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)

Activation of phospholipase C-beta (PLC-beta) by G protein-coupled receptors typically results in rapid but transient second messenger generation. Although PLC-beta deactivation may contribute to the transient nature of this response, the mechanisms governing PLC-beta deactivation are poorly characterized. We investigated the involvement of protein kinase C (PKC) in the termination of PLC-beta activation induced by endogenous P2Y(2) purinergic receptors and transfected M(3) muscarinic acetylcholine receptors (mAChR) in Chinese hamster ovary cells. Activation of P2Y(2) receptors causes Galpha(q/11) to associate with PLC-beta3, whereas M(3) mAChR activation causes Galpha(q/11) to associate with both PLC-beta1 and PLC-beta3 in these cells. Phosphorylation of PLC-beta3, but not PLC-beta1, is induced by activating either P2Y(2) receptors or M(3) mAChR. We demonstrate that PKC rather than protein kinase A mediates the G protein-coupled receptor-induced phosphorylation of PLC-beta3. The PKC-mediated phosphorylation of PLC-beta3 diminishes the interaction of Galpha(q/11) with PLC-beta3, thereby contributing to the termination PLC-beta3 activity. These findings indicate that the distinct temporal profiles of PLC activation by P2Y(2) receptors and mAChR may arise from the differential activation of PLC-beta1 and PLC-beta3 by the receptors, coupled with a selective PKC-mediated negative feedback mechanism that targets PLC-beta3 but not PLC-beta1.
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PMID:P2Y2 purinergic and M3 muscarinic acetylcholine receptors activate different phospholipase C-beta isoforms that are uniquely susceptible to protein kinase C-dependent phosphorylation and inactivation. 1099 76

Endothelin (ET)-1 is produced in ovarian carcinoma cells and is known to act through ET(A) receptors as an autocrine growth factor in vitro and in vivo. In OVCA 433 human ovarian carcinoma cells, ET-1 caused phosphorylation of the epidermal growth factor receptor (EGF-R) that was accompanied by phosphorylation of Shc and its recruitment complexed with Grb2. These findings suggested that an EGF-R/ras-dependent pathway may contribute to the activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) 2 and mitogenic signaling induced by ET-1 in these cells. Specific inhibition of EGF-R kinase activity by tyrphostin AG1478 prevented ET-1-induced transactivation of the EGF-R, as well as Shc phosphorylation and recruitment with Grb2. Furthermore, ET-1-induced activation of Erk 2 was partially inhibited by tyrphostin AG1478. In accord with this finding, the mitogenic action of ET-1 in OVCA 433 cells was also significantly reduced by a concentration of tyrphostin AG1478 that abolished the growth response of EGF-stimulated cells. Inhibition of protein kinase C activity, which contributes to the proliferative action of ET-1 in OVCA 433 cells, had no effect on the activation of Erk 2 by ET-1, which suggests that this effect of protein kinase C does not involve ras-independent activation of Erk 2. Inhibition by wortmannin of PI3-kinase activity, which has been implicated in ET-1 and other G protein-coupled receptor (GPCR)-mediated signaling pathways, reduced Erk 2 activation by ET-1 but had no effect on ET-1-induced EGF-R and Shc phosphorylation. These findings indicate that ET-1-induced stimulation of Erk 2 phosphorylation, and mitogenic responses in OVCA 433 ovarian cancer cells are mediated in part by signaling pathways that are initiated by transactivation of the EGF-R.
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PMID:Transactivation of the epidermal growth factor receptor in endothelin-1-induced mitogenic signaling in human ovarian carcinoma cells. 1101 63

Mitogenic signalling pathways from G protein-coupled receptors (GPCRs) to the mitogen-activated protein kinase (MAPK) cascade may involve alpha- or betagamma-subunits of heterotrimeric G proteins, receptor or non-receptor tyrosine kinases, adaptor molecules, phosphoinositide 3-kinases, protein kinase C, and probably other proteins. The majority of models describing the connection of different signalling proteins within a mitogenic pathway are based on experimental data obtained by co- and overexpression of epitope-tagged MAPK together with the respective GPCR and other signalling proteins of interest in transfectable cell lines. Here the link of the bradykinin B2 receptor (B2R) to MAPK in the COS-7 cell expression system is compared with mitogenic signalling pathways of bradykinin in various tumour cell lines. It becomes evident that in natural or tumour cells expressing individual amounts and different isoforms of signalling proteins completely other relations between B2R and MAPK may exist than in COS-7 cells, suggesting a high degree of cellular specificity in mitogenic signalling.
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PMID:Bradykinin signalling to MAP kinase: cell-specific connections versus principle mitogenic pathways. 1125 71

