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:3.4.11.18 (MAP)
7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many G protein-coupled receptors (GPCRs) activate MAP kinases by stimulating tyrosine kinase signaling cascades. In some systems, GPCRs stimulate tyrosine phosphorylation by inducing the "transactivation" of a receptor tyrosine kinase (RTK). The mechanisms underlying GPCR-induced RTK transactivation have not been clearly defined. Here we report that GPCR activation mimics growth factor-mediated stimulation of the epidermal growth factor receptor (EGFR) with respect to many facets of RTK function. beta(2)-Adrenergic receptor (beta(2)AR) stimulation of COS-7 cells induces EGFR dimerization, tyrosine autophosphorylation, and EGFR internalization. Coincident with EGFR transactivation, isoproterenol exposure induces the formation of a multireceptor complex containing both the beta(2)AR and the "transactivated" EGFR. beta(2)AR-mediated EGFR phosphorylation and subsequent beta(2)AR stimulation of extracellular signal-regulated kinase (ERK) 1/2 are sensitive to selective inhibitors of both EGFR and Src kinases, indicating that both kinases are required for EGFR transactivation. beta(2)AR-dependent signaling to ERK1/2, like direct EGF stimulation of ERK1/2 activity, is sensitive to inhibitors of clathrin-mediated endocytosis, suggesting that signaling downstream of both the EGF-activated and the GPCR-transactivated EGFRs requires a productive engagement of the complex with the cellular endocytic machinery. Thus, RTK transactivation is revealed to be a process involving both association of receptors of distinct classes and the interaction of the transactivated RTK with the cells endocytic machinery.
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PMID:The beta(2)-adrenergic receptor mediates extracellular signal-regulated kinase activation via assembly of a multi-receptor complex with the epidermal growth factor receptor. 1073 7

Endothelial cytosolic pH (pH(i)) modulates ion channel function, vascular tone, and cell proliferation. Steady shear induces rapid acidification in bicarbonate buffer. However, in vivo shear is typically pulsatile, potentially altering this response. We tested effects and mechanisms of pH(i) modulation by flow pulsatility, comparing pressurized steady versus pulse-flow responses in bovine aortic endothelial cells cultured within glass capillary tubes. Cells were loaded with the fluorescent pH(i) indicator carboxy seminaphthorhodafluor-1 and perfused with physiological pulsatile pressure and flow generated by a custom servo-control system. Raising mean pressure from 0 to 90 mm Hg at 0.5 mL/min steady flow in bicarbonate buffer induced sustained acidification (-0.33+/-0.09 pH units, P<0.01). A subsequent increase in steady flow resulted in further acidification. In contrast, if mean pressure and flow were unchanged but perfusion made pulsatile, pH(i) rose +0.3+/-0.03 (P<0. 0001) over 30 to 60 minutes. HCO(3)(-) removal and use of acid/base exchange inhibitors 5-(N-ethyl-N-isopropyl)amiloride or diisothiocyanato stilbene disulfonic acid identified both extracellular Na(+)-independent Cl(-)-HCO(3)(-) and Na(+)-H(+) exchangers as activated by static pressure, whereas pulsatility activated extracellular Na(+)-dependent Cl(-)-HCO(3)(-) and Na(+)-H(+) exchangers to raise pH(i). Pulse-perfusion alkalinization occurred with or without flow reversal and increased 1.6-fold in Ca(2+)-free buffer. Inhibition of c-Src tyrosine kinase (4-amino-5-[4-chlorophenyl]-7-[t-butyl]pyrazolo [3,4-d]pyrimidine; PP2) or MEK-1 (mitogen-activated protein kinase [MAP]/extracellular signal-regulated kinase [ERK]-1) (PD98059, blocking ERK1/2) blocked or reversed the pulsatile-flow pH(i) change to acidification. In contrast, PP2 had no effect on steady flow acidification, whereas MEK-1 inhibition converted it to alkalinization. Thus, pulsatile and steady flow trigger opposite effects on endothelial pH(i) by differential activation of acid/base exchangers linked to c-Src and MAP kinase phosphorylation, but not to Ca(2+). These data highlight specific signaling responses triggered by phasic shear profiles.
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PMID:Opposite effects of pressurized steady versus pulsatile perfusion on vascular endothelial cell cytosolic pH: role of tyrosine kinase and mitogen-activated protein kinase signaling. 1086 13

