EC:2.7.11.13 - FACTA Search

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)

Adherence of cells to extracellular matrix components modulates cellular responses. Here we compared the array of tyrosine phosphorylated proteins induced by the aggregation of the high affinity receptor for IgE (Fc epsilon RI) in fibronectin-adherent and in nonadherent rat basophilic leukemia (RBL-2H3) cells. Adherence to fibronectin in the absence of Fc epsilon RI aggregation induced tyrosine phosphorylation of 105-115-kDa proteins. This phosphorylation was reversed by EDTA and by a synthetic peptide containing the sequence Arg-Gly-Asp, demonstrating a requirement for fibronectin-integrin interaction. Aggregation of Fc epsilon RI in fibronectin-adherent cells markedly enhanced the tyrosine phosphorylation of the same 105-115-kDa proteins. There were minimal differences in tyrosine phosphorylation of other proteins induced by the aggregation of Fc epsilon RI in nonadherent and in fibronectin-adherent cells. Direct activation of protein kinase C and/or increase in calcium influx induced the phosphorylation of the 105-115-kDa proteins only in fibronectin-adherent cells. The magnitude of the phosphorylation of the 105-115-kDa proteins induced by the aggregation of Fc epsilon RI in fibronectin-adherent cells was substantially greater than the sum of that due to adherence to fibronectin and the aggregation of Fc epsilon RI in nonadherent cells. Therefore, cell adherence and the aggregation of Fc epsilon RI synergistically regulate tyrosine phosphorylation of the 105-115 kDa proteins.
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PMID:Cell adherence to fibronectin and the aggregation of the high affinity immunoglobulin E receptor synergistically regulate tyrosine phosphorylation of 105-115-kDa proteins. 844 98

In the present study, we have examined the regulation of attachment, onset of proliferation and the subsequent growth, in vitro, of chick retinal pigmented epithelial (RPE) cells as a function of the nature of the substratum and of either the activation or inhibition of protein kinase C (PKC). The RPE cells have an adhesive preference for protein carpets which contain laminin. This preference disappears gradually with time in culture. The adhesion of RPE cells to fibronectin is shown to be a receptor-mediated process which involves the RGD recognition signal. This study also demonstrates that a PKC activator, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), affects RPE cell adhesion in a substratum-dependent manner. Exposure of RPE cells to TPA lowers the cell attachment efficacy to ECM protein substrata but does not affect cell attachment to plastic. The onset of cell proliferation is accelerated by TPA on all of the substrata tested. The minimal duration of an effective TPA pulse exerting a long-lasting influence on RPE cell proliferation is between 1.5 and 3.5 hr. Stimulation of cell proliferation by TPA in long-term cultures is independent of the nature of the growth substratum. The acceleration of the onset of cell proliferation by TPA is sensitive to 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7), an inhibitor of conventional PKC, and thus appears to be dependent on the activation of conventional PKC. H7 also affects cell-cell contacts, causing an alteration in the shape ("squaring") of RPE cells packed into large colonies. Conversely, the effects of TPA on both the attachment and the long-term proliferation of RPE cells are not dependent a conventional PKC isotype, since H7 cannot abolish the influence of TPA on either process. We conclude that the effect of TPA on long-term proliferation of RPE cells is either dependent on a novel PKC isotype or independent of PKC.
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PMID:Adhesiveness and proliferation of epithelial cells are differentially modulated by activation and inhibition of protein kinase C in a substratum-dependent manner. 846 59

