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)

This study assessed if oxidative stress induced by treatment of PC12 cells with H2O2 modulated signaling cascades induced by nerve growth factor (NGF) or epidermal growth factor (EGF) because oxidative stress and impaired growth factor function are associated with aging and aging-associated diseases such as Alzheimer's disease. Phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK 1/2) and of p38 kinase was rapidly increased after treatment with NGF, EGF, or H2O2, with NGF causing more prolonged increases than the other agents. Pretreatment with H2O2 did not alter phosphorylation of ERK1/2 induced by either growth factor, but increased the phosphorylation of p38 kinase induced by treatment with NGF or EGF alone. CREB phosphorylation at SER 133 was rapidly increased by treatment with either NGF or EGF. Pretreatment with H2O2 reduced CREB phosphorylation induced by either growth factor. This seemed to be a direct effect because H2O2 also inhibited CREB phosphorylation induced by the adenylyl cyclase stimulator forskolin. These results demonstrate that oxidative stress can differentially modulate growth factor-initiated signaling cascades. Furthermore, because CREB is an evolutionarily preserved protein involved in the formation of long term memory, these results indicate a new target of oxidative stress that may be important in disorders involving impaired memory, such as Alzheimer's disease.
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PMID:Oxidative stress differentially modulates phosphorylation of ERK, p38 and CREB induced by NGF or EGF in PC12 cells. 1058 74

The docking protein FRS2 was implicated in the transmission of extracellular signals from the fibroblast growth factor (FGF) or nerve growth factor (NGF) receptors to the Ras/mitogen-activated protein kinase signaling cascade. The two members of the FRS2 family, FRS2alpha and FRS2beta, are structurally very similar. Each is composed of an N-terminal myristylation signal, a phosphotyrosine-binding (PTB) domain, and a C-terminal tail containing multiple binding sites for the SH2 domains of the adapter protein Grb2 and the protein tyrosine phosphatase Shp2. Here we show that the PTB domains of both the alpha and beta isoforms of FRS2 bind directly to the FGF or NGF receptors. The PTB domains of the FRS2 proteins bind to a highly conserved sequence in the juxtamembrane region of FGFR1. While FGFR1 interacts with FRS2 constitutively, independent of ligand stimulation and tyrosine phosphorylation, NGF receptor (TrkA) binding to FRS2 is strongly dependent on receptor activation. Complex formation with TrkA is dependent on phosphorylation of Y490, a canonical PTB domain binding site that also functions as a binding site for Shc (NPXpY). Using deletion and alanine scanning mutagenesis as well as peptide competition assays, we demonstrate that the PTB domains of the FRS2 proteins specifically recognize two different primary structures in two different receptors in a phosphorylation-dependent or -independent manner. In addition, NGF-induced tyrosine phosphorylation of FRS2alpha is diminished in cells that overexpress a kinase-inactive mutant of FGFR1. This experiment suggests that FGFR1 may regulate signaling via NGF receptors by sequestering a common key element which both receptors utilize for transmitting their signals. The multiple interactions mediated by FRS2 appear to play an important role in target selection and in defining the specificity of several families of receptor tyrosine kinases.
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PMID:FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors. 1062 55

Pheochromocytomas are rare tumours, with an incidence of 1-2 per million which arise from chromaffin cells of the adrenal medulla. They occur sporadically or as part of dominantly inherited cancer syndromes like multiple endocrine neoplasia 2 (MEN2A and 2B) and others. Continuous cell lines, not available so far, are essential tools for studies in these tumours. A continuous cell line (KNA) was established from a sporadic pheochromocytoma of the right adrenal gland of a 73-year-old woman. The KNA cells grow as suspensions of spheroids and show the morphological and immunocytochemical characteristics of neuronal chromaffin cells, such as neuroendocrine granules, and positive reactions to chromogranin- and related peptide-, neuron specific enolase and vasoactive intestinal peptide antibodies. Neurite-like processes are formed after addition of nerve growth factor. Chromosomal analyses revealed a diploid (46,XX,n = 50) to hypodiploid (43-45,XX,n = 15) karyotype. In hypodiploid metaphases most frequently #19, #17, #21 and #22 were missing. Chromosome arms 1p and 4q showed apparently consistent interstitial deletions: 6q, 8q, 13q and 22q showed clonal interstitial deletions. The cell line shows a heterozygous sequence variant TGC (cysteine) to TGG (tryptophan) in codon 611 in exon 10 of the RET proto-oncogene. So far, PC-12, a rat adrenal pheochromocytoma, has been the only continuous pheochromocytoma cell line available. KNA represents the first report on a human continuous pheochromocytoma cell line, the first report of structural chromosome aberrations in pheochromocytomas and the first report of a RET mutation TGC to TGG in exon 10 of the RET proto-oncogene in a sporadic pheochromocytoma.
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PMID:First continuous human pheochromocytoma cell line: KNA. Biological, cytogenetic and molecular characterization of KNA cells. 1064 Jan 77

