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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of p38 mitogen-activated protein kinase (MAPK) in responses of human fibroblasts and vascular endothelial cells to IL-1 was investigated by use of a pyridinyl imidazole compound (SB 203580), which specifically inhibits the enzyme. SB 203580 inhibited (50% inhibitory concentration approximately 0.5 microM) IL-1-induced phosphorylation of heat shock protein 27 (an indicator of p38 MAPK activity) in fibroblasts without affecting the other known IL-1-activated protein kinase pathways (p42/p44 MAPK, p54 MAPK/c-Jun N-terminal kinase and beta-casein kinase). SB 203580 significantly inhibited IL-1-stimulated IL-6, (30 to 50% at 1 microM) but not IL-8 production from human fibroblasts (gingival and dermal) and umbilical vein endothelial cells. IL-1 induction of steady state level of IL-6 mRNA was not significantly inhibited, which is consistent with p38 MAPK regulating IL-6 production at the translational level. SB 203580 strongly inhibited IL-1-stimulated PG production by fibroblasts and human umbilical vein endothelial cells. This was associated with the inhibition of the induction of PGH synthase-2 protein and mRNA. SB 203580 also inhibited the stimulation of collagenase-1 and stromelysin-1 production by IL-1 without affecting synthesis of the tissue inhibitor of metalloproteinases (TIMP)-1. SB 203580 prevented the increase in collagenase-1 and stromelysin-1 mRNA stimulated by IL-1. In a model of cartilage breakdown, short-term IL-1-stimulated proteoglycan resorption and inhibition of proteoglycan synthesis were unaffected by SB 203580, while longer term collagen breakdown was prevented. It is concluded that 1) p38 MAPK plays an important role in the regulation of some, but not all, responses to IL-1, and 2) it is involved in the regulation of mRNA levels of some IL-1-responsive genes.
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PMID:Actions of IL-1 are selectively controlled by p38 mitogen-activated protein kinase: regulation of prostaglandin H synthase-2, metalloproteinases, and IL-6 at different levels. 912 Feb 70

The 92 kDa type IV collagenase (MMP-9), which degrades type IV collagen, has been implicated in tissue remodeling. The purpose of the current study was to determine the role of Jun amino-terminal kinase (JNK)- and extracellular signal-regulated kinase- (ERK)-dependent signaling cascades in the regulation of MMP-9 expression. Towards this end, we first determined the transcriptional requirements for MMP-9 promoter activity in a cell line (UM-SCC-1) which is an avid secretor of this collagenase. Transfection of these cells with a CAT reporter driven by progressive 5' deleted fragments of the MMP-9 promoter indicated the requirement of a region spanning -144 to -73 for optimal promoter activity. DNase I footprinting revealed a protected region of the promoter spanning nucleotides -91 to -68 and containing a consensus AP-1 motif at -79. Mutation of this AP-1 motif practically abolished the activity of the MMP-9 promoter-driven CAT reporter. Mobility shift assays indicated c-Fos and Jun-D bound to this motif and transfection of the cells with a mutated c-Jun, which quenches the function of endogenous Jun and Fos proteins, decreased MMP-9 promoter activity by 80%. UM-SCC-1 cells contained a constitutively activated JNK and the expression of a kinase-deficient JNK1 reduced the activity of a CAT reporter driven either by the MMP-9 promoter or by three tandem AP-1 repeats upstream of a thymidine kinase minimal promoter. Conditioned medium collected from UM-SCC-1 cells transfected with the dominant negative JNK1 expression vector diminished 92 kDa gelatinolysis. Similarly, interfering with MEKK, which lies upstream of JNK1, using a dominant negative expression vector reduced MMP-9 promoter activity over the same concentration range which repressed the AP-1-thymidine kinase CAT reporter construct. UM-SCC-1 cells also contained a constitutively activated ERK1. MMP-9 expression, as determined by CAT assays and by zymography, was reduced by the co-expression of a kinase-deficient ERK1. Interfering with MEK1, which is an upstream activator of ERK1, either with PD 098059, which prevents the activation of MEK1, or with a dominant negative expression construct, reduced 92 kDa gelatinolysis and MMP-9 promoter activity respectively. c-Raf-1 is an upstream activator of MEK1 and a kinase-deficient c-Raf-1 expression construct decreased the activity of a promoter driven by either the MMP-9 promoter or three tandem AP-1 repeats. Conversely, treatment of UM-SCC-1 cells with PMA, which activates c-Raf-1, increased 92 kDa gelatinolysis. These data suggest that MMP-9 expression in UM-SCC-1 cells, is regulated by JNK- and ERK-dependent signaling pathways.
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PMID:Regulation of 92 kDa type IV collagenase expression by the jun aminoterminal kinase- and the extracellular signal-regulated kinase-dependent signaling cascades. 913 92

