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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Signals transmitted from mesenchyme to epithelia or vice versa constitute the basis of reciprocal epithelial-mesenchymal interactions. As a first step toward understanding epithelial-mesenchymal interactions on the ocular surface where the transit amplifying cell-containing corneal epithelium is anatomically separated from the stem cell-containing limbal epithelium, we sought to characterize the expression patterns of cytokines and their receptors by primary epithelial and early-passaged fibroblast cultures of human cornea and limbus. Northern hybridization with oligonucleotide and cDNA probes to a total of 25 cytokines and 12 of their receptors revealed that the positively expressed cytokines could be divided into the following four patterns. Type I: TGF-alpha, IL-1 beta, and PDGF-B were expressed exclusively by epithelial cells but their respective receptors EGFR and IL-1R were predominantly and PDGFR-beta was exclusively expressed by fibroblasts. Type II: IGF-I, TGF-beta 1, -beta 2, LIF, and bFGF, and their receptors were expressed by both epithelial cells and fibroblasts. FGFR-1 (flg) and FGFR-2 (bek) were expressed more by fibroblasts and bFGF was expressed more by corneal than limbal epithelial cells. Type III: keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF) were expressed exclusively by fibroblasts and their respective receptors, KGFR and c-met, were predominantly expressed by epithelial cells. Combined with RT-PCR, the quantity of KGF and KGFR transcripts was highest in limbal fibroblasts and epithelial cells, respectively. In contrast, the quantity of HGF and HGFR (c-met) transcripts was highest in corneal fibroblasts and epithelial cells, respectively. Type IV: M-CSF and IL-8 were expressed by fibroblasts and/or epithelial cells but their receptors were not expressed by epithelial cells nor fibroblasts, but by immune or inflammatory cells. In addition to these potential paracrine actions, autocrine actions mediated by TGF-alpha/EGFR, IL-1 beta/IL1-R, and bFGF/FGFR-1 were more expressed by corneal than limbal epithelial cells. Immunofluorescence staining on human corneoscleral cryosections confirmed that EGFR and bFGF were not expressed by the limbal basal epithelium, but expressed strongly by the corneal epithelium, a pattern consistent with Northern hybridization. These results indicate that ocular surface epithelial cells and fibroblasts can express a myriad of cytokines, among which the first three patterns constitute the network of potential epithelial-mesenchymal cytokine dialogues. The difference of certain cytokine expression between corneal and limbal regions suggests that this network participates in normal epithelial growth and differentiation, and plays an important role in wound healing.
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PMID:Three patterns of cytokine expression potentially involved in epithelial-fibroblast interactions of human ocular surface. 789 1

EGF receptors are expressed on most fetal and adult cells but their precise roles are not well known. We previously reported that, in P19 embryonal carcinoma cells, the expression of kinase-negative EGFR inhibits retinoic acid (RA)-induced differentiation to nervous tissue, suggesting that EGFR plays a role in differentiation (J.-X. Wu and E. D. Adamson (1993) Dev. Biol. 159, 208-222). Embryo stem (ES) cells differentiate into a wide range of tissue types after the removal of the cytokine LIF from the culture medium. We demonstrate here that the induction of some early markers of differentiation, tissue-type plasminogen activator (tPA), AFP and keratins 8 and 19 is inhibited, whilst brachyury and myosin are increased, in clones containing kinase-negative mutant EGFR. After an extended period of differentiation, the cell types present in mutant and control cultures differed. Mutant clones produced frequent cardiac and skeletal muscle as the predominant differentiated cell types in vitro; other cells types were sparse or absent. Teratocarcinomas formed by EGFR-deltakinase-expressing ES cells contained frequent skeletal and cardiac muscle as well as apoptotic nuclei, while normal ES cells produced no detectable muscle and less apoptoses. Since mutant differentiated cultures had slower growth rates and increased levels of cell death, we concluded that: (1) inactive EGFR does not allow some cell types to survive and/or proliferate; (2) tissues that do not require EGFR for their survival, development or function predominate in long-term mutant cultures; (3) EGFR activity is not necessary for cardiac and skeletal muscle or endoderm formation and (4) Impaired survival of EGF-dependent lineages leads to preferential selection of muscle in differentiating ES cells.
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PMID:Kinase-negative mutant epidermal growth factor receptor (EGFR) expression during embryonal stem cell differentiation favours EGFR-independent lineages. 889 44

