Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fibroblast growth factors (FGFs) are known to induce formation of new blood vessels, angiogenesis. We show that FGF-induced angiogenesis can be modulated using selectively desulfated heparin. Chinese hamster ovary cells (CHO677) deficient in heparan sulfate biosynthesis were employed to assess the function of heparin/heparan sulfate in FGF receptor-1 (FGFR-1) signal transduction and biological responses. In the presence of FGF-2, FGFR-1 kinase and subsequent mitogen-activated protein kinase Erk2 activities were augmented in a dose-dependent manner, whereas high concentrations of heparin resulted in decreased activity. The length of the heparin oligomer, minimally an 8/10-mer, was critical for the ability to enhance FGFR-1 kinase activity. The N- and 2-O-sulfate groups of heparin were essential for binding to FGF-2, whereas stimulation of FGFR-1 and Erk2 kinases by FGF-2 also required the presence of 6-O-sulfate groups. Sulfation at 2-O- and 6-O-positions was moreover a prerequisite for binding of heparin to a lysine-rich peptide corresponding to amino acids 160-177 in the extracellular domain of FGFR-1. Selectively 6-O-desulfated heparin, which binds to FGF-2 but fails to bind the receptor, decreased FGF-2-induced proliferation of CHO677 cells, presumably by displacing intact heparin. Furthermore, FGF-2-induced angiogenesis in chick embryos was inhibited by 6-O-desulfated heparin. Thus, formation of a ternary complex of FGF-2, heparin, and FGFR-1 appears critical for the activation of FGFR-1 kinase and downstream signal transduction. Preventing complex formation by modified heparin preparations may allow regulation of FGF-2 functions, such as induction of angiogenesis.
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PMID:Selectively desulfated heparin inhibits fibroblast growth factor-induced mitogenicity and angiogenesis. 1081 96

The interleukin-1 (IL-1) receptor colocalizes with focal adhesion complexes (FACs), actin-enriched structures involved in cell adhesion and signaling in fibroblasts and chondrocytes. The colocalization of FACs and IL-1 receptors has been implicated in the restriction of IL-1 signaling transduction to ERK; however, the mechanism of this restriction and the requirement of IL-1 receptor-associated proteins have not been characterized. We determined if the association kinetics of the interleukin-1 receptor-associated kinase (IRAK) colocalizes with FACs and the requirement for IRAK in IL-1-dependent ERK activation. Human gingival fibroblasts were incubated with collagen-coated beads to induce the assembly of FACs at sites of cell-bead contact. Immunoblot analysis of bead-isolated FACs showed a time-dependent assembly of the focal adhesion proteins beta-actin, vinculin, and talin, which was blocked by the actin monomer sequestering toxin latrunculin B. Although no IRAK was isolated with FACs from unstimulated cells, phosphorylated IRAK was transiently associated with FACs isolated from IL-1beta-stimulated fibroblasts. Fibroblasts plated on tissue culture plastic (which permitted the formation of focal adhesions) showed phosphorylation of ERK, JNK, and p38. Cells plated on poly-l-lysine (to prevent the formation of focal adhesions) showed activation only of JNK and p38. ERK activation was partially restored by incubating cells plated on poly-l-lysine with collagen-coated beads before IL-1 stimulation. Cells treated with latrunculin B or swinholide A, which caused a progressive depolymerization of actin filaments, showed a reduction or elimination of IL-1-induced ERK activation, respectively. Fibroblasts electroinjected with a mouse monoclonal anti-IRAK antibody to block the recruitment of IRAK into FACs failed to activate ERK after IL-1 treatment, indicating that FAC-associated IRAK is required for the activation of ERK. These data indicate that the integrity of actin filament arrays and the recruitment of IRAK into focal adhesions are involved in the restriction of IL-1 signaling to ERK.
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PMID:The recruitment of the interleukin-1 (IL-1) receptor-associated kinase (IRAK) into focal adhesion complexes is required for IL-1beta -induced ERK activation. 1082 34

