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)

Intraepithelial lymphocytes (IELs) from human intestinal epithelium are memory CD8+ T cells that bind to epithelial cells through human mycosal lymphocyte (HML)-1 and to mesenchymal cells through very late activation antigen-4 (VLA-4). Their binding of extracellular matrix proteins and the mechanism involved were tested. Activated 51Cr-labelled lymphocytes were incubated in protein-coated microwells with various additives. After washing, the adherent cells were detected by radioactivity. The percentages of activated IELs that bound to collagen types I and IV were 20 and 31%, respectively; fewer bound to fibronectin or laminin. Compared to interleukin-2-activated peripheral blood CD8+ T lymphocytes, more IELs bound collagen IV and fewer bound fibronectin. IEL adhesion to collagen (but not fibronectin or laminin) was up-regulated by antibody ligation of CD2 or by protein kinase C stimulation by phorbol ester; staurosporine reduced binding, while herbimycin, phytohaemagglutinin and CD3 ligation had no effect. Antibody-blocking of integrin VLA-1 subunits alpha1 (CD49a) and beta1 (CD18) inhibited adhesion to collagen type I by 82+/-6% and to type IV by 94+/-1% (P<0.001), implicating VLA-1 as the main collagen receptor for IELs. Cell adhesion was dependent on extracellular divalent cations, a characteristic event of VLA-1 never before shown for IELs: manganese and magnesium ions supported binding in a dose-dependent manner; calcium ions inhibited their effectiveness. Therefore, IELs bind collagen through integrin alpha1beta1 after protein kinase C activation. Adhesion is modulated by divalent cations.
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PMID:Integrin alpha1beta1 (VLA-1) mediates adhesion of activated intraepithelial lymphocytes to collagen. 1045 23

We have investigated transmembrane signaling for the regulation of desmosomes and hemidesmosomes, using a human squamous cell carcinoma cell line (DJM-1) and normal human keratinocytes. This review discusses the involvement of protein kinase C (PKC) in regulation of these junctions, and signaling pathways involved in cell-cell detachment induced by pemphigus vulgaris (PV) IgG in a culture system. Cells grown in low-Ca++ conditions, which lack desmosomes, rapidly form desmosomes upon a low-normal Ca++-shift in association with PKC-activation and, in turn, PKC-activation by 12-O-tetradecanoylphorbol-13-acetate (TPA) induces desmosome formation even in low-Ca++ conditions. TPA induces serine-phosphorylation of the 180 kDa-bullous pemphigoid antigen (BPAG2), generating 190 kDa-phosphorylated BPAG2, and dissociates BPAG2 from hemidesmosomes. TPA-treatment also causes secretion of urokinase-type plasminogen activator (uPA) and expression of its receptor (uPAR), which activates plasminogen to plasmin and may digest extracellular domains of desmosomes and hemidesmosomes. These results suggest that PKC may play a role in activation of desmosome turnover and dysfunction of hemidesmossomes, and thus a role in up-migration of keratinocytes. Binding of PV-IgG to Dsg3 induces activation of diverse isoenzymes of PKC, linked to uPA secretion and uPAR expression. Furthermore, PV-IgG binding alone induces the serine-phosphorylation of Dsg 3, associated with its dissociation from plakoglobin and its deletion from desmosomes. This PV-IgG-induced Dsg 3-phosphorylation and Dsg 3-deletion from desmosomes may impair desmosome formation, whereas PV-IgG-induced PKC signaling mediates the uPA secretion and uPAR expression leading to digestion of preexisting desmosomes from the outside of the cell. These two different PV-IgG-activated signaling pathways may play a key role in acantholysis in PV.
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PMID:Transmembrane signaling for adhesive regulation of desmosomes and hemidesmosomes, and for cell-cell datachment induced by pemphigus IgG in cultured keratinocytes: involvement of protein kinase C. 1053 88

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

Among other proteolytic enzymes, the urokinase-type plasminogen activator (u-PA)/plasmin cascade contributes to cell migration and the formation of capillary-like structures in a fibrinous exudate. The u-PA receptor (u-PAR) focuses proteolytical activity on the cell surface of the endothelial cell and hereby accelerates the pericellular matrix degradation. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF)-2 enhance u-PA receptor expression in human endothelial cells. In this paper we show that the protein kinase C (PKC) inhibitors Ro31-8220 and GF109203X inhibit VEGF165-induced u-PAR antigen expression in human endothelial cells, whereas PKC inhibition had no effect on FGF-2-induced u-PAR antigen enhancement. In addition, inhibition of PKC activity had no effect on VEGF165- or FGF-2-induced proliferation in human endothelial cells. We conclude that VEGF165 induces u-PAR via a PKC-dependent pathway, whereas proliferation is induced via a different pathway probably involving tyrosine phosphorylation of proteins downstream of the VEGF receptors.
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PMID:Vascular endothelial growth factor enhances the expression of urokinase receptor in human endothelial cells via protein kinase C activation. 1124 51

