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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of integrins in the processes of adhesion and migration makes them attractive potential participants in the complex events of embryo implantation and placentation. Recently, the role of the alpha(v)beta(3)-integrin pathway was shown in the insulin-like growth factor-I (IGF-I)-stimulated migration of extravillous trophoblast (EVT) cells. This study was designed to investigate the role of alpha(5)beta(1)-integrin in this respect. Using cultured EVT cells, migration assays were carried out for IGF-I-treated or untreated cells in the presence or absence of the GRGDSP and GRGESP hexapeptides, alphaIR3, and a blocking antibody against alpha(5)beta(1)-integrin. Immuno-electron microscopy and immunofluorescent staining were performed to localize the distribution of alpha(5)beta(1)- and alpha(v)beta(3)-integrins, Rab5a, paxillin, phospho-FAK (pFAK), and vinculin. The results showed that IGF-I-induced migration of EVT cells was abolished following treatment with GRGDSP hexapeptide, alphaIR3, and a blocking antibody against alpha(5)beta(1)-integrin. Further, statistical analysis showed that the area-related numerical density of the alpha(5)beta(1)-integrin in the perinuclear regions was significantly higher than in the cell extensions. Immunocytochemical experiments demonstrated an up-regulation in internalization rate of alpha(5)beta(1)-integrin in IGF-I-stimulated EVT cells. Furthermore, alpha(5)beta(1)-integrin exhibited co-localization with Rab5a, but not with alpha(v)beta(3)-integrin, pFAK, paxillin, and vinculin at the focal adhesions of the EVT cells. Taken together, these findings suggest an essential role for alpha(5)beta(1)-integrin in IGF-I-promoted migration of EVT cells. It is possible therefore that IGF-I-induced internalization of alpha(5)beta(1)-integrin may be an important event during the migration of EVT cells in the complex processes of implantation and placentation.
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PMID:The role of alpha(5)beta(1)-integrin in the IGF-I-induced migration of extravillous trophoblast cells during the process of implantation. 1474 93

After parturition, increased growth hormone (GH) secretion is important to preserve the metabolic homeostasis of energy-deficient dairy cows. Elevated plasma GH promotes lipid mobilization from adipose tissue, but paradoxically, is associated with depressed concentration of insulin-like growth factor-I (IGF-I), a growth factor produced in a GH-dependent fashion in liver. Primary factors regulating GH responses of liver and adipose tissue are poorly understood in periparturient dairy cows. Consistent with insulin being such a factor, its plasma concentration declined concomitantly with net energy balance (EB) and with plasma IGF-I in a group of 9 periparturient dairy cows. To test the role of insulin in regulating cellular determinants of GH responsiveness, hyperinsulinemic-euglycemic clamps were performed on 6 dairy cows in late pregnancy (28 d prepartum) before the reductions in EB, insulin, and IGF-I were initiated, and when they were completed in early lactation (10 d postpartum). Infusion of insulin nearly doubled the plasma concentration of IGF-I (P < 0.001) and hepatic levels of IGF-I mRNA during both states (P < 0.05). In liver, these responses were associated with increased abundance of the GH receptor protein (GHR; P < 0.05), whereas the abundance of intracellular mediators of GH actions (JAK2, STAT5, or STAT3) remained unaffected. Insulin also doubled GHR abundance in adipose tissue (P < 0.01), indicating that this effect is not liver specific. These results raise the possibility that insulin regulates the efficiency of GH signaling in liver and adipose tissue of dairy cows by acting as a rheostat of GHR synthesis.
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PMID:Insulin increases the abundance of the growth hormone receptor in liver and adipose tissue of periparturient dairy cows. 1511 39

