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)

Three classes of vasodilators mediate their effects through the activation of guanylate cyclase and the increased synthesis of cyclic GMP. Nitrovasodilators such as nitroglycerin, nitroprusside, hydroxylamine, azide, etc. result in the generation of the nitric oxide free radical that activates the cytosolic (soluble) isoenzyme form of guanylate cyclase. These agents have been useful in increasing cyclic GMP synthesis in numerous model systems and these effects are independent of extracellular calcium. The increased synthesis of cyclic GMP and the activation of cyclic GMP-dependent protein kinase result in the altered phosphorylation of many smooth muscle proteins including the dephosphorylation of myosin light chain, which is associated with vascular and tracheal smooth muscle relaxation. These latter effects may result from cyclic GMP decreasing cytosolic free calcium concentrations and the activity of myosin light chain kinase. Another class of vasodilators, designated endothelium-dependent vasodilators, includes a long list of agents such acetylcholine, histamine, A23187, ATP, thrombin, etc. that relax vessels only when the endothelium is intact. These agents result in the increased endothelial synthesis and/or release of a factor(s) designated endothelial-derived relaxant factor (EDRF), the structure of which is unknown. This labile factor also activates the soluble isoenzyme form of guanylate cyclase in the smooth muscle resulting in cyclic GMP accumulation and the same cascade of events as above. There is evidence that even under basal, non-stimulated conditions there is EDRF release that influences vascular tone due to the increased synthesis of cyclic GMP. A third class of vasodilators, atrial natriuretic factor (ANF) or atriopeptins, includes a family of peptides that are produced in cardiac atria and other tissues and influence cardiovascular volume and dynamics by causing natriuresis, diuresis, vasodilation and decreased renin, aldosterone and vasopressin secretion. These peptide hormones also increase cyclic GMP synthesis in vascular, renal, adrenal and other tissues. These effects are mediated through specific ANF receptors that couple to and activate the membrane (particulate) isoenzyme form of guanylate cyclase and increase cyclic GMP-dependent protein kinase activity. There are two ANF receptor subtypes in most cells and tissues that are 130,000 and 66,000 daltons. The ANF receptor of about 130,000 daltons, designated receptor ANF-R1 copurifies with particulate guanylate cyclase through numerous procedures and may be part of the membrane-associated guanylate cyclase complex.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation and role of guanylate cyclase-cyclic GMP in vascular relaxation. 289 Jan 72

Intact platelets were stimulated with thrombin and the amount of GTP-binding protein (G-protein) oligomers was assessed by measuring ADP ribosylation of 40-41 kDa protein by pertussis toxin in isolated membranes. The toxin substrate fell by 57-62% in 10-60 s, but then returned towards normal over 5 min. Recovery was greatly enhanced by removal of thrombin from receptors with hirudin. Phorbol myristate acetate increased ADP-ribosylatable protein, but only back to initial levels prior to PMA. In contrast prostaglandin D2 plus theophylline (which increase cyclic AMP) did not increase ADP ribosylation, but could completely block the fall of the toxin substrate caused by thrombin. These results indicate that activation of thrombin receptors promotes the dissociation of G-protein oligomers to release free alpha-subunits, and this effect can be modulated by protein kinase C and cyclic AMP-dependent protein kinase. The possible relationships of these findings to the regulation of stimulus-response coupling in platelets is discussed.
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PMID:Effects of thrombin, phorbol myristate acetate and prostaglandin D2 on 40-41 kDa protein that is ADP ribosylated by pertussis toxin in platelets. 301 84

Human platelets were depleted of intracellular Ca2+ and then made selectively permeable to external Ca2+ by addition of the ionophore ionomycin. In this cell system a rapid release of arachidonic acid was seen in direct response to added Ca2+ at concentrations corresponding to cytosolic Ca2+ levels measured in thrombin-stimulated platelets. Thrombin and other activators of Ca2+/phospholipid-dependent protein kinase (C-kinase) potentiated the Ca2+-stimulated arachidonic acid release while exerting little or no effect in the absence of added Ca2+. Agents which increase (R59022) or decrease (isoquinolinesulphonylmethylpiperazine) the activation of C-kinase correspondingly enhanced or inhibited, respectively, the potentiation of arachidonic acid release caused by thrombin. These results support the hypothesis that arachidonic acid release in human platelets is regulated by a co-operative action between intracellular Ca2+ and C-kinase.
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PMID:Thrombin and C-kinase activators potentiate calcium-stimulated arachidonic acid release in human platelets. 312 14

