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

---

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

Effects of 4-methycatechol (4MC), a potent stimulator of nerve growth factor and brain-derived neurotrophic factor (BDNF) synthesis, on phosphorylation of cellular molecules in cultured rat cortical neurons were examined. 4MC stimulated tyrosine phosphorylation of various proteins of molecular weight from 10-300 kDa including Trks, which are high-affinity neurotrophin receptors. Moreover, 4MC enhanced the phosphorylation of serine 133 of mitogen-activated protein kinase (MAPK/ERK) in a dose-dependent manner. Pretreatment of cultures with PD98059, a selective inhibitor of MAPK kinase (MEK-1), inhibited 4MC-induced phosphorylation of ERKs, demonstrating MEK-1-mediated activation. Therefore, it seems that 4MC triggered the phosphorylation of Trks, resulting in the activation of the subsequent MAPK/ERK signal cascade, or perhaps the involvement of BDNF action as 4MC can stimulate neuronal BDNF synthesis. The phosphorylation of MAPK/ERK was unaffected, however, in the presence of cycloheximide, a protein synthesis inhibitor, and K252a, a selective inhibitor of Trks, suggesting that the effect of newly synthesized BDNF was negligible on this event, and that primary sites of 4MC actions are not limited only to Trks. These results suggest that 4MC primarily activates multiple signal transduction molecules such as tyrosine kinases, including Trks. A significant increase in the survival rate of cortical neurons in the presence of 10 or 100 nM 4MC supported this idea, because the concentrations were much lower than those for stimulation of BDNF synthesis. Our results strongly suggest that the neurotrophic actions of 4MC found so far are mediated predominantly by direct activation of some intracellular signals including MAPK/ERK rather than by neurotrophin synthesis.
...
PMID:4-Methylcatechol stimulates phosphorylation of Trk family neurotrophin receptors and MAP kinases in cultured rat cortical neurons. 1239 93

Previous publications from our group [Gil, Chaib, Pelliccioni and Aguilera (2000) FEBS Lett. 481, 177-182; Gil, Chaib, Blasi and Aguilera (2001) Biochem. J. 356, 97-103] have reported the activation, in rat brain synaptosomes, of several phosphoproteins, such as neurotrophin tyrosine kinase (Trk) A receptor, phospholipase Cgamma-1, protein kinase C (PKC) isoforms and extracellular-signal-regulated kinases 1 and 2 (ERK-1/2). In the present study, we examined, by means of phospho-specific antibodies, the activation of the signalling cascades involving neurotrophin Trk receptor, Akt kinase and ERK pathway, in cultured cortical neurons from foetal rat brain, by tetanus toxin (TeTx) as well as by the C-terminal part of its heavy chain (H(C)-TeTx). TeTx and H(C)-TeTx induce fast and transient phosphorylation of Trk receptor at Tyr(674) and Tyr(675), but not at Tyr(490), although the potency of TeTx in this action was higher when compared with H(C)-TeTx action. Moreover, H(C)-TeTx and TeTx also induced phosphorylation of Akt (at Ser(473) and Thr(308)) and of ERK-1/2 (Thr(202)/Tyr(204)), in a time- and concentration-dependent manner. The detection of TeTx- and H(C)-TeTx-induced phosphorylation at Ser(9) of glycogen synthase kinase 3beta confirms Akt activation. In the extended analysis of the ERK pathway, phosphorylation of the Raf, mitogen-activated protein kinase kinase (MEK)-1/2 and p90Rsk kinases and phosphorylation of the transcription factor cAMP-response-element-binding protein were detected. The use of tyrphostin AG879, an inhibitor of Trk receptors, demonstrates their necessary participation in the H(C)-TeTx-induced activation of Akt and ERK pathways, as well as in the phosphorylation of phospholipase Cgamma-1. Furthermore, both pathways are totally dependent on phosphatidylinositol 3-kinase action, and they are independent of PKC action, as assessed using wortmannin and Ro-31-8220 as inhibitors. The activation of PKC isoforms was determined by their translocation from the cytosolic compartment to the membranous compartment, showing a clear H(C)-TeTx-induced translocation of PKC-alpha and -beta, but not of PKC- epsilon.
...
PMID:C-terminal fragment of tetanus toxin heavy chain activates Akt and MEK/ERK signalling pathways in a Trk receptor-dependent manner in cultured cortical neurons. 1271 Aug 87

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.
...
PMID:Endogenously produced neurotrophins regulate survival and differentiation of cortical progenitors via distinct signaling pathways. 1283 39

