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)

Study of gene and protein expression patterns is considered desirable for gaining new insight into cellular molecular mechanisms. The purpose of the present study was to compare the RNeasy (Qiagen) and PARIS (Ambion) protocols for protein and RNA clean-up. We found that the RNeasy protocol resulted in a significantly higher yield of both RNA and protein compared to the PARIS protocol. Western blot analysis of proteins isolated with these two methods, and with use of three different antibodies (PKB/Akt, c-fos and CREM), indicated that these methods were equal in regard to protein patterns, despite the protein precipitation step that is included in the RNeasy protocol. In some cases, Western blot performed on unprecipitated flow-through (Qiagen) may be satisfactory for Western blot analysis, but the amount of protein is probably decisive for detection.
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PMID:RNA and protein clean-up from the same specimen. Comparison between the Qiagen and Ambion protocols. 1803 92

Induction of tenascin-C mRNA by cyclic strain in fibroblasts depends on RhoA and Rho dependent kinase (ROCK). Here we show that integrin-linked kinase (ILK) is required upstream of this pathway. In ILK-deficient fibroblasts, RhoA was not activated and tenascin-C mRNA remained low after cyclic strain; tenascin-C expression was unaffected by ROCK inhibition. In ILK wild-type but not ILK-/- fibroblasts, cyclic strain-induced reorganization of actin stress fibers and focal adhesions, as well as nuclear translocation of MAL, a transcriptional co-activator that links actin assembly to gene expression. These findings support a role for RhoA in ILK-mediated mechanotransduction. Rescue of ILK -/- fibroblasts by expression of wild-type ILK restored these responses to cyclic strain. Mechanosensation is not entirely abolished in ILK -/- fibroblasts, since cyclic strain activated Erk-1/2 and PKB/Akt, and induced c-fos mRNA in these cells. Conversely, lysophosphatidic acid stimulated RhoA and induced both c-fos and tenascin-C mRNA in ILK -/- cells. Thus, the signaling pathways controlling tenascin-C expression are functional in the absence of ILK, but are not triggered by cyclic strain. Our results indicate that ILK is selectively required for the induction of specific genes by mechanical stimulation via RhoA-mediated pathways.
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PMID:Tenascin-C induction by cyclic strain requires integrin-linked kinase. 1826 18

One of the possible mechanisms of the angiogenic effect of laminin (Ln) involves modulation of the biological activity of VEGF by regulating poly ADP ribosylation (PAR). PAR modification of VEGF was found to be related with the changes in NAD(+) associated with a shift in LDH isoenzymes. Further investigations on LDH gene expression in HUVECs suggested that the effect of Ln was mediated through alpha(6)beta(4) integrin-FAK-src-p38 MAPK pathway. This was evidenced by (a) co-immunoprecipitation of beta(4) integrin with alpha(6) subunit, (b) activation by tyrosine phosphorylation of beta(4) integrin and FAK, (c) co-immunoprecipitation of FAK with beta(4) and with adapter protein, src, (d) increased phosphorylation of p38 MAPK in cells maintained on Ln and (e) blocking of effect of Ln on LDH-B gene expression by inhibition of p38 MAPK. Increase in serine phosphorylation of c-fos and c-jun and higher levels of heterodimers of AP-1 in the nucleus in cells maintained on Ln suggested activation of AP-1 transcription factor. These results provide evidence for modulation of endothelial cell function relevant to angiogenesis by Ln through alpha(6)beta(4) integrin.
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PMID:Endothelial cell-laminin interaction: modulation of LDH expression involves alpha6beta4 integrin-FAK-p38MAPK pathway. 1881 27

