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)

Since osteoblast proliferation is critical for bone development, the effect of bone extracellular matrix (ECM) proteins on osteoblast signaling and proliferation in serum-free medium was investigated. Proliferation was highest in primary rat calvarial osteoblasts cells grown on fibronectin but less on type I collagen; osteonectin and poly-L-lysine did not support early proliferation. Fibronectin and type I collagen binding requires integrins, whereas cell adhesion to osteonectin or poly-L-lysine does not involve integrins. Therefore, the role of integrins in osteoblast signaling, leading to the induction of AP-1 transcription factors (c-fos and c-jun) which are important in cell proliferation, was studied. c-fos and c-jun message levels were increased at 60 min in osteoblasts plated onto fibronectin or collagen, but not in cells on osteonectin or poly-L-lysine. Protein synthesis was not required for c-fos mRNA expression; however, kinase activity was necessary for c-fos induction. In cells plated onto fibronectin, c-fos mRNA levels were controlled by protein kinase C and phosphotyrosine kinase signaling pathways. In contrast, c-fos levels in collagen-adhering cells may involve protein kinase A. The signaling pathway involving the phosphorylation of focal adhesion kinase and mitogen-activated kinases was also shown to be transiently increased in osteoblasts on fibronectin and type I collagen, but not in cells on poly-L-lysine. These results demonstrate that osteoblast binding to the extracellular matrix through integrins induces c-fos and c-jun, and that both fibronectin and collagen affect these AP-1 transcription factors through protein kinase-sensitive pathways. Thus, osteoblast proliferation is modulated differentially by specific ECM components.
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PMID:Integrin-mediated signaling regulates AP-1 transcription factors and proliferation in osteoblasts. 1103 56

A novel growth phase-associated two-component-type regulator, Fas (fibronectin/fibrinogen binding/haemolytic activity/streptokinase regulator), of Streptococcus pyogenes was identified in the M1 genome sequence, based on homologies to the histidine protein kinase (HPK) and response regulator (RR) part of the Staphylococcus aureus Agr and Streptococcus pneumoniae Com quorum-sensing systems. The fas operon, present in all 12 tested M serotypes, was transcribed as polycystronic message (fasBCA) and contained genes encoding two potential HPKs (FasB and FasC) and one RR (FasA). Downstream of fasBCA, we identified a small 300 nucleotide monocistronic transcript, designated fasX, that did not appear to encode true peptide sequences. Measurements of luciferase promoter fusions revealed a growth phase-associated transcription of fasBCA and fasX, with peak activities during the late exponential phase. Insertional mutagenesis disrupting fasBCA and fasA led to a phenotype similar to agr-null mutations in S. aureus, with prolonged expression of extracellular matrix protein-binding adhesins and reduced expression of secreted virulence factors such as streptokinase and streptolysin S. In addition, fasX transcription was dependent on the RR FasA; however, deletion mutagenesis of fasX resulted in a similar phenotype to that of the fasBCA or fasA mutants. Complementation of the fasX deletion mutant, with the fasX gene expressed in trans from a plasmid, restored the wild-type fasBCA regulation pattern. This strongly suggested that fasX, a putative non-translated RNA, is the main effector molecule of the fas regulon. However, using spent culture supernatants from wild-type and fas mutant strains, we were not able to show an influence on the logarithmic growth phase expression of fas and dependent genes. Thus, despite structural and functional similarities between fas and agr, to date the fas operon appears not to be involved in group A streptococcal (GAS) quorum-sensing regulation.
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PMID:Group A streptococcal growth phase-associated virulence factor regulation by a novel operon (Fas) with homologies to two-component-type regulators requires a small RNA molecule. 1113 60

