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)

Platelet-activating factor (PAF) is a potent activator of angiogenesis and controls the motility and the shape of vascular endothelium. The mechanism(s) whereby PAF exerts its action are in part known. Here we report that the biological active (R)PAF enantiomer administrated to cultured endothelial cells induces the early phosphorylation in tyrosine residues of focal adhesion kinase (p125FAX) and paxillin, two molecules involved in the early signaling and cytoskeleton assembly in cells that undergo integrin-mediated adhesion or are challenged by neuropeptides or lysophosphatidic acid. The phenomenon is rapidly turned on, lasts for a few minutes and is adhesion-independent indicating that the chain of events induced by (R)PAF, including p125FAK activation, precedes adhesion. The inhibitory effect of WEB2086, a PAF receptor antagonist, and the lack of activity exerted by the (S)PAF enantiomer, indicate that (R)PAF-mediated p125FAK activation, is PAF receptor-dependent. Calphostin C, an inhibitor of protein kinase C blocks the effect of (R)PAF on p125FAK phosphorylation suggesting that protein kinase C activation is up-stream the activation of this tyrosine kinase. When endothelial cells are exposed to a substratum that allows adhesion and spreading. (R)PAF-stimulated cells, change their adhesive phenotype and start migrating. Inhibitors of tyrosine kinases, like 3-(1,4,-dihydroxytetralyl) methylen-2-oxindole and herbimycin A, reduce the cells migration, the transendothelial flux of albumin and the enhancement of p125FAK activity induced by (R)PAF. The observation that increased tyrosine phosphorylation of p125FAK and its ensuring association with focal adhesion occurs rapidly upon (R)PAF challenge indicates that this signaling molecule has a primary and independent role also in the signaling cascade initiated by (R)PAF.
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PMID:Platelet-activating factor (PAF) induces the early tyrosine phosphorylation of focal adhesion kinase (p125FAK) in human endothelial cells. 876 Feb 93

In order to reach the sites of inflammation, lymphocytes leave the bloodstream and migrate into peripheral tissues, in a process involving integrin-mediated adhesion to the vascular endothelium, followed by transmigration across the endothelial barrier and through the underlying interstitial matrix. We have investigated the role of the plasminogen activator/plasmin system in normal T cell migration. Receptors for urokinase plasminogen activator (uPAR) were not expressed in resting T lymphocytes, but could be efficiently induced at the mRNA and protein level by coclustering of the antigen receptor complex and beta1 or beta2 integrins, through a signalling pathway involving both protein kinase C activation and an increase in intracellular cyclic AMP. Catalytic activation of plasminogen by uPAR-expressing T cells promoted their migration through an extracellular matrix in vitro. Plasmin-induced invasion was inhibited by plasmin-and urokinase inhibitors and by anti-uPAR antibodies. Finally, cytofluorimetric and immunohistochemical analysis of primary human tumor specimens showed the presence of uPAR positive infiltrating T cells in vivo. Collectively, these findings suggest that plasminogen activation may play a role in lymphocyte migration in vivo, and that integrin-dependent expression of membrane-associated endopeptidases could represent an additional step in the regulated process of leukocyte transmigration.
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PMID:Integrin-dependent induction of functional urokinase receptors in primary T lymphocytes. 878 76

