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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the vestibular organs of the inner ear, an early postnatal decline in the capacity for cell proliferation appears to be responsible for limits to hair cell regeneration that are unique to mammals. We have investigated the time course of that decline in cell proliferation and its potential regulation by glycogen synthase kinase-3 (GSK3). Our immunoblots have revealed that inactive GSK3 beta decreases postnatally in the murine utricular epithelium, as E-cadherin and the active forms of GSK3 alpha and GSK3 beta each increase. In cultured utricular epithelia, pharmacological inhibition of GSK3 by LiCl and SB-216763 increased cell proliferation across a range of postnatal ages. LiCl treatments also led to increased levels of beta-catenin and Snail and decreased expression of E-cadherin. Transfection with a dominant-negative GSK3 beta enhanced proliferation in these epithelia in a cell-autonomous manner, while overexpression of wild-type GSK3 beta markedly reduced it. The evidence from these measurements and experimental manipulations indicates that the balance of active and inactive forms of GSK3 helps to determine whether mammalian vestibular supporting cells will proliferate; permitting proliferation during early development when inactive GSK3 predominates and progressively inhibiting proliferation, and thereby limiting the capacity for hair cell regeneration as more GSK3 becomes active during the first week of postnatal maturation.
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PMID:The influence of glycogen synthase kinase 3 in limiting cell addition in the mammalian ear. 1847 Aug 61

Cell movement is generated by a driving force provided by dynamic cytoskeletal organization. Two main cytoskeletal-dependent features, essential for migration, are the highly cell polarized structure and focal adhesion complexes. Cell migration and substrate anchorage are finely regulated by external signaling exerted by growth factors and hormones. In particular, the serine threonine kinase activated by the small GTPase Rho, the Rho-associated protein kinase (ROCK), participate in both processes through regulation of actin rearrangements in lamellipodia, filopodia, ruffles, and stress fibers. Melatonin, the main product secreted by the pineal gland has oncostatic properties. In MCF-7 cells, 1 nm melatonin reduces migration and invasiveness through increased expression of two cell surface adhesion proteins, E-cadherin and beta(1)-integrin. In this work, we studied the microfilament and microtubule rearrangements elicited by melatonin in migrating leader MCF-7 cells by a wound-healing assay. Additionally, cell anchorage was estimated by quantification of focal adhesions in MCF-7 cells cultured with melatonin. ROCK participation in the indole effects on anchorage and migration was explored by inhibition of the kinase activity with the specific inhibitor of ROCK, the Y-27632 compound. The results indicate that ROCK participates in the melatonin inhibitory effects on cell migration by changing cytoskeletal organization of leader MCF-7 cells. Also, they indicated that indole increased the number of focal contacts through ROCK. These results support the notion that melatonin inhibits cancer cell invasion and metastasis formation via ROCK-regulated microfilament and microtubule organization that converge in a migration/anchorage switch.
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PMID:ROCK-regulated cytoskeletal dynamics participate in the inhibitory effect of melatonin on cancer cell migration. 1848 40

Expression of E-cadherin in the peripheral nervous system is a highly regulated process that appears postnatally in concert with the development of myelinating Schwann cell lineage. As a major component of autotypic junctions, E-cadherin plays an important role in maintaining the structural integrity of noncompact myelin regions. In vivo, the appearance of E-cadherin in postnatal Schwann cell is accompanied by the disappearance of N-cadherin, suggesting reciprocal regulation of the two cadherins during Schwann cell development. The molecular signal that regulates the cadherin switch in Schwann cell is unclear. Using a neuron-Schwann cell co-culture system, here we show that E-cadherin expression is induced by components on the axonal membrane. We also show that the axonal effect is mediated through cAMP-dependent protein kinase A (cAMP-PKA) activation in the Schwann cell: (1) inhibition of cAMP-PKA blocks axon-induced E-cadherin expression and (2) cAMP elevation in the Schwann cell is sufficient to induce E-cadherin expression. In addition, cAMP-dependent E-cadherin expression is promoted by contact between adjacent Schwann cell membranes, suggesting its role in autotypic junction formation during myelination. Furthermore, cAMP-induced E-cadherin expression is accompanied by suppression of N-cadherin expression. Therefore, we propose that axon-dependent activation of cAMP-PKA serves as a signal that promotes cadherin switch during postnatal development of Schwann cells.
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PMID:E-cadherin expression in postnatal Schwann cells is regulated by the cAMP-dependent protein kinase a pathway. 1855 21

