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:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An increased oxidative stress may contribute to the accelerated atherosclerosis in diabetic patients. Here we show that 3-hydroxy-3-methylglutaryl CoA reductase inhibitor (statin) attenuates a high glucose-induced and a diabetes-induced oxidative stress through inhibition of vascular NAD(P)H oxidase. Exposure of cultured aortic endothelial cells and smooth muscle cells to a high glucose level (450 mg/dl) for 3 days significantly increased oxidative stress compared with a normal glucose level (100 mg/dl), as evaluated by the staining with 2',7'-dichlorofluorescein diacetate and electron spin resonance (ESR) measurement. This increase was completely blocked by the treatment with pitavastatin (5 x 10(-7)M) as well as a NAD(P)H oxidase inhibitor (diphenylene iodonium) or a PKC inhibitor (calphostin C) in parallel with the change of small GTPase Rac-1 activity, a cytosolic regulatory component of NAD(P)H oxidase. Next, using streptozotocin-induced diabetic rats, the effect of pitavastatin on oxidative stress was evaluated by in vivo ESR measurements, which is a sensitive, noninvasive method. Administration of pitavastatin (5 mg/kg/day) for 4 days attenuated the increased oxidative stress in diabetic rats to control levels. In conclusion, pitavastatin attenuated a high glucose-induced and a diabetes-induced oxidative stress in vitro and in vivo. Thus, our data may provide a new insight into antioxidative therapy in diabetes.
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PMID:Statin attenuates high glucose-induced and diabetes-induced oxidative stress in vitro and in vivo evaluated by electron spin resonance measurement. 1604 16

Wnt proteins are cysteine-rich glycosylated proteins named after the Drosophilia Wingless (Wg) and the mouse Int-1 genes that play a role in embryonic cell patterning, proliferation, differentiation, orientation, adhesion, survival, and programmed cell death (PCD). Wnt proteins involve at least two intracellular signaling pathways. One pathway controls target gene transcription through beta-catenin, generally referred to as the canonical pathway and a second pathway pertains to intracellular calcium (Ca(2+)) release which is termed the non-canonical or Wnt/ Ca(2+) pathway. The majority of Wnt proteins activate gene transcription through the canonical signaling pathway regulated by pathways that include the Frizzled transmembrane receptor and the co-receptor LRP-5/6, Dishevelled, glycogen synthase kinase-3beta (GSK-3beta), adenomatous polyposis coli (APC), and beta-catenin. In contrast, the non-canonical Wnt signaling pathway has two intracellular signaling cascades that consist of the Wnt/ Ca(2+) pathway with protein kinase C (PKC) and the Wnt/PCP pathway involving Rho/Rac small GTPase and Jun N-terminal kinase (JNK). Through a series of signaling pathways, Wnt proteins modulate cell development, proliferation, and cell fate. In regards to cell survival and fate through PCD, Wnt may be critical for the prevention of tissue pathology that involves cytokine and growth factor control during disorders such as neuropsychiatric disease, retinal disease, and Alzheimer's disease. Elucidation of the vital elements that shape and control the Wnt-Frizzled signaling pathway may provide significant prospects for the treatment of disorders of the nervous system.
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PMID:Vital elements of the Wnt-Frizzled signaling pathway in the nervous system. 1620 77

