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 X-ray crystal structure of sangivamycin, a potent nucleoside inhibitor of protein kinases, has been determined. Sangivamycin crystallizes from water with its purine ring in a conformation anti to its ribose sugar. Such an anti conformation has been detected in solution for sangivamycin and other potent protein kinase inhibitors and appears to correlate with inhibitor potency [(1990) Biochemistry (in press)]. An intramolecular hydrogen bond between purine ring substituents is detected in the X-ray structure and may be an important structural feature of sangivamycin related to its degree of inhibition of rhodopsin kinase and of protein kinases C and A.
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PMID:X-ray crystal structure of sangivamycin, a potent inhibitor of protein kinases. 236 59

The role of protein kinases in renal noradrenergic stimulation was examined using sphingosine, 1-(5-isoquinolinylsulfonyl)-2-methyl-piperizine (H7), using sphingosine, 1-(5-isoquinolinylsulfonyl)-2-methyl-piperizine (H7), or staurosporine to inhibit the responses to norepinephrine (NE, 60 nM) in isolated perfused rat kidneys. Sphingosine (20 mumol/L) increased the noradrenergic vasoconstrictor response. H7 (10 mumol/L) partially blocked the immediate vasoconstrictor response and completely inhibited it after 2 min without altering the antinatriuretic and antilithuretic responses. H7 also blocked the increase in free water produced by NE, which is consistent with the inhibition of protein kinase A linked to beta-adrenergic stimulation. Staurosporine (10 nmol/L) partially inhibited noradrenergic vasoconstriction and antinatriuresis, and it completely blocked the depression of gluconeogenic responses to NE in pyruvate-perfused kidneys. To examine the role of diacylglycerol and protein kinase C in the renal responses to NE, we used oleoyl-acetyl-glycerol (OAG, 50-100 microM) or phorbol-12-myristyl-13-acetate (TPA, 5-50 nM). TPA slowly vasoconstricted the kidney and reduced GFR and fractional Na+, Li+, and free water excretion. Amiloride (1 mM) prevented the TPA responses. OAG mimicked the effects of TPA except that vasoconstriction occurred more rapidly and was brief. Both TPA and OAG acted like alpha 1-adrenergic agonists. These results indicate that diaclyglycerol and protein kinase are involved in the prolonged effects of NE on vasoconstriction. GFR, and proximal tubular reabsorption.
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PMID:Diacylglycerol and protein kinase mediated noradrenergic responses in perfused rat kidneys. 239 Jul 42

The two most basic charge isomers of myelin basic protein (BP), components 1 and 2 (C1 and C2), which presumably differ in the degree of deamidation, were purified from bovine BP by cation-exchange chromatography. Two additional specific types of posttranslational modifications were introduced into the purified isomers: (1) C-terminal arginine deficient derivatives of C1 and C2 were prepared by incubating the isomers with a carboxypeptidase, and (2) phosphorylated derivatives of C1 (1.6 and 1.7 mol of phosphate/mol of protein) were prepared by incubating C1 with the protein kinase from rabbit muscle. The ability of these charge isomers to increase the permeability of multilamellar vesicles composed of phosphatidylserine/phosphatidylcholine (1:11.5 w/w) and sphingomyelin/cholesterol/phosphatidic acid (1:1:0.2 w/w/w) was measured by monitoring the release of a water-soluble spin-label (tempocholine chloride) from the vesicles. The increase in vesicle permeability caused by BP was taken as a measure of the degree of perturbation of the bilayer by the protein, most likely by penetration partly into the bilayer. All classes of charge isomers (naturally occurring or generated in vitro) were more effective at increasing vesicle permeability than was poly(L-lysine), a polycation that only interacts electrostatically with the bilayer. Although C1 and C2 and their C-terminal-deficient derivatives did not differ in the amount of marker released, the phosphorylated derivative of C1 caused a smaller increase in vesicle permeability than did the other isomers, suggesting that phosphorylation had altered the ability of the protein to perturb the bilayer.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Increase in vesicle permeability mediated by myelin basic protein: effect of phosphorylation of basic protein. 241 40

Vasopressin stimulates the introduction of aggregated particles, which may represent pathways for water flow, into the luminal membrane of toad urinary bladder. It is not known whether water transport pathways are degraded on removal from membrane or whether they are recycled. We examined the effect of the protein synthesis inhibitors cycloheximide and puromycin using repeated 30-min cycles of vasopressin followed by washout of vasopressin, all in the presence of an osmotic gradient, a protocol that maximizes aggregate turnover. "High dose" cycloheximide (200 micrograms/ml) inhibited flow immediately. "Low dose" cycloheximide (1 microgram/ml) did not affect initial flow; however, flow was inhibited by the fourth restimulation. On further rechallenge, inhibition persisted but did not increase. In the absence of vasopressin, inhibition did not develop. Despite the inhibition of flow in vasopressin-treated tissues, the cAMP-dependent protein kinase ratio (-cAMP/+cAMP), an index of in vivo cAMP effect, was elevated in cycloheximide-treated tissues, suggesting modulation at a distal site in the stimulatory cascade. Cycloheximide inhibited flow when 10 microM forskolin or 0.2 mM 8-BrcAMP was substituted for vasopressin in the fourth period; however, MIX (4 mM)-stimulated flow was enhanced by 1 microgram/ml cycloheximide but inhibited by 200 micrograms/ml cycloheximide. [14C]urea permeability was not inhibited by cycloheximide. Puromycin (0.5 mM) also inhibited water flow by the fourth challenge with vasopressin. The data suggest that protein synthesis inhibitors attenuate flow at a site that is distal to cAMP-dependent protein kinase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protein synthesis inhibitors attenuate water flow in vasopressin-stimulated toad urinary bladder. 244 2

