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 muscarinic receptor subtype-activated signal transduction mechanisms mediating rat urinary bladder contraction are incompletely understood. M(3) mediates normal rat bladder contractions; however, the M(2) receptor subtype has a more dominant role in contractions of the hypertrophied bladder. Normal bladder muscle strips were exposed to inhibitors of enzymes thought to be involved in signal transduction in vitro followed by a single cumulative concentration-response curve to the muscarinic receptor agonist carbachol. The outcome measures were the maximal contraction, the potency of carbachol, and the affinity of the M(3) -selective antimuscarinic agent darifenacin for inhibition of contraction. Inhibition of phosphoinositide-specific phospholipase C (PI-PLC) with 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphorylcholine (ET-18-OCH(3)) reduces carbachol potency and reduces darifenacin affinity, whereas inhibition of phosphatidyl choline-specific phospholipase C (PC-PLC) with O-tricyclo[5.2.1.02,6]dec-9-yl dithiocarbonate potassium salt (D609) attenuates the carbachol maximal contraction. Inhibition of rho kinase with (R)-(+)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride (Y-27632) reduces carbachol potency and increases darifenacin affinity. Inhibition of rho kinase, protein kinase A (PKA), and protein kinase G (PKG) with 1-(5-isoquinolinesulfonyl)-homopiperazine.HCl (HA-1077) reduces the carbachol maximal contraction, carbachol potency, and darifenacin affinity. Inhibition of protein kinase C (PKC) with chelerythrine increases darifenacin affinity, whereas inhibition of rho kinase, PKA, PKG, and PKC with 1-(5-isoquinolinesulfonyl)-2-methylpiperazine.2HCl (H7) reduces the carbachol maximum and carbachol potency while increasing darifenacin affinity. Inhibition of rho kinase, PKA, and PKG with N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide.2HCl (H89) reduces carbachol maximum and carbachol potency. Both the M(2) and the M(3) receptor subtype are involved in normal rat bladder contractions. The M(3)subtype seems to mediate contraction by activation of PI-PLC, PC-PLC, and PKA, whereas the M(2) signal transduction cascade may include activation of rho kinase, PKC, and an additional contractile signal transduction mechanism independent of rho kinase or PKC.
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PMID:M2 and M3 muscarinic receptor activation of urinary bladder contractile signal transduction. I. Normal rat bladder. 1624 61

Normal rat bladder contractions are mediated by the M(3) muscarinic receptor subtype. The M(2) receptor subtype mediates contractions of the denervated, hypertrophied bladder. This study determined signal transduction mechanisms mediating contraction of the denervated rat bladder. Denervated bladder muscle strips were exposed to inhibitors of enzymes thought to be involved in signal transduction in vitro followed by a cumulative carbachol concentration-response curve. Outcome measures were the maximal contraction, the potency of carbachol, and the affinity of darifenacin for inhibition of contraction. Inhibition of phosphoinositide-specific phospholipase C (PI-PLC) with 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphorylcholine (ET-18-OCH(3)) has no effect on denervated bladder contractions, whereas inhibition of phosphatidyl choline-specific phospholipase C (PC-PLC) with O-tricyclo[5.2.1.02,6]dec-9-yl dithiocarbonate potassium salt (D609) attenuates the carbachol maximum and potency. Inhibition of rho kinase with (R)-(+)-trans-4-(1-aminoethyl)-N-(4-pyridyl)cyclohexanecarboxamide dihydrochloride (Y-27632) reduces carbachol maximum, carbachol potency, and increases darifenacin affinity. Inhibition of rho kinase, protein kinase A (PKA), and protein kinase G (PKG) with 1-(5-isoquinolinesulfonyl)-homopiperazine.HCl (HA-1077) reduces the carbachol maximum and potency. Inhibition of PKC with chelerythrine increases darifenacin affinity, whereas inhibition of rho kinase, PKA, PKG, and protein kinase C (PKC) with 1-(5-isoquinolinesulfonyl)-2-methylpiperazine.2HCl (H7) reduces the carbachol potency while increasing darifenacin affinity. Inhibition of rho kinase, PKA, and PKG with N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide.2HCl (H89) increases darifenacin affinity. This study demonstrates that different signal transduction mechanisms mediate the contractile response in the denervated rat bladder than in normal rat bladder. In normal rat bladder, PI-PLC and PC-PLC mediate the contraction, but in denervated bladder only PC-PLC is involved. In the denervated bladder, the rho kinase pathway is more dominant than in normal bladders. PKA seems to mediate a contractile response in normal bladders, whereas it seems to inhibit contraction in denervated bladders.
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PMID:M2 and M3 muscarinic receptor activation of urinary bladder contractile signal transduction. II. Denervated rat bladder. 1624 62

