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)

Several cytogenetic alterations affect the distal part of the long arm of human chromosome 15, including recurrent rearrangements between 12p13 and 15q25, which cause congenital fibrosarcoma (CFS). We present here the construction of a BAC/PAC contig map that spans 2 Mb from the neurotrophin-3 receptor (NTRK3) gene region on 15q25.3 to the proximal end of the Bloom's syndrome region on 15q26.1, and the identification of a set of new chromosome 15 duplicons. The contig reveals the existence of several regions of sequence similarity with other chromosomes (6q, 7p, and 12p) and with other 15q cytogenetic bands (15q11-q13 and 15q24). One region of similarity maps on 15q11-q13, close to the Prader-Willi/Angelman syndromes (PWS/AS) imprinting center. The 12p similar sequence maps on 12p13, at a distance to the ets variant 6 (ETV6) gene that is equivalent on 15q26.1 to the distance to the NTRK3 gene. These two genes are the targets of the CFS recurrent translocations, suggesting that misalignments between these two chromosomes regions could facilitate recombination. The most striking similarity identified is based on a low copy repeat sequence, mainly present on human chromosome 15 (LCR15), which could be considered a newly recognized duplicon. At least 10 copies of this duplicon are present on chromosome 15, mainly on 15q24 and 15q26. One copy is located close to a HERC2 sequence on the distal end of the PWS/AS region, three around the lysyl oxidase-like (LOXL1) gene on 15q24, and three on 15q26, one of which close to the IQ motif containing GTPase-activating protein 1 (IQGAP1) gene on 15q26.1. These LCR15 span between 13 and 22 kb and contain high identities with the golgin-like protein (GLP) and the SH3 domain-containing protein (SH3P18) gene sequences and have the characteristics of duplicons. Because duplicons flank chromosome regions that are rearranged in human genomic disorders, the LCR15 described here could represent new elements of rearrangements affecting different regions of human chromosome 15q.
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PMID:Additional complexity on human chromosome 15q: identification of a set of newly recognized duplicons (LCR15) on 15q11-q13, 15q24, and 15q26. 1115 19

Activation of the extracellular signal-regulated kinase 1 (ERK1) and ERK2 by neurotrophins, neuronal activity, or cAMP has been strongly implicated in differentiation, survival, and adaptive responses of neurons during development and in the adult brain. Recently, a new member of the mitogen-activated protein (MAP) kinase family, ERK5, was discovered. Like ERK1 and ERK2, ERK5 is expressed in neurons, and ERK5 stimulation by epidermal growth factor is blocked by the MAP kinase/ERK kinase 1 (MEK1) inhibitors PD98059 and U0126. This suggests the interesting possibility that some of the functions attributed to ERK1/2 may be mediated by ERK5. However, the regulatory properties of ERK5 in primary cultured neurons have not been reported. Here we examined the regulation of ERK5 signaling in primary cultured cortical neurons. Our data demonstrate that, similar to ERK1/2, ERK5 is activated by neurotrophins including brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4. BDNF stimulation of ERK5 required the activity of MEK5. Surprisingly, ERK5 was not stimulated by cAMP or neuronal activity induced by glutamate or membrane depolarization. In contrast to ERK1/2, ERK5 strongly activated the transcriptional activity of myocyte enhancer factor 2C (MEF2C) in pheochromocytoma 12 (PC12) cells and was required for neurotrophin stimulation of MEF2C transcription in both PC12 cells and cortical neurons. Furthermore, ERK1/2, but not ERK5, induced transcription from Elk1 and the cAMP/ Ca(2+) response element in PC12 cells. Our data suggest that mechanisms for regulation of ERK5 and downstream transcriptional pathways regulated by ERK5 are distinct from those of ERK1/2 in neurons. Furthermore, ERK5 is the first MAP kinase identified whose activity is stimulated by neurotrophins but not by neuronal activity.
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PMID:Differential regulation of mitogen-activated protein kinases ERK1/2 and ERK5 by neurotrophins, neuronal activity, and cAMP in neurons. 1116 Apr 24

Tyrosine kinase fusion oncogenes that occur as a result of chromosomal translocations have been shown to activate proliferative and antiapoptotic pathways in leukemic cells, but the importance of autocrine and paracrine expression of hematopoietic cytokines in leukemia pathogenesis is not understood. Evidence that leukemic transformation may be, at least in part, cytokine dependent includes data from primary human leukemia cells, cell culture experiments, and murine models of leukemia. This report demonstrates that interleukin (IL)-3 plasma levels are elevated in myeloproliferative disease (MPD) caused by the TEL/tyrosine kinase fusions TEL/platelet-derived growth factor beta receptor (PDGFbetaR), TEL/Janus kinase 2 (JAK2), and TEL/neurotrophin-3 receptor (TRKC). Plasma granulocyte-macrophage colony-stimulating factor (GM-CSF) levels were elevated by TEL/PDGFbetaR and TEL/JAK2. However, all of the fusions tested efficiently induced MPD in mice genetically deficient for both GM-CSF and IL-3, demonstrating that these cytokines are not necessary for the development of disease in this model system. Furthermore, in experiments using normal marrow transduced with TEL/PDGFbetaR retrovirus mixed with marrow transduced with an enhanced green fluorescent protein (EGFP) retrovirus, the MPD induced in these mice demonstrated minimal stimulation of normal myelopoiesis by the TEL/PDGFbetaR-expressing cells. In contrast, recipients of mixed GM-CSF-transduced and EGFP-transduced marrow exhibited significant paracrine expansion of EGFP-expressing cells. Collectively, these data demonstrate that, although cytokine levels are elevated in murine bone marrow transplant models of leukemia using tyrosine kinase fusion oncogenes, GM-CSF and IL-3 are not required for myeloproliferation by any of the oncogenes tested.
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PMID:Induction of myeloproliferative disease in mice by tyrosine kinase fusion oncogenes does not require granulocyte-macrophage colony-stimulating factor or interleukin-3. 1122 91

Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) are three representative neurotrophins responsible for the differentiation and survival of neurons, and their high-affinity receptors are tropomyosin-receptor-kinase (TRK)A, TRKB, and TRKC, respectively. In this study, we investigated the expression of neurotrophins in a mouse periodontal ligament cell line (MPL), by reverse transcription-polymerase chain-reaction (RT-PCR) and enzyme-linked immunoabsorbent assay (ELISA). We also studied the expression of TRK receptors on MPL by immunostaining and the effects of neurotrophins on the proliferation of MPL, with a hypothesis of autocrine mechanism of neurotrophins. Each neurotrophin and TRK receptor was expressed, and neurotrophins enhanced the proliferation of MPL. These findings suggest that the MPL has functional neurotrophin receptors involved in an autocrine function of neurotrophins. The expression level of neurotrophins and TRKs showed the reverse pattern, and we propose an auto-regulatory mechanism of ligands and receptors in accordance with the level of synthesized neurotrophins.
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PMID:Mitogenic effects of neutrophins on a periodontal ligament cell line. 1137 89

Cultured embryonic cortical progenitor cells will mimic the temporal differentiation pattern observed in vivo, producing neurons first and then glia. Here, we investigated the role of two endogenously produced growth factors, the neurotrophins brain-derived neurotrophic factor and neurotrophin-3 (NT-3), in the early progenitor-to-neuron transition. Cultured cortical progenitors express BDNF and NT-3, as well as their receptors TrkB (tyrosine kinase receptor B) and TrkC. Inhibition of these endogenously expressed neurotrophins using function-blocking antibodies resulted in a marked decrease in the survival of cortical progenitors, accompanied by decreased proliferation and inhibition of neurogenesis. Inhibition of neurotrophin function also suppressed the downstream Trk receptor signaling pathways, PI3-kinase (phosphatidyl inositol-3-kinase) and MEK-ERK (MAP kinase kinase-extracellular signal-regulated kinase), indicating the presence of autocrine-paracrine neurotrophin:Trk receptor signaling in these cells. Moreover, specific inhibition of these two Trk signaling pathways led to distinct biological effects; inhibition of PI3-kinase decreased progenitor cell survival, whereas inhibition of MEK selectively blocked the generation of neurons, with no effects on survival or proliferation. Thus, neurotrophins made by cortical progenitor cells themselves signal through the TrkB and TrkC receptors to mediate cortical progenitor cell survival and neurogenesis via two distinct downstream signaling pathways.
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PMID:Endogenously produced neurotrophins regulate survival and differentiation of cortical progenitors via distinct signaling pathways. 1283 39

A number of cytokines including neurotrophins have been tested for their neuroprotective activity against different paradigms of neuronal death. However, as for neurotrophin-3 (NT-3), their mechanisms of action have not been fully identified. By using cultures of mouse cortical neurons, we have investigated the molecular mechanisms by which neurotrophin-3 could protect cortical neurons against apoptosis. In a model of caspase-dependent apoptosis leading to the recruitment of active initiators caspase-8 and -9 and of executioner caspase-3, we have evidenced that NT-3 displayed an anti-apoptotic effect in a dose-dependent manner. First, we showed that, in cultured cortical neurons, NT-3 could promote extracellular signal-regulated protein kinase/mitogen-activated protein kinase (ERK/MAPK) and phosphatidylinositol-3' (PI-3) kinase/Akt phosphorylation. Second, we showed that although the blockade of the Akt pathway prevented the anti-apoptotic effect of NT-3, blockade of the ERK pathway did not. Altogether, our data demonstrate that NT-3 displayed an anti-apoptotic effect on cultured cortical neurons through a mechanism involving the recruitment of the PI-3 kinase/Akt signaling pathway.
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PMID:Neurotrophin-3-induced PI-3 kinase/Akt signaling rescues cortical neurons from apoptosis. 1508 86