Different mitogens elicit similar effects on growth and differentiation of skeletal muscle, suggesting that potential overlap exists in the signaling cascades activated by such factors. To investigate this possibility, we examined the status of STAT and ERK proteins in C2C12 myoblasts and myotubes following stimulation with bFGF or LIF. Both STAT1 and STAT3 as well as ERK1 and ERK2 proteins were detectable in extracts of myoblasts. LIF stimulation of myoblasts lead to rapid phosphorylation on tyrosine of STAT3 and of ERKs 1 and 2. Similarly, bFGF stimulation of myoblasts resulted in the tyrosine phosphorylation of STAT3. However, unlike LIF, the bFGF induced tyrosine phosphorylation of STAT3 appeared cyclical, with recurrent peaks of phosphorylation even after prolonged exposure. By contrast, STAT1 remained unphosphorylated in myoblasts treated with bFGF or LIF. In differentiated myotubes, LIF treatment resulted in the tyrosine phosphorylation of both STAT3 and STAT1, but ERK phosphorylation was not detectable, and bFGF treatment did not lead to STAT1 or STAT3 tyrosine phosphorylation. Therefore these observations suggest that disparate mitogens car activate similar downstream effectors in proliferating myoblasts.
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PMID:bFGF and LIF signaling activates STAT3 in proliferating myoblasts. 890 46

We have developed an efficient serum free culture model for cloning human erythroid progenitors. Accordingly, human bone marrow or cord blood CD34+ cells if plated in our serum free medium and stimulated with a mixture of EpO + KL, grow erythroid colonies exclusively. Cells isolated from these cultures express glycophorin-A (GPA-A), are CD33-, IIb/IIIa-, and finally all become hemoglobinized. By employing this system we also found out that cord blood CD34+ mononuclear cells (MNC) contain more BFU-E than adult marrow CD34+ MNC, moreover, the erythroid colonies formed by cord blood progenitors are significantly larger then the ones formed by the marrow cells. We have also compared the influence of different cytokines and growth factors, which were reported in the literature to costimulate BFU-E growth on cloning efficiency of human BFU-E cultured in our serum free medium. We found that from 20 different growth factors and cytokines tested, EpO dependent bone marrow BFU-E growth is costimulated only by KL, and to lesser degree also by IL-3, GM-CSF, TpO and IL-9. In contrast to marrow cells we observed that cord blood BFU-E in addition to KL, IL-3, GM-CSF, TpO, LIF and IL-9 were also costimulated by NGF-beta, FGF-1, FGF-2 and STK-IL. We found simultaneously that TPO which possess only negligible costimulatory effect on erythroid colony formation by bone marrow CD34+ cells, significantly costimulated the formation of erythroid colonies grown by cord blood CD34+ cells. Therefore, the cord blood CD34+ cells are largely committed to erythroid differentiation, and, moreover, they respond to a wider spectrum of the growth factors than their bone marrow counterparts.
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PMID:An improved serum free system for cloning human "pure" erythroid colonies. The role of different growth factors and cytokines on BFU-E formation by the bone marrow and cord blood CD34+ cells. 960 18

The IL-6-related cytokines, LIF and cardiotrophin-1, are important growth promoting and cardioprotective agents for cardiomyocytes. However, factors that regulate their actions in the heart are poorly understood. In this study, we tested the hypothesis that endothelin-1, a peptide hormone that produces a pattern of cardiac hypertrophy distinct from LIF and cardiotrophin-1, modulates LIF-induced signaling in cardiomyocytes. Upon binding LIF or cardiotrophin-1, the LIF receptor alpha subunit (LIFRalpha) dimerizes with gp130, leading to activation of constitutively associated Jak1 proteins and LIFRalpha-gp130 tyrosine phosphorylation. We found that pretreatment of neonatal rat ventricular myocytes with endothelin-1 rapidly inhibited LIF-induced LIFRalpha tyrosine phosphorylation and Jak1 activation. This effect of endothelin-1 on LIFalpha and Jak1 was attenuated by the MEK1 inhibitor, PD98059, implicating involvement of the ERK kinases. Radioligand binding studies showed that inhibition of LIF signaling resulted from a reduction in cell surface LlFRalpha levels. Additionally, endothelin-1 was found to reduce LIF-induced STAT3 activation, as indexed by STAT3 Y705 phosphorylation. Finally, endothelin-1 and LIF were shown to induce opposite patterns of STAT3 activation in cardiomyocytes. LIF induced rapid, robust STAT3 Y705 phosphorylation; endothelin-1 produced a delayed, modest increase, and initially decreased STAT3 Y705 phosphorylation. Overall our findings indicate that endothelin-1 acts to temper IL-6-related cytokine signaling in cardiomyocytes, in particular STAT3 activation.
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PMID:Cytokine G-protein signaling crosstalk in cardiomyocytes: attenuation of Jak-STAT activation by endothelin-1. 1248 70

