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)

Aggregation of the FcepsilonRI, a member of the immune receptor family, induces the activation of proteintyrosine kinases and results in tyrosine phosphorylation of proteins that are involved in downstream signaling pathways. Here we report that Pyk2, another member of the focal adhesion kinase family, was present in the RBL-2H3 mast cell line and was rapidly tyrosine-phosphorylated and activated after FcepsilonRI aggregation. Tyrosine phosphorylation of Pyk2 was also induced by the calcium ionophore A23187, by phorbol myristate acetate, or by stimulation of G-protein-coupled receptors. Adherence of cells to fibronectin dramatically enhanced the induced tyrosine phosphorylation of Pyk2. Although Src family kinases are activated by FcepsilonRI stimulation and tyrosine-phosphorylate the receptor subunits, the activation and tyrosine phosphorylation of Pyk2 were downstream of Syk. In contrast, tyrosine phosphorylation of Pyk2 by stimulation of G-protein-coupled receptors was independent of Syk. Therefore, the FcepsilonRI-induced tyrosine phosphorylation of Pyk2 is downstream of Syk and may play a role in cell secretion.
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PMID:Activation of protein-tyrosine kinase Pyk2 is downstream of Syk in FcepsilonRI signaling. 940 54

Granulocyte-macrophage colony stimulating factor (GM-CSF) regulates many of the biological functions of human neutrophils. This includes the stimulation of protein synthesis and the tyrosine phosphorylation of various proteins among which is JAK2. The present study was aimed at characterizing in detail the pattern of activation by GM-CSF of the JAK/STAT pathway in human neutrophils. The results obtained show that the stimulation of human neutrophils by GM-CSF specifically led to tyrosine phosphorylation of JAK2 and had no effect on JAK1, JAK3, or TYK2. Furthermore, GM-CSF induced the tyrosine phosphorylation of STAT3 and STAT5 but not of STAT1, STAT2, STAT4, or STAT6. Tyrosine phosphorylation of STAT3 was transient reaching its maximum at 15 min. STAT5 presented a different pattern of tyrosine phosphorylation. The anti-STAT5 antibodies identified two proteins at 94 and 92 kDa. The 94-kDa STAT5 was constitutively tyrosine phosphorylated and showed no change upon GM-CSF stimulation. On the other hand, the 92-kDa STAT5 was tyrosine phosphorylated within 1 min of GM-CSF treatment and this was maintained for at least 30 min. By the use of specific antibodies, it was determined that only STAT5B, and not STAT5A, was tyrosine phosphorylated in GM-CSF-treated neutrophils. Furthermore, GM-CSF treatment induced an increase in the ability of STAT3 and STAT5B, but not STAT5A, to bind DNA probes. The specificity of the pattern of activation of the JAK/STAT pathway suggests that it may be directly linked to the modulation of the functions of mature nondividing, human neutrophils by GM-CSF.
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PMID:Granulocyte-macrophage colony-stimulating factor-activated signaling pathways in human neutrophils. Selective activation of Jak2, Stat3, and Stat5b. 942 69

Protein tyrosine phosphorylation was examined on a human glioblastoma cell line, T98G, after exposure to oxidative stress in vitro. Hydrogen peroxide (1 mM) markedly induced tyrosine phosphorylation of a 125 kDa protein at 30 min after stimulation. The 125-kDa molecule phosphorylated was revealed to be a focal adhesion kinase (FAK). Tyrosine phosphorylation of p125FAK continued at least up to 5 h, and decreased after 8 h concomitant with apoptosis. Tyrosine phosphorylation of p125FAK was blocked by herbimycin A, a potent inhibitor of protein tyrosine kinases, while apoptosis was accelerated. When T98G cells were incubated with FAK antisense oligonucleotide, apoptosis was also accelerated. These results suggest that tyrosine phosphorylation of p125FAK plays a suppressive role in hydrogen peroxide-induced apoptosis.
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PMID:A suppressive role of p125FAK protein tyrosine kinase in hydrogen peroxide-induced apoptosis of T98G cells. 943 84