The neurotrophin brain-derived neurotrophic factor (BDNF), via activation of its receptor, tyrosine receptor kinase B (trkB), regulates a wide variety of cellular processes in the nervous system, including neuron survival and synaptic plasticity. Although the expression of BDNF is known to be Ca2+-dependent, the regulation of trkB expression has not been extensively studied. Here we report that depolarization of cultured mouse cortical neurons increased the expression of the full-length, catalytically active isoform of trkB without affecting expression of the truncated isoform. This increase in protein expression was accompanied by increased levels of transcripts encoding full-length, but not truncated, trkB. Depolarization also regulated transcription of the gene, TRKB, via entry of Ca2+ through voltage-gated Ca2+ channels and subsequent activation of Ca2+-responsive elements in the two TRKB promoters. Using transient transfection of neurons with TRKB promoter-luciferase constructs, we found that Ca2+ inhibited the upstream promoter P1 but activated the downstream promoter P2. Ca2+-dependent stimulation of TRKB expression requires two adjacent, non-identical CRE sites located within P2. The coordinated regulation of BDNF and trkB by Ca2+ may play a role in activity-dependent survival and synaptic plasticity by enhancing BDNF signaling in electrically active neurons.
...
PMID:Ca(2+)-dependent regulation of TrkB expression in neurons. 1290 Apr 19

Peripheral nerve growth is regulated by the coordinated action of numerous external stimuli, including positively acting neurotrophin-derived growth cues and restrictive semaphorin cues. Here, we show that Semaphorin 3F (Sema 3F) can antagonize nerve growth factor (NGF)-stimulated TrkA (tyrosine receptor kinase A) signaling in sympathetic neurons, thereby apparently contributing to growth cone collapse. Sema 3F suppressed NGF-induced activation of the phosphatidylinositol 3 (PI3)-kinase-Akt and MEK (mitogen-activated protein kinase kinase)-ERK (extracellular signal-regulated kinase) pathways, both of which we show to be required to maintain growth cone structure. Sema 3F-induced growth cone collapse was partially reversed by sustained activation of the PI3-kinase and MEK pathways, which was achieved by overexpression of the Gab-1 (growth-associated binder 1) docking protein. These data indicate that a novel mechanism used by Sema 3F to collapse growth cones in sympathetic neurons is to dampen neurotrophin signaling, providing an intracellular mechanism for cross talk between positive and negative axon growth cues.
...
PMID:Semaphorin 3F antagonizes neurotrophin-induced phosphatidylinositol 3-kinase and mitogen-activated protein kinase kinase signaling: a mechanism for growth cone collapse. 1293 Jul 99

C6-ceramide protects sympathetic neurons from apoptosis caused by nerve growth factor (NGF) deprivation. Here, we report for the first time that ceramide generated "de novo" is also anti-apoptotic. Moreover, C6-ceramide is converted to long-chain ceramides in a process inhibited by fumonisin B1. The anti-apoptotic effect of C6-ceramide is due to the short analogue as to the long-chain ceramides. C6-ceramide shares mechanisms of action with NGF. C6-ceramide induces TrkA phosphorylation and selective activation of the phosphatidyl inositol 3-kinase (PI3-kinase)/Akt pathway but not the MAPK/ERK pathway. Importantly, the PI3-kinase inhibitor LY294002 abolishes the pro-survival effect of C6-ceramide. We identified a novel way to activate retrograde-mediated neuronal survival in the absence of NGF. Using compartmented cultures we show that addition of C6-ceramide exclusively to distal axons is sufficient to abort nuclear apoptosis. Our system offers a very unique alternative to understand the molecular bases of retrograde signaling in the absence of retrograde transport of neurotrophins. In search for a natural ligand that leads to ceramide generation we examined the activation of the sphingomyelin (SM) cycle downstream the p75 neurotrophin receptor (p75NTR). We found that in sympathetic neurons, selective activation of p75NTR by brain-derived neurotrophin factor or NGF plus K252a induces elevation of ceramide that correlates with SM hydrolysis. However, p75NTR activation does not generate sufficient ceramide to block apoptosis probably due to the rapid decrease in p75NTR expression that occurs upon NGF withdrawal.
...
PMID:Inhibition of rat sympathetic neuron apoptosis by ceramide. Role of p75NTR in ceramide generation. 1461 56

Protein ectodomain shedding, the proteolytic release of the extracellullar domain of membrane-tethered proteins, can dramatically affect the function of cell surface receptors, growth factors, cytokines, and other proteins. In this study, we evaluated the activities involved in ectodomain shedding of p75NTR, a neurotrophin receptor with critical roles in neuronal differentiation and survival. p75NTR is shed in a variety of cell types, including dorsal root ganglia cells and PC12 cells. In Chinese hamster ovary cells, inhibitors of the MEK/ERK and p38 MAP kinase pathways uncovered distinct signaling pathways required for the constitutive and stimulated shedding of p75NTR. Stimulated p75NTR shedding is abrogated in M2 mutant Chinese hamster ovary cells that lack functional tumor necrosis factor-alpha converting enzyme (TACE, also referred to as ADAM17) and in cells isolated from adam17-/- mice, but not in cells from adam9/12/15-/- or adam10-/- mice. Stimulated p75(NTR) shedding is strongly reduced by deletion of 15 amino acid residues in its extracellular membrane-proximal stalk domain. However, similar to other shed proteins, point mutations and overlapping shorter deletions within this region have little or no effect on shedding. Because ectodomain shedding of p75NTR releases a soluble ectodomain and could also be a prerequisite for its regulated intramembrane proteolysis, these findings may have important implications for the functional regulation of p75NTR.
...
PMID:Evidence for a critical role of the tumor necrosis factor alpha convertase (TACE) in ectodomain shedding of the p75 neurotrophin receptor (p75NTR). 1463 93