Rat eosinophil survival was prolonged by recombinant rat IL-5 prepared by the baculovirus expression system. The IL-5-induced prolongation of eosinophil survival was dose-dependently inhibited by the protein synthesis inhibitor cycloheximide, the DNA-dependent RNA synthesis inhibitor actinomycin D, and the tyrosine kinase inhibitor herbimycin A. The MEK-1 inhibitor PD98059 inhibited IL-5-induced phosphorylation of both p44 and p42 MAP kinases, but the IL-5-induced prolongation of eosinophil survival was not inhibited. In contrast, the JAK2 inhibitor AG490 inhibited the IL-5-induced prolongation of eosinophil survival. Treatment of eosinophils with IL-5 resulted in phosphorylation of STAT5 but not STAT1, and the IL-5-induced phosphorylation of STAT5 was inhibited by AG490. These findings suggest that recombinant rat IL-5 activates JAK2 tyrosine kinase, which phosphorylates STAT5, and induces protein synthesis required for the prolongation of rat eosinophil survival.
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PMID:Analysis of the prolongation of rat eosinophil survival induced by recombinant rat interleukin-5. 1086 6

Gap junction communication between microvascular endothelial cells has been proposed to contribute to the coordination of microvascular function. Septic shock may attenuate microvascular cell-to-cell communication. We hypothesized that lipopolysaccharide (LPS) attenuates communication between microvascular endothelial cells derived from rat hindlimb skeletal muscle. Endothelial cells grown in monolayers expressed mRNA for connexin 37, 40, and 43. The expression of connexin 43 protein was confirmed, but connexin 40 protein was not detected by immunocytochemistry or immunoblot analysis. Intercellular resistance between cells of the monolayer, calculated using a Bessel function model, was increased from 3.3 to 5.3 MOmega by LPS. The effect was seen after 1 h of exposure and required a minimum concentration of 10 ng/ml. Intercellular resistance returned to normal 1 h following removal of LPS. Neither the response to LPS, nor its reversal, was blocked by the protein synthesis inhibitor cycloheximide (10 microg/ml). Pretreatment of monolayers with the tyrosine kinase inhibitors PP-2 (10 nM), lavendustin-C (1 microM), and geldanamycin (200 nM) prevented this LPS response; geldanamycin was also able to reverse the response. Inhibitors of MAP kinases, PD 98059 (5 microM) and SB 202190 (5 microM), and PKC (500 nM bisindolylmaleimide I) were unable to block the LPS response. We propose that LPS attenuates cell-to-cell communication through a signaling pathway that is tyrosine kinase dependent.
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PMID:Endotoxin increases intercellular resistance in microvascular endothelial cells by a tyrosine kinase pathway. 1094 25