A rat pheochromocytoma cell line (PC12) transfected with ganglioside GD3 synthase gene showed a marked change in the ganglioside profile and enhanced proliferation and no response of neurite extension to nerve growth factor (NGF) stimulation. In these transfectant cells, a continuous phosphorylation of TrkA and the activation of ERK1/2 without NGF treatment were observed. Proliferation inhibition experiments with kinase inhibitors such as herbimycin A, K-252a, and PD98059 revealed that the enhanced proliferation was actually due to the activation of the Ras/MEK/ERK pathway. A TrkA dimer was detected in the GD3 synthase transfectant cells regardless of NGF treatment by cross-linking and immunoblotting. The increased expression of GD1b and GT1b in these transfectant cells might induce the conformational change of TrkA to form a dimer and to be activated continuously. These results may indicate regulatory roles of gangliosides in cell proliferation under physiological and malignant processes.
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PMID:GD3 synthase gene expression in PC12 cells results in the continuous activation of TrkA and ERK1/2 and enhanced proliferation. 1068 73

Conditioned medium from stimulated microglia and from the monocyte/macrophage cell line (RAW 264.7; MC-CM) promotes the differentiation of cholinergic neurons from undifferentiated progenitors in the septal nuclei and adjacent basal forebrain (BF). We have studied the regulation of this process by measuring the activity of choline acetyltransferase (ChAT) in cultured BF taken from embryonic day 16 rat brain. Inhibition of either xanthine oxidase with allopurinol or nitric oxide synthase with N(G)-monomethyl-l-arginine produces a small but significant improvement in the efficacy of MC-CM while inclusion of pyrrolidine dithiocarbamate, a hydroxyl radical scavenger widely used as an antioxidant, lowers MC-CM-induced ChAT activity. Addition of nerve growth factor (NGF) but not brain-derived neurotrophic factor or glial-derived neurotrophic factor together with MC-CM has a synergistic effect on both ChAT activity and ChAT mRNA, raising ChAT activity as much as 29-fold and ChAT mRNA almost 15-fold. While MC-CM raised mRNA for trkA, the effect was not synergistic with NGF. mRNA for the common neurotrophin receptor (p75NTR) showed a modest synergistic increase. Blockade of the Ras/Raf/ERK [extracellular signal-regulated kinase, also known as mitogen-activated protein [(MAP) kinase] signal transduction pathway with either PD28059 (an inhibitor of MAP kinase/ERK kinase kinase or MEK) or N-acetyl-S-farnesyl-l-cysteine (an inhibitor of Ras farnesylation and, hence, activation) inhibited the action of MC-CM. Moreover, a subpopulation of cells responded rapidly to MC-CM with an increased appearance of phosphorylated ERK. Because NGF also utilizes this pathway, synergy may occur along this signal transduction pathway.
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PMID:Macrophage cell-conditioned medium promotes cholinergic differentiation of undifferentiated progenitors and synergizes with nerve growth factor action in the developing basal forebrain. 1068 94

Ras promotes robust survival of many cell systems by activating the phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway, but little is understood about the survival functions of the Ras/ERK pathway. We have used three different effector-loop mutant forms of Ras, each of which activates a single downstream effector pathway, to dissect their individual contributions to survival of nerve growth factor (NGF)-dependent sympathetic neurons. The PI3-kinase pathway-selective protein Ras(Val-12)Y40C was as powerful as oncogenic Ras(Val-12) in preventing apoptosis induced by NGF deprivation but conferred no protection against apoptosis induced by cytosine arabinoside. Identical results were obtained with transfected Akt. In contrast, the ERK pathway-selective protein Ras(Val-12)T35S had no protective effects on NGF-deprived neurons but was almost as strongly protective as Ras(Val-12) against cytosine arabinoside-induced apoptosis. The protective effects of Ras(Val-12)T35S against cytosine arabinoside were completely abolished by the ERK pathway inhibitor PD98059. Ras(Val-12)E37G, an activator of RalGDS, had no survival effect on either death pathway, similar to RasS17N, the full survival antagonist. Thus, Ras provides two independent survival pathways each of which inhibits a distinct apoptotic mechanism. Our study presents one of the few clear-cut cases where only the Ras/ERK, but not the Ras/PI3K/Akt pathway, plays a dominant survival signaling role.
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PMID:The Ras/phosphatidylinositol 3-kinase and Ras/ERK pathways function as independent survival modules each of which inhibits a distinct apoptotic signaling pathway in sympathetic neurons. 1072 27

