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)

CD38 ligation with the specific mAb IB4 induced early and late signaling events in Jurkat T cells, as judged by the transient induction of tyrosine phosphorylation of phospholipase C-gamma1, c-Cbl, zeta-associated protein (ZAP)-70, Shc, extracellular signal-regulated protein kinase-2 (Erk-2) as mitogen-activated protein (MAP) kinase, and increased expression of the activation Ag CD69. In addition, CD38 ligation induced Ras-dependent events such as Erk-2 mobility shift and increased Erk-2 kinase activity. Further evidence that Erk-2 activation is regulated by CD38 ligation was obtained indirectly with the observed induction of Raf-1, Lck, and Sos-1 mobility shifts, processes that are believed to be dependent, at least in part, on MAP kinase activation. Using a protein tyrosine kinase inhibitor, herbimycin A, or a protein kinase C inhibitor, Ro-31-8220, we found that the anti-CD38-induced Erk-2 activation is both protein tyrosine kinase and protein kinase C dependent. CD38 ligation also resulted in increased CD3-zeta tyrosine phosphorylation and its association with ZAP-70. CD38 ligation in a Jurkat Lck-deficient mutant, JCam1, failed to induce substrate tyrosine phosphorylation and activation of Erk-2. These data indicated that in Jurkat T cells, CD38 receptor triggering results in Lck-regulated activation of both Raf-1/MAP kinase and CD3-zeta/ZAP-70/phospholipase C-gamma1 signaling pathways.
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PMID:CD38 ligation results in activation of the Raf-1/mitogen-activated protein kinase and the CD3-zeta/zeta-associated protein-70 signaling pathways in Jurkat T lymphocytes. 920 Apr 55

Csk is a protein tyrosine kinase that phosphorylates other protein tyrosine kinases of the Src family and down-regulates their activities. It is not known how Csk is regulated. We investigated the possibility that Csk is regulated through phosphorylation by examining if Csk can serve as an in vitro substrate for a panel of protein kinases. We found that Csk was phosphorylated by the cAMP-dependent protein kinase (PKA), but not by protein kinase C, Src, or the fibroblast growth factor receptor kinase. Csk phosphorylation in vitro by PKA is on a serine residue(s) and can reach a stoichiometry of approximately 0.6 mol phosphate per mole of enzyme. Furthermore, incubation with PKA in the presence of ATP and magnesium ion results in a time-dependent decrease in Csk kinase activity. A six-fold decrease in Csk activity (expressed as Vmax/Km ratio) was achieved due to a threefold increase in its Km and a twofold decrease in its Vmax value within 1 h of incubation with the catalytic subunit of PKA and ATP-Mg. Both phosphorylation and inactivation by PKA were blocked by a PKA-specific inhibitor. Csk mutants with a deleted SH2 or SH3 domain retained their ability to be phosphorylated and inactivated by PKA, indicating that the phosphorylation site is located within the catalytic domain. These studies suggest that the cAMP-dependent protein kinase can regulate Csk activity.
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PMID:Csk phosphorylation and inactivation in vitro by the cAMP-dependent protein kinase. 922 30

Csk (C-terminal Src kinase) is a protein tyrosine kinase that phosphorylates Src family member C-terminal tails, resulting in down-regulation of Src family members. The molecular basis of Csk's substrate specificity and catalytic mechanism with a protein substrate was investigated. Using a peptide library approach, preferential amino acids which are unrelated to the conserved Src C-terminal sequence were identified. The validity of these preferences was confirmed by synthesizing a short consensus peptide and demonstrating its high catalytic efficiency with Csk. These results underscore the difficulties of relying on amino acids neighboring tyrosine in protein sequences as predictors of protein kinase substrate specificity for in vivo analysis. In addition, a catalytically inactive version of the Src family member, Lck (lymphoid cell kinase), was expressed, purified, and evaluated as a Csk substrate. It was proven to be the most catalytically efficient substrate yet identified for Csk. The high efficiency of purified Csk phosphorylating a pure, unphosphorylated Src family member argues against the importance of an SH2-phosphotyrosine docking interaction or the involvement of extra recruitment proteins in facilitating Csk phosphorylation of Src family members. Kinetic studies revealed that the chemical step is at least partially rate-determining in Csk-mediated phosphoryl transfer to the Lck protein. Other properties including preferences for Mn over Mg, thio effects, and Km's for ATP also correlate fairly well between protein and peptide phosphorylation. The lack of a significant impact of increased salt on the Km for Lck phosphorylation differs from Csk-mediated poly(Glu,Tyr) phosphorylation, and argues against the importance of electrostatic effects in the Csk-Lck binding interaction. The failure of the Lck phosphorylation product (phosphotyrosine-505) to significantly inhibit Csk phosphorylation of Lck is consistent with a catalytic model involving multidomain structural interactions between substrate and enzyme.
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PMID:Peptide and protein phosphorylation by protein tyrosine kinase Csk: insights into specificity and mechanism. 942 36