The induction of senescence-like growth arrest has emerged as a putative contributor to the anticancer effects of chemotherapeutic agents. Clinical trials are underway to evaluate the efficacy of inhibitors for class I and II histone deacetylases to treat malignancies. However, a potential antiproliferative effect of inhibitor for Sirt1, which is an NAD(+)-dependent deacetylase and belongs to class III histone deacetylases, has not yet been explored. Here, we show that Sirt1 inhibitor, Sirtinol, induced senescence-like growth arrest characterized by induction of senescence-associated beta-galactosidase activity and increased expression of plasminogen activator inhibitor 1 in human breast cancer MCF-7 cells and lung cancer H1299 cells. Sirtinol-induced senescence-like growth arrest was accompanied by impaired activation of mitogen-activated protein kinase (MAPK) pathways, namely, extracellular-regulated protein kinase, c-jun N-terminal kinase and p38 MAPK, in response to epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I). Active Ras was reduced in Sirtinol-treated senescent cells compared with untreated cells. However, tyrosine phosphorylation of the receptors for EGF and IGF-I and Akt/PKB activation were unaltered by Sirtinol treatment. These results suggest that inhibitors for Sirt1 may have anticancer potential, and that impaired activation of Ras-MAPK pathway might take part in a senescence-like growth arrest program induced by Sirtinol.
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PMID:Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells. 1617 Mar 53

Insulin-like growth factor-I (IGF-I) has gained broad recognition as an important survival factor for epithelial cells in numerous tissues. The IGF-I receptor signaling pathway is deregulated in the majority of carcinomas, and such deregulation has also been reported to be tightly associated with enhanced tumor progression and metastasis. One of the key proteins that transduces IGF-I signals and is phospho-activated downstream of the IGF-I receptor, is the non-receptor serine/threonine kinase proto-oncogene protein kinase B (PKB, also known as Akt). This kinase serves as a major molecular node to control the function of many cell survival and death proteins through phosphorylation-mediated protein modification. The end result of the activation of Akt is enhanced cell survival and proliferation, pre-requisites for malignant transformation. Recent studies show that IGF-I signals cross-talk at multiple levels with various components of the TGF-beta signaling pathway, which depending on context may function either as tumor suppressor or as tumor promoter. Thus, a better understanding of how the IGF-I and TGF-beta signaling pathways are mutually interconnected is likely to unveil novel targets for the therapeutic intervention of many cancers.
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PMID:Cross-talk between IGF-I and TGF-beta signaling pathways. 1629 54

The potential role of butyrate to modulate cellular metabolism through integrin receptor led to evaluation of its effect on collagen biosynthesis in cultured fibroblasts. Confluent human dermal fibroblasts were treated with 2 mM and 4 mM of sodium butyrate (NaB) for 48 h. It was found that butyrate induced collagen biosynthesis and prolidase activity independently of alpha2beta1 integrin signaling. The expressions of both alpha2 and beta1 integrin subunits as well as integrin-induced activation of focal adhesion kinase (FAK) were not affected in the cells treated with NaB. Since insulin-like growth factor-I (IGF-I) is the most potent stimulator of collagen biosynthesis in fibroblasts, the effect of butyrate on IGF-I receptor (IGF-IR) expression was evaluated. It was found that the exposure of the cells to 4 mM butyrate contributed to a distinct increase in IGF-IR. It was accompanied by a parallel increase in the expression of Sos protein and MAP-kinases (ERK1, ERK2). The data suggests that butyrate-dependent stimulation of collagen biosynthesis in cultured human skin fibroblasts undergoes through IGF-IR signaling.
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PMID:Butyrate-induced collagen biosynthesis in cultured fibroblasts is independent on alpha2beta1 integrin signalling and undergoes through IGF-I receptor cascade. 1654 Nov 97