We show the cellular distribution of immunoreactivity (IR) for brain-derived-neurotrophic-factor (BDNF), neurotrophin-3 (NT-3) and tyrosine kinase receptors TRKB and TRKC in idiopathic Parkinson's disease (IPD) and controls at post-mortem. In both groups, nigral neurons, astrocytes, ramified and amoeboid microglia expressed all antigens. Caudate-putamen neurons expressed all antigens except BDNF with similar distribution between groups. In IPD nigra, increased numbers of BDNF-IR and, less frequently, NT-3-IR ramified glia surrounded fragmented neurons, accompanied by BDNF-IR in surrounding neuropil. Amoeboid microglia were abundant only in IPD nigral scars. In IPD, glia might up-regulate neurotrophins in response to signals released from failing nigral neurons.
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PMID:Elevated glial brain-derived neurotrophic factor in Parkinson's diseased nigra. 1517 62

Neurotrophin-induced neuroprotection against apoptosis was investigated using immature cultured cerebellar granule cells (CGC) from newborn rat pups. Apoptotic cell death induced by treatment with cytosine arabinoside (AraC) was confirmed by DNA fragmentation and quantified by cell survival assays. AraC was most effective in inducing apoptosis when added to CGC on the day of culture preparation, while less or no effect was observed when added at 24 or 48h after plating, respectively. Pretreatment of CGC cultures for 24h with brain-derived neurotrophic factor (BDNF) or neurotrophin-4 (NT-4), but not neurotrophin-3 (NT-3), robustly protected against AraC neurotoxicity. K252a, an inhibitor of the tropomyosin-related kinase (Trk) tyrosine kinase receptor family which showed no toxicity by itself, blocked BDNF protection of AraC-induced apoptosis in a concentration-dependent manner. Neither protein kinase C activation nor inhibition mimicked or affected BDNF protection against AraC neurotoxicity. BDNF, but not NT-3, treatment of immature CGC caused a marked, but transient activation of Akt through phosphatidylinositol (PI) 3-kinase. The neuroprotective effects of BDNF were suppressed by pretreatment with LY 294002 (a PI 3-kinase inhibitor). BDNF neuroprotection was also preceded by activation of mitogen activated protein kinase (MAPK) and suppressed by two MAPK/ERK (MEK)-selective inhibitors, PD 98059 and U-0126. Moreover, inhibitors of PI 3-kinase and MEK potentiated AraC-induced neurotoxicity. These results show that neurotrophins protect against AraC-induced apoptosis, at least in part, through TrkB-mediated activation of the PI 3-kinase/Akt and MEK signaling pathways.
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PMID:Neurotrophins protect against cytosine arabinoside-induced apoptosis of immature rat cerebellar neurons. 1556 16

The ETV6-NTRK3 (TEL-TRKC) gene fusion was discovered by breakpoint analysis of the t(12;15)(p13;q25) translocation associated with congenital fibrosarcoma, a pediatric soft tissue malignancy. ETV6-NTRK3 (EN) encodes the sterile alpha motif oligomerization domain of the ETV6 (TEL) transcription factor linked to the protein tyrosine kinase domain of the neurotrophin-3 receptor NTRK3 (TRKC). The EN chimeric oncoprotein links to multiple signaling cascades including Ras-MAP kinase and PI3K-AKT through the IRS-1 adapter protein. Recent evidence indicates that a functional insulin-like growth factor 1 receptor axis and higher order polymer formation are essential for EN oncogenesis. EN has been detected in other malignancies, including secretory breast carcinoma. This chimeric oncoprotein is therefore unique in being expressed in tumors derived from multiple cell lineages.
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PMID:ETV6-NTRK3: a chimeric protein tyrosine kinase with transformation activity in multiple cell lineages. 1582 36

In mammals, degeneration of peripheral auditory neurons constitutes one of the main causes of sensorineural hearing loss. Unfortunately, to date, pharmacological interventions aimed at counteracting this condition have not presented complete effectiveness in protecting the integrity of cochlear neural elements. In this context, the protein kinase C (PKC) family of enzymes are important signalling molecules that play a role in preventing neurodegeneration after nervous system injury. The present study demonstrates, for the first time, that the PKC signalling pathway is directly neurotrophic to axotomised spiral ganglion neurons (SGNs). We found that PKCbetaI was strictly expressed by postnatal and adult SGNs both in situ and in vitro. In cultures of SGNs, we observed that activators of PKC, such as phorbol esters and bryostatin 1, induced neuronal survival and neurite regrowth in a manner dependent on the activation of PKCbetaI. The neuroprotective effects of PKC activators were suppressed by pre-treatment with LY294002 (a PI3K inhibitor) and with U0126 (a MEK inhibitor), indicating that PKC activators promote the survival and neurite outgrowth of SGNs by both PI3K/Akt and MEK/ERK-dependent mechanisms. In addition, whereas combining the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) was shown to provide only an additive effect on SGN survival, the interaction between PKC and neurotrophin signalling gave rise to a synergistic increase in SGN survival. Taken together, the data indicate that PKCbetaI activation represents a key factor for the protection of the integrity of neural elements in the cochlea.
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PMID:Activation of protein kinase CbetaI constitutes a new neurotrophic pathway for deafferented spiral ganglion neurons. 1617 9


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