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 present study was undertaken to investigate the effects of transforming growth factor (TGF)-beta 1 on ovarian steroidogenesis in immature or moderately mature porcine granulosa cells in vitro. TGF-beta 1 (0.01-10 ng/ml) significantly attenuated progesterone release from the basal and follicle stimulating hormone-stimulated porcine granulosa cells, and significantly increased DNA synthesis. TGF-beta 1 also significantly increased the extracellular accumulation of cyclic AMP, but did not change the production of inositol phosphate or the intracellular calcium concentration in these cells. Thus, TGF-beta 1 appears to have a direct effect on porcine granulosa cell function, regulating the differential synthesis of progesterone mainly via the intracellular signal transduction of the cyclic AMP-protein kinase A pathway. This growth factor may play a physiologically significant role in controlling differentiation of immature and moderately mature porcine granulosa cells via an autocrine/paracrine mechanism.
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PMID:Autocrine/paracrine function of transforming growth factor-beta 1 in porcine granulosa cells. 786 83

Video microscopy and digital imaging were used to quantitatively analyze lymphocyte adhesion and formation of pseudopodia on the extracellular matrix protein fibronectin (FN). A morphology kinetics assay comparing pseudopodial extension values over a 24-h period showed that HPB-ALL T leukemic cells undergo a wave of morphologic change, returning to a round shape after 8 h. Using anti-alpha 4 and anti-alpha 5 mAbs and a panel of cell types that are single or double positive for expression of the alpha 4/beta 1 and alpha 5/beta 1 FN binding integrins, it was determined that cell adhesion to FN was influenced by both beta 1-integrins, whereas alpha 4/beta 1 was found to be the major FN receptor mediating pseudopodia extension. The protein kinase inhibitor staurosporine, the protein kinase C inhibitors calphostin C and chelerythrine, and the protein tyrosine kinase inhibitor herbimycin A blocked pseudopodial extension in HPB-ALL cells. In contrast, two cAMP-dependent protein kinase inhibitors H8 and H89 did not inhibit. Inhibitors of phospholipase A2, lipoxygenases, and cyclooxygenases could block formation of pseudopodia, yet had little or no effect on cell adhesion to FN. The preincubation of cells with arachidonic acid could prevent the inhibition mediated by the reversible phospholipase A2 inhibitor cibacron blue. We conclude that the formation of lymphocyte pseudopodia in response to FN can utilize the adhesive and signaling activities of the alpha 4/beta 1-integrin and the enzymatic activities of protein kinases and phospholipases.
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PMID:Regulation of lymphocyte pseudopodia formation by triggering the integrin alpha 4/beta 1. 786 87

We have cloned the gene for the rhesus macaque beta 1-adrenergic receptor. In addition to the protein coding block, we have sequenced its 5' (1424 bp) and 3' (1534 bp) flanking regions and aligned them with comparable sections of the rat beta 1-adrenergic receptor gene. The rhesus macaque gene contains a 1440 bp open reading frame which codes for a deduced protein of 480 amino acids that is 95% and 89% similar to the human and rat beta 1-adrenergic receptors, respectively. The rhesus macaque beta 1-adrenergic receptor contains conserved sites for potential N-linked glycosylation and cAMP-dependent protein kinase phosphorylation identified within the human and rat receptors, but differs in the structure and length of the third cytoplasmic loop. The 400 bases of 5' flanking sequence proximal to the protein coding block are highly conserved (84% similarity) between the rat and rhesus macaque genes. The entire 3' flanking sequence, which extends beyond two potential polyadenylation sites at 1050 and 1337 bp relative to the translation termination codon, is also highly conserved between the two species. Comparison of the flanking sequences of the two species reveals conserved regulatory sequences which may be important for beta 1-adrenergic receptor expression and transcriptional modulation.
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PMID:The rhesus macaque beta 1-adrenergic receptor gene: structure of the gene and comparison of the flanking sequences with the rat beta 1-adrenergic receptor gene. 798 8

The amino-terminal regulatory domain portion of each protein kinase C (PKC) family member (which in the case of PKC beta 1 includes the pseudosubstrate, C1, V1 and C2 domains) plays an important role in regulating the kinase activity of the carboxyl-terminal catalytic domain. To examine the possibility that this regulatory domain region (designated 'PAT') might have biological functions independent of the catalytic domain, we have developed derivatives of R6 cells which stably express a truncated PKC beta 1 cDNA that encodes the amino-terminal 317 amino acids, including the entire regulatory domain. These R6-plPAT cells express abundant amounts of a 38 kDa protein which binds a labeled phorbol ester, but lacks protein kinase activity. In contrast to the 79 kDa PKC beta 1 holoenzyme which, when overexpressed in R6 cells, is found mostly in the cytosol, the 38 kDa PAT protein is predominantly associated with the particulate subcellular fraction. Furthermore, the PAT protein fails to show down-regulation following treatment of R6-plPAT cells with 12-O-tetradecanoylphorbol-13-acetate (TPA). Evidence is also presented that TPA-stimulated growth is suppressed in R6-plPAT cells. These findings suggest that the PKC beta 1 regulatory domain could be involved in the suppression of mitogenic signaling.
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PMID:Suppression of mitogenic activity by stable expression of the regulatory domain of PKC beta. 800 Dec 56