Urokinase-type plasminogen activator (uPA) and its cell surface-receptor (uPAR) regulate cellular functions linked to adhesion and migration and contribute to pericellular proteolysis in tissue remodelling processes. Soluble uPAR (suPAR) is present in the circulation, peritoneal and ascitic fluid and in the cystic fluid from ovarian cancer. We have investigated the origin and the vascular distribution of the soluble receptor, which accounts for 10-20% of the total receptor in vascular endothelial and smooth muscle cells. Phase separation analysis of the cell conditioned media with Triton X-114 indicated that suPAR associates with the aqueous phase, indicative of the absence of the glycolipid anchor. There was a polarized release of suPAR from cultured endothelial cells towards the basolateral direction, whereas the membrane-bound receptor was found preferentially on the apical surface. Both, uPAR and suPAR became upregulated 2-4 fold after activation of protein kinase C with phorbol ester, which required de-novo protein biosynthesis. Interleukin-1beta (IL-1beta), basic fibroblast growth factor (bFGF) or vascular endothelial growth factor increased suPAR release from endothelial cells, whereas platelet derived growth factor-BB, bFGF or IL-1beta stimulated suPAR release from vascular smooth muscle cells. Immune electron microscopy indicated that in atherosclerotic vessels (s)uPAR was observed on cell membranes as well as in the extracellular matrix. These findings indicate that (s)uPAR from vascular cells is upregulated by proangiogenic as well as proatherogenic growth factors and cytokines, is preferentially released towards the basolateral side of endothelial cells and accumulates in the vessel wall.
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PMID:Release of soluble urokinase receptor from vascular cells. 1152 23

An important role for beta-catenin pathways in colorectal carcinogenesis was first suggested by the protein's association with adenomatous polyposis coli (APC) protein, and by evidence of dysregulation of beta-catenin protein expression at all stages of the adenoma-carcinoma sequence. Recent studies have, however, shown that yet more components of colorectal carcinogenesis are linked to beta-catenin pathways. Pro-oncogenic factors that also release beta-catenin from the adherens complex and/or encourage translocation to the nucleus include ras, epidermal growth factor (EGF), c-erbB-2, PKC-betaII, MUC1, and PPAR-gamma, whereas anti-oncogenic factors that also inhibit nuclear beta-catenin signaling include transforming growth factor (TGF)-beta, retinoic acid, and vitamin D. Association of nuclear beta-catenin with the T cell factor (TCF)/lymphoid enhancer factor (LEF) family of transcription factors promotes the expression of several compounds that have important roles in the development and progression of colorectal carcinoma, namely: c-myc, cyclin D1, gastrin, cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-7, urokinase-type plasminogen activator receptor (aPAR), CD44 proteins, and P-glycoprotein. Finally, genetic aberrations of several components of the beta-catenin pathways, eg, Frizzled (Frz), AXIN, and TCF-4, may potentially contribute to colorectal carcinogenesis. In discussing the above interactions, this review demonstrates that beta-catenin represents a key molecule in the development of colorectal carcinoma.
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PMID:Beta-catenin--a linchpin in colorectal carcinogenesis? 1183 57

Changes in urokinase-plasminogen activator (u-PA) and u-PA receptor (u-PAR) expression at the protein and mRNA level in resting neutrophils and in neutrophils activated by phorbol myristate acetate (PMA) were examined. Low amounts of u-PA were found intracellularly or membrane-bound in resting neutrophils. However, incubation of resting neutrophils with purified exogenous u-PA (10 IU/ml) revealed extensive binding of u-PA to cell membranes. Excess amino-terminal fragment of the u-PA molecule, a proteolytically inactive fragment of u-PA (amino acids 1-135) blocked binding of exogenous u-PA to the cell membrane. These results, collectively, indicate that the binding of u-PA is specific and that resting neutrophils have unoccupied u-PA receptors on their cell membrane. Addition of PMA led to an increase (P < 0.01) in total cell-associated, membrane-bound u-PA activity and u-PA mRNA expression by bovine neutrophils. In contrast. PMA increased u-PAR mRNA levels but this was accompanied by a decrease (2.5-fold; P < 0.01) in free, unoccupied u-PA binding sites. No significant effects on total cell-associated or membrane-bound u-PA were found when neutrophils were treated with 4-phorbol 12,13 didecanoate, a phorbol ester that does not activate protein kinase C (PKC). Furthermore, addition of 1-(5-isoquinolinesylphonyl)-2-methlylpiperazine dihydrochloride (H-7), a potent PKC inhibitor, blocked the effect of PMA on total cell-associated u-PA activity. Thus, PKC plays a role in the modulation of u-PA and u-PAR by PMA in bovine neutrophils.
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PMID:Expression of urokinase plasminogen activator receptor in resting and activated bovine neutrophils. 1222 98