A cascade of signal transduction events is initiated when cells make contact with each other or with a substrate. The nature of these signal transduction pathways is beginning to be elucidated. In particular, adhesive interactions between cells and their substrate, mediated by cell-surface integrins and extracellular matrix proteins, appears to activate the MAP kinase pathway. Here we show that in mouse fibroblasts and rat epithelial cells, tyrosine phosphorylation of a 62 kilodalton rasGAP-associated protein (GAPa-p62) is decreased upon cell-substrate interaction. Interaction between fibroblasts and various extracellular matrices such as fibronectin, vitronectin and collagen IV, but not laminin, results in tyrosine dephosphorylation of GAPa-p62. Cell-substrate mediated tyrosine dephosphorylation of GAPa-p62 is defective in transformed cell lines, suggesting a possible role for p62 in tumorigenic transformation. These studies suggest that in fibroblasts, and perhaps even in epithelial cells, the signal transduction pathway(s) triggered by different integrin engagement events converge on the rasGAP protein and alter the tyrosine phosphorylation and/or association of GAPa-p62.
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PMID:Specific changes in rasGAP-associated 62 kilodalton protein during integrin mediated cell-substrate interaction. 917 62

Phosphorylation and activation of cytosolic phospholipase A2 (PLA2) can occur independently of the activation of 42/44-kDa mitogen-activated protein (MAP) kinase in human platelets. We have investigated the hypothesis that the stress-activated p38 MAP kinase plays a role in the regulation of cytosolic PLA2. The specific inhibitor of p38 MAP kinase, SB 203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl) imidazole], completely blocked the collagen-stimulated phosphorylation of cytosolic PLA2 in the presence of a cyclooxygenase blocker, and reduced the release of [3H]arachidonic acid by low concentrations of collagen. Stimulation of platelets with collagen (100 microg/ml) enhanced in vitro PLA2 activity of platelet lysates twofold over basal levels. In vitro PLA2 activity was reduced to basal levels when platelets were stimulated in the presence of SB 203580, but not in the presence of an inhibitor of the kinase that activates p42/p44 MAP kinase. SB 203580 only partially inhibited phosphorylation of cytosolic PLA2 in platelets that had not been treated with a cyclooxygenase blocker indicating that secondary stimulation by thromboxane A2 induces cytosolic PLA2 phosphorylation, by kinase(s) other than p38 MAP kinase. Under these conditions, inhibition of p42/p44 MAP kinase did not result in a reduction of cytosolic PLA2 phosphorylation, which is in agreement with the results obtained in the presence of cyclooxygenase blockers. In contrast to collagen, both p38 MAP kinase and p42/p44 MAP kinase participated in the phosphorylation of cytosolic PLA2 in platelets stimulated by cross-linking of the low-affinity receptor for immune complexes, Fc gammaRIIA. The present results demonstrate an important role for p38 MAP kinase in the regulation of cytosolic PLA2 activity in collagen-stimulated human platelets.
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PMID:Phosphorylation and activation of cytosolic phospholipase A2 by 38-kDa mitogen-activated protein kinase in collagen-stimulated human platelets. 918 15

