Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thanatophoric dysplasia (TD) is a lethal skeletal disorder caused by recurrent mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene. The mitogenic response of fetal TD I chondrocytes in primary cultures upon stimulation by either FGF 2 or FGF 9 did not significantly differ from controls. Although the levels of FGFR 3 mRNAs in cultured TD chondrocytes were similar to controls, an abundant immunoreactive material was observed at the perinuclear level using an anti-FGFR 3 antibody in TD cells. Transduction signaling via the mitogen-activated protein kinase pathway was assessed by measuring extracellular signal-regulated kinase activity (ERK 1 and ERK 2). Early ERKs activation following FGF 9 supplementation was observed in TD chondrocytes (2 min) as compared with controls (5 min) but no signal was detected in the absence of ligand. By contrast ligand-independent activation of the STAT signaling pathway was demonstrated in cultured TD cells and confirmed by immunodetection of Stat 1 in the nuclei of hypertrophic TD chondrocytes. Moreover, the presence of an increased number of apoptotic chondrocytes in TD fetuses was associated with a higher expression of Bax and the simultaneous decrease of Bcl-2 levels. Taken together, these results indicate that FGFR 3 mutations in TD I fetuses do not hamper chondrocyte proliferation but rather alter their differentiation by triggering premature apoptosis through activation of the STAT signaling pathway.
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PMID:Fibroblast growth factor receptor 3 mutations promote apoptosis but do not alter chondrocyte proliferation in thanatophoric dysplasia. 958 36

Interleukin-1beta (IL-1beta) is cytotoxic to rat pancreatic beta-cells by inhibiting glucose oxidation, causing DNA damage and inducing apoptosis. Nitric oxide (NO) is a necessary but not sufficient mediator of these effects. IL-1beta induced kinase activity toward Elk-1, activation transcription factor 2, c-Jun, and heat shock protein 25 in rat islets. By Western blotting with phosphospecific antibodies and by immunocomplex kinase assay, IL-1beta was shown to activate extracellular signal-regulated kinase (ERK) 1/2 and p38 mitogen-activated protein kinase (p38) in islets and rat insulinoma cells. Specific ERK1/2 and p38 inhibitors individually reduced but in combination blocked IL-1beta-mediated islet NO synthesis, and reverse transcription-polymerase chain reaction of inducible NO synthase mRNA showed that ERK1/2 and p38 controlled IL-1beta-induced islet inducible NO synthase expression at the transcriptional level. Hyperosmolarity caused phosphorylation of Elk-1, activation transcription factor 2, and heat shock protein 25 and activation of ERK1/2 and p38 in islets comparable to that induced by IL-1beta but did not lead to NO synthesis. Inhibition of p38 but not of ERK1/2 attenuated IL-1beta-mediated inhibition of glucose-stimulated insulin release. We conclude that ERK1/2 and p38 activation is necessary but not sufficient for IL-1beta-mediated beta-cell NO synthesis and that p38 is involved in signaling of NO-independent effects of IL-1beta in beta-cells.
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PMID:Interleukin-1beta-induced rat pancreatic islet nitric oxide synthesis requires both the p38 and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases. 961 46

The RBCK1 protein was recently identified as a protein kinase C-interacting protein with a new type of RBCC (RING-B-Box-Coiled-coil) region, possessing both DNA-binding and transcriptional activities unlike other proteins in the RBCC protein family (Tokunaga et al. Biochem. Biophys. Res. Commun. 244, 353-359, 1998). To identify protein motifs in the RBCC region of RBCK1 essential for the transcriptional activity, RBCK1 mutant proteins have been constructed and analyzed by using the GAL4 chimeric transcription regulator system. We have found that both of the RING-finger and the B-Box motifs are indispensable for the transcriptional activity of RBCK1. This is the first observation that these protein motifs of the RBCC protein family play a crucial role in transcriptional activation. In addition, we have examined the effect of co-expression of several protein kinases on the transcriptional activity of RBCK1. Protein kinase A (PKA) was found to enhance the activity by about eightfold, whereas both ERK (extracellular signal-regulated kinase) activator kinase 1 (MEK1) and MEK kinase 1 (MEKK1) significantly repressed the activity. Because RBCC proteins are presumed to act as a proto-oncoprotein, these results suggest that the RBCK1 protein is involved in the intracellular signaling cascades along with PKA, MEK1, and MEKK1 and mediates cell growth and differentiation.
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PMID:Transcriptional activity of RBCK1 protein (RBCC protein interacting with PKC 1): requirement of RING-finger and B-Box motifs and regulation by protein kinases. 964 38

In this study, we investigated the activation of p42 extracellular signal-regulated kinase (ERK2) during renal regeneration after HgCl2-induced acute renal failure (ARF) in rat. ERK2 activation was observed at 5 and 29 hr after HgCl2 injection, respectively. The tyrosine phosphorylation of hepatocyte growth factor receptor (c-MET) occurred between 2.5 and 5 hr after the treatment. On the other hand, the phosphorylation of epidermal growth factor receptor (EGFR) was transiently observed at 29 hr after the injection. The peak of ornithine decarboxylase activity as a marker of G1 phase was at 10 hr, and subsequently the labeling index of proliferating cell nuclear antigen as a marker of S phase increased at 53 hr. These results indicate that the repetitive activation of ERK2 related to the phosphorylation of c-MET and EGFR is required for the renal regeneration in HgCl2-induced ARF of rat.
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PMID:The repetitive activation of extracellular signal-regulated kinase is required for renal regeneration in rat. 965 Nov 23