The metastatic subline of a rat pancreatic adenocarcinoma differs from the non-metastasizing subline by overexpression of 5 membrane molecules: CD44 variant isoforms, EpCAM, the tetraspanin D6.1A, an uPAR-related molecule and, as described here, the alpha6beta4 integrin. An antibody-defined molecule was identified by mass spectrometry and cloning as alpha6beta4 integrin. Transfection-induced expression of alpha6beta4 in the non-metastasizing subline did not support migration on laminin 5 or tumor progression. However, when the non-metastasizing subline was doubly transfected to express alpha6beta4 and the D6.1A tetraspanin, intraperitoneally injected tumor cells frequently formed liver metastasis. For the following reasons we assume that metastasis formation is supported by an interaction between alpha6beta4 and D6.1A. (i) The 2 molecules can associate and co-localize. (ii) Co-localization is strengthened by PKC stimulation. (iii) PKC stimulation, which induces a migratory phenotype, leads to a redistribution of alpha6beta4/D6.1A complexes. In resting cells, the molecules co-localize at the trail of the cell; during PKC stimulation they become transiently internalized and are (re-)expressed in the leading lamella. Thus, in the appropriate milieu, i.e. intraperitoneally, alpha6beta4 changes from an adhesion-supporting towards a migration-supporting molecule by its association with a tetraspanin. The findings provide a convincing experimental explanation for the repeatedly described involvement of alpha6beta4 in tumor progression.
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PMID:The association of the tetraspanin D6.1A with the alpha6beta4 integrin supports cell motility and liver metastasis formation. 1313 99

While cases of silicosis are often complicated by various autoimmune disorders, patients with asbestosis develop malignant tumors such as lung cancer and malignant mesothelioma. These differences may derive from different biological effects, particularly on immunological cells, of silica and asbestos. To find differences between silica and asbestos, the early activation antigen, CD69, on T cells was examined because dysregulated and continuous activation of T cells may promote the survival of self-recognizing T cells. After cultivation of peripheral blood mononuclear cells with or without silica or chrysotile-A, an asbestos, only silica induced CD69 expression on the lymphocytes. This induction of CD69 expression was mediated by protein kinase C activation. In addition, cell-cell contact mediated by HLA-DR was more important than soluble factors secreted from silica-phagocytosed cells such as IL-1beta, IL-6, and IL-8, even though IL-6 and IL-8 were produced during the culture of PBMCs with silica and chrysotile-A. It should be examined how these activated, CD69-expressing lymphocytes affect other immune systems as well as alter themselves in terms of cytokine production and cell-cell interaction, leading to autoimmune disorders in silicosis patients.
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PMID:Induction of CD69 antigen expression in peripheral blood mononuclear cells on exposure to silica, but not by asbestos/chrysotile-A. 1579 May 20

The urokinase-type plasminogen activator receptor (uPAR) sustains cell migration through its capacity to promote pericellular proteolysis, regulate integrin function, and mediate chemotactic signaling in response to urokinase. We have characterized the early signaling events triggered by the Ser-Arg-Ser-Arg-Tyr (SRSRY) chemotactic uPAR sequence. Cell exposure to SRSRY peptide promotes directional migration on vitronectin-coated filters, regardless of uPAR expression, in a specific and dose-dependent manner, with maximal effect at a concentration level as low as 10 nm. A similar concentration profile is observed in a quantitative analysis of SRSRY-dependent cytoskeletal rearrangements, mostly consisting of filamentous structures localized in a single cell region. SRSRY analogues with alanine substitutions fail to drive F-actin formation and cell migration, indicating a critical role for each amino acid residue. As with ligand-dependent uPAR signaling, SRSRY stimulates protein kinase C activity and results in ERK1/2 phosphorylation. The involvement of the high affinity N-formyl-Met-Leu-Phe receptor (FPR) in this process is indicated by the finding that 100 nm N-formyl-Met-Leu-Phe inhibits binding of D2D3 to the cell surface, as well as SRSRY-stimulated cell migration and F-actin polarization. Moreover, cell exposure to SRSRY promotes FPR-dependent vitronectin release and increased uPAR.alphavbeta5 vitronectin receptor physical association, indicating that alphavbeta5 activity is regulated by the SRSRY uPAR sequence via FPR. Finally, we provide evidence that alphavbeta5 is required for SRSRY-dependent ERK1/2 phosphorylation, whereas it is not required for protein kinase C activation. The data indicate that the ability of uPAR to stimulate cell migration and cytoskeletal rearrangements is retained by the SRSRY peptide alone and that it is supported by cross-talk between FPR and alphavbeta5.
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PMID:Cross-talk between fMLP and vitronectin receptors triggered by urokinase receptor-derived SRSRY peptide. 1586 65


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