Interleukin-6 (IL-6) is a pleiotropic cytokine with a pivotal role in normal hepatic growth and liver regeneration. Therefore, in the present study, we examined the effect of IL-6 on cell proliferation and the related signaling pathways in primary cultured chicken hepatocytes. IL-6 increased the level of [(3)H]thymidine incorporation in a time (>or= 6 hr)- and a dose (>or= 0.1 ng/ml)-dependent manner. Indeed, IL-6 increased the number of BrdU-positive cells and the total number of cells. IL-6 (10 ng/ml) increased the level of IL-6Ralpha and glycoprotein (gp) 130 (IL-6Rbeta) protein expression, Janus Kinase (JAK) 2, signal transducer and activator of transcription (STAT) 3, PKC, p44/42 MAPKs phosphorylation, and PPARdelta protein expression. Inhibition of each pathways blocked IL-6-induced [(3)H]thymidine incorporation increase. IL-6 increased c-fos, c-jun, and c-myc proto-oncogene mRNA levels and the percentage of cells in the S phase according to fluorescence-activated cell sorter (FACS) analysis. IL-6-induced G1/S phase progression was inhibited by AG 490 (2x10(-5) M, JAK2 inhibitor), a STAT3 inhibitor peptide (10(-5) M), bisindolylmaleimide I (10(-6) M, PKC inhibitor), PD 98059 (10(-5) M, p44/42 MAPKs blocker), or PPARdelta-specific small interfering RNAs (siRNAs). In conclusion, IL-6 stimulates the proliferation of primary cultured chicken hepatocytes through PKC, p44/42 MAPKs, and PPARdelta pathways.
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PMID:Role of interleukin-6 in the control of DNA synthesis of hepatocytes: involvement of PKC, p44/42 MAPKs, and PPARdelta. 1908 49

The immunomodulatory properties of growth hormone (GH) are well recognized. Enhanced production of NO and cytokines by macrophages on treatment with GH was reported by us recently. The present investigation elucidates the signaling mechanism(s) by which GH activates macrophages in vitro. It is observed that GH induces the phosphorylation (activation) of JAK2, PI3K, PKC and MAP kinases. Studies with pharmacological inhibitors of various signaling molecules also indicated that GH-induced proinflammatory responses in macrophages are mediated by JAK2/PI3K/PKC/ERK1/2, JAK2/JNK and JAK/STAT signaling cascades. It was further observed that GH induced the enhanced expression/phosphorylation of transcription factors c-fos, c-jun, Elk-1 and Stat1. It is also demonstrated that GH-induced ERK1/2 cascade regulates the production of TNF-alpha and IL-1beta in macrophages, whereas JNK cascade mediated the production of TNF-alpha, IFN-gamma and IL-12. These results suggest that JAK2 plays a central role in mediating proinflammatory responses of macrophages on GH treatment.
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PMID:Growth hormone-induced production of cytokines in murine peritoneal macrophages in vitro: role of JAK/STAT, PI3K, PKC and MAP kinases. 1925 Jun 98

The involvement of caveolin-1 in the regulation of embryonic stem (ES) cell growth by epidermal growth factor (EGF) is by no means clear cut. Thus we examined the relationship between EGF and caveolin-1 in mouse ES cell migration and proliferation. The results revealed that EGF increased Src, caveolin-1, focal adhesion kinase (FAK), Akt, and extracellular signal-regulated kinase-1/2 (ERK) phosphorylation levels. Especially, phosphorylation of caveolin-1 is attenuated by AG1478, herbimycin A (tyrosine kinase inhibitors), and pyrazolopyrimidine 2 (PP2, Src inhibitor) and EGF-induced ERK activation was blocked by PP2, methyl-beta-cyclodextrin (MbetaCD), caveolin-1 small interfering RNA (siRNA), LY-294002 [phosphoinositol-3 kinase inhibitor (PI3K)], and Akt inhibitor. In addition, EGF promoted the cell migration, which was attenuated by PP2, caveolin-1 siRNA, FAK siRNA, LY-294002, Akt inhibitor, and PD-98059. EGF also increased matrix metalloproteinase (MMP-2) expression levels and EGF-induced MMP2 expression was inhibited by caveolin-1 siRNA, FAK siRNA, LY-294002, Akt inhibitor, and PD-98059. Furthermore, EGF-induced increase of cell cycle proteins expression level and [3H]thymidine incorporation was blocked by MMP inhibitor. EGF also significantly increases [(3)H]thymidine incorporation and cell number, which were significantly blocked by AG 1478, PP2, MbetaCD, caveolin-1 siRNA, FAK siRNA, LY-294002, and PD-98059 (ERK inhibitor). EGF-induced increase of protooncogenes (c-fos, c-myc, and c-Jun) and cell cycle regulatory proteins (cyclin D1, CDK4, cyclin E, and CDK2) expression levels were also attenuated by caveolin-1 siRNA and FAK siRNA. In conclusion, these results demonstrated that EGF-induced DNA synthesis and cell migration are mediated by caveolin-1, which is activated by Src, FAK, PI3K/Akt, ERK, and MMP-2 signals in mouse ES cells.
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PMID:Caveolin-1 plays important role in EGF-induced migration and proliferation of mouse embryonic stem cells: involvement of PI3K/Akt and ERK. 1962 10