Rapamycin, a natural product inhibitor of the Raptor-mammalian target of rapamycin complex (mTORC1), is known to induce Protein kinase B (Akt/PKB) Ser-473 phosphorylation in a subset of human cancer cell lines through inactivation of S6K1, stabilization of insulin receptor substrate (IRS)-1, and increased signaling through the insulin/insulin-like growth factor-I/phosphatidylinositol 3-kinase (PI3K) axis. We report that A-443654, a potent small-molecule inhibitor of Akt serine/threonine kinases, induces Akt Ser-473 phosphorylation in all human cancer cell lines tested, including PTEN- and TSC2-deficient lines. This phenomenon is dose-dependent, manifests coincident with Akt inhibition and likely represents an alternative, rapid-feedback pathway that can be functionally dissociated from mTORC1 inhibition. Experiments performed in TSC2-/- cells indicate that TSC2 and IRS-1 cooperate with, but are dispensable for, A-443654-mediated Akt phosphorylation. This feedback event does require PI3K activity, however, as it can be inhibited by LY294002 or wortmannin. Small interfering RNA-mediated knockdown of mTOR or Rictor, components of the rapamycin-insensitive mTORC2 complex, but not the mTORC1 component Raptor, also inhibited Akt Ser-473 phosphorylation induced by A-443654. Our data thus indicate that Akt phosphorylation and activity are coupled in a manner not previously appreciated and provide a novel mode of Akt regulation that is distinct from the previously described rapamycin-induced IRS-1 stabilization mechanism.
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PMID:Akt inhibitor A-443654 induces rapid Akt Ser-473 phosphorylation independent of mTORC1 inhibition. 1733 90

During systemic inflammation, the liver becomes unresponsive to growth hormone (GH), resulting in decreased plasma insulin-like growth factor-I (IGF-I) with concomitant reductions in lean body mass. Transgenic mice that overexpress IL-6 also demonstrate impaired growth and decreased IGF-I. To determine whether IL-6 directly inhibits GH-inducible gene expression, CWSV-1 hepatocytes were incubated with IL-6 (10 ng/ml), then stimulated with recombinant human GH (500 ng/ml, 18 h). The increase in IGF-I and serine protease inhibitor 2.1 (Spi 2.1) mRNA in GH-treated cells was inhibited by treatment with IL-6 for 24 h. To investigate potential mechanisms, we examined the effects of IL-6 on GH receptor (GHR) expression and GH signaling via the JAK/signal transducer and activator of transcription (STAT) and MAP kinase pathways. Incubation of cells with IL-6 (10 ng/ml, 24 h) had no effect on GHR abundance or signaling proteins JAK2, STAT5b, and ERK1/2. Although GH transiently increased (2- to 5-fold) the tyrosine phosphorylation of GHR, JAK2, STAT5b, and ERK1/2, IL-6 did not alter these phosphorylation events. However, nuclear protein from IL-6-treated cells demonstrated reduced STAT5 DNA binding (by EMSA) at 15 min (-20%) and 60 min (-43%) after GH stimulation. To determine whether IL-6 inhibits GH-inducible promoter activity, CWSV-1 cells were transfected with Spi 2.1 or prolactin receptor promoter luciferase vectors, incubated with or without IL-6, then stimulated with GH. The induction of both Spi 2.1 (7.5-fold) and prolactin receptor (4-fold) promoter activity by GH was inhibited by IL-6. In summary, IL-6 mediates hepatic GH resistance by a time-dependent inhibition of GH-inducible promoter activity that is associated with reductions in STAT5 DNA binding.
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PMID:Interleukin-6 inhibits growth hormone-mediated gene expression in hepatocytes. 1739 96

