Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several monoclonal antibodies directed against a number of T cell surface molecules are used to elucidate the role of these molecules (cell surface molecules) in T cell activation. The activation of T cells via these molecules are both antigen-dependent (CD3/TcR complex) and antigen-independent. Irrespective of their antigen dependency, these monoclonal antibodies activate T cells by a classical signal transduction pathway, in which the binding of monoclonal antibodies to their cell surface receptors leads to activation of phospholipase C resulting in the depolarization of plasma membrane, hydrolysis of IP2 and IP3 and DAG, the 'second messengers'. IP3 leads to mobilization of intracellular calcium to contribute to an increase in [Ca++]i, whereas DAG causes activation and translocation of PKC and an increasing apparent affinity for Ca++. The role of IP4 in the mobilization of intracellular calcium is emerging. In addition, influx of extracellular calcium also contributes to increase in [Ca++]i. The increase in [Ca++]i following activation via some T cell surface antigen is predominantly due to intracellular mobilization of Ca++ (e.g. CD3/TcR complex), whereas activation via other T cell surface antigen, the increase in [Ca++]i is almost entirely due to an influx of extracellular calcium (e.g. CD5 antigen). All these molecules activate autocrine system of T cell growth, namely IL-2 production, IL-2 receptor expression and T cell proliferation.
Mol Cell Biochem
PMID:Mechanisms of transmembrane signalling in human T cell activation. 269 33

Protein kinase C (PKC) is a Ca2+- and phospholipid-dependent protein kinase that appears to play a critical role in the regulation of cell growth. Melittin was previously shown to inhibit Ca2+- and phosphatidylserine (PS)-dependent PKC activity with an inhibitory potency that was reduced as the PS concentration was elevated. In this report, we found that melittin could inhibit activation of PKC by Ca2+ and PS, with an IC50 of 3 microM. When the enzyme activity was released from regulation by Ca2+ and PS by the generation of an active catalytic fragment of PKC through limited proteolysis, melittin inhibited the enzyme activity with an IC50 of 25 microM. Through inhibitor binding studies and enzyme kinetics, we established that melittin binds directly to the catalytic domain of PKC and that the substrate MgATP can release bound melittin from PKC. Melittin bound to PKC in the absence of PKC cofactors, and MgATP completely disrupted the binding of melittin to PKC, whereas phosphoacceptor substrates did not. The catalytic fragment of PKC, which contains two potential ATP-binding sites according to sequence analysis of PKC-encoding cDNAs, also bound melittin. The kinetics of inhibition of the catalytic fragment were consistent with a noncompetitive inhibition with respect to the substrate ATP, providing evidence that the antagonism of the binding of melittin to PKC by MgATP is not due to a direct competition between MgATP and melittin at the active site of PKC.
Mol Pharmacol 1989 Sep
PMID:ATP-sensitive binding of melittin to the catalytic domain of protein kinase C. 277 22

Purified inhibitor of the cyclic AMP-dependent protein kinase (PKI) has been used as a probe to determine if hormone and cyclic AMP-induced activation of the cardiac alkaline triacylglycerol (TG) lipase is mediated through the cAMP-dependent protein kinase. Addition of CAM (cyclic AMP, Mg-ATP, and 3-isobutyl, 1-methylxanthine) to any of the four fractions (homogenate, 10,000 g supernatant, 105,000 g supernatant, or heparin-Sepharose eluate) from heparin perfused heart activated the TG lipase 60% to 110%. Preincubation of these fractions with 33 ng of PKI had no effect on control enzyme activity. Addition of PKI (33 ng) to extracts following CAM activation had little effect on homogenate TG lipase activity, but reduced activities in 10,000 g and 105,000 g supernatant fractions to their respective control levels, and inhibited TG hydrolase activity of activated heparin-Sepharose eluate to 50% below the control activity. If extracts were preincubated with PKI prior to CAM addition, TG lipase activity was reduced to approximately 50% below control levels in all fractions. PKI addition (33 ng) to 105,000 g supernatant obtained from hearts stimulated 60% by epinephrine perfusion reduced activity to 50% below the control level. PKI inhibition of TG lipase activity of 105,000 g supernatant could be reversed by adding 0.5 microgram of catalytic subunit of protein kinase (PKC) to the extract. The inhibition below control levels caused by CAM and PKI indicate that the PKI-PKC complex by itself or in combination with other extract molecules, has an inhibitory effect on the TG lipase.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Cell Cardiol 1987 Jul
PMID:Protein kinase inhibitor blocks the activation of a myocardial triacylglycerol lipase. 282 94