Analysis by two-dimensional gel electrophoresis and Western blotting of the atrial natriuretic factor (ANF) content of atrial granules revealed the presence of at least 15 immunoreactive spots whose molecular mass distribution ranged from 16.8 to 35 kDa and their pI values from 5.12 to 5.98. About 90% of the immunoreactive ANF material was contained within four spots (spot 1: 34.8 kDa, pI 5.67; spot 5: 16.8 kDa, pI 5.50; spot 6: 16.8 kDa, pI 5.67; spot 7: 16.8 kDa, pI 5.98). Investigation of the molecular nature of spot 1 indicated that it is a dimer of pro-ANF since it possesses the same immunoreactivity, the same charge, double its mass, and can be converted with dithiothreitol into a 16.8-kDa pro-ANF form. Alkaline phosphatase and protein kinase A treatments indicated that spots 5, 6, and 7 are probably not phosphorylated forms of pro-ANF. Carboxypeptide A and B treatments in conjunction with amino acid analysis suggested that spot 7 is ANF-(1-128); spot 6, the major one, ANF-(1-126); and spot 5, ANF-(1-123) or ANF-(1-124). Water deprivation or morphine injection, two maneuvers which are known to influence ANF secretion and atrial ANF content, failed to affect the molecular heterogeneity of pro-ANF except for spot 1. The formation of the dimer appeared to be time-dependent. These results emphasize the heterogeneity of the pro-ANF molecule stored in atrial granules. We suggest that this heterogeneity may be due, in part, to the action of some proteases, such as carboxypeptidase E or a tripeptidyl carboxyhydrolase.
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PMID:Molecular heterogeneity of pro-atrial natriuretic factor. 253 Feb 24

Proteins in lacrimal gland fluid are secreted primarily by the acinar cells. Secretory proteins are synthesized in the endoplasmic reticulum, modified in the Golgi apparatus, stored in secretory granules, and released upon a change in the cellular level of second messenger. The second messenger level is controlled by a process termed signal transduction. Agonists, primarily neurotransmitters in the lacrimal gland, bind to receptors in the basolateral membrane of secretory cells. This interaction activates enzymes in the membrane that cause production of second messengers. It has been hypothesized that second messengers stimulate secretion by activating specific protein kinases to phosphorylate proteins important for secretion. In the lacrimal gland, cholinergic agonists stimulate protein secretion. They act by activating phospholipase C to break down phosphatidylinositol bisphosphate into 1,4,5-inositol trisphosphate (1,4,5-IP3) and diacylglycerol (DAG). 1,4,5-IP3 causes release of Ca2+ from intracellular stores. This Ca2+, perhaps in conjunction with calmodulin, activates specific protein kinases that may be involved in secretion. DAG activates protein kinase C which stimulates protein secretion. alpha 1-Adrenergic agonists also stimulate lacrimal gland protein secretion. These agonists use a pathway that is separate from that utilized by cholinergic agonists and vasoactive intestinal peptide (VIP). The specific pathway has not been identified but may be DAG and protein kinase C. VIP, beta-adrenergic agonists, alpha-melanocyte stimulating hormone, and adrenocorticotropic hormone are lacrimal gland secretagogues. They activate adenylate cyclase to produce cAMP. cAMP stimulates protein kinase A, which perhaps causes protein secretion. Thus, three separate cellular pathways stimulate lacrimal gland protein secretion. Cholinergic agonists and VIP also stimulate lacrimal gland fluid secretion, and the same signal transduction pathways utilized by these agonists to stimulate protein secretion are most likely used for electrolyte and water secretion.
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PMID:Signal transduction and control of lacrimal gland protein secretion: a review. 254 11