The small GTPase, RhoA, and its downstream effecter Rho-kinase (ROK) are reported to be involved in various cellular functions, such as myosin light chain phosphorylation during smooth muscle contraction and exocytosis. Indeed, growing evidence suggests that the RhoA/Rho-kinase pathway plays an important role in regulating exocytosis in these cells. However, it is not known whether the RhoA/Rho-kinase pathway has an effect on catecholamine synthesis. Using the rat pheochromocytoma cell line, PC12, we examined the effects of either Rho-kinase inhibitor (Y27632) or RhoA inhibitor (C3 toxin) on nicotine-induced catecholamine biosynthesis. We show that nicotine (10 microM) induces a significant, though transient, increase in RhoA activation in these cells. Treatment with either Y27632 (1 microM) or C3 toxin (10 microg/ml) significantly inhibited the nicotine-induced increase of tyrosine hydroxylase (TH) mRNA and the corresponding enzyme activity. TH catalyzes the rate-limiting step in the biosynthesis of catecholamine. Y27632 significantly inhibited nicotine-induced phosphorylation of TH at Ser40 as well as Ser19, which are known to be phosphorylated by Ca(2+)/calmodulin kinase II. Furthermore, Y27632 (10 microM) as well as C3 toxin (10 microg/ml) significantly inhibited the nicotine-induced increase of TH at the protein level. Thus, we propose that activation of RhoA, and its downstream effecter Rho-kinase, is a prerequisite for catecholamine biosynthesis in PC12 cells. At the concentrations used in our experiments, Y27632 does not affect cAMP/PKA activity or PKC activity, indicating that the inhibitory effect of Y27632 can be attributed to the inhibition of Rho-kinase activity as observed in chromaffin cells. In contrast, neither Y27632 (10 microM) nor C3 toxin (10 microg/ml) significantly altered catecholamine secretion in PC12 cells. In conclusion, we have demonstrated that inhibition of the Rho/Rho-kinase pathway in chromaffin cells lowers TH activity, probably through CaMKII inhibition. By contrast, neither Y27632 nor C3 toxin affect the secretion of catecholamine.
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PMID:Inhibition of the RhoA/Rho kinase system attenuates catecholamine biosynthesis in PC 12 rat pheochromocytoma cells. 1621 24

Inwardly rectifying potassium channels Kir2.1-Kir2.3 are important regulators of membrane potential and, thus, control cellular excitability. However, little is known about the regulation of these channels. Therefore, we studied the mechanisms mediating the regulation of Kir2.1-Kir2.3 by the G-protein-coupled m1 muscarinic receptor using the whole-cell patch-clamp technique and recombinant expression in the tsA201 mammalian cell line. Stimulation of the m1 muscarinic receptor inhibited all subtypes of inward rectifier tested, Kir2.1-Kir2.3. The inhibition of each channel subtype was reversible and was attenuated by the muscarinic receptor antagonist, atropine. The protein kinase C activator phorbol 12-myristate 13-acetate (PMA) mimicked the effects of m1 receptor activation by inhibiting Kir2.1 currents. However, PMA had no effect on Kir2.2 or Kir2.3. Inclusion of 200-microM guanosine 5'-O-(2-thiodiphosphate) (GDPbetaS) in the patch pipette solution prevented the effects of m1 muscarinic receptor stimulation on all three of the channel subtypes tested, confirming the mediation of the responses by G-proteins. Cotransfection with the activated mutant of the small GTPase Rho reduced current density, while C3 exoenzyme, a selective inhibitor of Rho, attenuated the m1 muscarinic receptor-induced inhibition of Kir2.1-Kir2.3. Also, buffering the intracellular calcium concentration with a high concentration of EGTA abolished the m1 receptor-induced inhibition of Kir2.1-Kir2.3, implicating a role for calcium in these responses. These results indicate that all three of the Kir2 channels are similarly inhibited by m1 muscarinic receptor stimulation through calcium-dependent activation of the small GTPase Rho.
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PMID:Regulation of a family of inwardly rectifying potassium channels (Kir2) by the m1 muscarinic receptor and the small GTPase Rho. 1632 54

Neurite branching is essential for the establishment of appropriate neuronal connections during development and regeneration. We identify the small GTPase Ral as a mediator of neurite branching. Active Ral promotes neurite branching in cortical and sympathetic neurons, whereas Ral inhibition decreases laminin-induced branching. In addition, depletion of endogenous Ral by RNA interference decreases branching in cortical neurons. The two Ral isoforms, RalA and -B, promote branching through distinct pathways, involving the exocyst complex and phospholipase D, respectively. Finally, Ral-dependent branching is mediated by protein kinase C-dependent phosphorylation of 43-kD growth-associated protein, a crucial molecule involved in pathfinding, plasticity, and regeneration. These findings highlight an important role for Ral in the regulation of neuronal morphology.
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PMID:Ral GTPases regulate neurite branching through GAP-43 and the exocyst complex. 1633 Jul 13