Cigarette smoking is clearly linked with increased incidence of atherosclerosis and cardiovascular disease. The adherence of blood monocytes to the endothelium, followed by their migration beneath the endothelium, are initiating events in the formation of foam cells, promoting atherogenesis. We show that cigarette smoke condensate (CSC)-induced surface expression of a subset of cell adhesion molecules (CAM) [intercellular adhesion molecule 1 (ICAM-1), endothelial leukocyte adhesion molecule 1 (ELAM-1), and vascular cell adhesion molecule 1 (VCAM-1)] in human umbilical vein endothelial cells (HUVEC) is associated with an increase in the binding activity of nuclear transcription factor NF-kappa B to the consensus motif common to the CAM genes. Furthermore, CSC (25 microgram/ml) both increases the rate of transendothelial migration of vitamin D3-differentiated monocyte-like cells across the HUVEC monolayer by 200% and causes an approximately 10-fold increases in the phosphorylation of platelet endothelial CAM (PECAM-1), an adhesion molecule located at intercellular junctions and involved in endothelial cell-cell adhesion. Our results show that CSC-induced activation of protein kinase C in endothelial cells initiates a signaling pathways, leading to heightened binding of NF-kappa B to specific DNA sequences, which in turn increases surface expression of the subset of CAMs. Furthermore, our studies demonstrate a link between the phosphorylation of PECAM-1 and the migration of blood monocytes across vascular endothelium.
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PMID:Cigarette smoke condensate-induced adhesion molecule expression and transendothelial migration of monocytes. 892 67

A variety of physical forces exist in a dynamic equilibrium in the vascular endothelium (EC) monolayer and serve to maintain EC responsiveness while preserving the integrity of the EC monolayer and barrier properties. Thrombin has potent effects on EC permeabilities disrupting the equilibrium between tethering forces (cadherins, focal adhesion plaque) and forces that increase centripetal tension primarily via myosin light chain (MLC) phosphorylation. Like other EC effects, thrombin-induced MLC kinase (MLCK) activation is dependent upon receptor proteolysis, Ca2+ mobilization, and activation of protein kinase C (PKC). While EC gap formation is central to barrier dysfunction and dependent upon activation of MLCK, (which phosphorylates MLC) an obligatory event in smooth muscle cell contraction, little is known regarding the events that reverse inflammatory responses, halt the contractile response, and initiate relaxation. However, as these events likely include MLC dephosphorylation, further examination of the processes that regulate MLC protein phosphatase activity, focal intercellular junctions, and extracellular matrix adhesions is needed. These investigations should yield new information as to how receptor occupancy is transduced into specific cellular responses, such as increased permeability, which promotes pathological vascular processes such as tissue edema formation and organ dysfunction.
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PMID:Regulation of thrombin-mediated endothelial cell contraction and permeability. 894 15

Polymorphonuclear neutrophils (PMN) adhere to the vascular endothelium under hypoxic conditions, causing microvascular injury. The molecular mechanism of hypoxia-induced adhesion of PMN to and diapedesis through the vascular endothelium is poorly understood. We examined the effects of hypoxia on the transendothelial migration of monocytes. Exposure of human umbilical vein endothelial cells (HUVEC) cultured in Transwell chambers under low oxygen tension (3% O2 compared with 21% O2) resulted in an increased rate of migration of both monocyte-like HL-60 cells and human peripheral blood monocytes. Migration was inhibited by addition of an antibody to platelet endothelial cell adhesion molecule-1 (PECAM-1), a protein kinase C (PKC) inhibitor, or a platelet-activating factor (PAF)-receptor antagonist. In HUVEC, hypoxic conditions (1, 3, 5, and 14% O2) increased the phosphorylation of PECAM-1. The extent of phosphorylation of PECAM-1 was inversely related to the concentration of oxygen to which HUVEC were exposed. Hypoxia-induced phosphorylation of PECAM-1 was inhibited by either a PKC inhibitor or a PAF-receptor antagonist, indicating the involvement of hypoxia-induced release of PAF in both PKC activation and the concomitant phosphorylation of PECAM-1. These results were substantiated by the findings that treatment of HUVEC with 100 nM PAF under normoxic conditions augmented 11.8-fold the phosphorylation of PECAM-1 and twofold increase in the transendothelial migration of monocyte-like HL-60 cells. We conclude that PAF, produced by cultured endothelial cells in response to hypoxia, acts in an autocrine fashion to activate PKC, causing PECAM-1 phosphorylation and thus the transendothelial migration of monocytes.
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PMID:Hypoxia induces PECAM-1 phosphorylation and transendothelial migration of monocytes. 894 22