Granulocyte-macrophage colony-stimulating factor (GM-CSF) regulates differentiation, survival, and proliferation of myeloid progenitor cells. The biologic actions of GM-CSF are mediated by its binding to the alpha and beta subunits of the GM-CSF receptor (GM-CSFRalpha and betac, respectively). To determine whether identical regions of the betac protein mediate both cell growth and differentiation, we expressed cDNA constructs encoding the human wild-type (897 amino acids) and truncated betac (hbetac) subunits along with the wild-type human GM-CSFRalpha subunit in the murine WT19 cell line, an FDC-P1-derived cell line that differentiates toward the monocytic lineage in response to murine GM-CSF. Whereas the WT19 cell line carrying the C-terminal deleted hbetac subunit of 627 amino acids was still able to grow in human GM-CSF (hGM-CSF), 681 amino acids of the hbetac were necessary for cell differentiation. The addition of hGM-CSF to WT19 cell lines containing the hbetac627 subunit stimulated the phosphorylation of ERK (extracellular signal-regulated kinase) and induced the tyrosine-phosphorylation of SHP-2 and STAT5, suggesting that the activation of these molecules is insufficient to mediate the induction of differentiation. A point mutation of tyrosine 628 to phenylalanine (Y628F) within hbetac681 abolished the ability of hGM-CSF to induce differentiation. Our results indicate that the signals required for hGM-CSF-induced differentiation and cell growth are mediated by different regions of the hbetac subunit.
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PMID:Cytoplasmic domains of the human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor beta chain (hbetac) responsible for human GM-CSF-induced myeloid cell differentiation. 967 59

MEK1 and MEK2 contain a proline-rich insert not present in any other known MEK (MAP (mitogen-activated protein)/ERK (extracellular signal-regulated kinase) kinase) family members. We examined the effect of removing the MEK1 polyproline insert on MEK activity, its binding to Raf, and its ability to activate ERKs in cells. Deletion of the insert had no effect on either the activity of MEK1 or on its ability to bind to Raf-1. Both wild type and constitutively active MEK1 coimmunoprecipitated with Raf-1 whether or not the insert was present. Deletion of the insert did not reduce activation of MEK1 by EGF or activated Raf in cells. The proline-rich insert enhanced the ability of an otherwise equally active MEK1 protein to regulate endogenous ERKs in mammalian cells. Overexpression of either constitutively active MEK1 lacking the insert or ERK2 compensates for the weaker in vivo activity of the MEK1 deletion mutant. Expression of the insert in cells reduced activation of ERKs by EGF. We conclude that the proline-rich insert is not the site of the MEK-Raf interaction and that the polyproline insert is required for its efficient activation of downstream ERKs in cells.
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PMID:The MEK1 proline-rich insert is required for efficient activation of the mitogen-activated protein kinases ERK1 and ERK2 in mammalian cells. 967 29

Raf kinases are regulators of cellular proliferation, transformation, differentiation, and apoptosis. To identify downstream targets of Raf-1 in vivo, we used NIH 3T3 fibroblasts expressing a Raf-1 kinase domain-estrogen receptor fusion protein (BXB-ER), whose activity can be acutely regulated by estrogen. Proteins differentially phosphorylated 20 min after BXB-ER activation in living cells were displayed by two-dimensional electrophoresis. The protein with the most prominent newly induced phosphorylation was identified as stathmin, a phosphorylation-sensitive regulator of microtubule dynamics. Stathmin is rapidly phosphorylated on two ERK phosphorylation sites (serines 25 and 38) upon BXB-ER activation. The mitogen-activated protein kinase/extracellular signal-regulated kinase-kinase (MEK) inhibitor PD98059 abolished this phosphorylation, demonstrating that stathmin is targeted by BXB-ER via the MEK/ERK pathway. Prolonged BXB-ER activation resulted in the accumulation of a stathmin phosphoisomer with impaired microtubule-destabilizing activity. The appearance of this phosphoisomer after BXB-ER activation correlated with rearrangements in the microtubule network, resulting in the formation of long bundled microtubules extending toward the rim of the cells. Our results identify stathmin as a main target of the Raf/MEK/ERK kinase cascade in vivo and strongly suggest that ERK-mediated stathmin phosphorylation plays an important role for the microtubule reorganization induced by acute activation of Raf-1.
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PMID:Activated raf induces the hyperphosphorylation of stathmin and the reorganization of the microtubule network. 971 20

