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)

Activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway is required for ligand-dependent regulation of numerous cellular functions by receptor tyrosine kinases. We have shown previously that although many receptor tyrosine kinase ligands are mitogens for keratinocytes, cell migration and induction of the 92-kilodalton gelatinase/matrix metalloproteinase (MMP)-9 are selectively regulated by the epidermal growth factor and scatter factor/hepatocyte growth factor receptors. In this report we present evidence of an underlying mechanism to account for these observed differences in receptor tyrosine kinase-mediated response. Ligands that are mitogenic, but do not induce MMP-9 or colony dispersion, transiently activate the p42/p44 ERK/MAP kinases. In contrast, ligands that stimulate MMP-9 induction and colony dispersion induced sustained activation of these kinases. The functional significance of sustained MAPK activation was demonstrated by inhibition of the MAP kinase kinase MEK1. Disruption of the prolonged signal by addition of the MEK1 inhibitor PD 98059 up to 4 h after growth factor stimulation substantially impaired ligand-dependent colony dispersion and MMP-9 induction. These findings support the conclusion that duration of MAPK activation is an important determinant for certain growth factor-mediated functions in keratinocytes.
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PMID:Sustained activation of the mitogen-activated protein kinase pathway. A mechanism underlying receptor tyrosine kinase specificity for matrix metalloproteinase-9 induction and cell migration. 993 37

Our previous work has demonstrated that the insulin-like growth factors (IGFs), acting through a single receptor, stimulate both proliferation and differentiation of L6A1 myoblasts. This unique model system has enabled us to closely examine the switch that regulates these two opposing responses. We have previously shown, using specific inhibitors of the IGF-I signal transduction pathway, that the mitogenic response is mediated by the Ras/Raf/MAP kinase pathway and the myogenic response by the PI 3-kinase/p70s6k pathway (Coolican SA, Samuel DS, Ewton DZ, McWade FJ, Florini JR, J Biol Chem 1997; 272: 6653-62). In that study we found that PD098059, an inhibitor of MEK activation, inhibited the proliferative response, but dramatically enhanced IGF-stimulated differentiation which was associated with elevation of p70s6k activity. Since there have been reports of elevation of Raf-1 activity in PD098059-treated L6 myoblasts, and stimulation of p70s6k activity in cells expressing an activated Raf-1, it was important to determine whether or not Raf-1 elevation plays a role in the myogenic response. To test this, we have transfected L6A1 myoblasts with delta Raf-1:ER, an estradiol-regulated form of oncogenic Raf-1. We found that activation of Raf-1 by estradiol resulted in increased phosphorylation of p42 and p44 MAP kinases and stimulation of proliferation. In contrast, Raf-1 activation inhibited all measured aspects of the myogenic response: myogenin expression, creatine kinase elevation, and fusion of myoblasts to form myotubes. In addition, we found no elevation of p70s6k activity upon Raf-1 activation. These results indicate the following: (1) stimulation of myogenic differentiation by PD098059 treatment is not simply due to the elevation of Raf-1, (2) Raf-1 has a positive role in the MAP kinase pathway and myoblast proliferation, and (3) Raf-1 activation inhibits myogenesis, possibly by forcing cells to remain in the proliferative state.
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PMID:Raf-1 activation stimulates proliferation and inhibits IGF-stimulated differentiation in L6A1 myoblasts. 1022 82

The family of basic secretagogues of connective tissue mast cells act as receptor mimetic agents, which trigger exocytosis by directly activating G proteins. We now demonstrate that pertussis toxin (Ptx)-sensitive Gi proteins, activated by compound 48/80 (c48/80), a potent member of this family, also activate the p42/p44 MAP kinases (MAPKs). This activation was potentiated by the protein tyrosine phosphatase inhibitor vanadate, whereas the tyrphostin AG-18, a competitive inhibitor of protein tyrosine kinases (PTKs); the protein kinase C inhibitors K252a and GF109203X; the phosphatidylinositol-3-kinase (PI-3K) inhibitors wortmannin and LY294002; and EGTA have abolished this activation. These results suggest that c48/80 activated the p42/p44 MAPKs via a mechanism that involves PTKs, protein kinase C, phosphatidylinositol-3-kinase and Ca2+ as mediators. Protein tyrosine phosphorylation and activation of the p42/p44 MAPKs were closely correlated with stimulation of arachidonic acid (AA) release by c48/80 but not with histamine secretion. However, whereas PD98059, the inhibitor of the MAPK kinase has abrogated MAPK activation, this inhibitor failed to effect release of AA. We therefore conclude that by activating Ptx-sensitive Gi protein(s), the basic secretagogues of mast cells stimulate multiple signaling pathways, which diverge to regulate the production and release of the different inflammatory mediators. Whereas the signaling pathway responsible for triggering histamine release is PTK independent, the pathway responsible for the stimulation of AA release bifurcates downstream to PTKs but upstream to the activation of MAPKs.
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PMID:Gi-mediated activation of mitogen-activated protein kinase (MAPK) pathway by receptor mimetic basic secretagogues of connective tissue-type mast cells: bifurcation of arachidonic acid-induced release upstream of MAPK. 1033 65