We recently reported that Thy-1, a surface molecule induced on the rat endothelium, regulates vascular permeability at sites of inflammation. Although the rat inferior vena cava (IVC) did not express Thy-1 in vivo, cultured endothelial cells from the IVC did express Thy-1, thereby suggesting that the expression was acquired during cultivation of the cells in vitro, possibly by autoactivation by cytokine-like substances. Interleukin (IL)-1alpha but not tumor necrosis factor (TNF)-alpha or interferon (IFN)-gamma was detected in culture supernatants of rat endothelial cells (REC) by ELISA. The production of IL-1alpha by REC was augmented by exogenously added IL-1alpha, thereby implying the presence of autocrine regulation by IL-1alpha. The unaltered expression of Thy-1 by exogenously added IL-1alpha suggests that Thy-1 expression on REC had already been maximally induced by autologous cytokines; the expression of Thy-1 on REC was lowered by inhibiting protein kinase C and by depleting IL-1alpha activity from culture supernatants. Although cytokine-like regulators, other than IL-1alpha, TNF-alpha, or IFN-gamma, produced by REC may also modulate the expression of Thy-1, it is at least in part mediated by IL-1alpha in vitro. Moreover, Thy-1 expression was induced on rat vascular endothelium at the subcutis where recombinant IL-1alpha was injected. The evidence indicates that IL-1alpha functions as one regulator responsible for the induction of Thy-1 on REC, in vitro as well as in vivo.
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PMID:Interleukin-1alpha regulates Thy-1 expression on rat vascular endothelial cells. 905 77

The endothelins (ET-1, 2, and 3) constitute a family of 21 amino-acid peptides with potent biological activities. They are synthesized in several tissues, including the vascular endothelium (ET-1 exclusively) and smooth muscle cells. The production and release of endothelin is stimulated by many factors, hormonal and metabolic, and by growth factors, hypoxia, and shear stress. Released endothelin binds to the endothelin receptors ETA and ETB, the ETA receptors on vascular smooth muscle cells mediating vasoconstriction, and the ETB receptors on the endothelium linked to nitric oxide (NO) and prostacyclin release. The ETA receptors activate the PLC-IP3-DAG transduction pathway, which through an increase in cytosolic Ca2+ and protein kinase C (PKC) causes vasoconstriction and stimulation of vascular smooth muscle cell growth and proliferation. In the pathogenesis of vascular hypertrophy in hypertension, there is a complex interaction between endothelin, angiotensin II, alpha-adrenergic agonists, Ca2+, and other growth factors. In animal models of hypertension, endothelin causes vascular hypertrophy, more pronounced in deoxycorticosterone acetate (DOCA)-salt hypertension in the rat than in the spontaneously hypertensive rate. In humans there is an increase in the plasma concentration of endothelin in severe atherosclerotic disease, but not consistently in hypertension. Evidence for the role of endothelin in the vascular hypertrophy of human hypertension is scanty, but the development of nonpeptide and receptor subtype-selective antagonists will permit meaningful studies, including clinical trials of a new class of antihypertensive agents.
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PMID:Endothelin, vascular hypertrophy, and hypertension. 911 Jan 24

Naturally occurring polycations and cationic proteins are implicated in vascular disorders. It is known that activated leukocytes and platelets release polycations, such as polylysine (PLys), of varying molecular sizes into the vasculature, and some of these have been described to be bactericidal. Polycations interact with endothelial cells (ECs) and cause alterations in permeability and cellular functions. The precise mechanism(s) by which polycations bring about cellular changes is unknown. Here, we report that the polycations PLys and polyarginine (PArg) induce phospholipase D (PLD) activation in ECs. Polycation-mediated PLD activation was both time and concentration dependent, and activation of PLD was not due to cytotoxicity. PArg was more potent compared with PLys of the same molecular weight in stimulation of PLD. Treatment with bisindolylmaleimide, a specific protein kinase C (PKC) inhibitor, and heparin attenuated polycation-mediated PLD activation. Furthermore, downregulation of PKC by 12-O-tetradecanoylphorbol-13-acetate (100 nM, 18 h) also blocked polycation-mediated PLD stimulation. These data suggest that polycation-mediated PLD stimulation probably involves PKC and may represent an important cellular response to leukocyte/platelet activation in the vascular endothelium.
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PMID:Activation of endothelial cell phospholipase D by polycations. 914 32