A hallmark of transforming growth factorbeta (TGFbeta) action is the induction of the synthesis and secretion of extracellular-matrix adhesion molecules and induction of the cell-surface expression of integrin receptors for these molecules (termed extracellular-matrix remodeling). The signal pathways leading to extracellular-matrix remodeling and the significance of extracellular-matrix remodeling in TGFbeta function is not well-understood. In the epithelium-derived human colon cancer cell line Moser, TGFbeta induces extracellular-matrix remodeling in a protein kinase Calpha-dependent manner. In this study we showed that TGFbeta was a potent inducer of the homotypic cell-cell adhesion molecule E-cadherin and its undercoat-associated proteins, the catenins and dramatically increased the amount of E-cadherin/gamma-catenin complex formation. We found that the induction of E-cadherin and alpha- and beta-catenin by TGFbeta was also dependent on protein kinase Calpha, whereas the induction of gamma-catenin was independent of protein kinase Calpha but dependent on other protein kinase C isoforms. We also found that protein kinase Calpha-dependent induction of extracellular-matrix remodeling and subsequent cell-matrix interaction requiring both fibronectin and laminin were a prerequisite for the induction of E-cadherin (and alpha- and beta-catenin but not gamma-catenin) by TGFbeta. We therefore concluded that two signal pathways exist in TGFbeta-regulated expression of E-cadherin and the catenins. We also concluded that a functional significance of TGFbeta-induced extracellular matrix remodeling is the activation of signal transduction mechanisms through increased interaction between extracellular matrix fibronectin and laminin and their cell-surface integrin receptors, which lead to the induction of E-cadherin (and alpha- and beta-catenin).
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PMID:Requirement of protein kinase Calpha, extracellular matrix remodeling, and cell-matrix interaction for transforming growth factorbeta-regulated expression of E-cadherin and catenins. 1126 98

The molecular details of hypoxia-induced cellular responses have been difficult to identify since there is as yet no known oxygen receptor. We used cDNA microarray technology to extend our studies pertaining to these molecular details in human hepatocellular carcinoma (Hep3B) cells that produce erythropoietin (Epo) in response to hypoxia. Of approximately 1200 genes in the array, those associated with integrin-linked kinase (ILK), fibronectin precursor and glycogen synthase kinase-3beta (GSK-3beta) were markedly stimulated after exposure of Hep3B cells to low oxygen (1%) for 6 h. Epo, HIF-1, and von Hippel-Lindau cDNAs were measured in parallel as markers of low oxygen responses in Hep3B cells. ILK is a serine, threonine protein kinase that interacts with the cytoplasmic domains of integrin beta1 and beta3. This interaction localizes ILK to focal adhesion plaques. ILK is stimulated by cell-fibronectin interaction as well as insulin. It is regulated in a phosphatidylinositol 3-kinase dependent manner and can phosphorylate protein kinase B (PKB/AKT) and GSK-3beta. As a result of these and other activities ILK has been shown to affect anchorage-independent cell survival, cell cycle progression and tumorigenesis in nude mice. ILK has also been implicated in the Wnt pathway and as a critical target in PTEN-dependent tumor therapies. To our knowledge this is the first report implicating the ILK pathway in low oxygen responses. Other genes identified as a result of the microarray analysis not previously known to change as a result of low oxygen treatment were elongation factor-1alpha, glycyl-tRNA synthetase, and laminin receptor protein-1. These findings were all corroborated by RT-PCR assays and in some instances Western blot analysis.
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PMID:Gene microarray analysis reveals a novel hypoxia signal transduction pathway in human hepatocellular carcinoma cells. 1140 33

Extracellular matrix proteins, such as fibronectin, laminin, and collagen, have been implicated in a wide variety of cellular properties, which include cell adhesion, migration, differentiation, and proliferation. In this study, we investigated the modulation of protein kinase A (PKA) activity by matrix proteins at developing motoneurons. The cultures of spinal neurons and myotomal cells were prepared from 1-day-old Xenopus laevis embryos. Spontaneous synaptic currents (SSC) were recorded from innervated myocytes of natural synapses by whole-cell voltage-clamped recordings (V(h) = -60 to approximately -65 mV). Bath application of agents, which directly or indirectly activate PKA, such as forskolin (20 microM), dibutyryl cAMP (DBcAMP) (1 mM), isoproterenol (10 microM), or albuterol (10 microM), significantly increased SSC frequency in cultures grown on fibronectin (FN)-coated substratum, but not on laminin- or collagen-coated glasses. The evoked synaptic currents increased in response to forskolin in neurons grown on FN substratum. Triflavin, an Arg-Gly-Asp-dependent disintegrin, inhibited potentiating action of isoproterenol in neurons grown on FN substratum, suggesting that integrin is involved in the potentiation of the PKA pathway in the regulation of acetylcholine (ACh) release. There is collaboration of neurotrophic factors and the FN matrix in regulating synaptic transmission in response to DBcAMP. Chronic treatment with neurotrophic factors, such as ciliary neurotrophic factor (150 ng/ml), glial cell line-derived neurotrophic factor (30 ng/ml), or neurotrophin-3 (50 ng/ml), enhanced the SSC-increasing action of DBcAMP in neurons grown on FN-coated glasses. These results suggest that the FN matrix potentiates synaptic transmission in response to PKA activation. Neurotrophic factors may collaborate with FN to regulate spontaneous ACh secretion at developing motoneurons, which may play an important role in the maturation of embryonic neuromuscular synapses.
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PMID:Modulation of protein kinase A activation by fibronectin matrix proteins at developing neuromuscular synapses in Xenopus laevis cell cultures. 1145 22

