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)

MCF-7 breast cancer cells stably transfected with protein kinase C-alpha (MCF-7-PKC-alpha cells) show anchorage-independent growth and exhibit increased tumorigenicity in nude mice. Since integrins are involved in tumor growth and metastatic spread, we investigated whether integrin expression is differentially regulated in MCF-7-PKC-alpha cells. Fluorescence-activated cell sorting revealed that alphavbeta3 is highly expressed on MCF-7-PKC-alpha cells, but is undetectable on MCF-7V cells (MCF-7 cells transfected with vector only). In contrast, MCF-7-PKC-alpha cells have reduced expression of alphavbeta5. Blocking experiments with antibodies to alphavbeta3 and alphavbeta5 revealed that these receptors are used by MCF-7-PKC-alpha cells to adhere primarily to vitronectin and osteopontin. Consistent with heterodimer expression, MCF-7-PKC-alpha cells express increased beta3 and decreased beta5 on their surface. Surface expression of alphav on MCF-7-PKC-alpha cells is unchanged. Western blotting, Northern analysis, and nuclear run-on assays indicated that post-translational mechanisms increase the surface expression of beta3 on MCF-7-PKC-alpha cells. In contrast, reduced beta5 transcription diminishes beta5 surface expression on MCF-7-PKC-alpha cells. These results indicate that overexpression of PKC-alpha in MCF-7 cells alters beta5 and beta3 expression by transcriptional and post-translational mechanisms, respectively, resulting in altered heterodimer expression. These findings suggest that the increased metastatic capacity of tumor cells with elevated protein kinase C levels may result, in part, from modulation of integrin expression.
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PMID:Overexpression of protein kinase C-alpha in MCF-7 breast cancer cells results in differential regulation and expression of alphavbeta3 and alphavbeta5. 1037 5

Perturbation of adhesive interactions at cell-substratum and cell-cell contact sites is a critical event in the multistep process of cancer invasion. Recent studies indicate that the urokinase receptor (uPAR) is associated in large molecular complexes with other molecules, such as integrins. To test the possibility that uPAR may physically and functionally interact with vitronectin (Vn) receptors, we determined the expression level of uPAR, alpha(v)beta3, and alpha(v)beta5 Vn receptors in 10 human breast carcinomas. Here, we show the ability of uPAR to physically associate with alpha(v)beta5 in the breast carcinomas examined. The functional effects of this interaction were studied using HT1080 human fibrosarcoma and MCF-7 human breast carcinoma cell lines, both exhibiting a urokinase-dependent physical association between uPAR and alpha(v)beta5. Both cell lines respond to urokinase or to its noncatalytic amino-terminal fragment by exhibiting remarkable cytoskeletal rearrangements that are mediated by alpha(v)beta5 and require protein kinase C activity. On the contrary, binding of Vn to alpha(v)beta5 results in the protein kinase C-independent formation of F-actin containing microspike-type structures. Furthermore, alpha(v)beta5 is required for urokinase-directed, receptor-dependent MCF-7 and HT1080 cell migration. These data show that uPAR association with alpha(v)beta5 leads to a functional interaction of these receptors and suggest that uPAR directs cytoskeletal rearrangements and cell migration by altering alpha(v)beta5 signaling specificity.
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PMID:Urokinase receptor interacts with alpha(v)beta5 vitronectin receptor, promoting urokinase-dependent cell migration in breast cancer. 1053 14

Migration, proliferation, and tube formation of endothelial cells are regulated by a protein kinase C isoenzyme PKCtheta. A full-length cDNA encoding a novel 20-kD protein, whose expression was PKCtheta-dependent, was identified in endothelial cells, cloned, characterized, and designated as theta-associated protein (TAP) 20. Overexpression of TAP20 decreased cell adhesion and enhanced migration on vitronectin and tube formation in three-dimensional culture. An antiintegrin alphavbeta5 antibody prevented these TAP20 effects. Overexpression of TAP20 also decreased focal adhesion formation in alphavbeta3-deficient cells. The interaction between TAP20 and beta5 integrin cytoplasmic domain was demonstrated by protein coprecipitation and immunoblotting. Thus, the discovery of TAP20, which interacts with integrin beta5 and modulates cell adhesion, migration, and tube formation, further defines a possible pathway to angiogenesis dependent on PKCtheta.
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PMID:Enhancement of endothelial cell migration and in vitro tube formation by TAP20, a novel beta 5 integrin-modulating, PKC theta-dependent protein. 1057 26