Red blood cells (RBC) from patients with diabetes mellitus exhibit an increased propensity to adhere to cultured human umbilical vein endothelial cells (HUVEC) as a result of interaction of advanced glycation end products with their counter receptors, contributing to the pathogenesis of vascular complications. We determined whether the interaction of diabetic RBC with HUVEC induced cellular oxidant stress that would culminate in adherence and diapedesis of monocytes, these being initiating events in endothelial injury and atherogenesis. We show that the adherence of diabetic RBC (2% hematocrit), but not normal RBC, to HUVEC results in a fourfold increase in the production of lipid peroxides. Furthermore, diabetic RBC-induced oxidant stress causes a sixfold increase in platelet endothelial cell adhesion molecule-1 (PECAM-1) phosphorylation and doubles transendothelial migration of monocyte-like HL-60 cells; both are blocked by antioxidants and protein kinase C (PKC) inhibitors. Our results show that the adherence of diabetic RBC to endothelial cells initiates a cascade of cellular events resulting in PKC activation, causing PECAM-1 phosphorylation and concomitant transendothelial migration of monocytes. The increased diapedesis of monocytes, brought about by the interaction of diabetic RBC across vascular endothelium, may play an important role in accelerated atherosclerosis and cardiovascular disease in diabetics.
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PMID:Diabetic RBC-induced oxidant stress leads to transendothelial migration of monocyte-like HL-60 cells. 927 91

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is a multifunctional cytokine and growth factor that has important roles in both pathological and physiological angiogenesis. VPF/VEGF induces vascular hyperpermeability, cell division, and other activities by interacting with two specific receptor tyrosine kinases, KDR/Flk-1 and Flt-1, that are selectively expressed on vascular endothelium. The signaling cascade that follows VPF/VEGF interaction with cultured endothelium is only partially understood but is known to result in increased intracellular calcium, activation of protein kinase C, and tyrosine phosphorylations of both receptors, phospholipase C-gamma (PLC-gamma) and phosphatidylinositol 3'-kinase. For many reasons, signaling events elicited in cultured endothelium may not mimic mediator effects on intact normal or tumor-induced microvessels in vivo. Therefore, we developed a system that would allow measurement of VPF/VEGF-induced signaling on intact microvessels. We used mouse mesentery, a tissue whose numerous microvessels are highly responsive to VPF/VEGF and that we found to express Flk-1 and Flt-1 selectively. At intervals after injecting VPF/VEGF i.p., mesenteries were harvested, extracted, and immunoprecipitated. Immunoblots confirmed that VPF/VEGF induced tyrosine phosphorylation of several proteins in mesenteric microvessels as in cultured endothelium: Flk-1; PLC-gamma; and mitogen-activated protein kinase. Similar phosphorylations were observed when mesentery was exposed to VPF/VEGF in vitro, or when mesenteries were harvested from mice bearing the mouse ovarian tumor ascites tumor, which itself secretes abundant VPF/VEGF. Other experiments further elucidated the VPF/VEGF signaling pathway, demonstrating phosphorylation of both PYK2 and focal adhesion kinase, activation of c-jun-NH2-kinase with phosphorylation of c-Jun, and an association between Flk-1 and PLC-gamma. In addition, we demonstrated translocation of mitogen-activated protein kinase to the cell nucleus in cultured endothelium. Taken together, these experiments describe a new model system with the potential for investigating signaling events in response to diverse mediators on intact microvessels in vivo and have further elucidated the VPF/VEGF signaling cascade.
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PMID:Vascular permeability factor/vascular endothelial growth factor-mediated signaling in mouse mesentery vascular endothelium. 951 16


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