TCR signaling leads to the activation of kinases such as inducible tyrosine kinase (Itk), a key regulatory protein in T-lymphocyte activation and function. The homolog of Itk in B cells is Bruton's tyrosine kinase, previously shown to bind and phosphorylate the transcription factor TFII-I. TFII-I plays major roles in transcription and signaling. Our purpose herein was twofold: first, to identify some of the molecular determinants involved in TFII-I activation downstream of receptor crosslinking in T cells and second, to uncover the existence of Itk-TFII-I signaling in T lymphocytes. We report for the first time that TFII-I is tyrosine phosphorylated upon TCR, TCR/CD43, and TCR/CD28 co-receptor engagement in human and/or murine T cells. We show that Itk physically interacts with TFII-I and potentiates TFII-I-driven c-fos transcription. We demonstrate that TFII-I is phosphorylated upon co-expression of WT, but not kinase-dead, or kinase-dead/R29C mutant Itk, suggesting these residues are important for TFII-I phosphorylation, presumably via an Itk-dependent mechanism. Structural analysis of TFII-I-Itk interactions revealed that the first 90 residues of TFII-I are dispensable for Itk binding. Mutations within Itk's kinase, pleckstrin-homology, and proline-rich regions did not abolish TFII-I-Itk binding. Our results provide an initial step in understanding the biological role of Itk-TFII-I signaling in T-cell function.
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PMID:Characterization of a novel interaction between transcription factor TFII-I and the inducible tyrosine kinase in T cells. 1968 46

Protein phosphorylation is the main signaling system known to trigger synaptic changes underlying long-term potentiation (LTP). The timing of these phosphorylations plays an essential role to maintain the potentiated state of synapses. However, in mice a simultaneous analysis of phosphorylated proteins during early-LTP (E-LTP) has not been thoroughly carried out. Here we described phosphorylation changes of alphaCaMKII, ERK1/2, PKB/Akt and CREB at different times after E-LTP induced at Schaffer collateral/commissural fiber-CA1 synapses by 1 s 100 Hz tetanic stimulation in mouse hippocampal slices. We found that phosphorylation levels of all the molecules examined rapidly increased after tetanisation and remained above the basal level up to 30 min. Notably, we observed a sustained increment in the phosphorylation level of Akt at Ser473, whereas the phosphorylation level of Akt at Thr308 was unchanged. Unexpectedly, we also detected a marked increase of CREB target genes expression levels, c-fos, Egr-1 and exon-III containing BDNF transcripts. Our findings, besides providing a detailed timing of phosphorylation of the major kinases involved in E-LTP in mice, revealed that a modest LTP induction paradigm specifically triggers CREB-mediated gene expression.
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PMID:Phosphorylation changes of CaMKII, ERK1/2, PKB/Akt kinases and CREB activation during early long-term potentiation at Schaffer collateral-CA1 mouse hippocampal synapses. 1973 Oct 18

