Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platelets exposed to thrombin or thrombin receptor agonist peptide (SFLLRN) activate phospholipase C and protein kinase C (PKC), and accumulate 3-phosphorylated phosphoinositides (3-PPI) as a function of the activation and relocalization of two cytoskeletally-associated phosphoinositide 3-kinases (PI 3-K): p85/PI 3-K and PI 3-Kgamma. We now report that exposure of platelets to PKC-activating beta-phorbol myristate acetate (betaPMA) does not stimulate PI 3-Kgamma, but rather stimulates p85/PI 3-K, which associates with the cytoskeleton. Wortmannin is an inhibitor of both PI 3-Ks, known to act with more potency on p85/PI 3-K. betaPMA-stimulated 3-PPI accumulation is more sensitive to wortmannin (IC50 = 1.3 nM) than is SFLLRN- or thrombin-stimulated 3-PPI accumulation (IC50 = 10 nM). The activity of p85/PI 3-K in immunoprecipitates or in cytoskeletal fractions is inhibited more potently by exposure of platelets to wortmannin than is the activity of PI 3-Kgamma. betaPMA or SFLLRN promotes the conversion of platelet integrin alphaIIb/beta3 into a fibrinogen-binding form required for platelet aggregation. Activation of alphaIIb/beta3 in response to betaPMA or SFLLRN is inhibited by wortmannin with an IC50 of 1 nM in each case. Wortmannin inhibits neither activation of alphaIIb/beta3 by ligand-induced binding site antibody (anti-LIBS6 Fab) nor anti-LIBS6 Fab-induced platelet aggregation in the presence of fibrinogen, indicating that this type of "outside-in" signaling by alphaIIb/beta3 is largely PI 3-K-independent. We conclude that p85/PI 3-K, in preference to PI 3-Kgamma, contributes to activation of alphaIIb/beta3 when the thrombin receptor or PKC is stimulated.
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PMID:Phosphoinositide 3-kinase gamma and p85/phosphoinositide 3-kinase in platelets. Relative activation by thrombin receptor or beta-phorbol myristate acetate and roles in promoting the ligand-binding function of alphaIIbbeta3 integrin. 862 20

We present here the complete primary structure of human gp330, the human variant of the principal kidney autoantigen causing Heymann membranous glomerulonephritis in rats. The deduced 4655 amino acid residues give a calculated molecular mass of 519636 Da for the mature protein and consists of a probable 25-amino-acid N-terminal signal peptide sequence, an extracellular region of 4398 amino acids, a single transmembrane-spanning domain of 23 amino acids, and an intracellular C-terminal region of 209 amino acid residues. Three types of cysteine-rich repeats characteristic of the low density lipoprotein receptor (LDLR) superfamily are present in human gp330. In the extracellular region, there are a total of 36 LDLR ligand-binding repeats, comprising four distinct domains, 16 growth factor repeats separated by eight YWTD spacer regions, and one epidermal growth factor-like repeat. No consensus cleavage sequence for the processing endoprotease furin is detected in human gp330. The intracellular tail contains not only two copies of the F(X)NPXY coated-pit mediated internalization signal characteristic of LDLR superfamily members, but also intriguing and potentially functional motifs including several Src-homology 3 recognition motifs, one Src-homology 2 recognition motif for the p85 regulatory subunit of phosphatidylinositol 3-kinase, and additional sites for protein kinase C, casein kinase II and cAMP-/cGMP-dependent protein kinase. There is approximately 77% amino acid identity between human and rat gp330 with minor differences between the extracellular and intracellular regions. Recently gp330 has been implicated in Ca2+ regulation in the parathyroid, the placenta, and the renal tubule, but its overall physiological and pathological role still remains uncertain.
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PMID:Cloning and sequencing of human gp330, a Ca(2+)-binding receptor with potential intracellular signaling properties. 870 97

Protein kinase C consists of a family of at least 12 isoforms which exhibit clear differences in their cofactor dependence and responsiveness to phospholipids. Insulin effects on PKC translocation/activation are now clearly established but responsiveness to this hormone was observed so far only for the classical PKC-isoforms alpha and beta. While activation of the classical PKC's requires Ca2+ and occurs mainly through Diacylglycerol (DAG), stimulation of the atypical isoform PKC-zeta appears to function through a different mechanism involving PI-3-kinase activation. In the present study we used rat-1 fibroblasts stably over-expressing human insulin receptor to investigate whether insulin can activate PKC-zeta and whether such an effect might be related to insulin's effect on PI-3-kinase. After stimulation of the cells with insulin (10(-7) mol/l) for one to ten minutes, a rapid translocation of PKC-zeta to the plasma membrane was detectable, as determined by immunoblotting of plasma membrane proteins with antibodies against PKC-zeta. In parallel immunoblots applying antibodies against the regulatory subunit of PI-3-kinase (p85), an insulin-induced translocation of p85 was detectable within one minute after stimulation. The translocation of p85 was associated with an increase in PI-3-kinase activity at the plasma membrane. The data show that insulin stimulates translocation of PKC-zeta in rat-1 fibroblasts. The parallel kinetics of PI-3-kinase translocation/activation and PKC-zeta translocation are compatible with the idea that the insulin effect on PKC-zeta is transduced through PI-3-kinase activation.
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PMID:Insulin leads to a parallel translocation of PI-3-kinase and protein kinase C zeta. 875 May 65