gamma-Aminobutyric acid type A receptor subunits (GABAA) can be divided into five classes, alpha, beta, gamma, delta, and rho, based on sequence homology. We have used purified fusion proteins of the major intracellular domain of GABAA receptor subunits produced in Escherichia coli to examine the phosphorylation of these subunits by cGMP-dependent protein kinase (PKG) and multifunctional calcium/calmodulin-dependent protein kinase (CAM KII). Both PKG and CAM KII phosphorylated a purified beta 1 subunit fusion. Both of these kinases phosphorylated serine 409 within the beta 1 subunit; in addition, CAM KII also phosphorylated serine 384 as determined by site-specific mutagenesis. Fusion proteins of the major intracellular domains of the gamma 2S and gamma 2L subunits were produced. These proteins differ by 8 amino acids (LLRMFSFK). Both the gamma 2L and gamma 2S fusion proteins were excellent substrates of CAM KII. However, the gamma 2L fusion protein was phosphorylated to higher stoichiometry due to the phosphorylation of serine 343 within this 8-amino acid insertion. Both the gamma 2L and gamma 2S subunits were phosphorylated on common residues by CAM KII identified as serine 348 and threonine 350. These results identify specific sites of phosphorylation for CAM KII and PKG within GABAA receptor subunits, suggesting a role for these two kinases in modulating GABAA receptor function in vivo.
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PMID:Differential phosphorylation of intracellular domains of gamma-aminobutyric acid type A receptor subunits by calcium/calmodulin type 2-dependent protein kinase and cGMP-dependent protein kinase. 802 73

The protein kinase inhibitors (PKIs) are potent inhibitors of the catalytic (C) subunit of cAMP-dependent protein kinase. In this study, the interaction between Phe10 of PKI and the C subunit residues Tyr235 and Phe239 was investigated using site-directed mutagenesis. Previous peptide studies as well as the crystal structure suggested that these residues may play a key role in C-PKI binding. The C subunit codons for Tyr235 and Phe239 were changed singly and in combination to serine codons. The mutated C alpha proteins were overexpressed in Escherichia coli. The purified C alpha Y235S, C alpha F239S, and C alpha Y235S/F239S proteins did not exhibit any differences in their Km(app) for the peptide substrate Kemptide (Leu-Arg-Arg-Ala-Ser-Leu-Gly) or Vmax(app), with respect to wild-type C alpha. All of the C subunit mutants displayed less than 2-fold changes in their Km(app) for ATP. The PKI alpha isoform displayed increased IC50 values for C alpha Y235S (71-fold), C alpha F239S (150-fold), and C alpha Y235S/F239S (1800-fold). Similarly, the PKI beta 1 protein showed increased IC50 values against the C alpha Y235S, C alpha F239S, and C alpha Y235S/F239S proteins, 9.4-, 11-, and 44-fold, respectively. In addition, the PKI alpha F10 codon was altered to an alanine codon, and this mutation decreased its ability to inhibit C alpha kinase activity, but did not affect its ability to inhibit C alpha Y235S/F239S. The mutation of Tyr235 and Phe239 to serines, however, did not alter the ability of the type II R subunit to inhibit phosphotransferase activity. These results suggest that C alpha Y235 and C alpha F239 are important for specific inhibition by both PKI alpha and PKI beta but not the type II R subunit and that mutations at these residues would be useful for in vivo analysis of C-PKI interactions.
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PMID:Evidence for the importance of hydrophobic residues in the interactions between the cAMP-dependent protein kinase catalytic subunit and the protein kinase inhibitors. 802 74

The lipolytic action of the beta 3-adrenoceptor-selective agonist 4-[2-[(2-hydroxy-2-(3-chlorophenyl)ethyl)-amino]propyl]-phenoxyacetic acid (BRL 37344) was compared to that of isoprenaline in adipocytes derived from rat white adipose tissue. Concentration-response curves for activation of lipolysis by each agonist correlated well with the dose-response curves for activation of cAMP-dependent protein kinase (A-Kinase). Addition of propranolol at a concentration (0.1 microM) sufficient to block beta 1- and beta 2-adrenoceptors did not affect the stimulation of either parameter by BRL 37344 or isoprenaline, indicating that lipolysis was predominantly dependent on beta 3-adrenoceptor stimulation. Blockade of beta 3-adrenoceptors by 3 microM propranolol antagonized both A-Kinase activation and glycerol release. Activation of lipolysis by BRL 37344 was blocked by treatment of the cells with N-[2-p-(bromocinnamylamino)ethyl]-5-isoquinolinesulphonamide (H89) a potent and selective isoquinolinesulphonamide inhibitor of A-Kinase activity. Taken together, these results indicate that lipolysis in rat white adipocytes is primarily controlled by beta 3-adrenoceptors, and that cyclic AMP generation alone is responsible for activation of lipolysis in this tissue.
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PMID:Correlation of beta 3-adrenoceptor-induced activation of cyclic AMP-dependent protein kinase with activation of lipolysis in rat white adipocytes. 810 24