Integrin-mediated substrate adhesion of endothelial cells leads to intracellular signaling, including the activation of ERK 1/2 (extracellular regulated kinases 1 and 2), members of the mitogen-activated protein kinase (MAPK) family. MKP-1 is a dual-specificity protein phosphatase that may play an important role in regulating MAPK activity through dephosphorylation of threonine and tyrosine. Adhesion of human umbilical vein endothelial cells to fibronectin increased MKP-1 protein and mRNA levels, which reached a maximum at 60 min, while MAPK activity was maximal at 30 min. The MEK inhibitor PD98059 blocked activation of MAPK as well as the induction of MKP-1 during adhesion. The transcription inhibitor actinomycin D blocked MKP-1 induction and produced prolonged MAPK activation during adhesion. In contrast, endothelial adhesion to poly-L-lysine did not alter MAPK activity or MKP-1 levels. These findings demonstrate that integrin-mediated adhesion of endothelial cells to fibronectin results in transcriptional activation of MKP-1 through a MAPK-dependent mechanism. Regulation of MKP-1 by MAPK likely represents an important negative-feedback mechanism.
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PMID:Adhesion to fibronectin enhances MKP-1 activation in human endothelial cells. 1087 41

The mitogen-activated protein (MAP) kinase Mkp1 of the fungal pathogen Pneumocystis carinii is a functional MAP kinase that complements the loss of Slt2p, the MAP kinase component of the cell integrity pathway of Saccharomyces cerevisiae, and is activated within P. carinii in response to oxidative stress. Mkp1 displays an unusual feature in that it contains a phosphorylation motif repeat (TEYMTEY) within the activation loop not present in any other fungal MAPK identified to date. Mutagenesis of the T186,Y188 phosphorylation motif within the activation domain of Mkp1 results in the loss of detectable kinase activity but still retains partial complementation function. In addition to the ability of Mkp1 to restore partial activity to the cell integrity pathway in the absence of phosphorylatable residues within the activation loop, the association of Mkp1 with a substrate of Slt2p, the transcription factor Rlm1p, can also occur in the absence of MAP kinase activation. The results of this study suggest that the presence of phosphorylatable residues within the activation loop of Mkp1 is not absolutely required for functional (complementation) activity or for the association of Mkp1 with the transcription factor Rlm1p. In contrast, the catalytic lysine of the ATP-binding domain of Mkp1 is necessary for both complementation function and interaction with Rlm1p.
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PMID:Mkp1 of Pneumocystis carinii associates with the yeast transcription factor Rlm1 via a mechanism independent of the activation state. 1088 67

The intracellular signaling pathway for osteoblast adhesion to the orthopedic implant material Ti6Al4V (TIV) was investigated and compared to integrin-mediated adhesion to extracellular matrix proteins. Primary osteoblasts from fetal rat calvaria were plated onto TIV, fibronectin (FN), and poly-L-lysine (PLL) and the levels of focal adhesion kinase (FAK), mitogen-activated protein kinase (MAPK), and AP-1 transcription factors, c-fos and c-jun, were compared by Western and Northern blots. Cells on all substrates showed maximum FAK phosphorylation within 60 min and then a decrease at 2 and 24 h. However, the subsequent signal transduction pathway differed on PLL compared to TIV and FN. MAPK was phosphorylated similarly in osteoblasts attached to FN and TIV, whereas cells on PLL demonstrated no MAPK phosphorylation. On TIV and FN, c-fos and c-jun mRNA levels were maximal within 1 h and then plateaued or declined by 2 h. On PLL, they increased at 2 h. Within 1 h, c-fos protein was stimulated in cells attached to TIV and FN and decreased in cells on PLL. c-jun protein increased on all substrates compared to unplated cells. Cytoskeletal changes visualized by phalloidin fluorescence microscopy at 4 h of culture were delayed on TIV compared to FN. In addition, approximately 50% fewer cells adhered to TIV compared to FN or PLL. By 24 h, a well-spread cytoskeleton with focal adhesion sites was apparent on TIV and FN, but cells on PLL were rounded with minimal cell spreading. During 6 days of culture, cells on FN and TIV proliferated, whereas the number of cells on PLL remained the same or decreased, depending on the initial plating density. We conclude that osteoblast adhesion to TIV implants is similar to osteoblast adhesion to FN and leads to osteoblast proliferation. These data provide evidence for the biocompatibility of TIV at a molecular level.
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PMID:Integrin-mediated signaling in osteoblasts on titanium implant materials. 1103 57