Disassembly of the apical junctional complex (AJC) together with actin cytoskeleton alterations are among the initial events for the development of epithelial cancer. The cell signaling pathways for these processes have been analyzed separately. However, the existence of a link between these two events has not been defined. In this study, using the extracellular calcium depletion model, we analyzed the signaling pathways regulating AJC disassembly together with actin cytoskeleton organization in colon adenocarcinoma cells (Caco-2). Changes in the location of AJC proteins were examined by immunofluorescence and immunoblotting, and tight junction (TJ) functionality was observed by measuring the transepithelial electrical resistance and permeation to ruthenium red. The actin cytoskeleton was stained with rhodamine-phalloidin and analyzed by confocal microscopy. Rho-GTPase activation was assessed by its translocation to the membrane (a hallmark of RhoA activation) and immunoblotting. Pharmacological inhibition of protein kinase A (PKA) with H-89 [N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide)] prevented AJC disassembly and actin disorganization at the apical and medial regions caused by calcium depletion. Rho inhibition using toxin A induced AJC disassembly and actin cytoskeleton reorganization. Y-27632 [(R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-ciclohexanecarboxamide], a Rho-associated kinase inhibitor, reversed redistribution of E-cadherin, but not of TJ proteins and actin disorganization caused by calcium depletion. Calcium depletion and forskolin treatment caused activation of Rho, as evidenced by their translocation to the membrane, an event concurrent to Rac and RhoGDI translocation, and this effect was also reverted by H-89. Thus, our findings demonstrate a central role of a regulatory cascade that integrates PKA and Rho-family GTPases in the AJC disassembly and actin organization in tumor epithelial cells.
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PMID:A cross-link between protein kinase A and Rho-family GTPases signaling mediates cell-cell adhesion and actin cytoskeleton organization in epithelial cancer cells. 1879 Oct 66

Metastasis is the principal cause of death from breast cancer. ErbB2 (HER-2/neu) has been identified as an important regulator of metastatic potential of breast cancer. The present study investigated the molecular mechanism underlying the role of ErbB2 in malignant phenotypic conversion of MCF10A human breast epithelial cells which originally have 'normal' cell character. Here we report that ErbB2 induces invasion and migration of MCF10A cells though up-regulation of matrix metalloproteinase (MMP)-9. We also observed a marked reduction of an epithelial cell marker, E-cadherin, and an induction of vimentin in ErbB2-MCF10A cells, suggesting that epithelial-mesenchymal transition may play a role in the ErbB2-induced invasion and migration of MCF10A cells. Overexpression of ErbB2 significantly activated p38 MAPK and Akt, while Raf-1/MEK/ERK pathway was not activated by ErbB2. Using pharmacological inhibitors, we further show that p38 MAPK and Akt signaling pathways are crucial for the ErbB2-induced MMP-9 up-regulation, invasion and migration of MCF10A cells. Given that ErbB2 is one of the most important oncogenes in human breast cancer and thus is an attractive therapeutic target, our findings may provide a molecular basis for the promoting role of ErbB2 in breast cancer progression.
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PMID:Overexpression of ErbB2 induces invasion of MCF10A human breast epithelial cells via MMP-9. 1902 65

