: (1) the restrictive influence of PKA catalyzed phosphorylation of Raf-1 kinase and resultant effects on the MAP kinase cascade and transcription is lost, (2) the transcription of immediate early genes, including cyclooxygenase is stimulated, and (3) the stimulation of protein tyrosine phosphatase (PTPase) by PKA is in abeyance. These putative abnormalities are reversed by inhibition of cyclooxygenase-1 by sulindac. cAMP synthesis and PKA activity return to normal. PKA catalyzed phosphorylations block Raf-1 kinase at the confluence of the Ras and protein kinase C pathways. The MAP kinase cascade is inhibited as is transcription of immediate early genes. At the same time PKA stimulates PTPase, which dephosphorylates the cytoskeleton and restores cell-cell communication, adherence, and structure. The transformed phenotype is circumvented by adjustment of the phosphorylation state and mutant cells rejoin the epithelial community. The redox state of cytoplasm in mutant cells may be shifted toward reduction.
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PMID:Adenomatous polyposis coli, protein kinases, protein tyrosine phosphatase: the effect of sulindac. 772 69

Platelet-derived coagulation factor Va is the primary secreted substrate for a thrombin-stimulation-dependent platelet kinase. Human platelet factor Va, consisting of a molecular weight (M(r)) 105,000 heavy chain and an M(r) 74,000 light chain, incorporates phosphate in at least two sites on the light chain. Phosphorylated factor Va represents 50% of the secreted protein-associated phosphate. This modification occurs exclusively at serine residues and is inhibited by H-7 and staurosporine, which suggests a protein kinase C (PKC)-mediated event. Purified plasma factor V and Va are phosphorylated in the light chain region by rat brain PKC. The activity of platelet factor Va in prothrombinase on platelets is not altered when phosphorylation is inhibited by staurosporine. Plasma-derived factor Va in the presence of thrombin stimulated platelets is phosphorylated on both the heavy chain and the light chain. Plasma factor V and factor Va heavy chain phosphorylation occurs without light chain phosphorylation in the presence of added 32P gamma-ATP and non-stimulated or collagen-stimulated platelets or casein kinase II. This differential phosphorylation of factor Va heavy and light chain shows two independent platelet kinase activities that act on factor Va. The heavy chain factor V/Va kinase activity is similar to casein kinase II, which we have demonstrated previously to act on factor Va and accelerate activated protein C inactivation of the cofactor. Our data show platelet-dependent phosphorylation of platelet and plasma factor V and Va resulting in significant covalent modifications of the cofactor. These modifications may play a role in directing the extracellular distribution of factor V and factor Va.
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PMID:Platelet coagulation factor Va: the major secretory platelet phosphoprotein. 816 84

Sulindac suppresses the growth of colon polyps in Gardner syndrome and familial adenomatous polyposis. The mechanism of action is not known. The problems are to ascertain the significance of high prostaglandin concentrations in transformed cells, colon polyps and cancers and to explain how sulindac restores normal growth patterns. A few clinical observations and an abundance of experimental data can be integrated to produce a reasonable model based on current biochemical and physiologic concepts. A fundamental defect in the formation of colon polyps is mutation of the APC (adenomatous polyposis coli) gene that leads to inadequate suppression of proliferation. There is high PGE2 content in colon polyps and cancers, presumably the result of stimulation by protein kinase C (PKC). In small quantities it stimulates cyclic AMP production but with persistent high concentrations it desensitizes and down-regulates specific PG receptors and inactivates adenylate cyclase, cAMP synthesis, and the cAMP-dependent mechanism for control of proliferation. The PKC pathway is thereby unopposed. It is hypothesized that restriction of PG synthesis by sulindac is accompanied by resensitization of PG receptors, and reactivation of the cAMP-dependent pathway for control of cell growth. It is further postulated that restoration of cAMP synthesis and protein kinase A activity converts a functionally inadequate mutant APC suppressor gene to one sufficient to inhibit colon polyp formation.
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PMID:The effect of sulindac on colon polyps: circumvention of a transformed phenotype--a hypothesis. 828 54