Bradykinin B1 receptor (BKB1R) is involved in a variety of pathophysiological processes, particularly those related to inflammation. The gene for this receptor is known to be upregulated by interleukin (IL)-1beta, a proinflammatory cytokine. However, the molecular mechanisms involved in the regulation of the BKB1R gene expression have not been defined. We demonstrated that IL-1beta induces a rapid increase in BKB1R mRNA level and the binding of desArg10-kallidin in human embryo lung fibroblasts (IMR90). This increase in BKB1R mRNA level is protein synthesis-independent as indicated by treatment of cells with cycloheximide (CHX) or puromycin (PUR). By testing the IL-1beta effect on BKB1R mRNA degradation, we showed that the IL-1beta upregulation of BKB1R expression is achieved through both transcriptional activation and post-transcriptional mRNA stabilization. In addition to the IL-1beta effects, translation inhibitors, CHX and PUR increase the steady state BKB1R mRNA level by inhibiting BKB1R mRNA degradation. Removal of the CHX block with subsequent resumption of protein synthesis results in a sizable increase of desArg10-kallidin binding. Using signalling pathway inhibitors, we show that IL-1beta functions through a protein tyrosine kinase, not protein kinase C or protein kinase A. However, activation of protein kinase C by phorbol 12-myristate 13-acetate increases the level of BKB1R mRNA and the binding of desArg10-kallidin. This increase is blocked by NF-kappaB activation inhibitors.
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PMID:Roles for interleukin-1beta, phorbol ester and a post-transcriptional regulator in the control of bradykinin B1 receptor gene expression. 946 31

Computer analysis of protein phosphorylation site sequences revealed that transcriptional factors and viral oncoproteins are prime targets for regulation of proline-directed protein phosphorylation, suggesting an association of the proline-directed protein kinase (PDPK) family with neoplastic transformation and tumorigenesis. In this report, an immunoprecipitate activity assay of proline-directed protein kinase F(A)/glycogen synthase kinase-3alpha (PDPK F(A)/GSK-3alpha) has been optimized to demonstrate significantly increased (p < 0.01) activity in poorly differentiated human prostate carcinoma PC-3 cells (55.5+/-3.8 units/mg) when compared to well-differentiated LNCaP cells (28.1+/-2.3 units/mg). Immunoblotting analysis revealed that increased activity of this PDPK in PC-3 cells is due not to overexpression of the protein, but to enhanced tyrosine phosphorylation of the kinase. When treated with genistein (a protein tyrosine kinase PTK inhibitor), the enhanced tyrosine phosphorylation/activation of the kinase in PC-3 cells can be blocked. Conversely, when treated with vanadate (a protein tyrosine phosphatase PTP inhibitor), the phosphotyrosine content of PDPK F(A)/GSK-3alpha in LNCaP cells can be promoted to the level of PC-3 cells. In sharp contrast, the PTK inhibitor has little effect on the tyrosine phosphorylation level of the kinase in LNCaP cells, whereas the PTP inhibitor has little effect on the tyrosine phosphorylation level of the kinase in PC-3 cells. Taken together, the results provide initial evidence that the tyrosine phosphorylation/activation levels of this oncogenic PDPK can be differentially regulated in well- and poorly differentiated prostate carcinoma cells.
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PMID:Differential tyrosine phosphorylation/activation of oncogenic proline-directed protein kinase F(A)/GSK-3alpha in well and poorly differentiated human prostate carcinoma cells. 961 86

