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 alpha-catenin molecule links E-cadherin/ beta-catenin or E-cadherin/plakoglobin complexes to the actin cytoskeleton. We studied several invasive human colon carcinoma cell lines lacking alpha-catenin. They showed a solitary and rounded morphotype that correlated with increased invasiveness. These round cell variants acquired a more normal epithelial phenotype upon transfection with an alpha-catenin expression plasmid, but also upon treatment with the protein kinase C (PKC) activator 12-O-tetradecanoyl-phorbol-13-acetate (TPA). Video registrations showed that the cells started to establish elaborated intercellular junctions within 30 min after addition of TPA. Interestingly, this normalizing TPA effect was not associated with alpha-catenin induction. Classical and confocal immunofluorescence showed only minor TPA-induced changes in E-cadherin staining. In contrast, desmosomal and tight junctional proteins were dramatically rearranged, with a conversion from cytoplasmic clusters to obvious concentration at cell-cell contacts and exposition at the exterior cell surface. Electron microscopical observations revealed the TPA-induced appearance of typical desmosomal plaques. TPA-restored cell-cell adhesion was E-cadherin dependent as demonstrated by a blocking antibody in a cell aggregation assay. Addition of an antibody against the extracellular part of desmoglein-2 blocked the TPA effect, too. Remarkably, the combination of anti-E-cadherin and anti-desmoglein antibodies synergistically inhibited the TPA effect. Our studies show that it is possible to bypass the need for normal alpha-catenin expression to establish tight intercellular adhesion by epithelial cells. Apparently, the underlying mechanism comprises upregulation of desmosomes and tight junctions by activation of the PKC signaling pathway, whereas E-cadherin remains essential for basic cell-cell adhesion, even in the absence of alpha-catenin.
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PMID:Protein kinase C activation upregulates intercellular adhesion of alpha-catenin-negative human colon cancer cell variants via induction of desmosomes. 916 10

Most receptor-like protein tyrosine phosphatases (PTPases) display a high degree of homology with cell adhesion molecules in their extracellular domains. We studied the functional significance of processing for the receptor-like PTPases LAR and PTPsigma. PTPsigma biosynthesis and intracellular processing resembled that of the related PTPase LAR and was expressed on the cell surface as a two-subunit complex. Both LAR and PTPsigma underwent further proteolytical processing upon treatment of cells with either calcium ionophore A23187 or phorbol ester TPA. Induction of LAR processing by TPA in 293 cells did require overexpression of PKCalpha. Induced proteolysis resulted in shedding of the extracellular domains of both PTPases. This was in agreement with the identification of a specific PTPsigma cleavage site between amino acids Pro821 and Ile822. Confocal microscopy studies identified adherens junctions and desmosomes as the preferential subcellular localization for both PTPases matching that of plakoglobin. Consistent with this observation, we found direct association of plakoglobin and beta-catenin with the intracellular domain of LAR in vitro. Taken together, these data suggested an involvement of LAR and PTPsigma in the regulation of cell contacts in concert with cell adhesion molecules of the cadherin/catenin family. After processing and shedding of the extracellular domain, the catalytically active intracellular portions of both PTPases were internalized and redistributed away from the sites of cell-cell contact, suggesting a mechanism that regulates the activity and target specificity of these PTPases. Calcium withdrawal, which led to cell contact disruption, also resulted in internalization but was not associated with prior proteolytic cleavage and shedding of the extracellular domain. We conclude that the subcellular localization of LAR and PTPsigma is regulated by at least two independent mechanisms, one of which requires the presence of their extracellular domains and one of which involves the presence of intact cell-cell contacts.
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PMID:Cellular redistribution of protein tyrosine phosphatases LAR and PTPsigma by inducible proteolytic processing. 924 95

Several lines of evidence suggest that accumulation of cytoplasmic beta-catenin transduces an oncogenic signal. We show that beta-catenin is ubiquitinated and degraded by the proteosome and that beta-catenin stability is regulated by a diacylglycerol-independent protein kinase C-like kinase activity, which is required for beta-catenin ubiquitination. We also define a six-amino acid sequence found in both beta-catenin and the NF-kappaB regulatory protein IkappaBalpha, which, upon phosphorylation, targets both proteins for ubiquitination. Mutation of a single serine within the ubiquitination targeting sequence prevents ubiquitination of beta-catenin. Mutations within the ubiquitination targeting sequence of beta-catenin may be oncogenic.
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PMID:Serine phosphorylation-regulated ubiquitination and degradation of beta-catenin. 931 64

