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 aim of this study was to elucidate the cellular mechanisms of action of epidermal growth factor (EGF) inhibition of parietal cell secretion. EGF effects on histamine- and carbachol-stimulated [14C]aminopyrine (AP) uptake and intrinsic factor (IF) secretion were evaluated in isolated rabbit parietal cells. EGF inhibited histamine-stimulated [14C]AP uptake and IF secretion through a reduction in stimulated adenosine 3',5'-cyclic monophosphate (cAMP) levels. EGF decreased the phosphorylation of a cytosolic 30-kDa, histamine-stimulated, cAMP-dependent protein kinase substrate. These effects on histamine-stimulated activation were reversed by pertussis toxin preincubation. EGF inhibited carbachol-stimulated [14C]AP uptake and IF secretion, but did not alter the carbachol-stimulated Ca2+ transient. These results indicate that EGF inhibits histamine-stimulated secretion through the inhibitory Gi guanosine 5'-triphosphate-binding protein and carbachol-stimulated secretion through a mechanism independent of the activation of an increase in intracellular Ca2+.
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PMID:Effects of epidermal growth factor on signal transduction in rabbit parietal cells. 215 44

Past work described the partial purification and characterization of a novel serine protein kinase activity designated protein kinase N (PKN) that is activated by nerve growth factor (NGF) in cultured PC12 cells [Rowland et al. (1987) J. Biol. Chem. 262; 7504-7513]. We have now devised a rapid, sensitive technique for partially purifying and assaying PKN activity in cell extracts. This methodology was applied to the IARC-EW-1 osteosarcoma and several additional non-neuronal cell lines that possess NGF receptors but that lack both morphological and a variety of additional biochemical responses to NGF. In each case, NGF significantly elevated PKN activity. The assay also revealed activation of PKN activity in IARC-EW-1 cells by additional agents, including epidermal growth factor, fibroblast growth factor, phorbol ester, and a cAMP analog. Also tested were an NGF-receptor-deficient PC12 cell variant and sublines thereof into which human NGF receptors had been introduced [Hempstead et al. (1989) Science 243; 373-375]. Acquisition of the NGF receptors resulted in NGF-activatable PKN activity. These findings indicate that detection of PKN activity may serve as a sensitive means to test NGF responsiveness in cells lacking macroscopic responses to the factor and that non-neuronal cells may be useful for studying primary signaling events in the NGF mechanism of action.
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PMID:Nerve growth factor (NGF) responses by non-neuronal cells: detection by assay of a novel NGF-activated protein kinase. 215 63

Studies were performed to examine interactions between the adenylyl cyclase (AC) and phospholipase C (PLC) signaling systems in cultured rat inner medullary collecting duct cells. Stimulation of AC by either arginine vasopressin (AVP) or forskolin or addition of exogenous cAMP inhibits epidermal growth factor (EGF)-stimulated PLC. This inhibition is mediated by activation of cAMP-dependent kinase as it is prevented by pretreatment with the A-kinase inhibitor, N-[2-(methylamino)ethyl]-5-isoquinoline-sulfonamide (H8) but not by the C-kinase inhibitor, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7). Exposure to EGF eliminates AVP-stimulated cAMP generation. This is not mediated by a cyclooxygenase product as inhibition by EGF is observed even in the presence of the cyclooxygenase inhibitor, flurbiprofen. Inhibition by EGF is not due to an increase in inositol trisphosphate (IP3) as exposure of saponin-permeabilized cells to exogenous IP3 is without effect. Inhibition by EGF is prevented by pretreatment with the C-kinase inhibitor, H7, but not by the A-kinase inhibitor, H8. Exposure to the synthetic diacylglycerol (DAG), dioctanoylglycerol, also inhibits AVP-stimulated AC activity; therefore, inhibition by EGF is due to activation of protein kinase C. Thus, in cultured rat inner medullary collecting duct cells, cAMP and DAG function as mutually inhibitory second messengers with each impairing formation of the other.
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PMID:Cyclic adenosine monophosphate and diacylglycerol. Mutually inhibitory second messengers in cultured rat inner medullary collecting duct cells. 216 48