The kinase insert domain-containing receptor (KDR) is the human vascular endothelial growth factor (VEGF) receptor responsible for the mitogenic and angiogenic effects of VEGF. There is much experimental evidence to suggest that the VEGF/KDR pathway plays an important role in tumor angiogenesis, a process essential for tumor growth and metastasis. Here we produced a chimeric anti-KDR antibody (IgG1), c-p1C11, from a single chain (scFv) antibody isolated from a phage display library. C-p1C11 binds specifically to the extracellular domain of soluble as well as cell-surface expressed KDR. It effectively blocks VEGF-KDR interaction and inhibits VEGF-stimulated activation of KDR and MAP kinases p44/p42 of human endothelial cells. Furthermore, c-p1C11 efficiently neutralizes VEGF-induced mitogenesis of human endothelial cells. Our results suggest that antibodies against KDR have potential clinical applications in the treatment of cancer and other diseases where pathological angiogenesis is involved.
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PMID:Inhibition of vascular endothelial growth factor induced mitogenesis of human endothelial cells by a chimeric anti-kinase insert domain-containing receptor antibody. 1035 50

In addition to important roles in the regulation of cell growth and cell restitution, both pro- and anti-inflammatory effects have been ascribed to TGFbeta in intestinal epithelial cells. However, the mechanisms involved in TGFbeta-dependent anti-inflammatory activities remain to be determined. In the rat intestinal epithelial cell line IEC-6, TGFbeta attenuated the glucocorticoid-dependent increases in mRNA levels of the acute phase protein gene haptoglobin, and of C/EBP isoforms beta and delta. Supershift assays demonstrated a TGFbeta-mediated decrease in the binding of C/EBP isoforms beta and delta to the haptoA and haptoC C/EBP DNA-binding sites from the haptoglobin promoter. Mutations of both HaptoA and HaptoC sites abolished the glucocorticoid-dependent activation and the TGFbeta-mediated attenuation of the haptoglobin promoter, as assessed by transient transfection assays. TGFbeta induced p42/p44 MAP kinase activities. Treatment with the MEK 1/2 inhibitor PD 98059 abolished TGFbeta attenuation. These results suggest that C/EBP isoforms are involved both in the glucocorticoid-dependent induction and in the TGFbeta-mediated attenuation of haptoglobin expression. Furthermore, p42/p44 MAP kinases may function in a TGFbeta-dependent signaling pathway leading to attenuation of haptoglobin expression.
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PMID:Attenuation of haptoglobin gene expression by TGFbeta requires the MAP kinase pathway. 1036 55

The implication of MAP kinases in the proliferation control of pancreatic cancer cells is still unknown. This study was undertaken to examine the contribution of the p44/p42 and p38 MAP kinases in the mitogenic response to epidermal growth factor (EGF) and bombesin in human pancreatic cancer cells, MIA PaCa-2 and PANC-1. Data indicate that EGF and bombesin stimulated growth of both cell lines. In MIA PaCa-2 cells, EGF and bombesin stimulated the in gel activation of p38 while p44/p42 kinases exhibited high basal activity and no response to stimuli. Growth and p38 activation were inhibited by genistein, wortmannin, PD98059 and SB203580, specific inhibitors of tyrosine kinase, phosphatidylinositol 3-kinase, MEK-1 and p38 kinases, respectively. In PANC-1 cells, EGF and bombesin stimulated p42 in gel activation; p44 remained highly activated and unresponsive to stimuli and p38 did not respond. Stimulated growth and p42 activation were inhibited by genistein, wortmannin and PD98059. Estimation of MAPK activities with a specific anti-active MAP kinase antibody indicated, however, that EGF increased the intensity of the bands corresponding to p42 and p44 MAP kinases in both cell lines, indicating that the mitogenic factor can regulate MAP kinase activity. Data also pointed out that ATP is sufficient to increase MAP kinase activity within the in gel assay technique and may thus explain the discrepancies existing between the in gel assay data and those obtained with the anti-active MAP kinase antibody.
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PMID:Activation of MAP kinases in growth responsive pancreatic cancer cells. 1043 20