Interleukin-1 beta (IL-1 beta) is a multipotent cytokine participating in a variety of cardiovascular diseases. In this study, we examined the effects of IL-1 beta on the expression of vascular endothelial cell growth factor (VEGF) and pursued the molecular mechanisms underlying this effect. Treatment of cultured neonatal rat cardiac myocytes with IL-1 beta increased the levels of VEGF mRNA in a time- and a concentration-dependent manner. These effects were completely abolished by SB203580 and SB202190 (p38 MAPK inhibitors) but not by PD98059 (MEK1 inhibitor), calphostin C (protein kinase C inhibitor), or genistein (tyrosine kinase inhibitor). While IL-1 beta phosphorylated c-Jun N-terminus protein kinase (JNK) rapidly and transiently, the effect of IL-1 beta on p38 mitogen-activated protein kinase (MAPK) was gradual and persistent. Transient transfection assays showed that IL-1 beta increases the transcription from the VEGF promoter. A series of 5;-deletion and site-specific mutation analyses indicated that IL-1 beta as well as overexpression of p38 MAPK and JNK activate VEGF promoter activity through two G+C-rich sequences located at -73 and -62. Electrophoretic mobility shift and supershift assays showed Sp1 and Sp3 proteins specifically bind to the G+C-rich sequences. The half-life of VEGF mRNA was significantly increased in cells treated with IL-1 beta. Together, these results indicate that IL-1 beta induces VEGF gene expression at both transcriptional and post-transcriptional levels, and IL-1 beta evokes p38 MAPK and JNK signalings, which in turn stimulate the transcription of the VEGF gene through Sp1-binding sites. These findings suggest the role of IL-1 beta as a cytokine inducing VEGF in cardiac myocytes, and imply that activation of stress-activated MAP kinases regulate Sp1 sites-dependent transcription.
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PMID:Induction of VEGF gene transcription by IL-1 beta is mediated through stress-activated MAP kinases and Sp1 sites in cardiac myocytes. 1104 Jan 1

Vascular endothelial growth factor, VEGF, stimulates angiogenesis by directly acting on endothelial cells. The effects of VEGF are mediated by two tyrosine kinase receptors, VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1/KDR) that are highly related to receptors of the platelet derived growth factor (PDGF) receptor family. We are interested in early signalling events downstream from VEGF receptors that affect blood vessel homeostasis. Endothelial cells form multiple types of cell-cell junctions that are required for cellular organization into complex networks. These junctions also regulate communication among adjacent cells. Stimulation by various growth factors such as epidermal growth factor (EGF) or PDGF has been shown to disrupt cell-cell junctions, consequently affecting cell-to-cell communication. We investigated gap junctional communication (GJC) by monitoring the transfer of a low molecular mass fluorescent tracer molecule between adjacent cells using immunofluorescence microscopy. VEGF maximally blocked GJC 15 minutes after growth factor administration. The cells resumed communication via gap junctions within 1-2 hours after treatment. This early effect of VEGF on communication correlated with changes in the phosphorylation state of one of the proteins involved in gap junction formation, connexin 43 (Cx43). The signalling mechanisms involved in this phenomenon depend on activation of VEGFR-2, impinge on a tyrosine kinase of the Src family and activate the Erk family of MAP kinases. The function of VEGF-mediated disruption of GJC might be to restrict an increase in endothelium permeability to the environment affected by local injury to blood vessels.
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PMID:VEGF transiently disrupts gap junctional communication in endothelial cells. 1122 66

L-Selectin-mediated rolling of leukocytes on endothelial cells is an important step for lymphocyte homing and an early event in the immune response to pathogens or inflammatory stimuli. We have previously elucidated intracellular signaling cascades upon L-selectin engagement resulting in activation of Ras, Rac and JNK as well as cytoskeletal changes, oxygen release, ceramide synthesis and receptor capping. Activation of the src-tyrosine kinase p56lck is followed by phosphorylation of the L-selectin molecule and MAP-K. Here we show a tyrosine kinase dependent phosphorylation of the Cbl adapter protein after L-selectin engagement in lymphocytes. Phosphorylation of Cbl was absent in Jurkat cells that are pharmacologically treated with tyrosine kinase inhibitors and in lck-deficient JCaM cells. There is an activation induced association of tyrosine phosphorylated Cbl with Grb2 and CrkL, respectively, but not CrkII. Therefore, the adapter protein Cbl plays a role in L-selectin signaling and might modulate immune function by the specific recruitment of signaling molecules to multiprotein complexes.
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PMID:L-selectin tyrosine phosphorylates cbl and induces association of tyrosine-phosphorylated cbl with crkl and grb2. 1126 68