Protein kinase C betaII (PKC betaII) has been implicated in proliferation of the intestinal epithelium. To investigate PKC betaII function in vivo, we generated transgenic mice that overexpress PKC betaII in the intestinal epithelium. Transgenic PKC betaII mice exhibit hyperproliferation of the colonic epithelium and an increased susceptibility to azoxymethane-induced aberrant crypt foci, preneoplastic lesions in the colon. Furthermore, transgenic PKC betaII mice exhibit elevated colonic beta-catenin levels and decreased glycogen synthase kinase 3beta activity, indicating that PKC betaII stimulates the Wnt/adenomatous polyposis coli (APC)/beta-catenin proliferative signaling pathway in vivo. These data demonstrate a direct role for PKC betaII in colonic epithelial cell proliferation and colon carcinogenesis, possibly through activation of the APC/beta-catenin signaling pathway.
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PMID:Overexpression of protein kinase C betaII induces colonic hyperproliferation and increased sensitivity to colon carcinogenesis. 1033 Apr

The tumor suppressor function of the adenomatous polyposis coli protein (APC) depends, in part, on its ability to bind and regulate the multifunctional protein, beta-catenin. beta-Catenin binds the high mobility group box transcription factors, lymphocyte enhancer-binding factor (LEF) and T-cell factor, to directly regulate gene transcription. Using LEF reporter assays we find that APC-mediated down-regulation of beta-catenin-LEF signaling is reversed by proteasomal inhibitors in a dose-dependent manner. APC down-regulates signaling induced by wild type beta-catenin but not by the non-ubiquitinatable S37A mutant, beta-catenin. Bisindoylmaleimide-type protein kinase C inhibitors, which prevent beta-catenin ubiquitination, decrease the ability of APC to down-regulate beta-catenin-LEF signaling. All these effects on LEF signaling are paralleled by changes in beta-catenin protein levels. Lithium, an inhibitor of glycogen synthase kinase-3beta, does not alter the ability of APC to down-regulate beta-catenin protein and beta-catenin-LEF signaling in the colon cancer cells that were tested. These results point to a role for beta-catenin ubiquitination, proteasomal degradation, and potentially a serine kinase other than glycogen synthase kinase-3beta in the tumor-suppressive actions of APC.
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PMID:The ubiquitin-proteasome pathway and serine kinase activity modulate adenomatous polyposis coli protein-mediated regulation of beta-catenin-lymphocyte enhancer-binding factor signaling. 1034 31

The Armadillo protein p120(ctn) associates with the cytoplasmic domain of cadherins and accumulates at cell-cell junctions. Particular Armadillo proteins such as beta-catenin and plakophilins show a partly nuclear location, suggesting gene-regulatory activities. For different human E-cadherin-negative carcinoma cancer cell lines we found expression of endogenous p120(ctn) in the nucleus. Expression of E-cadherin directed p120(ctn) out of the nucleus. Previously, we reported that the human p120(ctn) gene might encode up to 32 protein isoforms as products of alternative splicing. Overexpression of p120(ctn) isoforms B in various cell lines resulted in cytoplasmic immunopositivity but never in nuclear staining. In contrast, upon expression of p120(ctn) cDNAs lacking exon B, the isoforms were detectable within both nuclei and cytoplasm. A putative nuclear export signal (NES) with a characteristic leucine-rich motif is encoded by exon B. This sequence element was shown to be required for nuclear export and to function autonomously when fused to a carrier protein and microinjected into cell nuclei. Moreover, the NES function of endogenously or exogenously expressed p120(ctn) isoforms B was sensitive to the nuclear export inhibitor leptomycin B. Expression of exogenous E-cadherin down-regulated nuclear p120(ctn) whereas activation of protein kinase C increased the level of nuclear p120(ctn). These results reveal molecular mechanisms controlling the subcellular distribution of p120(ctn).
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PMID:Nuclear localization of the p120(ctn) Armadillo-like catenin is counteracted by a nuclear export signal and by E-cadherin expression. 1039 33

In studies of developmental signaling pathways stimulated by the Wnt proteins and their receptors, Xenopus Wnt-5A (Xwnt-5A) and a prospective Wnt receptor, rat Frizzled 2 (Rfz2), have been shown to stimulate inositol signaling and Ca2+ fluxes in zebrafish [1] [2] [3]. As protein kinase C (PKC) isoforms can respond to Ca2+ signals [4], we asked whether expression of different Wnt and Frizzled homologs modulates PKC. Expression of Rfz2 and Xwnt-5A resulted in translocation of PKC to the plasma membrane, whereas expression of rat Frizzled 1 (Rfz1), which activates a Wnt pathway using beta-catenin but not Ca2+ fluxes [5], did not. Rfz2 and Xwnt-5A were also able to stimulate PKC activity in an in vitro kinase assay. Agents that inhibit Rfz2-induced signaling through G-protein subunits blocked Rfz2-induced translocation of PKC. To determine if other Frizzled homologs differentially stimulate PKC, we tested mouse Frizzled (Mfz) homologs for their ability to induce PKC translocation relative to their ability to induce the expression of two target genes of beta-catenin, siamois and Xnr3. Mfz7 and Mfz8 stimulated siamois and Xnr3 expression but not PKC activation, whereas Mfz3, Mfz4 and Mfz6 reciprocally stimulated PKC activation but not expression of siamois or Xnr3. These results demonstrate that some but not all Wnt and Frizzled signals modulate PKC localization and stimulate PKC activity via a G-protein-dependent mechanism. In agreement with other studies [1] [2] [3]. [6] [7] these data support the existence of multiple Wnt and Frizzled signaling pathways in vertebrates.
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PMID:Protein kinase C is differentially stimulated by Wnt and Frizzled homologs in a G-protein-dependent manner. 1039 42