Early studies considered that fibrinogen receptor (glycoprotein [GP] IIb-IIIa or platelet integrin alpha(IIb)beta(3)) is the binding site for low-density lipoprotein (LDL) and high-density lipoprotein type 3 (HDL(3)). Recent data, however, do not support the hypothesis that the binding of LDL to human intact resting platelets is related to integrin alpha(IIb)beta(3). In this study we present evidence that platelet integrin alpha(IIb)beta(3) is also not involved in the interaction of HDL(3) and human intact resting platelets. Firstly, specific ligands for platelet integrin alpha(IIb)beta(3), such as fibrinogen, vitronectin, von Willebrand factor and fibronectin, were unable to inhibit the binding of HDL(3) to intact resting platelets. Secondly, the HDL(3) binding characteristics (K(d) and B(max) values), the activation of protein kinase C (PKC) and the inhibition of thrombin-induced inositoltriphosphate (IP(3)) formation and calcium (Ca(2+)) mobilization mediated by HDL(3) particles were similar in platelets from control subjects and patients with type I and type II Glanzmann's thrombasthenia, which are characterized by total and partial lack of GPIIb-IIIa and fibrinogen, respectively. In contrast, nitrosylation of tyrosine residues of HDL(3) by tetranitromethane fully abolished both the ability of particles to interact with its specific binding sites and the functional effects. Thirdly, polyclonal antibodies against the GPIIb-IIIa complex (edu-3 and 5B12), human antiserums against platelet alloantigens (anti-Bak(a/B) and anti-PL(A1/2)), anti-integrin subunits (anti-alpha(V) and anti-beta(3)), and a wide panel of monoclonal antibodies (mAbs) against well-known epitopes of GPIIb (M3, M4, M5, M6, M8 and M95-2b) and GPIIIa (P23-7, P33, P37, P40, and P97) did not affect the binding of HDL(3) particles to human intact resting platelets. Overall results show that neither the GPIIb-IIIa complex nor GPIIb or GPIIIa individually are the membrane binding proteins for HDL(3)on intact resting platelets.
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PMID:Platelet HDL(3) binding sites are not related to integrin alpha(IIb)beta(3) (GPIIb-IIIa). 1113 79

The integrin vitronectin receptor alphavbeta3 is a mediator of cellular migration and invasion and has been identified as a marker of progression in malignant melanoma. Using a human melanoma model, we have previously shown that this receptor was coordinately expressed with the receptor for the urokinase plasminogen activator (uPAR). In our present study, the link between these receptors was further investigated by assessing the effect of alphavbeta3 ligation on uPAR transcription and function. Using the reverse transcription-polymerase chain reaction, we found that receptor ligation by immobilized monoclonal antibodies (MAbs) induced a rapid increase (up to 4.5 fold) in uPAR mRNA levels, which was maximal 4 hr after cell attachment. An increase was also noted in plasminogen activator inhibitor type-1 (PAI-1) mRNA levels (2.7-fold), but none was noted in uPA levels. In addition, ligation of alphavbeta3 resulted in a significant increase in cell surface-associated plasmin levels, which coincided with a 2- to 3-fold increase in cell invasion as measured in the Matrigel invasion assay. This increase in invasion could in turn be abolished by antibodies directed to uPA and uPAR and by the plasmin inhibitors epsilon-aminocaproic acid and aprotinin. Furthermore, ligation of the integrin alphavbeta3 triggered a rapid increase of up to 12-fold in total cellular PKC activity, and this coincided with the redistribution of PKCbeta, but not PKCalpha, from the cytosol to the membrane. Treatment of the cells with the PKCbeta-specific inhibitor LY379196 blocked uPAR and PAI-1 mRNA induction and reduced the increase in cell invasion due to alphavbeta3 ligation, confirming the involvement of this isoform in the response. The results provide evidence that the vitronectin receptor can enhance invasion by regulating the uPAR/uPA/plasmin system of proteolysis and implicate PKCbeta as an intermediate in the activation pathway.
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PMID:Regulation of urokinase plasminogen activator/plasmin-mediated invasion of melanoma cells by the integrin vitronectin receptor alphaVbeta3. 1116 51