Oncostatin M (OSM) is a member of the IL-6/LIF (or gp130) cytokine family, and its potential role in inflammation is supported by a number of activities identified in vitro. In this study, we investigate the action of murine OSM on expression of the CC chemokine eotaxin by fibroblasts in vitro and on mouse lung tissue in vivo. Recombinant murine OSM stimulated eotaxin protein production and mRNA levels in the NIH 3T3 fibroblast cell line. IL-6 could regulate a small induction of eotaxin in NIH 3T3 cells, but other IL-6/LIF cytokines (LIF, cardiotrophin-1 (CT-1)) had no effect. Cell signaling studies showed that murine OSM, LIF, IL-6, and CT-1 stimulated the tyrosine phosphorylation of STAT-3, suggesting STAT-3 activation is not sufficient for eotaxin induction in NIH 3T3 cells. OSM induced ERK-1,2 and p38 mitogen-activated protein kinase phosphorylation in NIH 3T3 cells, and inhibitors of ERK (PD98059) or p38 (SB203580) could partially reduce OSM-induced eotaxin production, suggesting partial dependence on mitogen-activated protein kinase signaling. OSM (but not LIF, IL-6, or CT-1) also induced eotaxin release by mouse lung fibroblast cultures derived from C57BL/6 mice. Overexpression of murine OSM in lungs of C57BL/6 mice using an adenovirus vector encoding murine OSM resulted in a vigorous inflammatory response by day 7 after intranasal administration, including marked extracellular matrix accumulation and eosinophil infiltration. Elevated levels of eotaxin mRNA in whole lung were detected at days 4 and 5. These data strongly support a role of OSM in lung inflammatory responses that involve eosinophil infiltration.
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PMID:Oncostatin M regulates eotaxin expression in fibroblasts and eosinophilic inflammation in C57BL/6 mice. 1249 42

The signal pathway mediating induction of p15(INK4b) and p16(INK4a) during HepG2 growth inhibition triggered by the phorbol ester tumor promoter TPA (12-O-tetradecanoylphorbol 13-acetate) and the Chinese herb Saikosaponin a was investigated. Western blot of three activated forms of mitogen-activated protein kinase (MAPK) (p-ERK, p-JNK and p-p38) demonstrated that phosphorylation of ERK is dramatically induced (11.6-fold ) by TPA during 15 min to 1 h and significantly induced (2.5-fold) by Saikosaponin alpha at 30 min, whereas phosphorylation of JNK was induced only by TPA during 30 min to 1 h. Phosphorylation of p38 was not induced by either drug. During this period, phosphorylation of one of the downstream transcriptional factors of MAPK cascade, ATF2, was 3.2- and 2.0-fold induced by TPA and Saikosaponin a, respectively, whereas that of another transcriptional factor, c-jun, was induced by TPA only. On the other hand, expressions of proto-oncogene c-jun, junB and c-fos were induced by TPA and Saikosaponin a during 30 min to 6 h of treatment. Pretreatment of 20 microg/ml PD98059, an inhibitor of MEK which is the upstream kinase of ERK, prevents the TPA- and Saikosaponin a-triggered HepG2 growth inhibition by 50 and 30%, respectively, accompanied by a 50 - 85% decrease of the p15(INK4b)/p16(INK4a) RNAs and proteins induced by both drugs. Inductions of c-fos RNA by both drugs and c-jun phosphorylation by TPA were also significantly reduced by PD98059 pretreatment. In addition, AP-1 DNA-binding assay using nonisotopic capillary electrophoresis and laser-induced fluorescence (CE/LIF) demonstrated that the AP-1-related DNA-binding activity was significantly induced by TPA and Saikosaponin a, which can be reduced by PD98059 pretreatment. These results suggested that activation of ERK together with its downstream transcriptional machinery mediated p15(INK4b) and p16(INK4a) expression that led to HepG2 growth inhibition.
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PMID:ERK signaling pathway is involved in p15INK4b/p16INK4a expression and HepG2 growth inhibition triggered by TPA and Saikosaponin a. 1259 82