The ezrin-radixin-moesin proteins provide a regulated linkage between membrane proteins and the cortical cytoskeleton, and also participate in signal-transduction pathways. Ezrin is localized to the apical membrane of parietal cells and couples the cAMP-dependent protein kinase activation cascade to the regulated HCl secretion in gastric parietal cells. Our recent studies have mapped the PKA-mediated phosphorylation site to Ser(66) and established its functional role in parietal cell activation [R. Zhou et al., Characterization of protein kinase A-mediated phosphorylation of ezrin in gastric parietal cell activation, J. Biol. Chem. 278 (2003) 35651-35659], but the underlying basis for this regulation is not known. Here, we provide the first evidence that PKA-mediated phosphorylation of Ser(66)regulates the interaction of ezrin with WWOX, a WW domain-containing protein. Our biochemical study reveals that ezrin directly binds to the first WW domain of WWOX via its C-terminal tyrosine-containing polyproline sequence (470)PPPPPPVY(477). Mutational analyses further demonstrate that tyrosine(477) is essential for the ezrin-WWOX interaction. In addition, our study shows that PKA-mediated phosphorylation of ezrin is essential and sufficient for the apical localization of WWOX protein as disruption of ezrin-WWOX interaction eliminated the apical localization of WWOX. Finally, our study demonstrates the essential role of ezrin-WWOX interaction in the apical membrane remodeling associated with H,K-ATPase recruitment. Taken together, these results define a novel molecular mechanism underlying phospho-regulation of ezrin function by PKA in parietal cell activation.
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PMID:PKA-mediated protein phosphorylation regulates ezrin-WWOX interaction. 1643 31

As a member of the CIP/KIP family of cyclin-dependent kinase inhibitors (CKIs), p57Kip2 binds tightly to G1 cyclin/cyclin-dependent kinase complexes to block cell cycle progression. CKIs play critical roles in regulating the transition from proliferation to differentiation in many tissues, including the nervous system. Conversely, CKI dys-regulation contributes to neoplasia and cancer progression. While the combined detection of CKI immunoreactivity and S phase entry using bromodeoxyuridine (BrdU) incorporation may be particularly informative, successful immunostaining may be limited due to "masked" antigen epitopes and acid-induced signal degradation. We now report an improved double immunofluorescent method for detecting p57Kip2 and BrdU in paraformaldehyde-fixed frozen sections of embryonic rat brain. We substituted deoxyribonuclease I (DNAse I) for HCl pre-treatment to expose antigenic sites in frozen sections, and employed a biotinylated tyramide-based system to enhance p57Kip2 visualization. We identified a time- and dose-dependent relationship between DNAse I treatment and double labeling of p57Kip2 and BrdU, increasing both the numbers and intensities of immunopositive nuclei. With excess DNAse I treatment, however, there was signal degradation for both BrdU and total DNA, as reflected by DAPI staining. The use of DNAse I pre-treatment significantly increases the reliability and sensitivity of immunodetection of CKI nuclear factors, and should be useful for both developmental neurobiology studies as well as cancer diagnostic applications.
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PMID:DNAse I pre-treatment markedly enhances detection of nuclear cyclin-dependent kinase inhibitor p57Kip2 and BrdU double immunostaining in embryonic rat brain. 1702 54