Y-1 adrenal tumor cells and rat fasciculata cells were shown to possess an enzyme with the properties of protein kinase C. Activity was stimulated by Ca2+ and phospholipid (specifically phosphatidylserine). Enzyme activity was stimulated by addition of phorbol ester to a cell homogenate (ED50 10 nM) and inhibited by trifluoperazine (ID50 10 microM). ACTH and cyclic AMP added to Y-1 cells increased the activity of protein kinase C. Dose-response curves with ACTH showed that the hormone was effective in stimulating protein kinase C at lower concentrations than those required to increase steroid synthesis. When phorbol ester was added to Y-1 cells, total kinase C activity was diminished. Neither phorbol ester nor ACTH causes redistribution of protein kinase C between membranes and cytosol. Phorbol ester also stimulates steroid production by Y-1 cells. Protein kinase C phosphorylates 5 proteins in Y-1 cells (67, 61, 32, 16 and less than 14.4 kDa). Puromycin and cycloheximide increase the activity of protein kinase C in adrenal cells. It is concluded that protein kinase C may play an ancillary role in regulation of adrenal steroid synthesis but does not mediate the classical steroidogenic response that results from activation of adenylate cyclase by ACTH.
Mol Cell Endocrinol 1985 Dec
PMID:Protein kinase C in adrenal cells: possible role in regulation of steroid synthesis. 300 Aug 51

The cellular actions of vasopressin (AVP) in the anterior pituitary were investigated. HPLC analysis of [3H]inositol-labeled cells indicated that AVP stimulated a rapid increase in inositol-1,4,5 trisphosphate (IP3), inositol-1,4 bisphosphate, and inositol-4 monophosphate levels. While CRF had no effect on basal IP3 levels, it blocked their stimulation by AVP. CRF-stimulated ACTH secretion and cAMP accumulation were potentiated by AVP. AFter dexamethasone (DEX) treatment (20 nM, 18 h), CRF-dependent ACTH secretion and cAMP accumulation were attenuated but AVP was still able to potentiate both of these actions of CRF suggesting that cellular actions of AVP may be resistant to DEX effects. Therefore, [3H]AVP binding was determined in control and DEX-treated cells. Pretreatment with DEX had no effect on either AVP receptor affinity or on the number of available binding sites. Consistently, stimulation of IP3 production by AVP in DEX-treated cells was comparable to that of control cells. Protein kinase C activators such as 12-O-tetradecanoyl-phorbol-13-acetate and dioctanoylglycerol were either near additive with CRF or also potentiated the action of CRF on ACTH secretion, respectively, even after DEX pretreatment. These results indicate that, in the anterior pituitary, distinct intracellular signaling pathways mediate the actions of CRF and AVP; cAMP mediates CRF actions and IP3/protein kinase C mediate the effects of AVP. Neuromodulation of ACTH secretion by dual effector mechanisms which exhibit a complex mode of interaction and only one of which is negatively influenced by glucocorticoids, provides these cells a mechanisms by which appropriate responses can be elicited under various physiological states.
Mol Endocrinol 1987 Jul
PMID:The cellular actions of vasopressin on corticotrophs of the anterior pituitary: resistance to glucocorticoid action. 315 72