The rapid and reversible upregulation of the functional activity of integrin receptors on T lymphocytes is a vital step in the adhesive interactions that occur during successful T cell recognition of foreign antigen and transendothelial migration. Although the ligation of several different cell surface receptors, including the antigen-specific CD3/T cell receptor complex, the CD2, CD7, and CD28 antigens, as well as several chemokine receptors, has been shown to rapidly upregulate integrin function, the intracellular signaling events that initiate this increase in adhesion remain poorly defined. In this study, we have used DNA-mediated gene transfer to explore the role of phosphatidylinositol 3-kinase (PI 3-K) in the upregulation of beta 1 integrin functional activity mediated by the CD2 antigen. CD2 was expressed in the myelomonocytic cell line HL60, which expresses beta 1 integrins that mediate adhesion to fibronectin and VCAM-1 in an activation-dependent manner. Antibody stimulation of CD2 expressed on HL60 transfectants resulted within minutes in increased beta 1-mediated adhesion to fibronectin and VCAM-1 at levels comparable to that obtained upon stimulation with the phorbol ester PMA. A role for PI 3-K in CD2-mediated increases in beta 1 integrin function is suggested by: (a) the ability of the PI 3-K inhibitor wortmannin to completely inhibit CD2-induced increases in beta 1 integrin activity; (b) the association of PI 3-K with CD2; and (c) induced PI 3-K activity upon CD2 stimulation. The mode of association of PI 3-K with CD2 is not mediated by tyrosine phosphorylation-dependent binding of PI 3-K via SH2 domains, since: (a) PI 3-K is associated with CD2 in unstimulated cells; (b) CD2 stimulation fails to increase the amount of associated PI 3-K; and (c) the CD2 cytoplasmic domain lacks tyrosine residues. A role for both protein kinase C and cytoskeletal rearrangements in CD2 regulation of integrin activity is also suggested, since a PKC inhibitor partially inhibits CD2-induced increases in beta 1 integrin function, and CD2 stimulation increases F-actin content in a wortmannin-sensitive manner. Analysis of human peripheral T cells indicated that CD2 stimulation also results in PI 3-K-dependent upregulation of beta 1 integrin activity. Thus, these results demonstrate that CD2 can function as an adhesion regulator in the absence of expression of the CD3/T cell receptor complex; and directly implicate PI 3-K as a critical intracellular mediator involved in the regulation of beta 1 integrin functional activity by the CD2 antigen.
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PMID:A role for phosphatidylinositol 3-kinase in the regulation of beta 1 integrin activity by the CD2 antigen. 855 53

Cardiac fibroblasts appear to be important in producing and maintaining the extracellular matrix (ECM) of the heart. The abnormal proliferation of cardiac fibroblasts and deposition of the ECM protein, collagen, associated with hypertension and myocardial infarction, may adversely affect the performance of the heart. Several groups of factors affect collagen gene expression and/or growth of cardiac fibroblasts. Angiotensin II, aldosterone and endothelins play a central role in the remodeling of the ECM in hypertension, and decrease collagenase activity and/or increase collagen synthesis in cultured cells. Regulatory peptides that are generally elevated at sites of injury, such as TGF-beta 1 and PDGF, increase collagen synthesis and/or stimulate mitogenesis. Mechanical stretch enhances collagen expression and cell proliferation, responses which could in part be due to integrin activation. Cytokines may stimulate or inhibit cell growth, the latter through prostaglandin formation. Angiotensin II is a principal determinant in vivo of cardiac fibroplasia and synthesis of the ECM proteins, collagen and fibronectin. Cardiac fibroblasts possess G-protein-coupled AT1 receptors for angiotensin II that couple to activation of multiple signalling pathways, including: phospholipase C-beta, with the subsequent release of Ca2+ from intracellular stores and activation of protein kinase C, mitogen-activated protein kinases, tyrosine kinases, phospholipase D, phosphatidic acid formation, and the STAT family of transcription factors. Cardiac fibroblasts respond to angiotensin II with hyperplastic/hypertrophic growth, and increased expression of collagen, fibronectin, and integrins. The mechanisms by which the AT1 receptor activates multiple signalling pathways are not known, although the receptor might interact at some level with both integrins and cytokine receptors. Different signalling pathways of the AT1 receptor may subserve different cellular responses, such as mitogenesis, ECM synthesis, or an inflammatory/stress response. Crosstalk among the signalling pathways of the AT1 receptor, and those of G-protein, cytokine, and growth-factor receptors, may determine the ultimate response of the cell.
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PMID:Molecular signalling mechanisms controlling growth and function of cardiac fibroblasts. 857 2

The regulation mechanism of glucose transporter 1 (GLUT1) gene expression was investigated in cultured bovine corneal endothelial cells. Epidermal growth factor (EGF) stimulated both GLUT1 mRNA expression and cell proliferation. Fetal bovine serum, in contrast, stimulated cell proliferation but did not increase GLUT1 mRNA. IGF-I, hyaluronic acid or fibronectin did not stimulate GLUT1 gene expression. These results suggest that GLUT1 gene expression is controlled, at least in part, by EGF and is related to neither cell proliferation, cell motility nor cell adhesion regulation. The EGF signal was transduced through a pathway including protein kinase C. GLUT1 is reported to work as a water transporter, and so EGF can be considered as one of the possible agent which stimulate water transport activity through the corneal endothelial cells. EGF could be useful in the therapy of corneal edema caused by endothelial dysfunction.
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PMID:Regulation of glucose transporter 1 (GLUT1) gene expression by epidermal growth factor in bovine corneal endothelial cells. 857 72