Previous studies of enzyme secretion from isolated pancreatic acinar cells and of isolated zymogen granules (ZG) have reported that both a Cl- and a K+ permeability are present on the ZG membrane. It has been suggested that ion influx via these permeability pathways, followed by water movement is required for granular swelling which appears to be intimately related to exocytosis. However, little is known about the regulation of these pathways by secretagogues. Evidence suggests that cAMP-protein kinase A and diacylglycerol-protein kinase C are second messengers in stimulation of exocytosis. In the present study we have examined ion permeability pathways in ZG isolated from control cells and from cells pretreated with the acetylcholine analog carbachol (Cch), with the peptide hormone cholecystokinin (CCK) and with second messengers of hormone action such as cAMP and the diacylglycerol analog 12-O-tetradecanoyl phorbol-13-acetate (TPA). Ion and water influx rates in ZG and consequent swelling and lysis of granules was monitored by measuring changes in optical densities of ZG suspensions at 540 nm following additions of the electrogenic or electroneutral ionophores valinomycin and nigericin, respectively. The data show that both a Cl- conductance and an anion exchange pathway are present in the granule membrane. Both pathways are activated by pretreatment of isolated cells with CCK or of isolated permeabilised cells with cAMP, whereas only the Cl- conductance is increased by pretreatment with Cch or with TPA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Secretagogue and second messenger-activated Cl- permeabilities in isolated pancreatic zymogen granules. 256 Jan 64

Since tyrosine-specific protein kinase (TPK) is much less abundant than Ser/Thr-specific kinases in cells, determination of TPK activity in crude cell extracts or column chromatography eluates has been difficult. This is compounded by the absence of a rapid, economical method for the separation of high endogenous protein phosphorylation background from exogenously added tyrosine-containing substrates. We have developed a new solid-phase assay, which provides high sensitivity and efficiency at a low cost for assaying the TPK activity of crude enzyme preparations. This assay utilizes immobilized tyrosine-containing synthetic polymers such as (Glu:Tyr, 4:1)n in polyacrylamide gels. The kinase reaction is started by adding crude enzyme solutions and [tau-32P]ATP-metal ion mixtures into microtiter-size wells made in the gels. After the phosphorylation reaction, the reaction mixtures are removed and the gels are prewashed in water followed by electrophoresis to completely remove free radioactive ATP. 32P incorporation into the immobilized TPK-specific substrate can be detected by autoradiography and quantitated by cutting the gel pieces and counting them with a liquid scintillation counter. The simple, rapid method should facilitate screening of TPK inhibitors and activators as well as examining the substrate specificity of TPKs. Other enzymes, including Ser/Thr-specific protein kinases, can also be analyzed by this technique.
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PMID:Solid-phase tyrosine-specific protein kinase assay in multiwell substrate-immobilized polyacrylamide gel. 260 46

Vasoactive intestinal peptide (VIP) induces phosphorylation of a basic 38,000 mol. wt protein in a human lymphoblastic cell line (Molt 4b) and a human colon carcinoma cell line (HT29). In both cell types, VIP interacts with specific high affinity receptors to activate adenylate cyclase and cAMP-dependent protein kinase. The two cell types appear to express homologous receptors with similar affinity and specificity for VIP, but the colonic epithelial cells express a greater number of receptors. HT29 colonic cells also exhibit a greater stimulation of adenylate cyclase and a higher phosphorylation index for the 38,000 mol. wt protein in response to VIP. This 38,000 mol. wt protein, which is phosphorylated in the presence of VIP, appears to be identical in both cell lines; it is phosphorylated in both lymphoblasts and colonic epithelial cells in the presence of forskolin, but not in the presence of phorbol 12-myristate 13-acetate. Phosphorylation of this 38,000 mol. wt protein may be an important step in VIP regulation of water and electrolyte secretion from colonic epithelial cells, and in VIP regulation of immunoglobulin and lymphokine secretion from lymphocytes.
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PMID:Comparison of vasoactive intestinal peptide-mediated protein phosphorylation in human lymphoblasts and colonic epithelial cells. 277 Jul 50

A model of angiotensin II action has been developed in which the flow of information from cell surface to cell interior proceeds by two temporally distinct branches: a calmodulin branch largely responsible for initiating the response; and a C-kinase branch for sustaining it. There are at least two initial events: a prompt and sustained increase in calcium influx rate, and prompt hydrolysis of phosphatidylinositol 4,5-bisphosphate. The latter leads to the generation of water-soluble inositol 1,4,5-trisphosphate and lipid soluble diacylglycerol. The rise in inositol 1,4,5-trisphosphate concentration causes the redistribution of intracellular calcium, a transient rise in the calcium concentration in the cytosol, and the activation of calmodulin-dependent enzymes, including protein kinase(s). As a result, several cellular proteins are rapidly phosphorylated and initiate the cellular response. The rise in calcium and these initial phosphorylation events are transient, however, so that an additional mechanism is necessary to sustain the response. The rise in diacylglycerol content, along with the transient rise in cytosolic calcium, leads to a shift of the C-kinase from a calcium-insensitive to a calcium-sensitive, plasma membrane-associated form. In this location, the activity of C-kinase is regulated by the rate of calcium flux across the plasma membrane. As a result of the activity of the C-kinase, a second set of cellular proteins becomes phosphorylated, and these control the sustained phase of the response.
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PMID:Calcium in the regulation of aldosterone secretion and vascular smooth muscle contraction. 282 62


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