In the present study we have examined the signaling cascades involved in insulin-like growth factor I (IGF-I)-induced mitogenesis in fetal rat brown adipocyte primary cultures, a model that constitutively expresses a high number of IGF-I receptors, where IGF-I is a complete mitogen at physiological concentrations. IGF-I rapidly stimulated beta-chain IGF-I receptor autophosphorylation, which peaked at a physiological/mitogenic concentration (1.4 nM) and also stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). Tyrosine-phosphorylated IRS-1 bound and subsequently activated phosphatidylinositol 3-kinase by 3.5-fold, whereas the tyrosine-phosphorylated IGF-I receptor was not directly associated with the p85 subunit of the phosphatidylinositol 3-kinase. Moreover, mitogenic concentrations of IGF-I enhanced glucose transport by 2.5-fold. In addition, tyrosine phosphorylation of the 46- and 52-kDa SHC proteins was high in the basal state and doubled after IGF-I treatment, whereas IGF-I enhanced by 4-fold tyrosine phosphorylation of the 66-kDa SHC band. Furthermore, a 2-fold increase in the Ras. GTP active form was induced upon IGF-I stimulation. Downstream from Ras, IGF-I increased both Raf kinase and protein kinase C (PKC) zeta activities by 3.5-fold. (Bu)2cAMP, an inhibitor of IGF-I-induced mitogenesis in fetal brown adipocyte primary cultures, did not block the very early steps of the IGF-I-induced mitogenic cascade, such as IGF-I receptor autophosphorylation, IRS-1 or SHC tyrosine phosphorylation, and Ras activation to its GTP active form. However, (Bu)2cAMP disrupted IGF-I-Raf and IGF-I-PKC zeta signaling pathways by preventing IGF-I-induced Raf-1 kinase and PKC zeta enzymatic activities, respectively. Our results show the first characterization in situ of an IGF-I mitogenic signaling cascade that downstream Ras diverges to the nucleus through two different serine/threonine kinases (Raf-1 kinase and PKC zeta) in mammalian fetal primary cells under physiological conditions. Both kinases represent a point of regulation primarily described for IGF-I-induced, cAMP-inhibited mitogenic pathways.
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PMID:Involvement of Raf-1 kinase and protein kinase C zeta in insulin-like growth factor I-induced brown adipocyte mitogenic signaling cascades: inhibition by cyclic adenosine 3',5'-monophosphate. 875 54

Pleckstrin, the prototypic protein containing two copies of the pleckstrin homology domain, is a prominent substrate of protein kinase C in platelets and neutrophils. Both cell types have p85 subunit-containing phosphoinositide 3-kinase (p85/PI3K) and non-p85-containing PI3K (PI3Kgamma) that is activated by betagamma subunits of heterotrimeric GTP-binding proteins. We have shown that a PI3K product, phosphatidylinositol (PI) 3,4,5-trisphosphate, promotes pleckstrin phosphorylation in platelets. Since pleckstrin homology domains are thought to interact with Gbetagamma heterodimers and/or PI(4,5)P2, we have examined the effects of recombinant pleckstrins on platelet PI3Kgamma and p85/PI3K activities. Depending upon its phosphorylation/charged state, pleckstrin inhibits PI3Kgamma, but not p85/PI3K. Pleckstrin-mediated inhibition of PI3Kgamma is overcome by excess Gbetagamma and is restricted to PI(4,5)P2 as substrate, i.e. pleckstrin does not inhibit phosphorylation of PI()P or PI. Consistent with this, activation of protein kinase C by exposure of platelets to beta-phorbol diester (to increase endogenous pleckstrin phosphorylation) prior to platelet lysis causes inhibition of Gbetagamma-stimulatable PI3K activity only with respect to PI(4,5)P2 substrate. This phosphopleckstrin-mediated inhibition is overcome by increasing concentrations of Gbetagamma. We propose that phosphorylation of pleckstrin may constitute an important inhibitory mechanism for PI3Kgamma-mediated cell signaling.
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PMID:Phosphopleckstrin inhibits gbetagamma-activable platelet phosphatidylinositol-4,5-bisphosphate 3-kinase. 881 Feb 77