PD 089828, a novel protein tyrosine kinase inhibitor of a new structural class, the 6-aryl-pyrido-[2,3-d]pyrimidines, was identified by screening a compound library with assays that measured protein tyrosine kinase activity. PD 089828 was found to inhibit human full-length fibroblast growth factor (FGF) receptor-1 (FGFR-1), platelet-derived growth factor (PDGF) receptor beta subunit (PDGFR-beta), Src nonreceptor tyrosine kinase (c-Src) and epidermal growth factor (EGF) receptor (EGFR) tyrosine kinases with half-maximal inhibitory potencies (IC50 values) of 0.15 +/- 0.02 (n = 4), 0.18 +/- 0.04 (n = 3), 1.76 +/- 0.28 (n = 4) and 5.47 +/- 0.78 (n = 6) microM, respectively. PD 089828 was further characterized as an ATP competitive inhibitor of the growth factor receptor tyrosine kinases (FGFR-1, PDGFR-beta and EGFR) but a noncompetitive inhibitor of c-Src tyrosine kinase with respect to ATP. In addition, PD 089828 inhibited PDGF- and EGF-stimulated receptor autophosphorylation in vascular SMC (VSMC) and basic FGF-mediated tyrosine phosphorylation in A121 cells with IC50 values similar to the potencies observed for inhibition of receptor tyrosine kinase activity. The inhibition of PDGF receptor autophosphorylation in VSMC by PD 089828 occurred rapidly, with maximal effects reached within 5 min of drug exposure. Inhibition after single exposure was long lasting but also rapidly reversible, occurring within 5 min after drug removal. The PDGF-induced association of downstream signaling proteins, including phosphoinositide-3-kinase (PI-3K), growth factor receptor binding protein-2 (GRB2), SH-2 domain and collagen like (Shc) and phospholipase Cgamma (PLCgamma), with VSMC PDGF receptors was also blocked as a result of the inhibition of PDGF-stimulated receptor autophosphorylation by PD 089828. PD 089828 also inhibited the PDGF-induced tyrosine phosphorylation of the 44- and 42-kDa mitogen-activated protein kinase isoforms. Moreover, the effects of PD 089828 were demonstrated in functional assays in which PDGF-stimulated DNA synthesis, PDGF-directed migration and serum-stimulated growth of VSMC were all inhibited to the same extent as PDGF receptor autophosphorylation (IC50 = 0.8, 4.5 and 1.8 microM, respectively). These results highlight the biological characteristics of PD 089828 as a novel, broadly active protein tyrosine kinase inhibitor with long-lasting but reversible cellular effects. The potential therapeutic use of these broadly acting, nonselective inhibitors as antiproliferative and antimigratory agents could extend to such diseases as cancer, atherosclerosis and restenosis in which redundancies in growth-signaling pathways are known to exist.
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PMID:Inhibition of growth factor-mediated tyrosine phosphorylation in vascular smooth muscle by PD 089828, a new synthetic protein tyrosine kinase inhibitor. 919 Aug 82

Using immunoprecipitation and phosphotyrosine detection by Western blotting, intracellular signaling intermediates were analyzed in human primary dermal fibroblasts, either seeded as monolayers on collagen I coats (2D) or seeded within three-dimensional collagen I lattices (3D). Previous results demonstrated that integrin activation in these systems resulted in a cascade of protein tyrosine phosphorylation, including focal adhesion kinase (D. Roeckel and T. Krieg, 1994, Exp. Cell Res. 211, 42-48). Further downstream signaling events are now shown to include coordinate activation of ERK1 and ERK2 at 2 h after cell-collagen contact, irrespective of 2D or 3D culture conditions. Applying U-73122, an inhibitor of PLC, inhibits collagen lattice contraction in a dose-dependent fashion. Immunoprecipitation identified the isoform PLCgamma-1 as playing a role as signaling intermediate in fibroblast-collagen interactions. PLCgamma-1 becomes phosphorylated within 10 min after culture initiation and declines after 2 h. So far, no qualitative differences in signaling intermediates between 2D and 3D cultures have been identified.
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PMID:Cell-matrix interactions induce tyrosine phosphorylation of MAP kinases ERK1 and ERK2 and PLCgamma-1 in two-dimensional and three-dimensional cultures of human fibroblasts. 928 48

Using a device that applies cyclical strain (1 Hz) to ventricular cardiocytes cultured on collagen-coated silicone elastomer surfaces, we have demonstrated strain-dependent increases in brain natriuretic peptide (BNP) secretion, BNP mRNA levels, and expression of a transiently transfected -1595 human BNP-luciferase reporter. When actinomycin D (10 microM) was introduced concomitantly with the strain stimulus, the strain-induced increase in BNP mRNA was eliminated, and the decay of transcripts was identical in the control and strained cells, indicating the lack of independent effects on transcript stability. Strain-dependent -1595 human BNP-luciferase activity was completely inhibited by chelerythrine, 2-aminopurine, genistein, and W-7 and only partially or not at all by KN-62, wortmannin, and H-89. The effects of these individual agents paralleled their effects on mitogen-activated protein kinase (MAPK) activity, but not c-Jun N-terminal kinase (JNK) activity, in the cells. Overexpression of wild-type MAPK and, to a lesser extent, JNK increased strain-dependent BNP promoter activity, whereas dominant-negative mutants of MAPK kinase, JNK kinase, or Ras completely blocked strain-dependent reporter activity. These findings provide the first demonstration that mechanical strain can increase myocardial gene expression through a transcriptional mechanism and suggest important roles for MAPK and JNK in mediating this effect.
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PMID:Mechanical strain increases expression of the brain natriuretic peptide gene in rat cardiac myocytes. 934 58

