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)

The modulation of adhesive interaction between lymphocyte progenitors and bone marrow stroma may critically determine the maturation and migration of B cell progenitors. mAb against CD9 and beta 1 integrins are reported to induce the homotypic adhesion of pre-B cells. We present evidence that the anti-CD9 mAb 50H.19 and ALB6 but not the proaggregatory anti-VLA-4 mAb 44H6 also enhance the Fc-independent heterotypic adhesion of the human pre-B cell lines NALM-6 and HOON to bone-marrow stromal fibroblasts (BM-FB) but not to bone marrow stroma. CD9-enhanced binding of NALM-6 cells to BM-FB was inhibited 58% by the anti-VLA-4 mAb HP2/1, 36% by the anti-VLA-5 mAb BIIG2, and 99% by their combination. The mAb effectively inhibited adhesion when prebound to NALM-6 cells but not when prebound to BM-FB. The anti-VCAM-1 mAb E1/6 inhibited CD9-enhanced adhesion by only 14% suggesting the involvement of other ligands. Adhesion was inhibited by mAbs against the COOH-terminus and central cell binding domains of fibronectin, as well as by the corresponding CS1 and RGD peptides. Adhesion was not affected by H-7 and sphingosine, inhibitors of protein kinase C. These results suggest that perturbation of CD9 on pre-B cells promotes recognition of stromal cell fibronectin by VLA-4 and VLA-5 and implicates CD9 as a novel regulator of inside-out signaling relevant to B lymphopoiesis.
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PMID:CD9-regulated adhesion. Anti-CD9 monoclonal antibody induce pre-B cell adhesion to bone marrow fibroblasts through de novo recognition of fibronectin. 751 26

Phorbol 12-myristate 13-acetate (PMA) is a tumour promotor that acts as a potent protein kinase C (PKC) activator that has significant effects on tumour cell attachment and spreading. We tested whether these effects of PMA may be observed in human melanoma cells, and whether a specific response to extracellular matrix proteins may be mediated by shifts in the expression of beta 1 integrins. We used cell attachment assays, video time lapse cell spreading assays, flow cytometry, function blocking monoclonal antibodies (MAbs) and PKC inhibitor Calphostin C to address these questions. We established that PMA induces a rapid and temporary enhancement of cell attachment and spreading which was not accompanied by a significant change in the expression of beta 1 integrins. Spreading of melanoma cells that were not stimulated with PMA could be significantly blocked with a function blocking MAb (clone P4C10) against the common beta 1 integrin subunit. The spreading and attachment of the PMA treated cells was also significantly reduced, but less so, after MAb treatment. The PMA enhanced cell attachment and spreading could be effectively blocked by RGD sequences and PKC inhibitor. Taken together, our data indicate that PMA induces a rapid and temporary ECM-dependent enhancement of melanoma cell attachment and spreading, and that the response to ECM components appears not to be due to significant shifts in beta 1 integrin expression, but rather to activation of beta 1 integrins.
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PMID:Phorbol ester induced rapid attachment and spreading of melanoma cells and the role of extracellular matrix proteins. 751 59

Regulation of the functional status of integrin receptors plays a critical role in inflammation and tissue remodeling, as it affects cell adherence and cytokine secretion. We have previously shown that in monocytes the binding of collagen to the alpha 2 beta 1 integrin induces the release of IL-1, an event that is potentiated by binding of fibronectin (Fn) to the alpha 5 beta 1 integrin. In this study, we have investigated the mechanisms leading to this phenomenon. Fn binding to alpha 5 beta 1 induced intracellular signals which increased the alpha 2 beta 1-dependent adhesiveness of monocytes to collagen without modifications of alpha 2 beta 1 expression. By using Abs against the intracellular region of the alpha 5 subunit of the alpha 5 beta 1 receptor, and specific inhibitors of protein kinase C (PKC), we found that the potentiation effect of Fn on monocyte IL-1 production and their adherence to collagen was dependent on an intact alpha 5 subunit cytoplasmic domain, and required PKC activation. Although the alpha 2 beta 1 could be activated by several intracellular second messengers, including protein kinase A and intracellular calcium, the potentiating effect of Fn was mediated only by PKC. These data provide an example of a novel regulatory mechanism: potentiation of beta 1 integrin-mediated events as a result of ligand binding to another integrin of the same class. They also show that the intracellular region of alpha 5 beta 1 plays a critical role in transducing signals generated by ligand binding to alpha 5 beta 1.
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PMID:Ligand binding to monocyte alpha 5 beta 1 integrin activates the alpha 2 beta 1 receptor via the alpha 5 subunit cytoplasmic domain and protein kinase C. 751 45