Insulin and tumor-promoting phorbol esters such as phorbol 12-myristate 13-acetate (PMA) share some biological activities in normal hepatocytes and in some lines of cultured hepatoma cells. To investigate the possibility that some of these common effects might involve a common pathway, we examined the effects of insulin and PMA on several biological processes in normal and protein kinase C-deficient H4IIE rat hepatoma cells. Protein kinase C deficiency was achieved by preincubating the cells in high concentrations of PMA, and was documented by direct enzyme measurement in soluble and particulate cellular fractions, and by analysis of immunoreactive protein kinase C concentrations in whole cellular homogenates. In the protein kinase C-deficient cells, the following actions of insulin remained at near normal levels: stimulated phosphorylation of the ribosomal protein S6; activation of a ribosomal S6 protein kinase; and increases in ornithine decarboxylase activity and mRNA accumulation. PMA stimulated all of these responses in the normal cells, but none of them in the PMA-pretreated cells. We conclude that insulin can exert some of its actions in a normal manner in protein kinase C-deficient H4IIE hepatoma cells (ATCC CRL 1548) and that some of the actions insulin holds in common with PMA may be due to common activation of one or more distal pathways. A candidate for such a distal step is activation of the ribosomal protein S6 protein kinase.
Mol Endocrinol 1987 Jan
PMID:Insulin action in normal and protein kinase C-deficient rat hepatoma cells. Effects on protein phosphorylation, protein kinase activities, and ornithine decarboxylase activities and messenger ribonucleic acid levels. 333 10

cDNA clones representing genes whose expression is modulated by treatment with mitogens and tumor promoters were isolated and characterized. TPA-S1 corresponds to an mRNA species whose abundance was increased markedly within 1 h of exposure to the tumor promoter 12-O-tetradecanoyl phorbol-13-acetate (TPA), and TPA-R1 represents an mRNA that was decreased in TPA-treated cells. The induction of TPA-S1 was blocked by actinomycin D but was not affected by cycloheximide, and it was specific for phorbol esters with tumor-promoting activity. The role of protein kinase C in the induction of TPA-S1 is supported by the following lines of evidence. (i) Agents that activated protein kinase C (TPA, platelet-derived growth factor, and diacylglycerol) also increased TPA-S1 mRNA levels. (ii) A potent PKC inhibitor blocked the induction of TPA-S1. (iii) Down-regulation of PKC activity, by treatment of cells with TPA for 24 h, resulted in a loss of responsiveness to TPA-S1 induction by subsequent TPA treatment. DNA sequence analysis of TPA-S1 predicts a cysteine-rich, secreted protein with a molecular weight of 22.6 X 10(3) that exhibits homology with sequences representing a protein with human erythroid-potentiating activity and protease inhibitory activity.
Mol Cell Biol 1987 Aug
PMID:Molecular cloning of gene sequences regulated by tumor promoters and mitogens through protein kinase C. 367 Feb 94

Neuropeptide Y (NPY) is a 36 amino acid peptide present in the central and peripheral nervous systems. Treatment with Nerve Growth Factor (NGF) induces an increase in NPY mRNA in PC12 cells, a rat pheochromocytoma cell line extensively used as a model of neuronal differentiation. Stimulators of both cAMP and calcium-phospholipid dependent protein kinases (PKA and PKC respectively) increase NPY mRNA levels in a similar way to NGF. Nevertheless, H-89, a specific inhibitor of PKA failed to block NGF stimulated NPY mRNA accumulation. Furthermore, direct measurement of PKA activity in cell extracts showed no increase following NGF, in contrast to forskolin. H7, an inhibitor of both PKC and PKA systems completely abolished the NGF induced increase in NPY mRNA, suggesting that PKC is necessary for NGF induction of the NPY gene. NGF also increased PKC activity in cell extracts in a similar way to phorbol myristate acetate (PMA). Use of a reporter function, chloramphenicol acetyl transferase, controlled by 700 base pairs of the 5' flanking region of the NPY gene demonstrated that NGF and phorbol ester stimulated transcription of the NPY gene. This stimulation could be blocked by pre-incubating PC12 cells with calphostin C, a specific inhibitor of PKC. Our results indicate that NGF induces NPY gene expression via activation of PKC system. Although an increase in adenylate cyclase activity affects the expression of the NPY gene, activation of PKA appears not to be involved in mediating the NGF effects.
Brain Res Mol Brain Res 1994 Jun
PMID:Role of protein kinase C in mediating NGF effect on neuropeptide Y expression in PC12 cells. 752 99