Wnt-5a is a non-transforming Wnt protein that is implicated in cell polarity, adhesion, and motility. We have previously shown that low expression of Wnt-5a is a predictor of shorter disease-free survival in human breast cancer. Here, we investigated whether beta-catenin/E-cadherin-mediated cell-cell adhesion was affected by loss of Wnt-5a in breast carcinomas, thereby promoting a metastatic behavior of the tumor. We show that Wnt-5a stimulation of human breast epithelial cells leads to an increased Ca(2+)-dependent cell-cell adhesion. Furthermore, Wnt-5a/casein kinase Ialpha (CKIalpha)-specific Ser-45 phosphorylation of beta-catenin is associated with an increased complex formation of beta-catenin/E-cadherin. Mutation of Ser-45 decreases the beta-catenin/E-cadherin association. Also, the inhibitory effect of Wnt-5a on breast epithelial cell invasion is reduced upon mutation of beta-catenin-Ser-45. The Wnt-5a-CKIalpha-induced Ser-45 phosphorylation does not lead to degradation of beta-catenin. Finally we show that human breast cancers lacking Wnt-5a protein have a significantly lower level of membrane-associated beta-catenin. Down-regulation of Wnt-5a expression and subsequent reduction of membrane-associated beta-catenin in invasive breast cancer, can therefore contribute to a decreased cell-cell adhesion and increased motility resulting in a higher probability for metastatic disease.
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PMID:Wnt-5a-CKI{alpha} signaling promotes {beta}-catenin/E-cadherin complex formation and intercellular adhesion in human breast epithelial cells. 1924 47

Migration is an important process during cellular activity and embryo development. We recently showed that Dickkopf-1(Dkk-1), an antagonist of Wnt/ beta-catenin signaling pathway, could promote trophoblast cell invasion during murine placentation. However, mechanism of Dkk-1 action on cell migration was not clear. The objective of this study was to further evaluate the effect of Dkk-1 on cell migration and to identify the underlining mechanisms. Functional assays with stable Dkk-1 transfected HEK293 cells revealed that Dkk-1 expression increased cell migration by decreasing cell-cell adhesion, not cell-matrix adhesion. Treatment with LiCl and Genistein (widely used inhibitor of glycogen synthase kinase-3 and tyrosine protein kinase, respectively.) could inhibit the migration effect of Dkk-1, and significantly increased the membrane localization of beta-catenin and E-cadherin in HEK293 cells transfected with Dkk-1. Further data showed that HEK293 cells transfected with Dkk-1 have significantly decreased accumulation of both beta-catenin and E-cadherin at the cell membrane. Together, our data suggest that Dkk-1 stimulates the release of beta-catenin from cell membrane and facilitates cell migration which accompanies degradation of beta-catenin/E-cadherin.
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PMID:Dickkopf-1 enhances migration of HEK293 cell by beta-catenin/E-cadherin degradation. 1927 95

Helicobacter pylori eradication can reverse gastric intestinal metaplasia (IM) in some but not all patients. H. pylori induces high levels of nuclear beta-catenin staining in IM tissues, as well as overexpression of cyclooxygenase-2 (COX-2). This study investigated whether the Wnt/beta-catenin pathway plays a role in IM regression following H. pylori eradication. Sixty-five H. pylori-infected patients with IM who had achieved successful H. pylori eradication provided paired gastric samples before and after eradication to analyse the persistence of IM, and to assess COX-2 and nuclear beta-catenin expression. The host genotypes of single nucleotide polymorphisms (SNPs) of the COX-2, beta-catenin (CTNNB1) and adenomatous polyposis coli (APC) genes were analysed. In addition, expression of beta-catenin, E-cadherin and phosphorylated and unphosphorylated glycogen synthase kinase 3beta (GSK-3beta) in cell lines challenged with H. pylori isolates from patients with and without IM persistence was compared by immunoanalysis. After a mean 33.9-month follow-up after H. pylori eradication, 44 patients (67.7%) with IM persistence had a higher rate of high-level nuclear beta-catenin expression in IM tissue than those without IM persistence (P=0.008). The patients with IM persistence had a higher rate of AA, GG and AA APC SNP genotypes at positions 4479, 5268 and 5465, respectively, than the patients without IM persistence (P=0.022). The H. pylori isolates from the patients with IM regression after H. pylori eradication induced more phospho-GSK-3beta in AGS cells than isolates from patients with IM persistence (P=0.011). It is likely that interactions with H. pylori and the patient's Wnt/beta-catenin genetic predisposition determine the outcome of IM persistence following H. pylori eradication.
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PMID:Host Wnt/beta-catenin pathway triggered by Helicobacter pylori correlates with regression of gastric intestinal metaplasia after H. pylori eradication. 1936 17