We used intracellular recording to investigate how muscarinic acetylcholine receptors and the serine kinase signal transduction cascade are involved in regulating transmitter release in the neuromuscular synapses of the levator auris longus muscle from adult rats. Experiments with M1 and M2 selective blockers show that these subtypes of muscarinic receptors were involved in enhancing and inhibiting acetylcholine (ACh) release, respectively. Because the unselective muscarinic blocker atropine considerably increased release, the overall presynaptic muscarinic mechanism seemed to moderate ACh secretion in normal conditions. This muscarinic function did not change when more ACh was released (high external Ca2+) or when there was more ACh in the cleft (fasciculin II). However, when release was low (high external Mg2+ or low external Ca2+) or when there was less ACh in the cleft (when acetylcholinesterase was added, AChE), the response of M1 and M2 receptors to endogenously released ACh shifted to optimize release, thus producing a net potentiation of the Mg2+-depressed level. Protein kinase A (PKA) (but not protein kinase C, PKC) has a constitutive role in promoting a component of normal release because when it is inhibited with N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide, 2 HCl, release diminishes. The imbalance of the muscarinic acetylcholine receptors (mAChRs) (with the selective block of M1 or M2) inverts the kinase function. PKC can then tonically stimulate transmitter release, whereas PKA is uncoupled. The muscarinic function can be explained by an increased M1-mediated PKC activity-dependent release and a decreased M2-mediated PKA activity-dependent release. In the presence of high external Mg2+ or low Ca2+, or when AChE is added, both mAChRs may potentiate release through an M2-mediated PKC mechanism and an M1-mediated mechanism downstream of the PKC.
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PMID:Coupling of presynaptic muscarinic autoreceptors to serine kinases in low and high release conditions on the rat motor nerve terminal. 1768 97

1. Infection with SARS coronavirus (SARS-CoV) induces a cellular stress condition known as the unfolded protein response (UPR). UPR induction is mediated primarily by viral spike (S) protein. The modulation of UPR by S protein involves activation of PERK protein kinase. Other branches of the UPR pathways controlled by IRE1 and ATF6 proteins, respectively, are not involved. 2. The protease inhibitor Ben-HCl effectively suppresses SARS-CoV infection by blocking virus entry. Viral infectivity is associated with the cleavage of S protein by the cellular protease factor Xa. 3. Two new aspects of the interaction between SARS-CoV S protein and the cell have been defined. These have important implications in the pathogenesis of SARS, providing opportunities for developing vaccines and antivirals against SARS-CoV. 4. Counteracting the UPR and targeting the cleavage of S protein with small molecule pharmaceutical agents represent two new anti-SARS-CoV strategies. 5. The receptor-binding domain of S protein delivered via adeno-associated virus can efficiently induce mucosal immunity and provide long-term protection against SARS-CoV infection.
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PMID:Roles of spike protein in the pathogenesis of SARS coronavirus. 1925 33

Glycogen synthase kinase-3 (GSK-3) is a multifunctional protein kinase that plays important roles in regulating both glycogen synthesis and protein synthesis. In the present study, we investigated GSK-3beta phosphorylation of silkworm eggs by immunoblotting with a conserved phospho-specific antibody to GSK-3beta. Results showed that the temporal changes in GSK-3beta phosphorylation were closely related to changes in glycogen levels previously reported by other researchers. In diapause eggs, an abrupt decrease in phosphorylation of GSK-3beta was found with the onset of diapause, and phosphorylation level of GSK-3beta reached a minimum level within 1 week after oviposition. However, when diapause eggs were incubated at 25 degrees C for 15 days and then transferred to 5 degrees C, a great increase in GSK-3beta phosphorylation was observed 5 days after transfer to 5 degrees C and high levels were maintained throughout the chilling period. In both non-diapause eggs and eggs whose diapause initiation was prevented by HCl, levels of GSK-3beta phosphorylation appeared to remain relatively high for several days and then greatly decreased 2 or 3 days before hatching. Moreover, GSK-3beta phosphorylation dramatically increased when dechorionated eggs were incubated in medium. The addition of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor, U0126, did not inhibit GSK-3beta phosphorylation in dechorionated eggs, although U0126 dose-dependently inhibited ERK phosphorylation. This result showed that ERK phosphorylation is not involved in upstream signaling for GSK-3beta phosphorylation and that there may be two distinct signaling pathways involved in diapause processing in Bombyx mori eggs.
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PMID:Phosphorylation of glycogen synthase kinase-3beta in relation to diapause processing in the silkworm, Bombyx mori. 1941