Previous work identified a protein kinase activity that phosphorylates the epidermal growth factor (EGF) receptor at Thr669. An assay for this protein kinase activity present in homogenates prepared from A431 human epidermoid carcinoma cells was developed using a synthetic peptide substrate corresponding to residues 663-681 of the EGF receptor (peptide T669). Here we report that a greater initial rate of T669 phosphorylation was observed in experiments using homogenates prepared from EGF- or phorbol ester-treated cells compared with control cells. EGF and 4 beta-phorbol 12-myristate 13-acetate (PMA) caused a 6-fold and a 2-fold increase in protein kinase activity, respectively. A kinetic analysis of T669 phosphorylation demonstrated that the increase in protein kinase activity observed was accounted for by an increase in Vmax. To examine the interaction between protein kinase C and signal transduction by the EGF receptor, the effect of pretreatment of cells with PMA on the subsequent response to EGF was investigated. Treatment of cells with PMA caused greater than 90% inhibition of the EGF-stimulated tyrosine phosphorylation of the EGF receptor and abolished the EGF-stimulated formation of soluble inositol phosphates. In contrast, PMA was not observed to inhibit the stimulation of T669 protein kinase activity caused by EGF. Thus, the apparent functional desensitization of the EGF receptor caused by PMA does not inhibit signal transduction mediated by the T669 protein kinase. Our results demonstrate that EGF receptor transmodulation alters the pattern of signal-transduction pathways that are utilized by the EGF receptor.
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PMID:Signal transduction by the epidermal growth factor receptor after functional desensitization of the receptor tyrosine protein kinase activity. 216 44

Treatment of PC12 cells with either nerve growth factor (NGF), a differentiating factor, or epidermal growth factor (EGF), a mitogen, resulted in 7-15-fold activation of a protein kinase activity in cell extracts that phosphorylated microtubule-associated protein (MAP) 2 on serine and threonine residues in vitro. Both the NGF-activated kinase and the EGF-activated kinase could be partially purified by sequential chromatography on DEAE-cellulose, phenyl-Sepharose and hydroxylapatite, and were identical with each other in their chromatographic behavior, apparent molecular mass (approximately 40 kDa) on gel filtration, substrate specificity, and phosphopeptide-mapping pattern of MAP2 phosphorylated by each kinase. Moreover, both kinases were found to be indistinguishable from a mitogen-activated MAP kinase previously described in growth-factor-stimulated or phorbol-ester-stimulated fibroblastic cells, based on the same criteria. Kinase assays in gels after SDS/polyacrylamide gel electrophoresis revealed further that the NGF- or EGF-activated MAP kinase in PC12 cells, as well as the EGF-activated MAP kinase in fibroblastic 3Y1 cells resided in two closely spaced polypeptides with an apparent molecular mass of approximately 40 kDa. In addition, these MAP kinases were inactivated by either acid phosphatase treatment or protein phosphatase 2A treatment. These results indicate that MAP kinase may be activated through phosphorylation by a differentiating factor as well as by a mitogen. MAP kinase activation by EGF was protein kinase C independent; it reached an almost maximal level 1 min after EGF treatment and subsided rapidly within 30-60 min. On the other hand, NGF-induced activation of MAP kinase was partly protein kinase C dependent and continued for at least 2-3 h.
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PMID:Microtubule-associated-protein (MAP) kinase activated by nerve growth factor and epidermal growth factor in PC12 cells. Identity with the mitogen-activated MAP kinase of fibroblastic cells. 217 61

We have previously found and characterized a mitogen-activated, serine/threonine-specific protein kinase that specifically phosphorylates microtubule-associated protein 2 (MAP2) in vitro, which we call here MAP2 kinase [Hoshi, M., Nishida, E. & Sakai, H. (1988) J. Biol. Chem. 263, 5396-5401; Hoshi, M., Nishida, E. & Sakai, H. (1989) Eur. J. Biochem. 184, 477-486]. In this study, we have found another serine/threonine-specific protein kinase that is activated by various mitogens. The activated kinase utilized microtubule-associated protein 1B (MAP1B) as the major substrate in vitro, so we tentatively call it MAP1B kinase (M1BK). M1BK was maximally activated 20-30 min after treatment of quiescent rat fibroblastic 3Y1 cells with epidermal growth factor (EGF), while MAP2 kinase was maximally activated within 5-10 min of EGF treatment. The EGF-activated M1BK was eluted at about 0.15 M NaCl on a DEAE-cellulose column, while the activated MAP2 kinase was eluted at about 0.1 M NaCl under the conditions used. The EGF-activated M1BK was eluted as a single peak just after the activated MAP2 kinase on an HPLC gel-filtration column. Histone, casein and ribosomal protein S6 were very poor substrates for the M1BK, while MAP2 and myelin basic protein were moderate substrates. The M1BK activity in cell extracts was inhibited by Ca2+, glycerol 2-phosphate and Zn2+, and slightly enhanced by heparin. These data suggested that M1BK is distinct from previously described mitogen-activated kinases such as MAP2 kinase, casein kinase II and S6 kinase. Pretreatment with cycloheximide or puromycin did not block the M1BK activation by EGF. Furthermore, incubation of the EGF-activated M1BK with acid phosphatase inactivated the kinase activity. Therefore, M1BK may be activated by phosphorylation in EGF-treated cells. In addition to EGF, 12-O-tetradecanoylphorbol 13-acetate, platelet-derived growth factor and insulin-like growth factor-I also induced the activation of M1BK in quiescent cells.
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PMID:Activation of a serine/threonine kinase that phosphorylates microtubule-associated protein 1B in vitro by growth factors and phorbol esters in quiescent rat fibroblastic cells. 222 68