Differential expression of PAI-1 in connective tissues has been associated etiologically with some forms of arthritis. Our objective was to delineate the mechanisms by which PGE2 and IL-1 beta, inflammatory mediators commonly found at sites of inflammation, regulate the expression and synthesis of PAI-1 in human synoviocytes. PGE2 (and PGE1) inhibited PAI-1 mRNA expression and secretion in a dose-dependent manner with an IC50 (for antigen secretion) of 4.6 x 10(-10) M and 8.7 x 10(-10) M, respectively. Cyclic AMP agonists forskolin, Sp-cAMP, and IBMX mimic the effects of the PGEs. rhIL-1 beta stimulated the secretion of PAI-1 in a dose-dependent fashion under basal culture conditions; the effect was reversed by actinomycin D and the protein kinase inhibitors H7 and staurosporine but not KT-5720. PMA, an activator of protein kinase C, transiently increased (maximum 3 h) the expression of PAI-1 mRNA by approximately 10-fold, especially the 3.2 kb species. However, there was no significant increase in PAI-1 antigen secreted into the culture medium after PMA (100-300 nM) treatment. The half-life (t1/2) of PAI-1 mRNA, both the 3.2 and 2.2 transcripts was about 9.6 h (mean n = 3) and PGE2 has no affect on the stability of both messages. PGE2 reduced the rate of PAI-1 gene transcription as judged by run-off assays. The NSAID naproxen (30 micrograms/ml) induced the expression of PAI-1 mRNA over basal levels and super-induced the inhibitor's expression above rhIL-1 beta stimulated levels. Our results suggest that PGE2 suppresses PAI-1 expression and synthesis by activation of the cAMP/PKA system and inhibition of the rate of gene transcription. Data concerning the activation of PKC suggest that the expression, synthesis and release of the PAI-1 may be differentially regulated in normal human synoviocytes.
Mol Cell Endocrinol 1994 Jul
PMID:Transcriptional regulation of plasminogen activator inhibitor-1 expression in human synovial fibroblasts by prostaglandin E2: mediation by protein kinase A and role of interleukin-1. 752 83

Stimulation of human platelets causes a dramatic increase in phosphorylation of various proteins at tyrosine residues. The abundance of protein tyrosine kinases of the src-family in platelets, particularly pp60c-src, suggests an important role of these kinases in response to stimulation events. We have shown that pp60c-src is activated on agonist-induced platelet stimulation with respect to its substrate affinity. This was accompanied by phosphorylation of pp60c-src at Ser-12, a residue which is phosphorylated by PKC. Inhibition of PKC with a specific inhibitor, Ro-31-8220, suppressed thrombin-induced translocation of pp60c-src to the cytoskeleton. On the basis of our data, we suggest that the cytoskeletal association of pp60c-src is dependent on phosphorylation of pp60c-src at Ser-12 by PKC. Phosphorylation at Ser-12 in the membrane-binding domain might be the signal that displaces pp60c-src from the plasma membrane and, accompanied with the increased substrate affinity, facilitates phosphorylation of putative substrates.
Cell Mol Biol (Noisy-le-grand) 1994 Jul
PMID:The protein tyrosine kinase pp60c-src is activated upon platelet stimulation. 752 17


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