Rabbit serum is shown to contain a cAMP-dependent protein kinase (biochemically characterized as type II) that specifically phosphorylates a 135-kDa endogenous protein. This endogenous phosphorylation can be reproduced with platelet-rich plasma, after stimulation with thrombin, but not with plasma devoid of platelets. Stimulation of isolated platelets ("washed" by gel filtration) with either thrombin or ADP brings about a release of this kinase. The supernatant of these stimulated platelets, which contains the kinase, does not undergo a cAMP-dependent endogenous phosphorylation because it does not contain the 135-kDa protein substrate. On the other hand, plasma devoid of platelets does not contain cAMP-dependent protein kinase. By combining the supernatant of the physiologically stimulated platelets with the plasma devoid of platelets, it is possible to reconstitute the system and to reproduce the specific endogenous phosphorylation of the 135-kDa target substrate. On the basis of the above evidence it is proposed that upon physiological stimulation of platelets, they release into the blood a cAMP-dependent protein kinase in addition to the well-known release of MgATP. This kinase specifically phosphorylates the 135-kDa plasma protein.
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PMID:Platelet stimulation releases a cAMP-dependent protein kinase that specifically phosphorylates a plasma protein. 317 51

Tyrosine phosphorylation of a 42-kD, cytosolic protein is a rapid consequence when quiescent cells are stimulated with any one of a diverse group of mitogenic agents. Among the inducers of this tyrosine phosphorylation are activators of protein kinase C, raising the possibility that this serine/threonine-specific protein kinase plays a role in mitogen-induced tyrosine phosphorylation. Using fibroblastic cells depleted of protein kinase C by chronic treatment with the tumor promoter tetradecanoyl phorbol acetate (TPA), we now show that protein kinase C is required for the tyrosine phosphorylation of the 42-kD protein, even when epidermal growth factor (EGF), whose receptor is a tyrosine-specific protein kinase, provides the initial stimulus. EGF is able to induce other cellular phosphorylations independent of protein kinase C, whereas thrombin appears to require the protein kinase C-dependent pathway. These findings suggest that phosphorylation of the 42-kD protein is part of a protein kinase C-dependent kinase cascade involved in intracellular signalling.
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PMID:Mitogen-stimulated tyrosine phosphorylation of a 42-kD cellular protein: evidence for a protein kinase-C requirement. 325 83

Inositol 1,4,5-trisphosphate (Ins(1,4,5)P3), an intracellular second messenger produced from the hydrolysis of phosphatidylinositol 4,5-bisphosphate, interacts with cytoplasmic membrane structures to elicit the release of stored Ca2+. Ins(1,4,5)P3-induced Ca2+ mobilization is mediated through high affinity receptor binding sites; however, the biochemical mechanism coupling receptor occupation with Ca2+ channel opening has not been identified. In studies presented here, we examined the effects of naphthalenesulfonamide calmodulin antagonists, W7 and W13, and a new selective antagonist, CGS 9343B, on Ca2+ mobilization stimulated by Ins(1,4,5)P3 in neoplastic rat liver epithelial (261B) cells. Intact fura-2 loaded cells stimulated by thrombin, a physiological agent that causes phosphatidylinositol 4,5-bisphosphate hydrolysis and Ins (1,4,5)P3 release, responded with a rise in cytoplasmic free Ca2+ levels that was dose dependently inhibited by W7(Ki = 25 microM), W13 (Ki = 45 microM), and CGS 9343B (Ki = 110 microM). Intracellular Ca2+ release stimulated by the addition of Ins(1,4,5)P3 directly to electropermeabilized 261B cells was similarly inhibited by pretreatment with anti-calmodulin agents. W7 and CGS 9343B, which potently blocked Ca2+/calmodulin-dependent protein kinase, had no significant effect on protein kinase A or C in dose range required for complete inhibition of Ca2+ mobilization. Ca2+ release channels and Ca2+-ATPase pump activity were also unaffected by calmodulin antagonist treatment. These results indicate that calmodulin is tightly associated with the intracellular membrane mechanism coupling Ins(1,4,5)P3 receptors to Ca2+ release channels
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PMID:Inhibition of inositol trisphosphate-stimulated calcium mobilization by calmodulin antagonists in rat liver epithelial cells. 326 69

The major interaction site for tumor-promoting phorbol esters is the calcium-activated, phospholipid-dependent protein kinase (protein kinase C), a key-element in signal transduction. Binding of phorbol esters results in enzyme activation which mediates, at least in part, the action of these agents. We have investigated the effects of tumor promoter chloroform on protein kinase C activity. Like thrombin and 12-O-tetradecanoylphorbol-13-acetate (TPA), chloroform was able to activate protein kinase C in intact rabbit platelets. In addition, chloroform stimulated enzyme activity as well as TPA binding capacity in cell-free system. Scatchard analysis of the data has shown that chloroform increased the number of phorbol ester binding sites. Structurally related compounds, carbon tetrachloride and methylene chloride, activated the enzyme similarly.
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PMID:Tumor promoter chloroform is a potent protein kinase C activator. 382