The involvement of the small GTPase Rap1b in platelet integrin alpha2beta1-dependent outside-in signaling was investigated. Platelet adhesion to 4 different specific ligands for integrin alpha2beta1, monomeric collagen, decorin, and collagen-derived peptides CB8(II) and CB11(II), induced a robust and rapid activation of Rap1b. This process did not require secreted ADP or thromboxane A2 production but was critically regulated by phospholipase C (PLC)-derived second messengers. Both Ca2+ and protein kinase C were found to organize independent but additive pathways for Rap1b activation downstream of integrin-alpha2beta1, which were completely blocked by inhibition of PLC with U73122. Moreover, integrin alpha2beta1 engagement failed to trigger Rap1b activation in murine platelets lacking CalDAG-GEFI, a guanine nucleotide exchange factor regulated by Ca2+ and diacylglycerol, despite normal phosphorylation and activation of PLCgamma2. In addition, CalDAG-GEFI-deficient platelets showed defective integrin alpha2beta1-dependent adhesion and spreading. We found that outside-in signaling through integrin alpha2beta1 triggered inside-out activation of integrin alphaIIbbeta3 and promoted fibrinogen binding. Similarly to Rap1b stimulation, this process occurred downstream of PLC activation and was dramatically impaired in murine platelets lacking the Rap1 exchange factor CalDAG-GEFI. These results demonstrate that Rap1b is an important element in integrin-dependent outside-in signaling during platelet adhesion and regulates the cross talk between adhesive receptors.
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PMID:The small GTPase Rap1b regulates the cross talk between platelet integrin alpha2beta1 and integrin alphaIIbbeta3. 1635 24

Differentiation of skin stem cells into hair follicles (HFs) requires the inhibition of beta-catenin degradation, which is controlled by a complex containing axin and the protein kinase GSK3beta. Using conditional gene targeting in mice, we show now that the small GTPase Cdc42 is crucial for differentiation of skin progenitor cells into HF lineage and that it regulates the turnover of beta-catenin. In the absence of Cdc42, degradation of beta-catenin was increased corresponding to a decreased phosphorylation of GSK3beta at Ser 9 and an increased phosphorylation of axin, which is known to be required for binding of beta-catenin to the degradation machinery. Cdc42-mediated regulation of beta-catenin turnover was completely dependent on PKCzeta, which associated with Cdc42, Par6, and Par3. These data suggest that Cdc42 regulation of beta-catenin turnover is important for terminal differentiation of HF progenitor cells in vivo.
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PMID:Cdc42 controls progenitor cell differentiation and beta-catenin turnover in skin. 1651 Aug 73

Protein kinase C (PKC) zeta has been implicated in insulin-induced glucose uptake in skeletal muscle cell, although the underlying mechanism remains unknown. In this study, we investigated the effect of PKCzeta on actin remodeling and glucose transport in differentiated rat L6 muscle cells expressing myc-tagged glucose transporter 4 (GLUT4). On insulin stimulation, PKCzeta translocated from low-density microsomes to plasma membrane accompanied by increase in GLUT4 translocation and glucose uptake. Z-scan confocal microscopy revealed a spatial colocalization of relocated PKCzeta with the small GTPase Rac-1, actin, and GLUT4 after insulin stimulation. The insulin-mediated colocalization, PKCzeta distribution, GLUT4 translocation, and glucose uptake were inhibited by wortmannin and cell-permeable PKCzeta pseudosubstrate peptide. In stable transfected cells, overexpression of PKCzeta caused an insulin-like effect on actin remodeling accompanied by a 2.1-fold increase in GLUT4 translocation and 1.7-fold increase in glucose uptake in the absence of insulin. The effects of PKCzeta overexpression were abolished by cell-permeable PKCzeta pseudosubstrate peptide, but not wortmannin. Transient transfection of constitutively active Rac-1 recruited PKCzeta to new structures resembling actin remodeling, whereas dominant negative Rac-1 prevented the insulin-mediated PKCzeta translocation. Together, these results suggest that PKCzeta mediates insulin effect on glucose transport through actin remodeling in muscle cells.
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PMID:Protein kinase Czeta mediates insulin-induced glucose transport through actin remodeling in L6 muscle cells. 1652 20