IL-11 and IL-6 are fibroblast-derived cytokines with overlapping biologic properties. To determine whether IL-11 and IL-6 are similarly regulated, we characterized the effects of rIL-1 and TGF-beta (beta 1 and beta 2) on human lung fibroblast IL-11 production and compared this regulation with that of IL-6. Unstimulated fibroblasts did not produce significant amounts of IL-11, whereas rIL-1 alpha and TGF-beta were dose-dependent stimulators of IL-11 protein production, mRNA accumulation, and gene transcription. rIL-1 alpha and TGF-beta also interacted in a synergistic fashion to further increase IL-11 protein production and mRNA accumulation. The effects of rIL-1 and TGF-beta individually were not altered by the cyclic nucleotide-dependent protein kinase inhibitor HA1004, protein kinase C (PKC) inhibition with staurosporine, or chronic phorbol ester preincubation, or the calmodulin antagonists W7 and TFP. The effects of rIL-1 alpha and TGF-beta in combination were also unaltered by HA1004, staurosporine, and chronic phorbol ester exposure. A23187, however, did induce IL-11 mRNA accumulation and W7 and TFP did reverse the synergistic stimulation caused by rIL-1 and TGF-beta in combination. In contrast with the regulation of IL-11, TGF-beta did not effectively stimulate IL-6 mRNA accumulation, rIL-1 alpha was a more potent stimulator of IL-6 than IL-11 production, and rIL-1-induced IL-6 mRNA accumulation was augmented by W7 and TFP. These studies demonstrate that: 1) rIL-1, TGF-beta, and agents that increase intracellular calcium stimulate lung fibroblast IL-11; 2) the IL-11 stimulatory effects of rIL-1 and TGF-beta are, at least partially, transcriptionally mediated and are the result of signal transduction pathways that are largely PKC, cyclic nucleotide, and calmodulin independent; and 3) rIL-1 and TGF-beta interact in a synergistic fashion to further increase fibroblast IL-11 production and that this synergy is mediated by a largely PKC- and cyclic nucleotide-independent and calmodulin-dependent activation pathway. Importantly, they also demonstrate that rIL-1 and TGF-beta stimulate lung fibroblast IL-6 and IL-11 production via distinct and differentially regulatable activation pathways.
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PMID:IL-1 and transforming growth factor-beta regulation of fibroblast-derived IL-11. 813 53

The nonobese diabetic (NOD) mouse is subject to autoimmune disease-associated lymphocytic attack on the salivary glands with a corresponding loss of exocrine function. Downregulation of stimulus response to the beta-adrenoceptor agonist, isoproterenol, appears to be related to a decline in beta-adrenergic receptor density, changes in the level of intracellular second messenger signaling component adenosine 3',5'-cyclic monophosphate, and protein kinase A activity. An autoantibody to the beta 1-adrenergic receptor present in the sera of diabetic NOD mice may be involved in the reduced agonist response by virtue of its ability to retard dihydroalprenolol radioligand binding to receptors in the membranes of salivary glands from control mice and recognition of purified beta 1-adrenergic receptor by immunoblotting techniques.
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PMID:Downregulation of beta-adrenergic receptors and signal transduction response in salivary glands of NOD mice. 816 82

Bearing in mind the importance of upper-body obesity for the insulin resistance (or metabolic) syndrome and the abnormalities in free fatty acid metabolism associated with this disorder, the regulation of lipolysis in isolated subcutaneous adipocytes was investigated in 13 72-yr old upper-body obese men with insulin resistance and glucose intolerance and in 10 healthy 72-yr-old men. There was a marked resistance to the lipolytic effect of noradrenaline in the metabolic syndrome due to defects at two different levels in the lipolytic cascade. First, an 80-fold decrease in sensitivity to the beta 2-selective agonist terbutaline (P < 0.001) which could be ascribed to a 50% reduced number of beta 2-receptors (P < 0.005) as determined with radioligand binding. The groups did not differ as regards dobutamine (beta 1) or clonidine (alpha-2) sensitivity, nor beta 1-receptor number. The mRNA levels for beta 1- and beta 2-receptors were similar in the two groups. Second, the maximum stimulated lipolytic rate was markedly reduced in the metabolic syndrome. This was true for isoprenaline (nonselective beta-agonist), forskolin (activating adenylyl cyclase), and dibutyryl cAMP (activating protein kinase). In regression analysis, the observed abnormalities in lipolysis regulation correlated in an independent way with the degree of glucose intolerance (r = -0.67) and beta 2-receptor number with insulin resistance (r = 0.67). In conclusion, the results of this study indicate the existence of lipolytic resistance to catecholamines in the adipose tissue of elderly men with the metabolic syndrome, which may be of importance for impaired insulin action and glucose intolerance. The resistance is located at a posttranscriptional level of beta 2-receptor expression and at the protein kinase-hormone sensitive lipase level.
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PMID:Multiple lipolysis defects in the insulin resistance (metabolic) syndrome. 820 Sep 97


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