1. The mechanisms of the antiproliferative effect of epigallocatechin, one of the catechin derivatives found in green tea, in vascular smooth muscle cells were studied. The proliferative response was determined from the uptake of tritiated thymidine. 2. In the concentration range of 10(-6) to 10(-4) M, catechin, epicatechin, epigallocatechin, epicatechin gallate and epigallocatechin, epigallocatechin gallate, concentration-dependently inhibited the proliferative response stimulated by serum in rabbit cultured vascular smooth muscle cells. Catechin and epicatechin were less effective in inhibiting the serum-stimulated smooth muscle cell proliferation, indicating that the galloyl group may be important for full inhibitory activity. 3. Epigallocatechin (EGC) inhibited the proliferative responses in different cells including rat aortic smooth muscle cells (A7r5 cells), rabbit cultured aortic smooth muscle cells, human coronary artery smooth muscle cells, and human CEM lymphocytes in a concentration-dependent manner. The possible mechanisms of the antiproliferative effect of EGC were further studied in A7r5 cells. 4. The membranous protein tyrosine kinase activity stimulated by serum in A7r5 cells was significantly reduced by 10(-5) M EGC. In contrast, the cytosolic protein kinase C activity stimulated by phorbol ester was unaffected by directly incubating with EGC (10(-6)-10(-4) M). 5. We also performed Western blot analysis using the anti-phosphotyrosine monoclonal antibody PY20. EGC (10(-5) M) reduced the levels of tyrosine phosphorylated proteins with different molecular weights, indicating that EGC may inhibit the protein tyrosine kinase activity or stimulate the protein phosphatase activity. 6. Reverse transcription-polymerase chain reaction analysis of c-fos, c-jun and c-myc mRNA levels demonstrated that c-jun mRNA level after serum-stimulation was significantly reduced by 10(-5) M EGC. However, the reduction of c-fos and c-myc mRNA levels by 10(-5) M EGC did not achieve significance. 7. Western blot analysis using the antibody against JNK (c-jun N-terminal kinase) and ERK (extracellular signal-regulated kinase) demonstrated that the level of phosphorylated JNK1, but not phosphorylated ERK1 and ERK2, was reduced by 10(-5) M EGC. Direct measurement of kinase activity by immune complex kinase assay confirmed that JNK1 activity was inhibited by EGC treatment. These results demonstrate that EGC preferentially reduced the activation of JNK/SAPK (stress-activated protein kinase) signal transduction pathway. 8. It is suggested that the antiproliferative effect of epigallocatechin on vascular smooth muscle cells may partly be mediated through inhibition of protein tyrosine kinase activity, reducing c-jun mRNA expression and inhibiting JNK1 activation. Tea catechins may be useful as a template for the development of drugs to prevent the pathological changes of atherosclerosis and post-angioplasty restenosis.
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PMID:Epigallocatechin suppression of proliferation of vascular smooth muscle cells: correlation with c-jun and JNK. 972 Jul 95

D-type cyclins are induced in response to mitogens and are essential and rate-limiting for G1 phase progression in normal mammalian cells. Macrophages proliferating in response to colony-stimulating factor-1 (CSF-1) express cyclin D1 and to a lesser extent cyclin D2 but not cyclin D3. Previously we showed that the macrophage-activating agent lipopolysaccharide (LPS) blocks CSF-1-induced proliferation and cyclin D1 expression in macrophages. Here we report upon the effect of LPS on expression of cyclin D2 in normal mouse bone marrow-derived macrophages (BMM). Unexpectedly we found that this anti-mitogen raised levels of CSF-1-stimulated cyclin D2 mRNA and protein. Furthermore, LPS alone induced cyclin D2 but not cyclin D1. Inhibition of the MEK/ERK (MAPK/ERK kinase/extracellular signal-regulated kinase) mitogen-activated protein kinase pathway repressed LPS-induced cyclin D2 mRNA, whereas inhibition of the p38 mitogen-activated protein kinase enhanced expression. However, in contrast to cyclin D1, cyclin D2 in bone marrow-derived macrophages did not appear to be regulated by protein kinase A pathways. The present data (a) show elevation of a D-type cyclin in the absence of proliferation, (b) demonstrate inverse regulation of two distinct D-type cyclins under identical conditions, and (c) suggest that cyclin D2 plays a role in macrophage activation by LPS.
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PMID:Proliferation-independent induction of macrophage cyclin D2, and repression of cyclin D1, by lipopolysaccharide. 972 38

Signal transduction is controlled both by regulation of enzyme activation and by organization of enzymatic complexes with nonenzymatic adapters, scaffolds, and anchor proteins. The extracellular signal-regulated kinase (ERK) cascade is one of several evolutionarily conserved mitogen-activated protein (MAP) kinase cascades important in the regulation of growth, apoptosis, and differentiation. A two-hybrid screen was conducted to identify nonenzymatic components of this signaling cascade that might be important in regulating its activity. A protein called MP1 (MEK Partner 1) was identified that bound specifically to MEK1 and ERK1 and facilitated their activation. When overexpressed in cultured cells, MP1 enhanced activation of ERK1 and activation of a reporter driven by the transcription factor Elk-1. Expression of MP1 in cells increased binding of ERK1 to MEK1. MP1 apparently functions as an adapter to enhance the efficiency of the MAP kinase cascade.
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PMID:MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. 976 29


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