A perforated patch recording method was used to determine the effects of genistein (Gen), a protein tyrosine kinase (PTK) inhibitor, on basal L-type Ca2+ current (ICa,L) in feline atrial myocytes. Gen (50 microM) elicited biphasic changes in ICa,L: an initial inhibition (-55 +/- 4%; phase 1) followed by a secondary stimulation (34 +/- 9%; phase 2) of ICa,L. Withdrawal of Gen elicited a further potentiation of ICa,L (152 +/- 19%; phase 3) above control (n = 46). In general, phase 1 inhibition and phase 3 potentiation varied directly with Gen concentration, and phase 2 stimulation exhibited biphasic concentration-dependent changes compared with control. When cells were dialyzed using a ruptured patch recording method, Gen elicited only inhibition of ICa,L; phases 2 and 3 were abolished. Vanadate (1 mM), an inhibitor of protein tyrosine phosphatase, abolished both Gen-induced inhibition and stimulation of ICa,L. Daidzein (50 microM), a weakly active analog of Gen, exerted no significant effects on ICa,L, and withdrawal of daidzein failed to potentiate ICa,L. In a few cells, Gen elicited a prominent vanadate-sensitive stimulation of ICa,L in the absence of any significant inhibition of ICa,L. Gen-induced changes in ICa,L were unaffected by either 100 microM 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA)-acetoxymethyl ester (AM) or 1 microM ryanodine, agents that alter intracellular Ca2+; 4 microM H-89 or 50 microM Rp diastereomer of adenosine 3',5'-monophosphothioate (RP-cAMPS), inhibitors of protein kinase A (PKA); 0.1 microM calphostin C or 2 microM chelerythrine, inhibitors of protein kinase C (PKC); or 100 microM NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide (NO) synthase. We conclude that in feline atrial myocytes, Gen acts via membrane-bound PTKs to inhibit ICa,L and via cytosolic PTKs to stimulate ICa,L. Gen-induced changes in ICa,L are not related to changes in intracellular Ca2+ or to secondary interactions with either PKA, PKC, or NO signaling pathways. These results indicate that in atrial myocytes ICa,L is regulated by two independent and competing PTK signaling mechanisms.
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PMID:Genistein elicits biphasic effects on L-type Ca2+ current in feline atrial myocytes. 968 15

Ozone is one of the most common air pollutants humans routinely inhale. We have previously shown that in vitro ozone exposure induces the DNA-binding activities of NF-kappaB and NF-IL6 as well as the expression of interleukin 8 in respiratory epithelial cells. In this study, we investigated intracellular signaling steps mediating ozone-induced inflammatory mediator release. A549 cells, a type II like alveolar epithelial cell line, were exposed in vitro to air or 0.1 ppm of ozone in the presence of several kinase inhibitors. Exposure to ozone increased interleukin 8 expression and transcription factor activities in a protein tyrosine kinase (PTK)-dependent and protein kinase A (PKA)-dependent, yet protein kinase C (PKC)-independent, manner. Furthermore, ozone-induced PTK and PKA activities but failed to induce PKC activity. In addition, our results suggest that ozone-induced PTK and PKA activities were reactive oxygen intermediate dependent and occurred in parallel, because specific inhibitors for PTK and PKA failed to block the other kinase's activity. These results indicate that PTK and PKA activities are early events in the signal transduction cascade mediating the ozone-induced activation of NF-kappaB and NF-IL6 as well as the release of interleukin 8.
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PMID:Induction of interleukin-8 by ozone is mediated by tyrosine kinase and protein kinase A, but not by protein kinase C. 976 28