New strategies in the therapy for malignant diseases depend on a targeted influence on signal transduction pathways that regulate proliferation, cell growth, differentiation, and apoptosis by the activation of serine/threonine kinases. Enzastaurin (LY317615.HCl), a selective inhibitor of protein kinase Cbeta (PKCbeta), is one of these new drugs and causes inhibition of proliferation and induction of apoptosis. Pemetrexed, a multitarget inhibitor of folate pathways, is broadly active in a wide variety of solid tumors. Therefore, the effect of enzastaurin and the combination treatment with pemetrexed was analyzed when applied to the drug-sensitive ovarian cancer cell line HEY and various subclones with drug resistance against cisplatin, etoposide, docetaxel, and paclitaxel, as well as pemetrexed, and gemcitabine. In these novel chemoresistant subclones, the expression of the enzastaurin targets PKCbetaII and glycogen synthase kinase 3beta (GSK3beta) was analyzed. Exposition to enzastaurin showed various inhibitory effects on phosphorylated forms of GSK3beta and the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2. Cell proliferation experiments identified the cell line-specific half-maximal inhibitory concentration values of enzastaurin and a synergistic inhibitory effect by cotreatment with the antifolate pemetrexed. Induction of apoptosis by enzastaurin treatment was investigated by Cell Death Detection ELISA and immunoblot analyses. Simultaneous treatment with pemetrexed resulted in an enhanced inhibition of proliferation and induction of apoptosis even in partial enzastaurin-resistant cells. Therefore, the combinational effect of enzastaurin and pemetrexed can have promise in clinical application to overcome the fast-growing development of resistance to chemotherapy in ovarian cancer.
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PMID:Combination of enzastaurin and pemetrexed inhibits cell growth and induces apoptosis of chemoresistant ovarian cancer cells regulating extracellular signal-regulated kinase 1/2 phosphorylation. 1970 1

Due to our interest in protein kinase modulating compounds, we developed syntheses for benzo[cd]azulenes. By using very common catalysts and reagents, such as t-BuOK, HCl, and mCPBA, the commercially available guaiazulene is converted in three steps into tricyclic tropone derivatives. Electrophilic aromatic substitution reactions of guaiazulene proceed without a catalyst. Complex one-pot reactions convert 1'-hydroxyalkyl azulenes into tricyclic heptafulvenes, and finally, the mild oxidant mCPBA cleaves the semicyclic C horizontal lineC double bonds to furnish tropones.
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PMID:Benzo[cd]azulene skeleton: azulene, heptafulvene, and tropone derivatives. 1990 21

The ezrin-radixin-moesin proteins provide a regulated linkage between membrane proteins and the cortical cytoskeleton and also participate in signal transduction pathways. Ezrin is localized to the apical membrane of parietal cells and couples the protein kinase A activation cascade to the regulated HCl secretion. Our recent proteomic study revealed a protein complex of ezrin-ACAP4-ARF6 essential for volatile membrane remodeling (Fang, Z., Miao, Y., Ding, X., Deng, H., Liu, S., Wang, F., Zhou, R., Watson, C., Fu, C., Hu, Q., Lillard, J. W., Jr., Powell, M., Chen, Y., Forte, J. G., and Yao, X. (2006) Mol. Cell Proteomics 5, 1437-1449). However, knowledge of whether ACAP4 physically interacts with ezrin and how their interaction is integrated into membrane-cytoskeletal remodeling has remained elusive. Here we provide the first evidence that ezrin interacts with ACAP4 in a protein kinase A-mediated phosphorylation-dependent manner through the N-terminal 400 amino acids of ACAP4. ACAP4 locates in the cytoplasmic membrane in resting parietal cells but translocates to the apical plasma membrane upon histamine stimulation. ACAP4 was precipitated with ezrin from secreting but not resting parietal cell lysates, suggesting a phospho-regulated interaction. Indeed, this interaction is abolished by phosphatase treatment and validated by an in vitro reconstitution assay using phospho-mimicking ezrin(S66D). Importantly, ezrin specifies the apical distribution of ACAP4 in secreting parietal cells because either suppression of ezrin or overexpression of non-phosphorylatable ezrin prevents the apical localization of ACAP4. In addition, overexpressing GTPase-activating protein-deficient ACAP4 results in an inhibition of apical membrane-cytoskeletal remodeling and gastric acid secretion. Taken together, these results define a novel molecular mechanism linking ACAP4-ezrin interaction to polarized epithelial secretion.
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PMID:Phospho-regulated ACAP4-Ezrin interaction is essential for histamine-stimulated parietal cell secretion. 2036 10


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