The transcriptional coactivator CBP displays an intrinsic histone acetyl transferase (HAT) activity which seems to participate in transcriptional activation through the destabilization of nucleosome structure. CBP is involved in the activity of several transcription factors that are nuclear endpoints of intracellular signal transduction pathways. In some instances, the transcription factors are phosphorylated upon cell activation, which induces their interaction with CBP. CBP itself is a phosphoprotein and can be phosphorylated by cycle-dependent kinases or by MAP kinases. Here we show that CBP phosphorylation by p44 MAP kinase/ERK1 results in the stimulation of its HAT enzymatic activity. The p44 MAP kinase/ERK1 phosphorylation sites are located in the C-terminal part of the protein, outside of the HAT domain. These sites are required for enzymatic stimulation, suggesting that phosphorylation by p44 MAP kinase/ERK1 induces a conformational change of the CBP molecule. Our data suggest that, in some instances, CBP itself might be a target for signal transduction pathways.
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PMID:Phosphorylation by p44 MAP Kinase/ERK1 stimulates CBP histone acetyl transferase activity in vitro. 1044 85

Interleukin 1 (IL-1) activates p42/p44 and p38 mitogen-activated protein kinases (MAP kinases) in target cells. Here we have used two specific inhibitors, PD98059 which inhibits MAP kinase kinase (MEK), and SB203580 which inhibits p38 MAP kinase to explore the involvement of these kinases in the induction of IL-2 by IL-1 in the murine thymoma cell line EL4.NOB-1. Both kinase inhibitors suppressed IL-1-stimulated IL-2 production. PD98059 blocked IL-2 mRNA accumulation and the induction of a reporter gene linked to the IL-2 promoter. In contrast, SB203580 only marginally inhibited IL-2 promoter-linked reporter gene expression and had no inhibitory effect on IL-2 mRNA levels. Neither PD98059 nor SB203580 had an inhibitory effect on NFkappaB-driven reporter gene expression in response to IL-1. Surprisingly, higher concentrations of SB203580 (30 microM) potentiated the IL-1 responses. PD98059 also inhibited induction of IL-2 by phorbol 12-myristate 13-acetate (PMA), and AP1-linked reporter gene expression in response to PMA but not IL-1. These results indicate that p42/p44 MAP kinase is involved in the regulation of IL-2 gene transcription by IL-1, whilst p38 MAP kinase has a post-transcriptional target. Additional IL-1 signalling pathways can clearly compensate for the lack of p38 MAP kinase which result in potentiation of the IL-1 responses observed at high-dose SB203580.
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PMID:Distinct roles for p42/p44 and p38 mitogen-activated protein kinases in the induction of IL-2 by IL-1. 1047

Intracellular distribution of p42/p44 MAP-kinases in HER14 and A431 cell lines was investigated. Using subcellular fractionation and immunofluorescence approaches we have shown that in quiescent cells of both types MAP-kinases are associated with endoplasmic reticulum. Moreover, ER-localized MAP-kinases were shown to exist only in a nonphosphorylated form. In HER14 cells the epidermal growth factor (EGF) elevates the level of the ER-associated MAP-kinases. In contrast, exposure of A431 cells to EGF leads to a significant decrease in the observed association. The physiological role of this association is discussed.
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PMID:[Association of MAP kinases with the endoplasmic reticulum in NIH3T3 (HER14) and A431 cells]. 1049 11

The presence of protein in the urine of patients with renal disease is an adverse prognostic feature. It has therefore been suggested that proteinuria per se may be responsible for the development of renal tubulo-interstitial scarring and fibrosis, and disturbances in tubular cell growth and proliferation. We have used the opossum kidney proximal tubular cell line to investigate the effects of albumin on cell growth. The effect of albumin on cell proliferation was investigated by cell counting and measurement of [(3)H]thymidine incorporation. We studied the effect of recombinant human albumin on the activity of p44/p42 extracellular-signal-regulated mitogen-activated protein kinase (MAP kinase ) using an in vitro kinase assay, and immunoblotting with antibodies against active extracellular-signal-regulated kinase (ERK). The effects of the ERK inhibitor PD98059 were also examined. Recombinant human albumin was found to stimulate proliferation of opossum kidney cells in a dose-dependent manner, with maximal stimulation at a concentration of 1 mg/ml. In addition, recombinant human albumin activated ERK in a time-dependent (maximal after 5 min) and dose-dependent (maximal at 1 mg/ml) fashion. These effects on cell proliferation and ERK activity were inhibited by PD98059, and were not reproduced by ovalbumin or mannitol. The data therefore indicate that albumin is able to stimulate growth and proliferation of proximal tubular cells that is dependent on the ERK family of MAP kinases. The potential importance of this pathway in the development of renal disease is discussed.
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PMID:Albumin stimulates p44/p42 extracellular-signal-regulated mitogen-activated protein kinase in opossum kidney proximal tubular cells. 1067 88


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