Originally thought of as a stomach-derived endocrine peptide acting via its receptors in the central nervous system to stimulate food intake and growth hormone expression, ghrelin and its receptor (growth hormone secretagogue receptor (GHS-R)) are widely expressed in a number of organ systems, including cancer cells. However, the direct functional role of ghrelin and its receptor in tumors of central nervous system origin remains to be defined. Here, we demonstrate that the human astrocytoma cell lines U-118, U-87, CCF-STTG1, and SW1088 express 6-, 11-, 15-, and 29-fold higher levels of GHS-R compared with primary normal human astrocytes. The ligation of GHS-R by ghrelin on these cells resulted in an increase in intracellular calcium mobilization, protein kinase C activation, actin polymerization, matrix metalloproteinase-2 activity, and astrocytoma motility. In addition, ghrelin led to actin polymerization and membrane ruffling on cells, with the specific co-localization of the small GTPase Rac1 with GHS-R on the leading edge of the astrocytoma cells and imparting the tumor cells with a motile phenotype. Disruption of the endogenous ghrelin/GHS-R pathway by RNA interference resulted in diminished motility, matrix metalloproteinase activity, and Rac expression, whereas tumor cells stably overexpressing GHS-R exhibited increased cell motility. The relevance of ghrelin and GHS-R expression was verified in clinically relevant tissues from 20 patients with oligodendrogliomas and grade II-IV astrocytomas. Analysis of a central nervous system tumor tissue microarray revealed that strong GHS-R and ghrelin expression was significantly more common in high grade tumors compared with low grade ones. Together, these findings suggest a novel role for the ghrelin/GHS-R axis in astrocytoma cell migration and invasiveness of cancers of central nervous system origin.
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PMID:Ghrelin and the growth hormone secretagogue receptor constitute a novel autocrine pathway in astrocytoma motility. 1652 11

Although receptor-mediated regulation of small G-proteins and the cytoskeleton is intensively studied, the mechanisms for attenuation of these signals are poorly understood. In this study, we have identified the Rac-GAP beta2-chimaerin as an effector of the epidermal growth factor receptor (EGFR) via coupling to phospholipase Cgamma (PLCgamma) and generation of the lipid second messenger diacylglycerol (DAG). EGF redistributes beta2-chimaerin to promote its association with the small GTPase Rac1 at the plasma membrane, as determined by FRET. This relocalization and association with Rac1 were impaired by disruption of the beta2-chimaerin C1 domain as well as by PLCgamma1 RNAi, thus defining beta2-chimaerin as a novel DAG effector. On the other hand, GAP-deficient beta2-chimaerin mutants show enhanced translocation and sustained Rac1 association in the FRET assays. Remarkably, RNAi depletion of beta2-chimaerin significantly extended the duration of Rac activation by EGF, suggesting that beta2-chimaerin serves as a mechanism that self-limits Rac activity in response to EGFR activation. Our results represent the first direct evidence of divergence in DAG signaling downstream of a tyrosine-kinase receptor via a PKC-independent mechanism.
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PMID:Phospholipase Cgamma/diacylglycerol-dependent activation of beta2-chimaerin restricts EGF-induced Rac signaling. 1662 18


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