We have previously reported that CD7 expressed on resting human NK cells is a signal-transducing molecule, which upon ligation with mAb induces a rapid increase in cytoplasmic free calcium, secretion of IFN-gamma, and augmented NK activity against K562 targets. We now demonstrate that Ab-mediated clustering of CD7 molecules on NK cells results in enhanced phosphorylation on tyrosine residues of intracellular proteins of 60, 70, 80, 97, and 120 kDa. In the presence of genistein, a specific inhibitor of protein tyrosine kinase, the enhanced level of tyrosine phosphorylation was blocked, indicating that CD7 may induce signaling via activation of tyrosine kinases. Cross-linking of CD7 or CD16 molecules with primary and secondary Abs, as well as stimulation of NK cells with phorbol ester (PMA) or with calcium ionophore A23187 also induced beta 1 integrin-mediated adhesion of these cells to fibronectin (FN)-coated plastic surfaces. In contrast, cross-linking of CD2 expressed on the surface of NK cells had no significant effect on NK cell adhesion to FN. This adhesion was not associated with up-regulation of expression of alpha 4 beta 1 or alpha 5 beta 1 FN receptors on NK cells, but it required an intact cytoskeleton. The CD7-induced adhesion to FN was mediated by alpha 4 beta 1 and alpha 5 beta 1 integrins, as it was partially blocked by FN connective segment-1 peptide (EILDVPST), the alpha 4 beta 1-binding domain, as well as by RGD-containing peptides, the alpha 5 beta 1-binding domain, but not by EILEVPST or RGE control peptides. NK cell binding to FN was also partially inhibited by mAb to alpha 4, alpha 5, and beta 1 integrins. The mechanism by which cross-linking of CD7 or CD16 on NK cells induced adhesion to FN appeared to involve both protein tyrosine kinase and protein kinase C, because this adhesion was blocked in the presence of either genistein or a protein kinase C inhibitor, staurosporin. Our data demonstrate that signals transduced via triggering of either CD7 or CD16 molecules are involved in the regulation of the functional activity of beta 1 integrins on NK cells.
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PMID:Signaling via CD7 molecules on human NK cells. Induction of tyrosine phosphorylation and beta 1 integrin-mediated adhesion to fibronectin. 752 96

We have examined the effects of phorbol derivatives which show selective activation of protein kinase C (PKC) isozymes in vitro, on several parameters of thyroid function. Functions examined were iodide uptake and organification, iodocompound secretion and insulin-like growth factor binding protein (IGFBP) secretion, all of which have been shown previously to be modulated by 12-O-tetradecanoylphorbol 13-acetate (TPA), a pan activator of PKC isozymes. All of the agents examined, including DOPPA (12-deoxyphorbol-13-O-phenylacetate-20 acetate), which is specific for the beta 1 isozyme in vitro, were able to mimic the effects of TPA. These effects were evident by 2 h in the iodide uptake and organification assays, by 4 h in the secretion assays and by 8 h in the IGFBP secretion assays. The phorbol derivatives differed from TPA in their ability to down-regulate total PKC activity, DOPPA being weakly effective at 8 h (14.7% inhibition) when TPA had effected > 70% down-regulation of PKC. As the effects of DOPPA were detected by 8 h at the latest, these data indicate that the effects observed were due to PKC activation rather than down-regulation. Furthermore, the differences in down-regulation profiles between DOPPA and TPA suggest that in vivo, DOPPA may maintain its in vitro specificity. We conclude that inhibition of thyroid iodide uptake and its organification, stimulation of iodocompound secretion and stimulation of IGFBP-2 and IGFBP-3 secretion may be effected through the modulation of a limited number of PKC isozymes and possibly initially, only through PKC beta 1.
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PMID:Phorbol esters showing selective activation of PKC isozymes in vitro regulate thyroid function and insulin-like growth factor binding protein secretion. 752 96

The plasma protein fibronectin is an important opsonin in wound repair and host defense. To better understand the process of fibronectin-mediated phagocytosis, we have transfected K562 cells, which endogenously express alpha 5 beta 1, with alpha v beta 3. In these transfectants, antibodies to alpha v beta 3 block phagocytosis of fibronectin-opsonized beads completely, even though half the ingestion occurs through endogenous alpha 5 beta 1 receptors. alpha 5 beta 1-mediated adhesion to fibronectin-coated surfaces is unaffected by alpha v beta 3 ligation. Neither alpha v beta 5 nor alpha M beta 2 ligation affects alpha 5 beta 1 phagocytic function in transfectants expressing these receptors. Pharmacologic data suggest that alpha v beta 3 ligation suppresses the phagocytic competence of high affinity alpha 5 beta 1 receptors through a signal transduction pathway, perhaps involving protein kinase C. In addition to its significance for phagocytosis, alpha v beta 3 regulation of alpha 5 beta 1 function may be significant for its roles in cell migration, metastasis, and angiogenesis.
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PMID:Integrin alpha v beta 3 differentially regulates adhesive and phagocytic functions of the fibronectin receptor alpha 5 beta 1. 752 3