Receptor tyrosine kinases are integral components of cellular signaling pathways and are frequently deregulated in malignancies. The NTRK family of neurotrophin receptors mediate neuronal cell survival and differentiation, but altered NTRK signaling has also been implicated in oncogenesis. The ETV6-NTRK3 (EN) gene fusion occurs in human pediatric spindle cell sarcomas and secretory breast carcinoma, and encodes the oligomerization domain of the ETV6 transcription factor fused to the protein-tyrosine kinase domain of NTRK3. The EN protein functions as a constitutively active protein-tyrosine kinase with potent transforming activity in multiple cell lineages, and EN constitutively activates both the Ras-MAPK and phosphatidylinositol 3-kinase-Akt pathways. EN transformation is associated with constitutive tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). Further, IRS-1 functions as the adaptor protein linking EN to downstream signaling pathways. However, the exact nature of the EN-IRS-1 interaction remains unknown. We now demonstrate that EN specifically binds the phosphotyrosine binding domain of IRS-1 via an interaction at the C terminus of EN. An EN mutant lacking the C-terminal 19 amino acids does not bind IRS-1 and lacks transforming ability. Moreover, expression of an IRS-1 polypeptide containing the phosphotyrosine binding domain acts in a dominant negative manner to inhibit EN transformation, and overexpression of IRS-1 potentiates EN transforming activity. These findings indicate that EN.IRS-1 complex formation through the NTRK3 C terminus is essential for EN transformation.
...
PMID:A highly conserved NTRK3 C-terminal sequence in the ETV6-NTRK3 oncoprotein binds the phosphotyrosine binding domain of insulin receptor substrate-1: an essential interaction for transformation. 1466 42

The role played by PDGF in testis morphogenesis is still incompletely understood. The present study investigates the expression and potential role of platelet-derived growth factor-BB (PDGF-BB) and its receptor, PDGF receptor beta (PDGFR-beta), during mouse testis cord formation, and the possibility that the growth factor may be involved in the migration to the gonad of mesenchymal cells of mesonephric origin. Studies from this laboratory have previously shown that mesenchymal cells that migrate from the mesonephros into the gonad, to form peritubular myoid cells and most of the intertubular cells, can be identified by the presence on their surface of the p75 neurotrophin receptor (p75NTR), and can be isolated to near-purity by immunomagnetic selection with anti-p75NTR antibody. We show here that mesonephric p75NTR(+) cells also bear the PDGFR-beta, and are able to migrate and proliferate in vitro in response to PDGF-BB. PDGF-BB is expressed at higher levels in male than female developing gonads, suggesting a role for this factor in testis development. Such a role is further supported by the observation that addition of PDGF-BB to serum-free medium is sufficient to allow organ-cultured male 11.5 days post-coitum urogenital ridges to form testis cords. Finally, we show that mesonephric cell motility and growth induced by exposure to PDGF-BB involve mitogen-activated protein kinases (MAPK) and phosphatidylinositol-3 kinase (PI3-K) pathways, as MAPK inhibitor U0126 and PI3K inhibitor Ly294002 inhibit migration and proliferation in vitro assays. The present findings support the hypothesis that the PDGF/PDGFR system plays a key role in testis morphogenesis in the mouse embryo.
...
PMID:Expression and role of PDGF-BB and PDGFR-beta during testis morphogenesis in the mouse embryo. 1499 38

Neuronal precursor cells have the capacity to engage the Raf-MEK-ERK signal module to drive either of two distinctly different regulatory programs, proliferation and differentiation. This is, at least in part, a consequence of stimulus-specific shaping of the kinase cascade response. For example, the mitogen EGF induces a transient ERK activation, whereas the neurotrophin NGF induces prolonged ERK activation. Here we define a novel component of the regulatory machinery contributing to the selective integration of MAP kinase signaling with discrete biological responses. We show that the scaffold/adaptor protein CNK2/MAGUIN-1 is required for NGF- but not EGF-induced ERK activation. In addition, CNK2 makes a separate, essential contribution to the coupling of NGF signaling to membrane/cytoskeletal remodeling. We propose that CNK2 integrates multiple regulatory pathways that must function in concert to drive an appropriate biological response to external stimuli.
...
PMID:CNK2 couples NGF signal propagation to multiple regulatory cascades driving cell differentiation. 1502 21


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---