Cell surface heparan sulfate proteoglycans have been implicated as co-receptors facilitating cell adhesion and growth factor binding. Recent studies on the role of a family of transmembrane heparan sulfate proteoglycans, syndecans, in cell adhesion has identified one member, syndecan-4, to be present within focal contacts. The current study investigates the mechanisms regulating the association of syndecan-4 with focal contacts based upon its immunolocalization with vinculin in quiescent, serum-stimulated, and 12-0-tetradecanoylphorbol 13-acetate (TPA)-induced cultures. In quiescent cells, syndecan-4 did not localize to focal contacts. However, activation of protein kinase C by TPA or serum induces the active recruitment of syndecan-4 into focal contacts. This induction preferentially localizes syndecan-4 to focal contacts behind the leading lamella, the subnuclear region, and along the trailing edge of migratory cells. Focal contacts in either freshly adhered cells or in the leading lamellae of migrating cells did not stain for syndecan-4. In addition to the observed subcellular distribution and recruitment, syndecan-4 was observed to co-localize with endogenously synthesized fibronectin fibrils within focal contacts as well as with fibrils present in the matrix. These findings suggest that protein kinase C activation results in syndecan-4 recruitment to focal contacts and its association with sites of matrix deposition.
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PMID:Protein kinase C regulates the recruitment of syndecan-4 into focal contacts. 858 52

The interactions between tumour cells and the microvasculature, including the adhesion of tumour cells to endothelium and extracellular matrix (ECM) as well as their migratory ability, are prerequisites for metastasis to occur. In this study we showed that thrombin is capable of enhancing in vitro tumour cell metastatic potential in terms of adhesive properties and migratory response. Following exposure to subclotting concentrations of thrombin, SW-480 human colon adenocarcinoma cells exhibited increased adhesion to both the endothelium and ECM component (i.e. fibronectin). Likewise, the pretreatment of thrombin enhanced the migratory ability of SW-480 cells. The enhanced adhesion was significantly inhibited by complexing of thrombin with its inhibitor hirudin, or by serine proteinase inhibition with 3,4-DCI, but was unaffected by pretreatment of tumour cells with actinomycin D or cycloheximide. The effect of thrombin resulted in an upregulated cell-surface expression of beta 3 integrins, a group of receptors mediating interactions between tumour cells and endothelial cells, and between tumour cells and ECM. Antibodies against beta 3 integrins effectively blocked both the enhanced adhesion and migration. This thrombin-mediated up-regulation of beta 3 integrins involved the activation of protein kinase C (PKC) as thrombin-enhanced adhesion was diminished by PKC inhibition. Rhodostomin, an Arg-Gly-Asp-containing antiplatelet snake venom peptide that antagonises the binding of ECM toward beta 3 integrins on SW-480 cells, was about 600 and 500 times, more potent that RGDS in inhibiting thrombin-enhanced adhesion and migration respectively. Our data suggest that PKC inhibitors as well as rhodostomin may serve as inhibitory agents in the prevention of thrombin-enhanced metastasis.
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PMID:Thrombin enhances the adhesion and migration of human colon adenocarcinoma cells via increased beta 3-integrin expression on the tumour cell surface and their inhibition by the snake venom peptide, rhodostomin. 861 4