1. It has been demonstrated that oxidized low-density lipoprotein (OX-LDL) is a risk factor in atherosclerosis by stimulating vascular smooth muscle cell (VSMC) proliferation. However, the mechanisms of OX-LDL-induced cell proliferation are not completely understood. Therefore, we investigated the effect of OX-LDL on cell proliferation associated with mitogen-activated protein kinase (MAPK) activation in rat cultured VSMCs. 2. Both native-LDL (N-LDL) and OX-LDL induced a time- and concentration-dependent incorporation of [(3)H]-thymidine in VSMCs. 3. OX-LDL induced time- and concentration-dependent phosphorylation of p42/p44 MAPK. Pretreatment of these cells with pertussis toxin or U73122 attenuated the OX-LDL-induced responses. 4. Pretreatment with PMA for 24 h, preincubation with a PKC inhibitor staurosporine or the tyrosine kinase inhibitors, genistein and herbimycin A for 1 h, substantially reduced [(3)H]-thymidine incorporation and p42/p44 MAPK phosphorylation induced by OX-LDL. 5. Removal of Ca(2+) by BAPTA/AM or depletion of the internal Ca(2+) pool by thapsigargin significantly inhibited OX-LDL-induced [(3)H]-thymidine incorporation and p42/p44 MAPK phosphorylation. 6. OX-LDL-induced [(3)H]-thymidine incorporation and p42/p44 MAPK phosphorylation was inhibited by PD98059 (an inhibitor of MEK1/2) and SB203580 (an inhibitor of p38 MAPK) in a concentration-dependent manner. 7. Overexpression of dominant negative mutants of Ras (H-Ras-15A) and Raf (Raf-N4) significantly suppressed MEK1/2 and p42/p44 MAPK activation induced by OX-LDL and PDGF-BB, indicating that Ras and Raf may be required for activation of these kinases. 8. These results suggest that the mitogenic effect of OX-LDL is mediated through a PTX-sensitive G protein-coupled receptor that involves the activation of the Ras/Raf/MEK/MAPK pathway similar to that of PDGF-BB in rat cultured VSMCs.
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PMID:Mitogenic effect of oxidized low-density lipoprotein on vascular smooth muscle cells mediated by activation of Ras/Raf/MEK/MAPK pathway. 1126 47

We used a cultured murine cell model of the inner medullary collecting duct (mIMCD-3 cells) to examine the regulation of the ubiquitous sodium-proton exchanger, Na+/H+ exchanger isoform 1 (NHE-1), by a prototypical G protein-coupled receptor, the bradykinin B2 receptor. Bradykinin rapidly activates NHE-1 in a concentration-dependent manner as assessed by proton microphysiometry of quiescent cells and by 2'-7'-bis[2-carboxymethyl]-5(6)-carboxyfluorescein fluorescence measuring the accelerated rate of pH(i) recovery from an imposed acid load. The activation of NHE-1 is blocked by inhibitors of the bradykinin B2 receptor, phospholipase C, Ca2+/calmodulin (CaM), and Janus kinase 2 (Jak2), but not by pertussis toxin or by inhibitors of protein kinase C and phosphatidylinositol 3'-kinase. Immunoprecipitation studies showed that bradykinin stimulates the assembly of a signal transduction complex that includes CaM, Jak2, and NHE-1. CaM appears to be a direct substrate for phosphorylation by Jak2 as measured by an in vitro kinase assay. We propose that Jak2 is a new indirect regulator of NHE-1 activity, which modulates the activity of NHE-1 by increasing the tyrosine phosphorylation of CaM and most likely by increasing the binding of CaM to NHE-1.
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PMID:Bradykinin B2 receptors activate Na+/H+ exchange in mIMCD-3 cells via Janus kinase 2 and Ca2+/calmodulin. 1127 60

Heterotrimeric G protein alpha,beta, and gamma subunits are subject to several kinds of co- and post-translational covalent modifications. Among those relevant to G protein-coupled receptor signaling in normal cell function are lipid modifications and phosphorylation. N-myristoylation is a co-translational modification occurring for members of the G(i) family of Galpha subunits, while palmitoylation is a post-translational modification that occurs for these and most other Galpha subunits. One or both modifications are required for plasma membrane targeting and contribute to regulating strength of interaction with the Gbetagamma heterodimer, effectors, and regulators of G protein signaling (RGS proteins). Galpha subunits, including those with transforming activity, are often inactive when unable to be modified with lipids. The reversible nature of palmitoylation is intriguing in this regard, as it lends itself to a regulation integrated with the activation state of the G protein. Several Galpha subunits are substrates for phosphorylation by protein kinase C and at least one is a substrate for phosphorylation by the p21-activated protein kinase. Phosphorylation in both instances inhibits the interactions of these subunits with the Gbetagamma heterodimer and RGS proteins. Several Galpha subunits are also substrates for tyrosine phosphorylation. A Ggamma subunit is phosphorylated by protein kinase C, with the consequence that it interacts more tightly with a Galpha subunit but less well with an effector.
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PMID:Regulation of G proteins by covalent modification. 1131 12