Myofibroblasts, characterised by high expression of alpha-smooth muscle actin (alpha-SMA), are important and transient cells in normal wound healing but are found in increased number in various pathological conditions of the lung including asthma and pulmonary fibrosis. The mechanisms that regulate the myofibroblast phenotype are unknown but are likely to involve signals from the extracellular matrix transmitted via specific integrins. Vitronectin is a glycoprotein released during inflammation and has been shown to regulate the phenotype of vascular smooth muscle cells via alpha v and beta 1 integrins. In the current study we have examined whether vitronectin influences the phenotype and function of normal human lung fibroblasts (HFL-1). Incubation of HFL-1 cells with vitronectin induced a concentration-dependent reduction in alpha-SMA expression. By contrast, function-blocking monoclonal antibodies to the vitronectin integrins alpha v, beta 1, alpha v beta 3 and alpha v beta 5 induced the expression of alpha-SMA and its organization into stress fibers. Expression of alpha-SMA induced by all function-blocking monoclonal antibodies was abrogated by inhibition of protein kinase C and phosphatidylinositol-3 kinase, but the effects of inhibition of other signalling pathways was integrin dependent. Exposure to other extracellular matrix proteins such as fibronectin, collagen or their integrins did not influence expression of alpha-SMA. The expression and organization of alpha-SMA induced by exposure to function-blocking antibodies was translated into an augmented capacity of HFL-1 cells to contract fibroblast populated collagen gels. By contrast, contraction of collagen gels following incubation with vitronectin was not significantly different to control. This study has shown that vitronectin influences the phenotype and behaviour of HFL-1 cells by downregulating the expression of alpha-SMA and reducing their contractile ability. By contrast, occupancy of specific integrins by function-blocking antibodies upregulated the expression of alpha-SMA and induced the formation of functional stress fibers capable of contracting collagen gels. These results suggest that vitronectin modulates the fibroblast-myofibroblast phenotype, implying an important role in the remodelling process during lung development or response to injury.
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PMID:Regulation of human lung fibroblast phenotype and function by vitronectin and vitronectin integrins. 1168 10

Expression of the beta(3) integrin subunit in melanoma in situ has been found to correlate with tumor thickness, the ability to invade and metastasize, and poor prognosis. Transition from the radial growth phase (RGP) to the vertical growth phase (VGP) is a critical step in melanoma progression and survival and is distinguished by the expression of beta(3) integrin. The molecular pathways that operate in melanoma cells associated with invasion and metastasis were examined by ectopic induction of the beta(3) integrin subunit in RGP SBcl2 and WM1552C melanoma cells, which converts these cells to a VGP phenotype. We used cDNA representational difference analysis subtractive hybridization between beta(3)-positive and -negative melanoma cells to assess gene expression profile changes accompanying RGP to VGP transition. Fourteen fragments from known genes including osteonectin (also known as SPARC and BM-40) were identified after three rounds of representational difference analysis. Induction of osteonectin was confirmed by Northern and Western blot analysis and immunohistochemistry and correlated in organotypic cultures with the beta(3)-induced progression from RGP to VGP melanoma. Expression of osteonectin was also associated with reduced adhesion to vitronectin, but not to fibronectin. Osteonectin expression was not blocked when melanoma cells were cultured with anti-alpha(v)beta(3) LM609 mAb, mitogen-activated protein kinase, or protein kinase C inhibitors, indicating that other signaling pathway(s) operate through alpha(v)beta(3) integrin during conversion from RGP to VGP.
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PMID:Osteonectin/SPARC induction by ectopic beta(3) integrin in human radial growth phase primary melanoma cells. 1178 82