Epidermal growth factor (EGF) increases 12-lipoxygenase mRNA by about 2-fold with a lag period of 4 to 8 hr, which precedes the increase in 12-lipoxygenase activity by 2 to 4 hr in human epidermoid carcinoma A431 cells. Induction of 12-lipoxygenase expression in human erythroleukemia cells by phorbol 12-myristate 13-acetate (PMA) has been reported previously. The present report describes a study of the involvement of protein kinase C (PKC) in EGF-induced 12-lipoxygenase expression in A431 cells. EGF-induced 12-lipoxygenase expression was inhibited by methyl 2,5-dihydroxycinnamate, a tyrosine kinase inhibitor. Staurosporine and calphostin C, which are two PKC inhibitors, inhibited EGF-induced enzyme activity and mRNA expression of 12-lipoxygenase. 1,2-Dioctanoyl-sn-glycerol (a membrane-permeant diacylglycerol) and PMA significantly induced enzyme activity and mRNA expression. Simultaneous treatment of cells with EGF and PMA did not exhibit an additive effect, suggesting that EGF and PMA share a common biochemical pathway in 12-lipoxygenase induction. Expression of mRNA for PKC alpha, delta and zeta was detected in A431 cells, whereas no mRNA expression for PKC beta 1, gamma and epsilon was observed. Taken together, these results suggest that EGF-induced 12-lipoxygenase expression is at least in part mediated by the PKC signal transduction pathway.
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PMID:Induction of 12-lipoxygenase expression by epidermal growth factor is mediated by protein kinase C in A431 cells. 752 31

A confluent endothelial monolayer can be induced to form vascular tubes in response to collagen. We investigated possible mechanisms of collagen-induced tube formation by using antibodies to the VLA-2 integrin receptor and protein kinase C inhibitors. Pre-incubation of cells with anti-VLA-2 (which recognises both the alpha 2 and beta 1 chains) and AK7 (which recognises only the alpha 2 chain) showed a dose-dependent inhibition of tube formation. At 50 micrograms/ml, anti-VLA-2 completely inhibited collagen-induced tube formation, whereas AK7 caused only partial inhibition. Both chlorpromazine and trifluoperazine, at concentrations of 10 microM, prevented tube formation (> 40% inhibition). In summary, the VLA-2 integrin receptor plays a role in the induction of tube formation by type I collagen. Protein kinase C may be activated during this process.
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PMID:VLA-2 mediates the interaction of collagen with endothelium during in vitro vascular tube formation. 752 76

Ligation of beta 1 integrin receptors resulted in increased tyrosine phosphorylation of at least five proteins (Mrest = 110, 85, 55, 30 and 24 kD) from rat pancreatic acinar cells. Increased protein kinase C (PKC) activity and elevated amounts of immunoreactive PKC alpha were demonstrated in membrane fractions from integrin-ligated acinar cells. Membrane translocation of PKC alpha was confirmed using scanning confocal laser microscopy in immunocytochemical preparations of acinar cells following beta 1 integrin ligation. These studies establish the presence of a beta 1 integrin-linked protein tyrosine phosphorylation system in exocrine pancreatic cells and provide evidence for integrative activity of this system with PKC, a primary signalling pathway of central importance in these cells.
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PMID:Integrin-linked tyrosine phosphorylation increases membrane association of protein kinase C alpha in pancreatic acinar cells. 753 28

Guinea pig bone marrow megakaryocytes were cultured on a type I rat tail collagen gel which stimulated proplatelet formation. Proplatelet formation was inhibited by monoclonal antibody LM609 to the alpha v beta 3 integrin (VnR), but not by monoclonal antibodies to the alpha 5, alpha 6, beta 1, or IIb beta 3(GPIIb-IIIa) integrin proteins. Megakaryocytes cultured on a plastic surface and stimulated with thrombin undergo a spreading and an adhesion reaction. This reaction is blocked in a dose-dependent manner by the tetrapeptide RGDS and by the monoclonal antibody PG2 to the GPIIb-IIIa integrin, but not by the monoclonal antibody LM609 to the VnR. Immunoprecipitation and affinity chromatography experiments demonstrate that guinea pig megakaryocytes have distinct GPIIb-IIIa and VnR integrins with similar electrophoretic mobility. Spreading was significantly inhibited in a dose-dependent fashion by drugs which elevate cellular cyclic AMP, including forskolin, dibutyryl cAMP, and isobutylmethylxanthine. In contrast to spreading, megakaryocyte proplatelet formation was stimulated by these agents in a dose-dependent manner. Megakaryocyte spreading was stimulated by the protein kinase C (PKC) activator phorbol myristate acetate (PMA) and inhibited by the PKC inhibitors Calphostin C and K5720 in a dose-dependent manner. PKC inhibitors did not inhibit megakaryocyte proplatelet formation. These results demonstrate that the closely related VnR and GPIIb-IIIa integrins regulate different aspects of megakaryocyte morphological change and appear to be associated with different second messenger systems.
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PMID:Differential regulation of integrin-mediated proplatelet formation and megakaryocyte spreading. 753 14


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