To determine relationships between the hormonal activation of casein kinase II and its phosphorylation state, epidermal growth factor (EGF)-treated and EGF-naive human A-431 carcinoma cells were cultured in the presence of [32P]orthophosphate. Immunoprecipitation experiments indicated that casein kinase II in the cytosol of EGF-treated cells contained approximately 3-fold more incorporated [32P]phosphate than did its counterpart in untreated cells. Levels of kinase phosphorylation paralleled levels of kinase activity over a wide range of EGF concentrations as well as over a time course of hormone action. Approximately 97% of the incorporated [32P]phosphate was found in the beta subunit of casein kinase II. Both activated and hormone-naive kinase contained radioactive phosphoserine and phosphothreonine but no phosphotyrosine. On the basis of proteolytic mapping experiments, EGF treatment of A-431 cells led to an increase in the average [32P]phosphate content (i.e., hyperphosphorylation) of casein kinase II beta subunit peptides which were modified prior to hormone treatment. Finally, the effect of alkaline phosphatase on the reaction kinetics of activated casein kinase II indicated that hormonal stimulation of the kinase resulted from the increase in its phosphorylation state.
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PMID:Stimulation of casein kinase II by epidermal growth factor: relationship between the physiological activity of the kinase and the phosphorylation state of its beta subunit. 230 May 66

Hormonal regulation in the production of a plasminogen activator (PA) was studied in rat hepatocytes in primary culture. Insulin and epidermal growth factor had no effect on the hepatic PA activity. However, glucagon and epinephrine augmented the activity, whereas dexamethasone suppressed it by lowering the production of hepatic PA rather than by inducing plasmin inhibitors or a plasminogen activator inhibitor (PAI). Dibutyryl cAMP, an analogue of cAMP, also augmented hepatic PA activity. The augmented activity level was lowered by either H-8, cycloheximide, or actinomycin D, suggesting that A-kinase and protein biosynthesis are closely associated with the augmentation. Glucocorticoid and hormones that act to raise the intracellular cAMP level may participate in hepatic PA production by the liver.
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PMID:Hormonal regulation of plasminogen activator production by rat hepatocytes in primary culture. 238 27

Two site-specific antibodies that immunoprecipitate the human insulin receptor have been prepared by immunizing rabbits with chemically synthesized peptides derived from the cDNA-predicted amino acid sequence of the beta subunit of the proreceptor. Antibodies to the carboxyl terminus (AbP5) and to a domain around tyrosine-960 (AbP4) specifically recognize the beta subunit of the receptor on immunoblots. Both antibodies immunoprecipitated 125I-labeled insulin-receptor complexes and the autophosphorylated receptor. Although neither antibody inhibited insulin binding to the receptor, both insulin-dependent autophosphorylation and exogenous substrate phosphorylation were inhibited by AbP4. Inhibition by AbP4 was dependent upon the phosphorylation state of the receptor; it was not detected when the receptor was autophosphorylated prior to addition of AbP4. AbP4 did not inhibit activity of the related epidermal growth factor (EGF)-receptor tyrosine protein kinase nor did it inhibit the activity of cAMP-dependent kinase or protein kinase C. The observation that an antibody directed to residues 952-967 of the proreceptor neutralizes the protein kinase activity of the beta subunit suggests that this region may play a critical role in the function of the hormone-dependent, protein tyrosine-specific kinase activity of the insulin receptor.
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PMID:An antipeptide antibody that specifically inhibits insulin receptor autophosphorylation and protein kinase activity. 241 75

The proliferation of cells in vivo and in culture is regulated by polypeptide growth factors, such as epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). Growth factors initiate their action by binding to specific cell surface receptors. Receptor occupancy triggers a cascade of physiological changes in the target cell which ultimately lead to DNA synthesis and cell division. Immediate consequences of receptor activation include tyrosine-specific protein phosphorylations, a sustained increase in cytoplasmic pH (pHi) and a transient rise in free Ca2+. The rise in pHi has a permissive effect on DNA synthesis and is mediated by an otherwise quiescent Na+/H+ exchange mechanism in the plasma membrane, which is turned on by protein kinase C, the cellular receptor for phorbol esters. The rapid Ca2+ signal is due to either release from internal stores (PDGF) or net entry via a voltage-independent channel in the plasma membrane (EGF). Phorbol esters, acting via kinase C, inhibit the growth factor-induced Ca2+ signals without affecting resting Ca2+ levels. Monoclonal antibodies against the human EGF receptor can act as partial agonists in that they activate the tyrosine-specific protein kinase without inducing any of the ionic signals. These antibodies fail to induce DNA synthesis when added to quiescent fibroblasts, indicating that the Ca2+ and pHi signals can be dissociated from tyrosine kinase activity and suggesting that these signals are indispensable for the stimulation of cell proliferation.
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PMID:Ionic signalling by growth factor receptors. 242 6


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