Ethacrynic acid (ECA) increases aqueous humor outflow facility in human and animal model systems, and causes cellular retraction in cultured trabecular meshwork (TM) cells. ECA-induced retraction, a possible correlate to the opening of spaces in the outflow pathway in vivo, takes place coincident with disruption of cell-cell attachments and actin stress fibers. Tyrosine phosphorylated proteins are located predominantly where actin filaments terminate at sites of cell-to-cell and cell-to-substrate adhesion, and are understood to regulate cellular adhesions and filamentous (F) actin organization in many cell types. In the present study we investigated whether ECA might affect cell adhesions and F-actin in TM cells by altering levels of phosphotyrosine. We analysed levels of phosphotyrosine in cultured human TM and calf pulmonary artery endothelial cells after exposure to ECA. Using immunoflourescence microscopy and antibodies to phosphotyrosinated proteins we found a rapid decrease in phosphotyrosine levels at the focal contacts of cells treated with ECA. Immunoblots of whole cell extracts showed a decrease in phosphotyrosine predominantly in a band running at about 120 kD, with a more subtle decrease in a band about 65 kD. Reprobing the blot with antibodies to pp120 focal adhesion kinase (FAK) or paxillin indicated that the 120 kD band was FAK and the 65 kD band was likely paxillin. Immunoprecipitation of FAK or paxillin and probing the resulting blot with antibodies to phosphotyrosine confirmed that these proteins were rapidly dephosphorylated after ECA addition. Loss of FAK and paxillin proteins in cells was then confirmed using immunofluorescence microscopy. Dephosphorylation of these proteins was detected before the onset of retraction, stress fiber disruption, or complete disruption of focal adhesions. A pure microtubule inhibitor (colchicine), did not cause stress fiber disruption or decrease focal adhesion phosphorylation. We postulate that dephosphorylation of FAK and paxillin by ECA disrupts signaling pathways that normally maintain the stability of the actin cytoskeleton and cellular adhesions, and that this action leads both to cell shape change in culture, and to facility changes in vivo.
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PMID:A mechanism for trabecular meshwork cell retraction: ethacrynic acid initiates the dephosphorylation of focal adhesion proteins. 946 81

Tyrosine phosphorylation of focal adhesion-associated proteins may be involved in the regulation of the cytoskeleton and in the control of signals for growth and survival. The focal adhesion kinase (FAK) functions in regulating tyrosine phosphorylation of several of these proteins, including paxillin, tensin, and p130(cas). Protein- tyrosine phosphatases, the counterparts of protein-tyrosine kinases, also presumably regulate phosphorylation of these proteins. We have tested the hypothesis that FAK intimately associates with a protein-tyrosine phosphatase. Protein-tyrosine phosphatase activity associated with the recombinant C-terminal domain of FAK in vitro and could be coimmunoprecipitated with both FAK and paxillin from lysates of chicken embryo cells. However, the interaction with FAK appeared to be indirect and mediated via paxillin. The protein-tyrosine phosphatase was subsequently identified as protein-tyrosine phosphatase-PEST, a nonreceptor protein-tyrosine phosphatase. The C-terminal noncatalytic domain of protein-tyrosine phosphatase-PEST directly bound to paxillin in vitro. The association of both a protein-tyrosine kinase and a protein-tyrosine phosphatase with paxillin suggests that paxillin may play a critical role in the regulation of the phosphotyrosine content of proteins in focal adhesions.
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PMID:Direct association of protein-tyrosine phosphatase PTP-PEST with paxillin. 949 81