Several non-peptidic opioids have been synthesized recently as part of a program to develop selective delta receptor agonists. In this study, the affinities of a set of compounds for cloned delta and mu opioid receptors expressed in HEK 293 cell lines were determined by competition analysis of [3H]bremazocine binding to membrane preparations. All compounds studied exhibited high affinity and selectivity, with apparent dissociation constants in the range of 0.6-1.7 nM for the delta opioid receptor and 240-1165 nM for the mu opioid receptor. We next sought to determine which domain of the delta receptor was critical for mediating the highly selective binding by analysis of ligand affinities for mu/delta receptor chimeras. Receptor binding profiles suggested that a critical site of receptor/ligand interaction was located between transmembrane domain 5 (TM5) and TM7 of the delta receptor. Substitution of tryptophan 284, located at the extracellular surface of TM6, with lysine, which is found at the equivalent position in the mu opioid receptor, led to a spectrum of effects on affinities, depending on the ligand tested. Affinities of SB 219825 and SB 222941 were particularly sensitive to the substitution, displaying a 50-fold and 70-fold decrease in affinity, respectively. Activities of the delta receptor-selective agonists were tested in two functional assays. Brief exposure of HEK 293 cells expressing delta opioid receptors with selective ligands induced phosphorylation of MAP kinase, although the non-peptidic ligands were less efficacious than the enkephalin derivative DADL (Tyr-D-Ala-Gly-Phe-D-Leu). Similarly, chronic exposure of HEK 293 cells expressing delta opioid receptors with selective, non-peptidic ligands, with the exception of SB 206848, caused receptor down-regulation, however, the SB compounds were less efficacious than DADL.
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PMID:Pharmacological profiles of selective non-peptidic delta opioid receptor ligands. 1103 49

We compared the Vif sequences from more than 100 group M and O strains of HIV-1 isolated from diverse geographical regions and various subtypes, in order to identify regions of high variability and those amino acid residues that were highly conserved or invariant. Our analysis found that there were 10 highly conserved domains with additional invariant residues located throughout the protein. Our analysis revealed that in the highly conserved amino-terminal domain, all subtype C isolates examined had a methionine-to-leucine substitution at position 8 and most subtype C isolates had an arginine-to-lysine substitution at position 17 of the protein. Our analysis revealed that the MAP kinase phosphorylation sites, and the cysteine residues at positions 114 and 133, were conserved in Vif sequences from group M, group O, and SIV cpz isolates. Our analysis also shows that the RKKR motif at positions 90--93, proposed as a nuclear transport inhibition signal (NTIS), was conserved neither in different geographical group M and O HIV-1 isolates nor in SIVcpz.
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PMID:Comparison of Vif sequences from diverse geographical isolates of HIV type 1 and SIV(cpz) identifies substitutions common to subtype C isolates and extensive variation in a proposed nuclear transport inhibition signal. 1117 96