The human neuroblastoma cell line SH-SY5Y is a well characterized model for sympathetic neuronal differentiation in vitro. Several differentiation protocols exist, one of which, the addition of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) in the presence of serum, has been thoroughly studied. Wild-type SH-SY5Y cells are unresponsive to nerve growth factor (NGF), but cells transfected with the high-affinity NGF receptor TrkA (SH-SY5Y/TrkA) differentiate in response to NGF. In the present study, we have addressed the existence of a differentiation-specific mode of activation and subcellular distribution of the extracellular signal-regulated kinases ERK1 and ERK2 in SH-SY5Y/wt and SH-SY5Y/TrkA. Both TPA and NGF induced a sustained activation and nuclear accumulation of ERK that was accompanied by transactivation of a serum response element (SRE)-driven reporter and of the c-fos gene. However, activation and nuclear accumulation of ERK were not sufficient to induce neuronal differentiation in SH-SY5Y, as demonstrated by the response to TPA in serum-free cultures. Nuclear accumulation but not activation of ERK was demonstrated to require active protein kinase C (PKC). The effect of specific PKC inhibitors on subcellular distribution of ERK and ERK-dependent transcription suggests a functional role for PKC in the regulation of nuclear ERK activity in SH-SY5Y neuroblastoma cells.
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PMID:Activation and protein kinase C-dependent nuclear accumulation of ERK in differentiating human neuroblastoma cells. 1077 18

To clarify the roles of neurotrophins and their receptors in bone formation, expression of neurotrophins and their receptors (TRK) in a model of mouse fracture healing was investigated. A total of 120 male ICR mice were studied. The right eighth rib of 70 mice was fractured. For sham operation as a control, the right eighth rib of 50 mice was similarly exposed but not fractured. Localization of TRKA, TRKB, and TRKC in a rectangular region of the rib together with surrounding soft tissues was investigated by immunostaining. Localizations of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) at the fracture callus were also investigated by immunostaining, and their mitochondrial RNA (mRNA) expressions were investigated by reverse transcriptase-polymerase chain reaction (RT-PCR). As a result, we observed two types of neurotrophin receptors in the bone forming area: immunostaining by anti-TRKA was observed in almost all bone forming cells, and staining with anti-TRKC was observed in osteoblast-like cells and hypertrophic chondrocytes, but no staining was observed with anti-TRKB. On the other hand, localization of NGF was observed in almost all bone forming cells, localization of BDNF was observed in osteoblast-like cells, and localization of NT-3 was observed in osteoblast-like cells and hypertrophic chondrocytes at the fracture callus. Expression levels of the mRNA of three neurotrophins in the fractured rib were increased during the process of healing, especially those of NGF and NT-3, which peaked at 2 days after the fracture. The level of BDNF mRNA increased gradually over 8 days. These findings show that neurotrophins and their receptors were expressed in bone forming cells, and suggest that they are involved in the regulation of bone formation as an autocrine and paracrine factor in vivo.
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PMID:Expression of neurotrophins and their receptors (TRK) during fracture healing. 1083 35

Differentiation of PC12 cells triggered by nerve growth factor (NGF) is characterized by several well-defined events including induction of a set of neuron-specific genes, gain of membrane excitability, and morphological changes such as neurite outgrowth. Here we report that K252a, a protein kinase inhibitor, converts the proliferation signal of epidermal growth factor (EGF) into the morphological differentiation signal without inducing the sustained activation of ERK and the expression of neurofilament. Major effects of EGF/K252a, found also in the NGF-treated cells, are the sustained mobility shift of paxillin in SDS-PAGE and the promoted association of Crk-II with paxillin. These effects explain the prominent and robust development of peripheral focal adhesion assembly and stress fiber-like structures observed in the early stages of PC12 cell differentiation. These results suggest a model that cytoskeletal reorganization via focal adhesion assembly triggered by NGF provides a signal required for the morphological differentiation of PC12 cells.
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PMID:Sustained formation of focal adhesions with paxillin in morphological differentiation of PC12 cells. 1085 Jun 58

Oncogenic variants of the receptor tyrosine kinase, Ret, cause formation of tumors of neuroendocrine derivation in the multiple endocrine neoplasia type 2 and, thus, likely interfere with antiproliferative and/or differentiative extracellular signals. Here we took advantage of two rat pheochromocytoma-derived cell lines (PC12/MEN2A and PC12/MEN2B) to investigate whether Ret-induced nerve growth factor (NGF) unresponsiveness might involve impairment of ERK signaling. In fact, these cells, stably transfected with distinct forms of the active ret oncogene, fail to block proliferation, even upon NGF stimulation. In these cells we show the presence of both chronic ERKs activity and high expression levels of MKP-3, an ERK-specific phosphatase. Despite the presence of MKP-3, ERK activity can be further stimulated by NGF, but it fails to translocate into the nucleus and consequently to induce immediate-early gene transcription. Because of the presence of MKP-3, our results suggest the existence of a negative regulatory feedback acting on ERKs as a mechanism responsible for the abrogation of NGF-induced terminal differentiation. Indeed, MKP-3 seems to be implicated in the persistence of ERKs in cell cytoplasm. This interpretation is further supported by the observation that in ret-transfected cells, forced expression of an active form of MEK-1 may overcome this block; it restores transcription from the c-fos promoter, induces translocation of ERKs into the nucleus, and inhibits cell proliferation.
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PMID:Abrogation of nerve growth factor-induced terminal differentiation by ret oncogene involves perturbation of nuclear translocation of ERK. 1085 59


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