The integrins are a family of cell surface receptors which mediate cellular adhesion and signalling events. Our goal was to evaluate integrin function and signalling pathways in ovarian cancer cells. Ovarian cancer cell lines, NIH:OVCAR-3 and NIH:OVCAR-5, exhibited distinct extracellular matrix (ECM) binding preferences which were mediated primarily through beta1 integrin interactions. Western blot analysis was used to identify changes in cellular phosphotyrosine, focal adhesion kinase (FAK) and mitogen activated protein (MAP) kinase. Tyrosine phosphorylation of integrin-associated phosphoproteins was not enhanced in either cell type in response to adhesion onto ECM components or receptor crosslinking. FAK expression was greater in NIH:OVCAR-5 cells while MAP kinase activity was higher in NIH:OVCAR-3 cells. The data suggest that these two ovarian cancer cell lines exhibit specific ECM binding preferences and distinct differences in phosphotyrosine, focal adhesion and MAP kinase expression profiles.
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PMID:Integrin-mediated adhesion and signalling in ovarian cancer cells. 950 18

Peroxynitrite may contribute to oxidative stress involving neurodegeneration in several disorders, including Alzheimer's disease. As with other reactive oxygen species, peroxynitrite might affect neuronal signalling systems, actions that could contribute to adaptive or deleterious cellular outcomes, but such effects have not previously been studied. To address this issue directly, peroxynitrite (50-500 microM) was administered to human neuroblastoma SH-SY5Y cells to assess its effects on protein tyrosine nitration, phosphoinositide signalling and protein tyrosine phosphorylation. Peroxynitrite rapidly increased the nitrotyrosine immunoreactivity of numerous proteins, primarily in the cytosol. Peroxynitrite inhibited, in a concentration-dependent manner, phosphoinositide hydrolysis stimulated by activation of muscarinic receptors with carbachol and the inhibition was greater after the depletion of cellular glutathione. In comparison, muscarinic receptor-stimulated phosphoinositide hydrolysis in human astrocytoma 1321N1 cells was less vulnerable to inhibition by peroxynitrite either without or with prior depletion of glutathione. There was a large, rapid and reversible increase in the tyrosine phosphorylation of the p120 Src substrate in peroxynitrite-treated SH-SY5Y cells, a response that was potentiated by glutathione depletion; in contrast, peroxynitrite decreased the tyrosine phosphorylation of focal adhesion kinase and paxillin. Tyrosine phosphorylation of p120 in 1321N1 astrocytoma cells was less sensitive to modulation by peroxynitrite. Thus alterations in phosphoinositide signalling and protein tyrosine phosphorylation were greater in neuroblastoma than astrocytoma cells, and modulation of these signalling processes probably contributes to neuronal mechanisms of the response to peroxynitrite.
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PMID:Peroxynitrite modulates tyrosine phosphorylation and phosphoinositide signalling in human neuroblastoma SH-SY5Y cells: attenuated effects in human 1321N1 astrocytoma cells. 953 3

Mouse melanoma B16 cells are characterized by the predominant presence of ganglioside GM3 and adhere to lactosylceramide- or Gg3-coated plates through interaction of GM3 with lactosylceramide or Gg3, whereby not only adhesion but also spreading and enhancement of cell motility occur (Kojima, N., Hakomori, S. (1991) J. Biol. Chem. 266, 17552-17558). We now report that the adhesion process is based essentially on a glycosphingolipid-enriched microdomain (GEM) at the B16 cell surface, since >90% of GM3 present in the original cells is found in GEM, and GEM is also enriched in several signal transducer molecules, e.g. c-Src, Ras, Rho, and focal adhesion kinase (FAK). GEM was isolated as a low density membranous fraction by homogenization of B16 cells in lysis buffer under two different conditions (i.e. buffer containing 1% Triton X-100, or hypertonic sodium carbonate without detergent), followed by sucrose density gradient centrifugation. A close association of GM3 with c-Src, Rho, and FAK was indicated by co-immunoprecipitation of GM3 present in GEM by anti-GM3 monoclonal antibody DH2, followed by Western blotting with antibodies directed to these transducer molecules. The following data indicate that GEM is a structural and functional unit for initiation of GM3-dependent cell adhesion coupled with signal transduction. 1) Tyrosine phosphorylation in FAK was greatly enhanced in B16 cells adhered to Gg3-coated plates but was minimal in cells adhered to GM3-coated, GlcCer-coated, or noncoated plates. 2) GTP loading on Ras and Rho increased significantly when cells were adhered to Gg3-coated plates, compared with GM3-coated, GlcCer-coated, or noncoated plates. Since Ras and Rho are closely associated with GM3 in GEM, cell adhesion/stimulation through GM3 in GEM may induce activation of Ras and Rho through enhanced GTP binding.
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PMID:GM3-enriched microdomain involved in cell adhesion and signal transduction through carbohydrate-carbohydrate interaction in mouse melanoma B16 cells. 953 3