Regulation of nuclear receptor gene expression involves dynamic and coordinated interactions with histone acetyl transferase (HAT) and deacetylase complexes. The estrogen receptor (ERalpha) contains two transactivation domains regulating ligand-independent and -dependent gene transcription (AF-1 and AF-2 (activation functions 1 and 2)). ERalpha-regulated gene expression involves interactions with cointegrators (e.g. p300/CBP, P/CAF) that have the capacity to modify core histone acetyl groups. Here we show that the ERalpha is acetylated in vivo. p300, but not P/CAF, selectively and directly acetylated the ERalpha at lysine residues within the ERalpha hinge/ligand binding domain. Substitution of these residues with charged or polar residues dramatically enhanced ERalpha hormone sensitivity without affecting induction by MAPK signaling, suggesting that direct ERalpha acetylation normally suppresses ligand sensitivity. These ERalpha lysine residues also regulated transcriptional activation by histone deacetylase inhibitors and p300. The conservation of the ERalpha acetylation motif in a phylogenetic subset of nuclear receptors suggests that direct acetylation of nuclear receptors may contribute to additional signaling pathways involved in metabolism and development.
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PMID:Direct acetylation of the estrogen receptor alpha hinge region by p300 regulates transactivation and hormone sensitivity. 1127 35

Changes in gene expression are thought to be involved in neuronal plasticity associated with learning and memory. Although acetylation of lysine residues on histones by histone acetyltransferases (HAT) is an obligatory component of transcription, HAT activity has been largely ignored in studies of the nervous system. We developed a new model for studying novel taste learning using novel solid food presentation to nondeprived animals. Using this behavioral paradigm, we investigated short- and long-term regulation of lysine acetyltransferase activity and the ERK/mitogen-activated protein kinase (MAPK)/RSK cascade in insular cortex, a CNS region known to be crucial for the formation of novel taste memories. We observed that novel taste learning elicited biphasic (acute and long-lasting) activation of two distinct lysine acetyltransferase activities along with the ERK/MAPK cascade in insular cortex. In vitro studies revealed that the ERK cascade could regulate the lysine acetylation of a 42 kDa lysine acetyltransferase substrate, suggesting a causal relationship between ERK activation and lysine acetyltransferase activity in insular cortex. Overall, our studies reveal an unanticipated long-lasting activation of insular cortex signal transduction cascades in novel taste learning. Furthermore, our studies suggest the hypothesis that acute and long-term ERK activation and lysine-histone acetyltransferase activation may play a role in regulating gene expression in single-trial learning and long-term memory formation.
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PMID:Increased histone acetyltransferase and lysine acetyltransferase activity and biphasic activation of the ERK/RSK cascade in insular cortex during novel taste learning. 1133 68

Ras p21 signaling is involved in multiple aspects of growth, differentiation, and stress response [1-2]. There is evidence pointing to superoxides as relays of Ras signaling messages. Chemicals with antioxidant activity suppress Ras-induced DNA synthesis. The inhibition of Ras significantly reduces the production of superoxides by the NADPH-oxidase complex [3]. Kirsten and Harvey are nonallelic Ras cellular genes that share a high degree of structural and functional homology. The sequences of Ki- and Ha-Ras proteins are almost identical. They diverge only in the 20-amino acid hypervariable domain at the COOH termini. To date, their functions remain indistinguishable [4]. We show that Ki- and Ha-Ras genes differently regulate the redox state of the cell. Ha-Ras-expressing cells produce high levels of reactive oxygen species (ROS) by inducing the NADPH-oxidase system. Ki-Ras, on the other hand, stimulates the scavenging of ROS by activating posttranscriptionally the mitochondrial antioxidant enzyme, Mn-superoxide dismutase (Mn-SOD), via an ERK1/2-dependent pathway. Glutamic acid substitution of the four lysine residues in the polybasic stretch at the COOH terminus of Ki-Ras completely abolishes the activation of Mn-SOD, although it does not inhibit ERK1/2-induced transcription. In contrast, an alanine substitution of the cysteine of the CAAX box has very little effect on Mn-SOD activity but eliminates ERK1/2- dependent transcription.
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PMID:Opposing functions of Ki- and Ha-Ras genes in the regulation of redox signals. 1136 7


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