Hyperglycemia-induced alterations in mesangial (MES) cell function and extracellular matrix protein accumulation are seen in diabetic glomerulopathy. Recent studies have demonstrated that some of the effects of high glucose (HG) on cellular metabolism are mediated by the hexosamine biosynthesis pathway (HBP), in which fructose-6-phosphate is converted to glucosamine 6-phosphate by the rate-liming enzyme glutamine:fructose-6-phosphate amidotransferase (GFA). In this study, we investigated the role of HBP on HG-stimulated fibronectin protein synthesis, a matrix component, in SV-40-transformed rat kidney MES cells. Treatment of MES cells with 25 mmol/l glucose (HG) for 48 h increases cellular fibronectin levels by two- to threefold on Western blots when compared with low glucose (5 mmol/l). Glucosamine (GlcN; 1.5 mmol/l), which enters the hexosamine pathway distal to GFA action, also increases fibronectin synthesis. Azaserine (AZA; 0.5 micromol/l), an inhibitor of GFA, blocks the HG- but not the GlcN-induced fibronectin synthesis. Fibronectin contains cAMP responsive element (CRE) consensus sequences in its promoter and the phosphorylation of CRE-binding protein (CREB) may regulate its expression. On Western blots, HG and GlcN stimulate two- to threefold the phosphorylation of CREB at Ser 133, whereas CREB protein content was unaltered by either HG or GlcN. In addition, nuclear CREB activity was increased by HG and GlcN on gel-shift assays using (32)P-CRE oligonucleotides. AZA impeded the HG-enhanced CREB phosphorylation and CRE binding but had no effect on GlcN-mediated CREB phosphorylation and CRE binding. Pharmacologic inhibition of protein kinase C (PKC) and protein kinase A (PKA), which are involved in hexosamine-mediated matrix production, blocked the CREB phosphorylation and fibronectin synthesis seen in HG and GlcN conditions. We conclude that the effects of HG on fibronectin synthesis in the mesangium are mediated by the HBP possibly via hexosamine regulation of CREB and PKC/PKA signaling pathways. These results support the hypothesis that the HBP is a sensor and regulator of the actions of glucose in the kidney.
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PMID:Hexosamine-induced fibronectin protein synthesis in mesangial cells is associated with increases in cAMP responsive element binding (CREB) phosphorylation and nuclear CREB: the involvement of protein kinases A and C. 1157 20

Fibroblasts are the major source of extracellular connective tissue matrix, and the recruitment, accumulation, and stimulation of these cells are thought to play important roles in both normal healing and the development of fibrosis. Prostaglandin E(2) (PGE(2)) can inhibit this process by blocking fibroblast proliferation and collagen production. The aim of this study was to investigate the inhibitory effect of PGE(2) on human plasma fibronectin (hFN)- and bovine bronchial epithelial cell-conditioned medium (BBEC-CM)-induced chemotaxis of human fetal lung fibroblasts (HFL1). Using the Boyden blind well chamber technique, PGE(2) (10(-7) M) inhibited chemotaxis to hFN 40.8 +/- 5.3% (P < 0.05) and to BBEC-CM 49.7 +/- 11.7% (P < 0.05). Checkerboard analysis demonstrated inhibition of both chemotaxis and chemokinesis. The effect of PGE(2) was concentration dependent, and the inhibitory effect diminished with time. Other agents that increased fibroblast cAMP levels, including isoproterenol (10(-5) M), dibutyryl cAMP (10(-5) M), and forskolin (3 x 10(-5) M) had similar effects and inhibited chemotaxis 54.1, 95.3, and 87.0%, respectively. The inhibitory effect of PGE(2) on HFL1 cell chemotaxis was inhibited by the cAMP-dependent protein kinase (PKA) inhibitor KT-5720, which suggests a cAMP-dependent effect mediated by PKA. In summary, PGE(2) appears to inhibit fibroblast chemotaxis, perhaps by modulating the rate of fibroblast migration. Such an effect may contribute to regulation of the wound healing response after injury.
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PMID:Prostaglandin E(2) inhibits fibroblast chemotaxis. 1159 18