To understand the function of B cell antigen receptor (BCR)-related complex on pre-B cells (pre-BCR, Vpre-B/lambda 5/mu heavy chain/Ig-alpha/Ig-beta), we examined pre-BCR- and BCR-mediated signaling events in human and mouse pre-B (Nalm-6, 697, NFS-5), immature B (IgM+ Daudi, WEHI-231) and mature B (IgM+ IgD+ BALL1) cell lines. Anti-mu cross-linking induced tyrosine phosphorylation of the cytoplasmic proteins in each cell type, but did not induce a detectable Ca2+ mobilization response in pre-B cells. While the pre-B cells expressed Syk protein at levels similar to those found in B cell lines, pre-BCR cross-linkage did not induce phosphorylation of Syk tyrosine residues. Different protein kinase C isozymes were expressed by pre-B (PKC-alpha), immature B (PKC-alpha and -beta) and mature B (PKC-beta) cell lines. Anti-mu cross-linking induced PKC translocation from the cytosolic to the membrane compartment in immature and mature B cells, but did not have this effect in a pre-B cell line. Anti-mu cross-linking induced tyrosine phosphorylation of the p85 and p110 subunits of phosphatidylinositol 3-kinase (P13-kinase) in both pre-B and B cell lines, but the pre-BCR induced P13-kinase activation was Syk independent. Ligation of the pre-BCR complex thus triggers a characteristic signaling pattern in pre-B cells.
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PMID:Cross-linking of B cell antigen receptor-related structure of pre-B cell lines induces tyrosine phosphorylation of p85 and p110 subunits and activation of phosphatidylinositol 3-kinase. 891 97

Phosphatidylinositol 3-kinase (PI3-kinase) is a cytosolic enzyme that plays key roles in mediating signaling through many receptors. The heterodimeric form of PI3-kinase is made up of a regulatory subunit, p85, and a catalytic subunit, p110. Although granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to activate PI3-kinase, the mechanisms by which this activation is mediated and regulated are incompletely understood. Here we show that treatment of human neutrophils with GM-CSF induced both time- and concentration-dependent increases in the level of tyrosine phosphorylation of p85. The ability of GM-CSF to activate PI3-kinase was abolished by pretreating the cells with erbstatin, a tyrosine kinase inhibitor. The simultaneous treatment of the cells with GM-CSF and phorbol esters such as phorbol 12-myristate 13-acetate (PMA) and phorbol 12,13-dibutyrate (PDBu) significantly inhibited both the tyrosine phosphorylation of p85 and the activation of PI3-kinase. The inhibitory effects of phorbol esters were not induced by their inactive analogues and they were selective to the stimulation of tyrosine phosphorylation of p85 since phorbol esters did not alter the enhancement of the pattern of tyrosine phosphorylation of other cellular proteins, including that of Jak2 induced by GM-CSF. However, PMA significantly inhibited the in situ tyrosine phosphorylation and the activation of lyn observed in response to GM-CSF. The results suggest that the activation of PI3-kinase by GM-CSF is mediated by the tyrosine phosphorylation of p85 and that this activation is downregulated by PKC possibly via the inhibition of lyn.
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PMID:Granulocyte-macrophage colony-stimulating factor-activated signaling pathways in human neutrophils. I. Tyrosine phosphorylation-dependent stimulation of phosphatidylinositol 3-kinase and inhibition by phorbol esters. 902 36

The isoform identity of activated protein kinase C (PKC) and its regulation were investigated in bacterial lipopolysaccharide (LPS)-treated human monocytes. Resolution of detergent-soluble lysates prepared from LPS-treated, peripheral blood monocytes using Mono Q anion-exchange chromatography revealed two principal peaks of myelin basic protein kinase activity. Immunoblotting and immunoprecipitation with isoform-specific anti-PKC antibodies showed that the major and latest eluting peak is accounted for by PKC-zeta. In addition to primary monocytes, activation of PKC-zeta in response to LPS was also observed in the human promonocytic cell lines, U937 and THP-1. Consistent with its identity as PKC-zeta, the kinase did not depend upon the presence of lipids, Ca2+, or diacylglycerol for activity. In addition, the kinase phosphorylates peptide epsilon and myelin basic protein with equal efficiency but phosphorylates Kemptide and protamine sulfate poorly. Translocation of PKC-zeta from the cytosolic to the particulate membrane fraction upon exposure of monocytes to LPS provided further evidence for activation of the kinase. Preincubation of monocytes with the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitors, wortmannin or LY294002, abrogated LPS-induced activation of PKC-zeta. Furthermore, activation of PKC-zeta failed to occur in U937 cells transfected with a dominant negative mutant of the p85 subunit of PI 3-kinase. PKC-zeta activity was also observed to be enhanced in vitro by the addition of phosphatidylinositol 3,4,5P3. These findings are consistent with a model in which PKC-zeta is activated downstream of PI 3-kinase in monocytes in response to LPS.
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PMID:Phosphatidylinositol 3-kinase-dependent activation of protein kinase C-zeta in bacterial lipopolysaccharide-treated human monocytes. 919 53