Embryonic mouse striatal neurons and human neurons derived from the NT2/hNT stem cell line can be induced, in culture, to express the dopaminergic (DA) biosynthetic enzyme tyrosine hydroxylase (TH). The novel expression of TH in these cells is signaled by the synergistic interaction of factors present in the media, such as fibroblast growth factor 1 (FGF1) and one of several possible coactivators [DA, phorbol 12-myristate 13-acetate (TPA), isobutylmethylxanthine (IBMX), or forskolin]. Similarly, in vivo, it has recently been reported that the expression of TH in the developing midbrain is mediated by the synergy of FGF8 and the patterning molecule sonic hedgehog (Shh). In the present study, we examined whether the putative in vivo DA differentiation factors can similarly signal TH in our in vitro cell systems. We found that FGF8 and Shh induced TH expression in fewer than 2% of NT2/hNT cells and less than 5% of striatal neurons. The latter could be amplified to as much as 30% by increasing the concentration of growth factor 10-fold or by the addition of other competent coactivators (IBMX/forskolin, TPA, and DA). Additivity/inhibitor experiments indicated that FGF8 worked through traditional tyrosine kinase-initiated MAP/MEK signaling pathways. However, the Shh signal transduction cascade remained unclear. These data suggest that cues effective in vivo may be less successful in promoting the differentiation of a DA phenotype in mouse and human neurons in culture. Thus, our ability to generate DA neurons from different cell lines, for use in the treatment of Parkinson's disease, will depend on the identification of appropriate differentiation signals for each cell type under investigation.
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PMID:Sonic hedgehog and FGF8: inadequate signals for the differentiation of a dopamine phenotype in mouse and human neurons in culture. 1131 56

Recombinant rat interleukin (IL)-5-induced prolongation of rat eosinophil survival in culture was inhibited in a concentration-dependent manner by the protein synthesis inhibitor cycloheximide, the DNA-dependent RNA synthesis inhibitor actinomycin D, and the tyrosine kinase inhibitor herbimycin A when examined 96 h after incubation. The MEK-1 inhibitor PD98059 inhibited IL-5-induced phosphorylation of both p44 and p42 MAP kinases, but the IL-5-induced prolongation of eosinophil survival was not inhibited. In contrast, the JAK2 inhibitor AG490 inhibited the IL-5-induced prolongation of eosinophil survival. Treatment of eosinophils with IL-5 resulted in phosphorylation of STAT5 but not STAT1, and the IL-5-induced phosphorylation of STAT5 was inhibited by AG490. These findings suggest that the activation of JAK2 tyrosine kinase and protein synthesis are required for the prolongation of rat eosinophil survival induced by recombinant rat IL-5. STAT5 phosphorylation might also participate in the IL-5-induced survival of rat eosinophils.
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PMID:Possible participation of a JAK2 signaling pathway in recombinant rat interleukin-5-induced prolongation of rat eosinophil survival. 1133 6

Cellular proliferation, and differentiation of cells in response to extracellular signals, are controlled by the signal transduction pathway of Ras, Raf and MAP (mitogen-activated protein) kinase. The mechanisms that regulate this pathway are not well known. Here we describe two structurally similar tyrosine kinase substrates, Spred-1 and Spred-2. These two proteins contain a cysteine-rich domain related to Sprouty (the SPR domain) at the carboxy terminus. In Drosophila, Sprouty inhibits the signalling by receptors of fibroblast growth factor (FGF) and epidermal growth factor (EGF) by suppressing the MAP kinase pathway. Like Sprouty, Spred inhibited growth-factor-mediated activation of MAP kinase. The Ras-MAP kinase pathway is essential in the differentiation of neuronal cells and myocytes. Expression of a dominant negative form of Spred and Spred-antibody microinjection revealed that endogenous Spred regulates differentiation in these types of cells. Spred constitutively associated with Ras but did not prevent activation of Ras or membrane translocation of Raf. Instead, Spred inhibited the activation of MAP kinase by suppressing phosphorylation and activation of Raf. Spred may represent a class of proteins that modulate Ras-Raf interaction and MAP kinase signalling.
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PMID:Spred is a Sprouty-related suppressor of Ras signalling. 1149 23


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