Interaction of type I collagen (COL(I)) with alpha2beta1 integrin causes differentiation and transforming growth factor (TGF)-beta receptor down-regulation in osteoblastic cells (Takeuchi, Y., Nakayama, K., and Matsumoto, T. (1996) J. Biol. Chem. 271, 3938-3644). The TGF-beta receptor down-regulation enables cells to escape from the inhibition of differentiation by TGF-beta. To clarify how the cell-matrix interaction regulates these phenotypic changes, signaling pathways were examined in murine MC3T3-E1 cells. Attachment of cells to COL(I) stimulated tyrosine phosphorylation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK), a mitogen-activated protein kinase (MAPK), and enhanced MAPK activity. Inhibition of tyrosine kinase by herbimycin A, destruction of focal adhesion by cytochalasin D, or overexpression of antisense FAK mRNA prevented the activation of ERK/MAPK and the increase in alkaline phosphatase (ALP) activity. Transient expression of a MAPK-specific phosphatase, CL100, also suppressed the elevation of ALP activity. In addition, introduction of a constitutively active MAPK kinase enhanced ALP activity in the absence of collagen production. TGF-beta receptor down-regulation was abrogated by treatments that inactivate FAK, whereas the expression of CL100 had no effect. These results demonstrate that COL(I)-alpha2beta1 integrin interaction facilitates differentiation and down-regulates TGF-beta receptors via the activation of FAK and its diverse downstream signals. These signaling pathways may play an important role in the sequential differentiation of osteoblasts during bone formation.
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PMID:Differentiation and transforming growth factor-beta receptor down-regulation by collagen-alpha2beta1 integrin interaction is mediated by focal adhesion kinase and its downstream signals in murine osteoblastic cells. 936 Oct 11

To determine whether p185HER2 overexpression per se triggers p185HER2 cellular signaling or whether an extracellular signal is required, we transfected PC12 cells with the human erbB-2 proto-oncogene, and established a cell line that overexpresses p185HER2. PC12-HER2 cells, maintained in suspension culture or plated on a collagen layer, showed the same morphology and growth rate as PC12 and PC12 mock-transfected control cells. When treated with monoclonal antibody (MAb) MGr6 or other anti-p185HER2 MAbs, PC12-HER2 cells specifically underwent neuronal differentiation comparable to that induced by nerve growth factor (NGF), and the differentiation-inducing effect of the MAb was dramatically enhanced by the addition of a second anti-mouse IgG. MAb-induced cell differentiation correlated with p185HER2 phosphorylation, recruitment of Shc and Grb-2 transducer molecules into complexes, and MAPK phosphorylation. These data indicate the requirement for a specific binding-induced activation of the overexpressed p185HER2 receptor in inducing PC12 cell differentiation. PC12-HER2 cells represent a suitable system for selection of p185HER2-activating ligands (peptides, phage-displayed peptides or proteins) or specific inhibitors of its tyrosine kinase activity.
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PMID:Binding-induced activation of overexpressed p185HER2 is essential in triggering neuronal differentiation of PC12 cells. 936 Nov 87

Guinea pig bone marrow megakaryocytes were isolated and cultured on collagen gels to promote proplatelet formation. In control cultures 15.6% of the cells formed proplatelets. Both IL6 and TPO stimulated dose dependent increases in the percent of proplatelet forming cells up to 26.7% at 100ng/mal IL6 and 26.8% at 100 ng/ml TPO. IL1 and IL3 had no effect on proplatelet formation. IL3 in combination with IL6 and TPO blocked the increase in proplatelet formation observed with IL6 or TPO alone. IL3 was also found to stimulate thymidine incorporation in megakaryocytes. The role of phosphorylation in proplatelet formation was studied using certain inhibitors. The tyrosine kinase inhibitor genestien had no effect on proplatelet formation at concentrations up to 100 microg/ml. The phosphatase inhibitors calyculin A and okadaic acid both inhibited proplatelet formation. Studies on protein phosphorylation revealed that IL6, but not TPO, stimulated phosphorylation of JAK1, JAK2 and MAP kinase. TPO did stimulate tyrosine phosphorylation of Tyk-2. Although IBMX stimulated proplatelet formation, it inhibited phosphorylation of JAK1 and MAP kinase. Adhesion of megakaryocytes to collagen gel also inhibited phosphorylation of JAK1 and JAK2, while MAP kinase phosphorylation was unaffected. These data show that IL6 and TPO stimulate megakaryocyte proplatelet formation. In addition, although these cytokines increase phosphorylation of signal transduction proteins in the JAK/STAT pathway, it appears that a different signal transduction pathway regulated by a combination of phosphatase activity and cAMP levels, leads to proplatelet formation.
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PMID:Effect of recombinant interleukin-6 and thrombopoietin on isolated guinea pig bone marrow megakaryocyte protein phosphorylation and proplatelet formation. 941 Apr 69


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