Inorganic phosphate (Pi) is a major regulator of cell metabolism. The Pi transport activity in the plasma membrane is a main determinant of the intracellular level of this ion. In bone-forming cells, Pi transport is important for the calcification of the bone matrix. In this study, the effect of platelet-derived growth factor (PDGF) on Pi transport activity and the signaling mechanism involved in this cellular response were analyzed. The results indicate that PDGF is a potent and selective stimulator of sodium-dependent Pi transport in the mouse calvaria-derived MC3T3-E1 osteoblast-like cells. The change in Pi transport induced by PDGF-BB was dependent on translational processes and affected the Vmax of the Pi transport system. These observations suggested that enhanced Pi transport activity in response to PDGF resulted from insertion of newly synthesized Pi transporters in the plasma membrane. The role of activation of mitogen activated protein (MAP) kinase, phospholipase C (PLC)gamma or phosphatidylinositol 3-kinase (PI-3-kinase), in mediating this effect of PDGF, was investigated. A selective inhibitor of the PDGF receptor tyrosine kinase activity (CGP 53716) completely blocked PDGF-induced protein tyrosine phosphorylation of several proteins including the PDGF receptor, PLCgamma, MAP kinase, and association of the p85 subunit of PI-3'-kinase. Associated with this effect, the increase in Pi transport induced by PDGF was completely blunted by 5 microM CGP 53716. Inhibition of MAP kinase activity by cAMP agonists did not influence Pi transport stimulation induced by PDGF. However, inhibitors of protein kinase C completely blocked this response. A selective inhibitor of PI-3-kinase, LY294002, also significantly reduced this effect of PDGF. In summary, these results indicate that PDGF is a potent and selective stimulator of Pi transport in osteoblastic cells. The mechanism responsible for this effect is not mediated by MAP kinase but involves tyrosine phosphorylation-dependent activation of PLCgamma and PI-3-kinase.
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PMID:Platelet-derived growth factor stimulates sodium-dependent Pi transport in osteoblastic cells via phospholipase Cgamma and phosphatidylinositol 3' -kinase. 924 Jul 23

Biochemical and immunochemical data from the present investigation reveal the existence of a p85/p110 phosphoinositide 3-kinase (PI 3-kinase) in rat liver nuclei. 32P-Labeling of membrane phosphoinositides by incubating intact nuclei with [gamma-32P]ATP results in the formation of [32P]phosphatidyl-inositol 3,4, 5-trisphosphate [PtdIns(3,4,5)P3], accompanied by small quantities of [32P]phosphatidylinositol 3-phosphate [PtdIns(3)P]. Studies with subnuclear fractions indicate that the PI 3-kinase is not confined to nuclear membranes. The nuclear soluble fraction also contains PI 3-kinase and an array of inositide-metabolizing enzymes, including phospholipase C (PLC), phosphoinositide phosphatase, and diacylglycerol (DAG) kinase. As a result, exposure of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] to the nuclear extract in the presence of [gamma-32P]ATP generates a series of 32P-labeled D-3 phosphoinositides and phosphatidic acid (PA) in an interdependent manner. On the basis of the immunological reactivity and kinetic behavior, the nuclear PI 3-kinase is analogous, if not identical, to PI 3-kinase alpha, and constitutes about 5% of the total PI 3-kinase in the cell. Moreover, we test the premise that nuclear PI 3-kinase may, in part, be regulated through the control of substrate availability by PtdIns(4,5)P2-binding proteins. Effect of CapG, a nuclear actin-regulatory protein, on PI 3-kinase activity is examined in view of its unique Ca2+-dependent PtdIns(4, 5)P2-binding capability. In vitro data show that the CapG-mediated inhibition of nuclear PI 3-kinase is prompted by PKC phosphorylation of CapG and elevated [Ca2+]. This CapG-dependent regulation provides a plausible link between nuclear PLC and PI 3-kinase pathways for cross-communications. Taken together, these findings provide definite data concerning the presence of an autonomous PI 3-kinase cycle in rat liver nuclei. The nuclear location of PI 3-kinase may lead to a better understanding regarding its functional role in transducing signals from the plasma membrane to the nucleus in response to diverse physiological stimuli.
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PMID:Phosphoinositide 3-kinase in rat liver nuclei. 954 60


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