Capillary endothelial cells can be switched between growth and apoptosis by modulating their shape with the use of micropatterned adhesive islands. The present study was carried out to examine whether cytoskeletal filaments contribute to this response. Disruption of microfilaments or microtubules with the use of cytochalasin D or nocodazole, respectively, led to levels of apoptosis in capillary cells equivalent to that previously demonstrated by inducing cell rounding with the use of micropatterned culture surfaces containing small (<20 microm in diameter) circular adhesive islands coated with fibronectin. Simultaneous disruption of microfilaments and microtubules led to more pronounced cell rounding and to enhanced levels of apoptosis approaching that observed during anoikis in fully detached (suspended) cells, indicating that these two cytoskeletal filament systems can cooperate to promote cell survival. Western blot analysis revealed that the protein kinase Akt, which is known to be critical for control of cell survival became dephosphorylated during cell rounding induced by disruption of the cytoskeleton, and that this was accompanied by a decrease in bcl-2 expression as well as a subsequent increase in caspase activation. This ability of the cytoskeleton to control capillary endothelial cell survival may be important for understanding the relationship among extracellular matrix turnover, cell shape changes, and apoptosis during angiogenesis inhibition.
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PMID:Cooperative control of Akt phosphorylation, bcl-2 expression, and apoptosis by cytoskeletal microfilaments and microtubules in capillary endothelial cells. 1159 93

Cell migration requires precise coordination of many signaling pathways to achieve directed motility. We report here that NIH3T3 fibroblasts expressing a dominant negative PKA subunit (dnPKA) show diminished migration in response to serum or growth factors. This effect is not a general effect on cell motility, but rather a decreased capacity to enhance migration in response to stimuli. Control (neo) and dnPKA cells show very similar haptotactic migration toward fibronectin, but dnPKA cells show reduced stimulation of migration in response to EGF/PDGF or serum. These effects were not due to alterations in cell growth or adhesion to fibronectin. Forskolin, which elevates cyclic adenosine monophosphate (cAMP) levels, dramatically inhibited neo cell motility in a scrape migration assay, although dnPKA cell migration was unaffected. The MEK selective inhibitor U0126 and the phosphatidyl-inositol-3 kinase (PI3K) inhibitor LY294002 inhibited migrating neo cells and were able to further inhibit residual dnPKA cell migration. Our data show that intermediate or well-controlled levels of PKA activity are required for optimal growth factor-stimulated migration in fibroblasts. PKA may play an important role in the signaling processes that lead to motility.
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PMID:Inhibition of PKA blocks fibroblast migration in response to growth factors. 1164 Aug 85

Progesterone is a critical steroid hormone that controls cell proliferation and differentiation in the female reproductive tract. Progesterone acts through two nuclear receptor isoforms, progesterone receptors A and B (PRA and PRB, respectively), each with unique cellular effects. Loss of PRB has recently been linked to the development of poorly differentiated endometrial tumors, a lethal form of cancer. To study the molecular effects of progesterone, progesterone receptors were introduced into Hec50co endometrial cancer cells by adenoviral vectors encoding either PRA or PRB. Progesterone induced the cyclin-dependent kinase inhibitors p21 and p27, thereby significantly reducing the percentage of proliferating cells. Cancer cell invasion was also markedly inhibited as measured by Matrigel invasion studies. Similarly, a differentiated, secretory phenotype was induced by progesterone in cells expressing PRB. However, replicative senescence was induced by progesterone only in cells expressing PRA. Expression array analysis followed by confirmatory semiquantitative reverse transcription-PCR experiments demonstrated a significant progesterone-dependent inhibition of expression of a cadre of cellular adhesion molecules, including fibronectin, integrin alpha3, integrin beta1, integrin beta3, and cadherin 6. The level of down-regulation of adhesion molecule expression was significantly greater in the presence of the B isoform, demonstrating that progesterone acts principally through B receptors to inhibit cancer cell invasiveness modulated by adhesion molecules.
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PMID:Progesterone inhibits human endometrial cancer cell growth and invasiveness: down-regulation of cellular adhesion molecules through progesterone B receptors. 1183 May 47


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