RAV12 is a high-affinity immunoglobulin G(1) (IgG(1)) chimeric antibody recognizing an N-linked carbohydrate epitope expressed on a number of human carcinomas and adenocarcinomas. RAV12 is efficacious in treating colon, gastric, and pancreatic tumors in xenograft models in vivo. Insulin-like growth factor-I receptor (IGF-IR) is a protein widely overexpressed in tumor-derived cell lines that promotes cell survival and prevents apoptosis. We found the RAV12 epitope (RAAG12) decorated the IGF-IR proteins of RAV12-responsive cell lines such as COLO201, COLO205, and SNU-16. Here, we report findings of IGF-IR signaling manipulation by RAV12. We found that RAV12 caused a significantly accelerated IGF-I-mediated IGF-IR phosphorylation and desensitization in COLO205. We also observed significant changes in some of the major downstream signaling components of IGF-IR. Data suggested that RAV12 treatment accelerated the desensitization of Akt/PKB through IRS1, and such activation could be attenuated by Tyrphostin AG538 (IGF-IR inhibitor), LY294002, or Wortmannin (phosphoinositide-3-kinase inhibitor). Furthermore, RAV12-inhibited IGF-I stimulated COLO205 growth, and the inhibition could be significantly augmented by mitogen-activated protein kinase inhibitor.
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PMID:RAV12 accelerates the desensitization of Akt/PKB pathway of insulin-like growth factor I receptor signaling in COLO205. 1787 27

The mechanism of protective action of hyaluronic acid (HA) on collagen metabolism disturbances in tissues during inflammation is not known. Insulin-like growth factor-I (IGF-I) receptor and beta1-integrin receptor signaling plays an important role in the regulation of collagen biosynthesis at both transcriptional and post-transcriptional levels. The present study was undertaken to evaluate the effect of IL-1beta (inductor of experimental inflammation) on the signaling pathways as well as on collagen biosynthesis, gelatinases and prolidase activity in cultured human chondrocytes and the effect of HA on these processes. It was found that IL-1beta-dependent inhibition of collagen biosynthesis was accompanied by increase in beta1-integrin receptor, NF-kB expressions, and increase in phosphorylation of FAK, that resulted in stimulation of metalloproteinase MMP-2 and MMP-9 activities, but not prolidase activity and expression. Simultaneously, decrease in expression of IGF-I receptor and phosphorylation of Akt and p38 were found. All those processes were counteracted by HA. This suggests that cross talk between beta1-integrin and IGF-I receptors is disturbed by IL-1beta, and HA recovers their proper signaling in cultured chondrocytes. We propose that IGF-I receptor and beta1-integrin signaling may play an important role in protective effect of hyaluronic acid on interleukin-1-induced inhibition of collagen biosynthesis in cultured human chondrocytes.
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PMID:Protective effect of hyaluronic acid on interleukin-1-induced deregulation of beta1-integrin and insulin-like growth factor-I receptor signaling and collagen biosynthesis in cultured human chondrocytes. 1789 16

We examined the possibility of culturing muscle cells of gilthead sea bream in vitro and assessed variations in insulin-like growth factor-I (IGF-I) binding during myocyte development. The viability of the cell culture was determined by fluorescence-activated cell-sorting analysis, which showed that the percentage of dead cells decreased with cell differentiation. The intracellular reduction of MTT into formazan pigment was preferentially carried out as cells differentiated (from day 4) indicating an increase in metabolic activity. IGF-I-binding assays demonstrated that the number of receptors increased from 190 +/- 0.09 fmol/mg protein in myocytes at day 5 to 360 +/- 0.09 fmol/mg protein in myotubes at day 12. The affinity of IGF-I receptors did not change significantly during cell development (from 0.89 +/- 0.09 to 0.98 +/- 0.09 nM). The activation of various kinase (ERK 1/2 MAPK and Akt/PKB) proteins by IGFs and insulin was studied by means of Western blot analysis. Levels of MAPK-P increased after IGF and insulin treatment during the first stages of cell culture, with a low response being observed at day 15, whereas IGFs displayed a stimulatory effect on Akt-P throughout the cell culture period, even on day 15. This study thus shows that (1) gilthead sea bream myocytes can be cultured, (2) they express functional IGF-I receptors that increase in number as they differentiate in vitro; (3) IGF signalling transduction through IGF-I receptors stimulates the MAPK and Akt pathways, depending on the development stage of the muscle cell culture.
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PMID:IGF-I binding and receptor signal transduction in primary cell culture of muscle cells of gilthead sea bream: changes throughout in vitro development. 1794 Aug 2


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