Interstitial flow in and around bone tissue is oscillatory in nature and affects the mechanical microenvironment for bone cell growth and formation. We investigated the role of oscillatory shear stress (OSS) in modulating the proliferation of human osteoblast-like MG63 cells and its underlying mechanisms. Application of OSS (0.5 +/- 4 dynes/cm(2)) to MG63 cells induced sustained activation of phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR/p70S6K (p70S6 kinase) signaling cascades and hence cell proliferation, which was accompanied by increased expression of cyclins A and D1, cyclin-dependent protein kinases-2, -4, and -6, and bone formation-related genes (c-fos, Egr-1, and Cox-2) and decreased expression of p21(CIP1) and p27(KIP1). OSS-induced activation of PI3K/Akt/mTOR/p70S6K and cell proliferation were inhibited by specific antibodies or small interference RNAs of alpha(v)beta(3) and beta(1) integrins and by dominant-negative mutants of Shc (Shc-SH2) and focal adhesion kinase (FAK) (FAK(F397Y)). Co-immunoprecipitation assay showed that OSS induces sustained increases in association of Shc and FAK with alpha(v)beta(3) and beta(1) integrins and PI3K subunit p85, which were abolished by transfecting the cells with FAK(F397Y) or Shc-SH2. OSS also induced sustained activation of ERK, which was inhibited by the specific PI3K inhibitor LY294002 and was required for OSS-induced activation of mTOR/p70S6K and proliferation in MG63 cells. Our findings provide insights into the mechanisms by which OSS induces osteoblast-like cell proliferation through activation of alpha(v)beta(3) and beta(1) integrins and synergistic interactions of FAK and Shc with PI3K, leading to the modulation of downstream ERK and Akt/mTOR/p70S6K pathways.
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PMID:Oscillatory flow-induced proliferation of osteoblast-like cells is mediated by alphavbeta3 and beta1 integrins through synergistic interactions of focal adhesion kinase and Shc with phosphatidylinositol 3-kinase and the Akt/mTOR/p70S6K pathway. 1988 38

Proliferation and expansion of interstitial fibroblasts are predominant features of progressive chronic kidney diseases. However, how interstitial fibroblast proliferation is controlled remains ambiguous. Here we show that tissue-type plasminogen activator (tPA) is a potent mitogen that promotes interstitial fibroblast proliferation through a cascade of signaling events. In vitro, tPA promoted cell proliferation of rat kidney fibroblasts (NRK-49F), as assessed by cell counting, cell proliferation assay, and bromodeoxyuridine labeling. tPA also accelerated NRK-49F cell cycle progression. Fibroblast proliferation induced by tPA was associated with an increased expression of numerous proliferation-related genes, including c-fos, c-myc, proliferating cell nuclear antigen, and cyclin D1. The mitogenic effect of tPA was independent of its protease activity, but required LDL receptor-related protein 1. Interestingly, inhibition of beta1 integrin signaling prevented tPA-mediated fibroblast proliferation. tPA rapidly induced tyrosine phosphorylation of focal adhesion kinase (FAK), which led to activation of its downstream mitogen-activated protein kinase signaling. Blockade of FAK, but not integrin-linked kinase, abolished the tPA-triggered extracellular signal-regulated protein kinase 1/2 activation, proliferation-related gene induction, and fibroblast proliferation. In vivo, proliferation of interstitial myofibroblasts in tPA null mice was attenuated after obstructive injury, compared with the wild-type controls. These studies illustrate that tPA is a potent mitogen that promotes renal interstitial fibroblast proliferation through LDL receptor-related protein 1-mediated beta1 integrin and FAK signaling.
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PMID:tPA is a potent mitogen for renal interstitial fibroblasts: role of beta1 integrin/focal adhesion kinase signaling. 2063 53


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