Integrin-linked kinase (ILK) is an intracellular serine/threonine protein kinase that regulates cell adhesion, survival, and epithelial-to-mesenchymal transition (EMT). In this study, we investigated the kinase activity of ILK during tubular EMT induced by TGF-beta1 and examined the therapeutic potential of an ILK inhibitor in obstructive nephropathy. TGF-beta1 induced a biphasic activation of ILK in renal tubular epithelial cells, with rapid activation starting at 5 min and the second wave of activation peaking at 24 h; the latter paralleled the induction of ILK protein expression. Pharmacologic inhibition of ILK with small-molecule inhibitor QLT-0267 abolished TGF-beta1-induced phosphorylation of Akt and glycogen synthase kinase-3beta, suppressed cyclin D1 expression, and largely restored the expression of E-cadherin and zonula occludens 1. Inhibition of ILK also blocked TGF-beta1-mediated induction of fibronectin, Snail1, plasminogen activator inhibitor 1, and matrix metalloproteinase 2. In a mouse model of obstructive nephropathy, administration of QLT-0267 inhibited beta-catenin accumulation; suppressed Snail1, alpha-smooth muscle actin, fibronectin, vimentin, and type I and type III collagen expression; and reduced total tissue collagen content. Inhibition of ILK did not affect kidney structure or function in normal mice. These findings suggest that increased ILK activity mediates EMT and the progression of renal fibrosis. Pharmacologic inhibition of ILK signaling may hold therapeutic potential for fibrotic kidney diseases.
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PMID:Inhibition of integrin-linked kinase attenuates renal interstitial fibrosis. 1954 9

Lysophosphatidic acid (LPA), a bioactive phospholipid, induces a wide range of cellular effects, including gene expression, cytoskeletal rearrangement, and cell survival. We have previously shown that LPA stimulates secretion of pro- and anti-inflammatory cytokines in bronchial epithelial cells. This study provides evidence that LPA enhances pulmonary epithelial barrier integrity through protein kinase C (PKC) delta- and zeta-mediated E-cadherin accumulation at cell-cell junctions. Treatment of human bronchial epithelial cells (HBEpCs) with LPA increased transepithelial electrical resistance (TER) by approximately 2.0-fold and enhanced accumulation of E-cadherin to the cell-cell junctions through Galpha(i)-coupled LPA receptors. Knockdown of E-cadherin with E-cadherin small interfering RNA or pretreatment with EGTA (0.1 mm) prior to LPA (1 microm) treatment attenuated LPA-induced increases in TER in HBEpCs. Furthermore, LPA induced tyrosine phosphorylation of focal adhesion kinase (FAK) and overexpression of the FAK inhibitor, and FAK-related non-kinase-attenuated LPA induced increases in TER and E-cadherin accumulation at cell-cell junctions. Overexpression of dominant negative protein kinase delta and zeta attenuated LPA-induced phosphorylation of FAK, accumulation of E-cadherin at cell-cell junctions, and an increase in TER. Additionally, lipopolysaccharide decreased TER and induced E-cadherin relocalization from cell-cell junctions to cytoplasm in a dose-dependent fashion, which was restored by LPA post-treatment in HBEpCs. Intratracheal post-treatment with LPA (5 microm) reduced LPS-induced neutrophil influx, protein leak, and E-cadherin shedding in bronchoalveolar lavage fluids in a murine model of acute lung injury. These data suggest a protective role of LPA in airway inflammation and remodeling.
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PMID:Lysophosphatidic acid enhances pulmonary epithelial barrier integrity and protects endotoxin-induced epithelial barrier disruption and lung injury. 1958 6


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