We present evidence that gastrin, binding to a G protein-coupled receptor, activates the p38-mitogen-activated protein kinase (MAPK) pathway. Blockage of protein kinase C (PKC) by GF109203X, depletion of intracellular calcium by thapsigargin or inhibition of Src family kinases by PP2 prevented p38-MAPK activation and the Src kinase activity stimulated by gastrin. Inhibition of the PI 3-kinase by wortmannin or LY294002 did not affect these responses. In addition, the p38-MAPK inhibitor, SB203580, repressed gastrin-induced [(3)H]thymidine incorporation, indicating a major role of p38-MAPK in the growth-promoting effect of gastrin. Our results demonstrate that gastrin-induced DNA synthesis requires p38-MAPK activation through mechanisms that involve calcium mobilization, PKC and Src family kinases.
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PMID:Gastrin-induced DNA synthesis requires p38-MAPK activation via PKC/Ca(2+) and Src-dependent mechanisms. 1134

ATP, acting via P2Y, G protein-coupled receptors (GPCRs), is a mitogenic signal and also synergistically enhances fibroblast growth factor-2 (FGF-2)-induced proliferation in astrocytes. Here, we have examined the effects of ATP and FGF-2 cotreatment on the main components of the extracellular-signal regulated protein kinase (ERK) cascade, cRaf-1, MAPK/ERK kinase (MEK) and ERK, key regulators of cellular proliferation. Surprisingly, ATP inhibited activation of cRaf-1 by FGF-2 in primary cultures of rat cortical astrocytes. The inhibitory effect did not diminish MEK and ERK activation; indeed, cotreatment resulted in a greater initial activation of ERK. ATP inhibition of cRaf-1 activation was not mediated by an increase in cyclic AMP levels or by protein kinase C activation. ATP also inhibited the activation of cRaf-1 by other growth factors, epidermal growth factor and platelet-derived growth factor, as well as other MEK1 activators stimulated by FGF-2, MEK kinase 1 (MEKK1) and MEKK2. Serotonin, an agonist of another GPCR coupled to ERK, did not inhibit FGF-2-induced cRaf-1 activation, thereby indicating specificity in the ATP-induced inhibitory cross-talk. These findings suggest that ATP stimulates an inhibitory activity that lays upstream of MEK activators and inhibits growth factor-induced activation of cRaf-1 and MEKKS: Such a mechanism might serve to integrate the actions of receptor tyrosine kinases and P2Y-GPCRS:
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PMID:Extracellular ATP stimulates an inhibitory pathway towards growth factor-induced cRaf-1 and MEKK activation in astrocyte cultures. 1135 65

Protein kinase D (PKD)/protein kinase C (PKC) mu is a serine/threonine protein kinase that can be activated by physiological stimuli like growth factors, antigen-receptor engagement and G protein-coupled receptor (GPCR) agonists via a phosphorylation-dependent mechanism that requires PKC activity. In order to investigate the dynamic mechanisms associated with GPCR signaling, the intracellular translocation of a green fluorescent protein-tagged PKD was analyzed by real-time visualization in fibroblasts and epithelial cells stimulated with bombesin, a GPCR agonist. We found that bombesin induced a rapidly reversible plasma membrane translocation of green fluorescent protein-tagged PKD, an event that can be divided into two distinct mechanistic steps. The first step, which is exclusively mediated by the cysteine-rich domain in the N terminus of PKD, involved its translocation from the cytosol to the plasma membrane. The second step, i.e. the rapid reverse translocation of PKD from the plasma membrane to the cytosol, required its catalytic domain and surprisingly PKC activity. These findings provide evidence for a novel mechanism by which PKC coordinates the translocation and activation of PKD in response to bombesin-induced GPCR activation.
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PMID:Rapid protein kinase D translocation in response to G protein-coupled receptor activation. Dependence on protein kinase C. 1141 May 87

Parathyroid hormone (PTH)-related peptide (PTHrP) can modulate the proliferation and differentiation of a number of cell types including osteoblasts. PTHrP can activate a G protein-coupled PTH/PTHrP receptor, which can interface with several second-messenger systems. In the current study, we have examined the signaling pathways involved in stimulated type I collagen and alkaline phosphatase expression in the human osteoblast-derived osteosarcoma cells, MG-63. By use of Northern blotting and histochemical analysis, maximum induction of these two markers of osteoblast differentiation occurred after 8 h of treatment with 100 nM PTHrP-(1-34). Chemical inhibitors of adenylate cyclase (H-89) or of protein kinase C (chelerythrine chloride) each diminished PTHrP-mediated type I collagen and alkaline phosphatase stimulation in a dose-dependent manner. These effects of PTHrP could also be blocked by inhibiting the Ras-mitogen-activated protein kinase (MAPK) pathway with a Ras farnesylation inhibitor, B1086, or with a MAPK inhibitor, PD-98059. Transient transfection of MG-63 cells with a mutant form of Galpha, which can sequester betagamma-subunits, showed significant downregulation of PTHrP-stimulated type I collagen expression, as did inhibition of phosphatidylinositol 3-kinase (PI 3-kinase) by wortmannin. Consequently, the betagamma-PI 3-kinase pathway may be involved in PTHrP stimulation of Ras. Collectively, these results demonstrate that, acting via its G protein-coupled receptor, PTHrP can induce indexes of osteoblast differentiation by utilizing multiple, perhaps parallel, signaling pathways.
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PMID:Induction of osteoblast differentiation indexes by PTHrP in MG-63 cells involves multiple signaling pathways. 1150 Mar 4


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