Interleukin-9 (IL-9) is a cytokine with pleiotropic effects on mast cell and T cell lines. It exerts its effects through the IL-9R complex consisting of IL-9Ralpha and the common gammac subunit. Here we report functional evidence for receptor heteromerization for efficient signal transduction, and we define minimal requirements in the two receptor subunits for IL-9R function. Tyrosine 336 of the IL-9Ralpha and the membrane-proximal segment of gammac are both crucial for signaling. The activated IL-9R complex employs the Janus kinases JAK1 and JAK3 for subsequent activation of the signal transducer and activator transcription (STAT) factors STAT-1, STAT-3, and STAT-5. This process is independent of Tyk2. We demonstrate further that the activated STAT complexes consist of STAT-1 and STAT-5 homodimers and STAT-1-STAT-3 heterodimers. Finally, we show that IL-9R signaling in a T cell line does not result in detectable mitogen-activated protein kinase activation and leads to unsustained proliferation. Nonetheless, these T cells are efficiently protected from dexamethasone-induced apoptosis. These results further define the molecular architecture of the IL-9R and its specific connections to various biologic responses.
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PMID:Heteromerization of the gammac chain with the interleukin-9 receptor alpha subunit leads to STAT activation and prevention of apoptosis. 953 18

Interaction of IL-3 with its receptor is known to activate STAT-3 via phosphorylation of Tyrosine 701, which facilitates its dimerization and translocation to the nucleus, leading to the transcription of its target genes. In this communication, we have investigated the nature of tyrosine kinases that mediate STAT-3 phosphorylation during IL-3-mediated activation of myeloid cell proliferation. Our results show that interaction of IL-3 with its receptor leads to the activation of c-Src kinase activity, which in turn facilitates the binding of c-Src to STAT-3. This association leads to the phosphorylation of STAT-3, allowing this transcription factor to translocate to the nucleus. Expression of a dominant negative mutant of src (AMSrc) in these cells results in a block to IL-3 mediated phosphorylation of STAT-3, and its ability to bind to DNA. On the other hand, expression of a dominant negative mutant of JAK2 (JAK2KE) had no effect on IL-3-mediated activation of STAT-3. Our results also show that AMSrc does not affect the phosphorylation of JAK2, suggesting that JAK and STAT phosphorylation events are mediated by two independent pathways. Inhibition of c-Src activation by AMSrc, which leads to a block to STAT-3 activation, results in a dramatic inhibition of cell proliferation mediated by IL-3. However, expression of AMSrc does not activate apoptotic pathways. In contrast, expression of JAK2KE results in accelerated apoptosis of 32Dcl3 cells grown in the absence of IL-3 with concomitant down-regulation of Erk-2 kinase activity. These results suggest that Src family kinases mediate the phosphorylation of STATs and play a critical role in signal transduction pathways associated with myeloid cell proliferation while JAK kinases mediate the activation of Erk-2 pathway which appears to provide antiapoptotic signals. Thus the activation of JAKs and STATs appear to be two independent but related events, which dictate two separate biological outcomes, the combination of which results in proliferation and survival of myeloid precursor cells.
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PMID:Src kinases and not JAKs activate STATs during IL-3 induced myeloid cell proliferation. 958 23


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