Beta-catenin has a number of roles in early development including involvement in cell adhesion, cell signaling, and developmental fate specification. This study investigates the mechanisms that regulate embryonic compaction, the first cell adhesion event in early mammalian development. Mammalian embryos can be induced to compact at an earlier developmental stage than normal by treatment with agonists that activate protein kinase C (PKC), and this treatment is used to identify and analyze the minimum essential changes required for embryonic compaction. It was predicted that: (1) since activation of PKC can induce compaction prematurely in mouse embryos, phosphorylation of the protein components of the adherens complex would occur during induced compaction and that these components would be required for the cell adhesive event; (2) these same proteins should be phosphorylated during compaction in normal development; (3) new, highly-specific inhibitors of PKC activity would inhibit compaction during normal development and induced compaction; and (4) some PKC isotypes would become localized to the junctional membranes during the process of compaction. In agreement with these predictionst, beta-catenin became phosphorylated on serine/threonine residues both during induced compaction and normal development. Inhibitors to PKC, but not inhibitors to other kinases, blocked compaction. Furthermore, the alpha isotype of PKC is recruited to the membranes of the apposing blastomeres both during induced compaction and during normal development immediately before compaction begins and before beta-catenin becomes part of the detergent-resistant cytoskeleton at the junction.
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PMID:Regulation of cell adhesion during embryonic compaction of mammalian embryos: roles for PKC and beta-catenin. 1047 73

The purpose of this study was to test the hypothesis that tyrosine phosphorylation signaling events and protein kinase C (PKC) activation mediate vascular endothelial growth factor-A(165) (VEGF)-induced endothelial cell (EC) proliferation and barrier dysfunction in bovine pulmonary artery EC monolayers. A size-selective permeability assay showed that VEGF stimulated a delayed, prolonged (6-45 h), concentration-dependent (50-200 ng/ml, approximately 1-4 nM) increase in the number of predominantly small-"pore" transport pathways (<60 A) across EC monolayers. The tyrosine kinase inhibitor herbimycin A (HA) and the selective PKC inhibitor bisindolylmaleimide (BIM) prevented this phenomenon. After 6-24 h, VEGF-treated monolayers displayed an HA- and BIM-sensitive reorganization of beta-catenin adherens junctions with fingerlike projections and the loss of beta-catenin at sites of small paracellular hole formation. HA and BIM prevented the VEGF-induced increase in EC growth. HA blocked the VEGF-induced rapid and prolonged (10 min-45 h) increases in the phosphotyrosine (PY) contents of VEGF receptor 2, phospholipase C-gamma1, paxillin, and beta-catenin as well as approximately 140- and 128- to 117-kDa proteins, whereas BIM inhibited only the tyrosine phosphorylation of beta-catenin. These data suggest that VEGF initiates increased EC growth and chronic, small-pore endothelial barrier dysfunction by PY signaling through beta-catenin that depends on PKC.
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PMID:VEGF stimulates tyrosine phosphorylation of beta-catenin and small-pore endothelial barrier dysfunction. 1056 61

Alterations in the transcriptional activity of the beta-catenin-Tcf complex have been associated with the earlier stages of colonic transformation. We show here that the activation of protein kinase C by the phorbol ester PMA in several intestinal cell lines increases the levels of beta-catenin detected in the nucleus and augments the transcriptional activity mediated by beta-catenin. The response to PMA was not related to modifications in the cytosolic levels of beta-catenin and was observed not only in cells with wild-type adenomatous polyposis coli protein (APC) but also in APC-deficient cells. Binding assays in vitro revealed that PMA facilitates the interaction of the beta-catenin with the nuclear structure. Our results therefore show that beta-catenin-mediated transcription can be regulated independently of the presence of APC.
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PMID:Adenomatous polyposis coli protein (APC)-independent regulation of beta-catenin/Tcf-4 mediated transcription in intestinal cells. 1056 41


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