The goal of this study was to investigate if a three dimensional matrix, loaded homogeneously with Schwann cells and the neurotrophic factor LIF (leukemia inhibitory factor), enhances regeneration in a biodegradable nerve guidance channel as compared to non-structured cell suspensions. Therefore a 10 mm nerve gap in the buccal branch of the rat's facial nerve was bridged with tubular PCL (poly-epsilon-caprolactone) conduits filled with no matrix, Schwann cells, the three dimensional fibrin/Schwann cell matrix or the fibrin/Schwann cell matrix added with LIF Four weeks after the nerve defects were bridged histological and morphometric analyses of the implants were performed. In conclusion, the three dimensional fibrin/Schwann cells matrix enhanced the quantity and the quality of peripheral nerve regeneration through PCL conduits. The application of LIF prevented hyperneurotization. Therefore, tissue engineered fibrin/Schwann cells matrices are new invented biocompatible and biodegradable devices for enhancing peripheral nerve regeneration as compared to non-structured cell suspensions without neurotrophic factors.
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PMID:Fibrin/Schwann cell matrix in poly-epsilon-caprolactone conduits enhances guided nerve regeneration. 1506 7

The interleukin-6 (IL6) family of cytokines signals through the common receptor subunit gp130, and subsequently activates Stat3, MAPK, and PI3K. Stat3 controls cell death and tissue remodeling in the mouse mammary gland during involution, which is partially induced by IL6 and LIF. However, it is not clear whether Stat3 activation is mediated solely through the gp130 pathway or also through other receptors. This question was explored in mice carrying two distinct mutations in the gp130 gene; one that resulted in the complete ablation of gp130 and one that led to the loss of Stat3 binding sites (gp130Delta/Delta). Deletion of gp130 specifically from mammary epithelium resulted in a complete loss of Stat3 activity and resistance to tissue remodeling comparable to that seen in the absence of Stat3. A less profound delay of mammary tissue remodeling was observed in gp130Delta/Delta mice. Stat3 tyrosine and serine phosphorylation was still detected in these mice suggesting that Stat3 activation could be the result of gp130 interfacing with other receptors. Experiments in primary mammary epithelial cells and transfected COS-7 cells revealed a p44/42 MAPK and EGFR-dependent Stat3 activation. Moreover, the gp130-dependent EGFR activation was independent of EGF ligands, suggesting a cytoplasmic interaction and cross-talk between these two receptors. These experiments establish that two distinct Stat3 signaling pathways emanating from gp130 are utilized in mammary tissue.
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PMID:Mammary gland remodeling depends on gp130 signaling through Stat3 and MAPK. 1529 6

The standard method for isolation of ES cells from strain 129 mice does not give rise to ES lines of CBA origin. We investigated the effect of inhibition of MEK/ERK signaling in combination with increased stimulation of gp130 signaling on derivation of ES cells from CBA blastocysts. Inhibition of MEKI and MEKII using the drug U0126 and stimulation of gp130 signaling by elevating the level of LIF present gave rise to ES-like lines in 22.6% of explants. No lines arose when MEK was inhibited in the absence of additional LIF stimulation, nor when additional LIF stimulation occurred in the absence of MEK inhibition. Typically for ES cell lines, CBA-derived cells contributed to chimeric mice and differentiated broadly in vitro. Increased levels of gp130 signaling led to similar levels of STAT3 activation in strain 129 and CBA ES cells. We conclude that CBA ES cells have a requirement for additional STAT3 activation.
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PMID:Increased gp130 signaling in combination with inhibition of the MEK/ERK pathway facilitates embryonic stem cell isolation from normally refractory murine CBA blastocysts. 1599 12


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