The activation of endothelial cells during angiogenesis requires cell spreading and migration. These processes are influenced by extracellular signals such as chemoattractants from the local microenvironment. We have shown previously that transmembrane Ca++ influx is necessary for motility and cell spreading, thus we hypothesized that the extracellular divalent cations Mg++ and Ca++ may regulate human umbilical vein endothelial cell (HUVEC) spreading and act as chemoattractants. Studies demonstrated that extracellular Mg++ induced a statistically better spread phenotype when cells were plated on multiple extracellular matrix substrata; Ca++ promoted cell spreading only on vitronectin. Mg++ but not Ca++ acted as a potent chemoattractant when HUVEC migrated on gelatin- and type IV collagen- but not on vitronectin-coated filters. A checkerboard analysis of migration showed that Mg++ induces both chemokinetic and chemotactic migration peaking at 0.1 and 10 mM, respectively. An equivalent effect of oligomycin was seen on motility to Mg++ or to vascular endothelial growth factor (VEGF) in extracellular Mg(++)-free conditions, ruling out an exclusive role for Mg++ as a migration energy producer. The Mg(++)-stimulated chemotaxis was inhibited > 60% by pertussis toxin, d-erythrosphingosine, and tyrphostin B48, but unaffected by cholera toxin exposure. These data suggest that Mg(++)-induced chemotaxis may be promoted through a Gi protein-coupled receptor pathway with a requirement for protein kinase C activity and protein tyrosine phosphorylation. Thus, Mg++ may be a newly recognized receptor-mediated chemoattractant for endothelial cells.
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PMID:Mg(++)-induced endothelial cell migration: substratum selectivity and receptor-involvement. 1182 74

Atherosclerotic lesions display a nonuniform distribution throughout the vascular tree. Mechanical forces produced by local alterations in blood flow may play an important role in the localization of atherosclerosis. One such force, cyclic strain, has been hypothesized to promote atherogenesis by inducing oxidative stress in endothelial cells, resulting in enhanced endothelial adhesiveness for monocytes. To investigate the signal transduction systems involved, human aortic endothelial cells were plated on flexible silicone strips that were either non-coated or adsorbed with poly-L-lysine, vitronectin, fibronectin, or collagen I. Cells were then subjected to uniform sinusoidal stretch (10%) for 6 h. Endothelial superoxide anion production was increased in cells exposed to cyclic strain compared to static conditions. Furthermore, endothelial oxidative response to stretch was matrix protein-dependent, whereas cells grown on fibronectin and collagen I produced significantly more superoxide. The oxidative response to cyclic strain was reduced by coincubation with RGD peptides, blocking antibodies to alpha2- and beta-integrins antibodies, as well as inhibitors of protein kinase C. To investigate the effect of oxidative stress on gene transcription, endothelial cells grown on collagen I were transfected with an NFkappaB-sensitive luciferase construct. Cells that underwent cyclic strain displayed a tenfold induction of NFkappaB activation compared to static controls. Strain-induced luciferase activity was blunted by coincubation with RGD peptides or calphostin C. Thus, exposure of endothelial cells to cyclic strain led to integrin activation of a PKC-sensitive pathway that results in increased superoxide anion production and mobilization of NFkappaB.
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PMID:Mechanotransduction of endothelial oxidative stress induced by cyclic strain. 1182 81

Microglia are highly plastic cells that participate in inflammatory and injury responses within the CNS and that can migrate extensively after activation. Because astrocytes and their extracellular matrix (ECM) form a large part of the CNS parenchyma, we undertook to study the adhesive interactions between microglia and these substrates in vitro. In contrast to oligodendrocyte precursor cells, microglia formed only weak interactions with astrocytes and their ECM. On specific ECM substrates the microglia adhered strongly to fibronectin, vitronectin, and plastic but only weakly to laminin. Microglial adhesion to laminin was increased significantly by the proinflammatory cytokines TNF, IFN-alpha, and IFN-gamma but was decreased by TGF-beta1, with the TGF-beta1 effect being dominant over the other cytokines. Fluorescence-activated cell sorting (FACS) analysis and immunoprecipitation showed that microglia constitutively express the alpha6beta1 integrin, a well characterized laminin receptor, and that alpha6beta1 expression levels did not change after cytokine treatment. Function-blocking studies showed that microglial adhesion to laminin is mediated entirely by the alpha6beta1 integrin, strongly suggesting that the cytokine regulation of adhesion to laminin is mediated by changes in the activation state of alpha6beta1. Analysis of signaling pathways revealed that activation of alpha6beta1 is mediated by a PKC-dependent mechanism. In light of the evidence that laminin expression is upregulated after CNS injury, the findings suggest that cytokine regulation of microglial adhesion to laminin may play a fundamental role in determining the extent of microglial infiltration into and retention at the site of injury.
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PMID:Cytokines regulate microglial adhesion to laminin and astrocyte extracellular matrix via protein kinase C-dependent activation of the alpha6beta1 integrin. 1188 Apr 86


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