Myosin light chain kinase plays a central role in the regulation of smooth muscle contraction. The activity of this enzyme is controlled by protein-protein interaction (the Ca2+-dependent binding of calmodulin) and by phosphorylation catalyzed by cAMP-dependent protein kinase. The effects of these two regulatory mechanisms on the conformation of myosin light chain kinase and the locations of the phosphorylation sites, the calmodulin-binding site, and the active site have been probed by limited proteolysis. Phosphorylated and nonphosphorylated myosin light chain kinases were subjected to limited digestion by four proteases having different peptide bond specificities (trypsin, chymotrypsin, Staphylococcus aureus V8 protease, and thrombin), both in the presence and in the absence of bound calmodulin. The digests were compared in terms of gel electrophoretic pattern, distribution of phosphorylation sites, and Ca2+ dependence of kinase activity. A 24 500-dalton chymotryptic peptide containing both sites of phosphorylation was purified and tentatively identified as the amino-terminal peptide. The following conclusions can be drawn: neither phosphorylation nor calmodulin binding induces dramatic changes in the conformation of the kinase; the kinase contains two regions that are particularly susceptible to proteolytic cleavage, one located approximately 25 000 daltons from the amino terminus and the other near the center of the molecule; the two phosphorylation sites are located within 24 500 (probably 17 500) daltons of the amino terminus; the active site is located close to the center of the molecule; the calmodulin-binding site is located in the amino-terminal half of the molecule, between the sites of phosphorylation and the active site, and this region is very susceptible to cleavage by trypsin.
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PMID:Limited proteolysis of smooth muscle myosin light chain kinase. 384 33

We have investigated the epidermal growth factor (EGF)-stimulated tyrosine-specific protein kinase activity in quiescent cultures of diploid human fibroblasts that have a well characterized mitogenic response to EGF. We developed a method of permeabilizing cells with digitonin or other agents that permitted the rapid labeling of cellular proteins with exogenously added [gamma-32P]ATP while allowing only about 25% of marker cytosolic enzymes to escape from the cells. When phosphatases were inhibited with zinc and vanadate, EGF induced up to 8-fold stimulation of the incorporation of radioactivity from [gamma-32P]ATP into a 35-kDa band on sodium dodecyl sulfate gels. Alkali treatment of gels showed that EGF stimulated the phosphorylation of bands with apparent molecular masses of 170, 45, 35, 26, 22, and 21 kDa. Phosphoamino acid analysis was performed on the 170- and 35-kDa bands and revealed that the EGF-stimulated phosphorylation was on tyrosyl residues. The 35-kDa band was resolved into four spots by two-dimensional gel electrophoresis. The most acidic form was the most prominent and it was precipitated by an antiserum against a 35-kDa protein from A-431 cells; heretofore, this protein has only been reported to be phosphorylated in an EGF-dependent manner by A-431 membranes in vitro (Fava, R. A., and Cohen, S. (1984) J. Biol. Chem. 259, 2636-2645). This antiserum also precipitated a 35-kDa phospho-protein from extracts of intact [32P]orthophosphate-labeled fibroblasts which was phosphorylated on tyrosine in an EGF-dependent manner. None of the forms of the 35-kDa phosphoproteins labeled in permeabilized cells were immunologically related to the 34-kDa protein that is a substrate for the tyrosyl kinase encoded by Rous sarcoma virus. Other mitogens (serum, insulin, platelet-derived growth factor, and thrombin) did not detectably stimulate phosphorylation in permeabilized cells.
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PMID:Epidermal growth factor stimulates tyrosine phosphorylation of specific proteins in permeabilized human fibroblasts. 387 22

The influence of the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), a direct activator of the Ca2+-activated, phospholipid-dependent protein kinase (protein kinase C), was studied on regulation of human platelet adenylate cyclase. Intact platelets were pretreated with the phorbol ester and, thereafter, membranes were prepared and the regulation of the hormone-sensitive adenylate cyclase in these membranes was studied. The following data were obtained: The TPA treatment applied had apparently no effect on the activity of the catalytic moiety of the platelet adenylate cyclase nor on the stimulatory NS protein nor on stimulatory hormone receptors (prostaglandin E1) and the mutual interactions of these components of the stimulatory hormone-sensitive pathway. However, the TPA treatment of intact platelets largely impaired the GTP-dependent, hormone-sensitive inhibitory pathway to the adenylate cyclase, involving the inhibitory Ni protein. The pretreatment led to a large reduction or loss of adenylate cyclase inhibition by GTP itself and by the inhibitory agonists, epinephrine and thrombin, inhibiting the untreated enzyme via separate receptors by an Ni-mediated process. In contrast, platelet adenylate cyclase inhibition not involving the Ni protein was not affected by the TPA treatment. The observed effects of TPA were very rapid in onset and were not shared by a derivative of TPA which did not activate protein kinase C. The data obtained suggest than protein kinase C activated by the phorbol ester interferes with the platelet adenylate cyclase system, leading to a specific alteration of the Ni-protein-mediated signal transduction to the adenylate cyclase.
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PMID:Modulation of adenylate cyclase of human platelets by phorbol ester. Impairment of the hormone-sensitive inhibitory pathway. 404 Aug 56


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