Mesangial cell growth and accumulation of extracellular matrix proteins constitute key features of progressive glomerular injury. Endothelin-1 (ET-1) and angiotensin II (Ang II), two potent vasoconstrictor agents, evoke a number of similar responses in mesangial cells. In rat mesangial cells, we compared ET-1 and Ang II effects on matrix protein production and cell proliferation as well as the potential interaction between the two hormones. When cells in 0.5% fetal calf serum were incubated for 24 hours with various concentrations of ET-1 or Ang II, both peptides stimulated, in a dose-dependent manner, fibronectin and type IV collagen mRNA expression, fibronectin synthesis, and mitogenesis. Incubation with specific receptor antagonists of both hormones demonstrated that endothelin subtype A (ETA) and angiotensin type 1 (AT1) receptors were involved. Preincubation of cells with two different protein kinase C inhibitors or with a neutralizing anti-transforming growth factor-beta antibody, but not an unrelated IgG, diminished the peptide-induced fibronectin synthesis. A dual interrelation seems to exist between ET-1 and Ang II. Thus, the AT1 receptor antagonist losartan and the angiotensin-converting enzyme inhibitors quinaprilat and captopril diminished the ET-1-mediated effects, whereas, the ETA receptor antagonist BQ-123 diminished the Ang II-induced fibronectin synthesis and mesangial cell proliferation. Our results suggest that ET-1 and Ang II stimulate matrix protein synthesis and mesangial cell mitogenesis through ETA and AT1 receptors, respectively, by complicated mechanisms, implicating protein kinase C activation, synthesis of transforming growth factor-beta, and release of one peptide by the other. These data could be important for a better understanding of the participation of vasoactive substances in the pathogenesis of glomerulosclerosis.
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PMID:Effects and interactions of endothelin-1 and angiotensin II on matrix protein expression and synthesis and mesangial cell growth. 861 64

We have investigated the regulation of adhesion of metastatic human breast carcinoma cells to various protein substrates in the presence or absence of the protein kinase C (PKC) activator, 12-tetradecanoyl phorbol 13-acetate (TPA) or calcium ionophore A23187 (A23187). Both TPA and A23187 dramatically enhanced MDA-MB-435 cell adhesion to type IV collagen (collagen IV), vitronectin, and, to some extent, fibronectin and laminin. Adhesion to BSA and polylysine were not affected. TPA and A23187 induced substantial dose-dependent effects that were apparent after 30- and 60-min incubations, respectively, whereas a phorbol ester, which does not activate PKC, had no effect. A23187, but not TPA, induced a release of arachidonic acid (AA) from MDA-MB-435 cells. Nordihydroguaiaretic acid, a lipoxygenase inhibitor, prevented A23187 and exogenous AA, but not TPA, from stimulating cell adhesion to collagen IV. In contrast, the increase in adhesion to vitronectin induced by A23187 and AA was, at best, only partially inhibited by nordihydroguaiaretic acid treatment. Calphostin C, a PKC inhibitor, blocked the stimulation of adhesion by A23187, exogenous AA, and TPA to both collagen IV and vitronectin. Together, these results suggest that calcium mobilization activates the release of AA and its metabolism through a lipoxygenase pathway leading to a rapid increase of MDA-MB-435 cell adhesion to collagen IV, whereas other mechanisms regulate adhesion to vitronectin. Finally, PKC activation, occurring downstream from calcium mobilization or the AA effects, is a key event involved in the regulation of adhesion to both proteins.
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PMID:Regulation of the adhesion of a human breast carcinoma cell line to type IV collagen and vitronectin: roles for lipoxygenase and protein kinase C. 861 73

The mechanism of human bladder cancer cell invasion is not clear, but it appears that extracellular matrix components, such as fibronectin, may be involved. To investigate the role of fibronectin in tumor cell invasion and progression, we used an in vitro invasion assay to define the motility stimulating fragment of fibronectin for invasive human bladder cancer T24 cells. Using a modified Boyden chamber assay and purified fragments of fibronectin, we demonstrated that both the 120 kDa chymotrypsin generated fragment of fibronectin (containing the cell attachment RGD motif and additional sequences towards the carboxyl-terminal heparin binding domain), as well as the trypsin generated 60 kDa fragment of fibronectin (containing the carboxyl-terminal heparin binding domain and additional sequences towards the cell attachment RGD motif), were able to stimulate the migration of invasive human bladder cancer T24 cells. Control fragments containing only the amino-terminal gelatin binding region of fibronectin did not stimulate the motility of the human bladder cancer T24 cells. To determine the molecular mechanism in which these fragments may stimulate the migration of the T24 cells, we assayed for intracellular signal transduction pathway protein kinase C (PKC). We demonstrated that both the 120 kDa and the 60 kDa fragments were able to stimulate the activation of protein kinase C. Non-motility stimulating fragments of fibronectin were not able to activate protein kinase C. We conclude that the PKC signal transduction pathway may be involved in matrix mediated motility, and suggest that the inhibition of such pathway(s) may alter the malignant phenotype of human bladder cancer.
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PMID:Specific sequences of fibronectin activate the protein kinase C signal transduction pathway in invasive bladder cancer. 862 Apr 37

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