Lysophosphatidic acid (LPA) is a bioactive lipid that acts through G protein-coupled plasma membrane receptors and mediates a wide range of cellular responses. Here we report that LPA activates a K+ current in NIH3T3 mouse fibroblasts that leads to membrane hyperpolarization. The activation occurs with an EC50 value of 1.7 nM LPA. The K+ current is Ca2+-dependent, voltage-independent, and completely blocked by the K+ channel blockers charybdotoxin, margatoxin, and iberiotoxin with IC50 values of 1.7, 16, and 62 nM, respectively. The underlying K+ channels possess a single channel conductance of 33 pS in symmetrical K+ solution. Pretreatment of cells with pertussis toxin (PTX), Clostridium sordellii lethal toxin, or a farnesyl protein transferase inhibitor reduced the K+ current amplitude in response to LPA to about 25% of the control value. Incubation of cells with the protein tyrosine kinase inhibitor genistein or microinjection of the neutralizing anti-Ras monoclonal antibody Y13-259 reduced it by more than 50%. In contrast, the phospholipase C inhibitor U-73122 and the protein kinase A activator 8-bromo-cAMP had no effect. These results indicate that the K+ channel activation by LPA is mediated by a signal transduction pathway involving a PTX-sensitive G protein, a protein tyrosine kinase, and Ras. LPA is already known to activate Cl- channels in various cell types, thereby leading to membrane depolarization. In conjunction with our results that demonstrate LPA-induced membrane hyperpolarization by activation of K+ channels, LPA appears to be significantly involved in the regulation of the cellular membrane potential.
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PMID:Activation of a Ca2+-dependent K+ current in mouse fibroblasts by lysophosphatidic acid requires a pertussis toxin-sensitive G protein and Ras. 984 Apr 18

The role of mitogen-activated protein (MAP) kinase in mouse egg activation induced by protein kinase inhibitors and a protein tyrosine kinase (PTK) inhibitor was investigated. Separated egg proteins were first probed with anti-Active MAP kinase antibody and then re-probed with anti-ERK2 antibody. Staurosporine and Ro-31-8220, at concentrations that normally inhibit protein kinase C, did not affect egg activation or MAP kinase activity, while higher dosages caused egg activation. Staurosporine at 2 microM induced the metaphase-interphase transition without emission of the second polar body (PB2), while Ro-31-8220 at 40 microM induced PB2 emission, first cleavage, and then the transition to interphase. Half the eggs were also activated by the PTK inhibitor genistein. In each treatment, the proportion of eggs that entered interphase was well correlated with the degree of MAP kinase inactivation. Artificial activation of this kinase by okadaic acid overcame the interphase transition. These data suggest that protein kinase inhibitors and a protein tyrosine kinase inhibitor induce the interphase transition by inactivating MAP kinase in mouse eggs.
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PMID:Protein kinase inhibitors induce the interphase transition by inactivating mitogen-activated protein kinase in mouse eggs. 985

Since oxyhemoglobin (OxyHb) is implicated in the pathogenesis of cerebral vasospasm, we have investigated the role of protein tyrosine phosphorylation in OxyHb-mediated signalling in canine cerebral arteries and cultured canine cerebrovascular smooth muscle cells. OxyHb produced a contraction of basilar artery preparations, which was reversed by genistein, an inhibitor of tyrosine kinases, and PD098059, an inhibitor of mitogen-activated protein kinase. In cerebrovascular smooth muscle cells, OxyHb induced tyrosine phosphorylation of 42, 46, 54-60 and 80-100 kDa proteins with a time-course which paralleled the contractile action of OxyHb, suggesting that these events might be functionally linked. The 42 and 60 kDa proteins were immunologically related to the mitogen-activated protein kinase, extracellular signal regulated protein kinase (ERK2), and to p60c-Src (c-Src), respectively. The increase in protein tyrosine phosphorylation was attenuated by genistein, and the phosphorylation of the 42 kDa protein (ERK2) was inhibited by PD098059. These results suggest that OxyHb-mediated signalling utilizes a protein tyrosine kinase-based mechanism.
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PMID:Novel mechanism by which hemoglobin induces constriction of cerebral arteries. 986 22


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