Platelet activation leads to the incorporation of 32[PO4(2-)] into bovine coagulation factor Va and recombinant human factor VIII. In the presence of the soluble fraction from thrombin-activated platelets and (gamma-32P) adenosine triphosphate, radioactivity is incorporated exclusively into the M(r) = 94,000 heavy chain (H94) of factor Va and into the M(r) = 210,000 to 90,000 heavy chains as well into the M(r) = 80,000 light chain of factor VIII. Proteolysis of the purified phosphorylated M(r) = 94,000 factor Va heavy chain by activated protein C (APC) gave products of M(r) = 70,000, 24,000, and 20,000. Only the intermediate M(r) = 24,000 fragment contained radioactivity. Because the difference between the M(r) = 24,000 and M(r) = 20,000 fragments is located on the COOH-terminal end of the bovine heavy chain, phosphorylation of H94 must occur within the M(r) = 4,000 peptide derived from the carboxyl-terminal end of H94 (residues 663 through 713). Exposure of the radioactive factor VIII molecule to thrombin ultimately resulted in a nonradioactive light chain and an M(r) = 24,000 radioactive fragment that corresponds to the carboxyl-terminal segment of the A1 domain of factor VIII. Based on the known sequence of human factor VIII, phosphorylation of factor VIII by the platelet kinase probably occurs within the acidic regions 337 through 372 and 1649 through 1689 of the procofactor. These acidic regions are highly homologous to sequences known to be phosphorylated by casein kinase II. Results obtained using purified casein kinase II gave a maximum observed stoichiometry of 0.6 mol of 32[PO4(2-)]/mol of factor Va heavy chain and 0.35 mol of 32[PO4(2-)]/mol of factor VIII. Phosphoamino acid analysis of phosphorylated factor Va by casein kinase II or by the platelet kinase showed only the presence of phosphoserine while phosphoamino acid analysis of phosphorylated factor VIII by casein kinase II showed the presence of phosphothreonine as well as small amounts of phosphoserine. The platelet kinase responsible for the phosphorylation of the two cofactors was found to be inhibited by several synthetic protein kinase inhibitors. Finally, partially phosphorylated factor Va was found to be more sensitive to APC inactivation than its native counterpart. Our findings suggest that phosphorylation of factors Va and VIIIa by a platelet casein kinase II-like kinase may downregulate the activity of the two cofactors.
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PMID:Phosphorylation of factor Va and factor VIIIa by activated platelets. 842 63

In addition to the contractile proteins actin and myosin, contractile filaments of striated muscle contain other proteins that are important for regulating the structure and the interaction of the two force-generating proteins. In the thin filaments, troponin and tropomyosin form a Ca-sensitive trigger that activates normal contraction when intracellular Ca is elevated. In the thick filament, there are several myosin-binding proteins whose functions are unclear. Among these is the myosin-binding protein C (MBP-C). The cardiac isoform contains four phosphorylation sites under the control of cAMP and calmodulin-regulated kinases, whereas the skeletal isoform contains only one such site, suggesting that phosphorylation in cardiac muscle has a specific regulatory function. We isolated natural thick filaments from cardiac muscle and, using electron microscopy and optical diffraction, determined the effect of phosphorylation of MBP-C on cross bridges. The thickness of the filaments that had been treated with protein kinase A was increased where cross bridges were present. No change occurred in the central bare zone that is devoid of cross bridges. The intensity of the reflections along the 43-nm layer line, which is primarily due to the helical array of cross bridges, was increased, and the distance of the first peak reflection from the meridian along the 43-nm layer line was decreased. The results indicate that phosphorylation of MBP-C (i) extends the cross bridges from the backbone of the filament and (ii) increases their degree of order and/or alters their orientation. These changes could alter rate constants for attachment to and detachment from the thin filament and thereby modify force production in activated cardiac muscle.
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PMID:Alteration of myosin cross bridges by phosphorylation of myosin-binding protein C in cardiac muscle. 879 43

We show here that the fission yeast gene products Cut9 and Nuc2 are the subunits of the 20S complex, the putative APC (anaphase promoting complex)/cyclosome which contains ubiquitin ligase activity required for cyclin and Cut2 destruction. The assembly of Cut9 into the 20S complex requires functional Nuc2, and vice versa. The size of fission yeast APC/cyclosome is similar to that of higher eukaryotes, but differs greatly from that (36S) of budding yeast. The 20S complex is present in cells arrested at different stages of the cell cycle, and becomes slightly heavier in mitosis than interphase. Cut9 in the 20S complex is hyperphosphorylated specifically at the time of metaphase. The truncated forms of Cut9 block entry into mitosis, however. The 20S assembly impaired in the cut9 mutant can be restored by elevating the level of a novel gene product Hcnl, similar to budding yeast Cdc26. Furthermore, deletion of protein kinase PKA (Pkal) suppresses the phenotype of the cut9 mutation and reduces phosphorylation of Cut9. In contrast, PP1 (Dis2) phosphatase mutation shows the reverse effect on the phenotype of cut9. The Cut9 subunit is likely to be a target for regulating APC/ cyclosome function through protein-protein interactions and phosphorylation.
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PMID:Distinct subunit functions and cell cycle regulated phosphorylation of 20S APC/cyclosome required for anaphase in fission yeast. 926 66


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