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)

Overexpression of the growth factor receptor subunit c-erbB2, leading to its ligand-independent homodimerization and activation, has been implicated in the pathogenesis of mammary carcinoma. Here, we have examined the effects of c-erbB2 on the adhesive properties of a mammary epithelial cell line, HB2/tnz34, in which c-erbB2 homodimerization can be induced by means of a transfected hybrid "trk-neu" construct. trk-neu consists of the extracellular domain of the trkA nerve growth factor (NGF) receptor fused to the transmembrane and cytoplasmic domains of c-erbB2, allowing NGF-induced c-erbB2 homodimer signaling. Both spreading and adhesion on collagen surfaces were impaired on c-erbB2 activation in HB2/tnz34 cells. Antibody-mediated stimulation of alpha(2)beta(1) integrin function restored adhesion, suggesting a direct role for c-erbB2 in integrin inactivation. Using pharmacological inhibitors and transient transfections, we identified signaling pathways required for suppression of integrin function by c-erbB2. Among these was the MEK-ERK pathway, previously implicated in integrin inactivation. However, we could also show that downstream of phosphoinositide-3-kinase (PI3K), protein kinase B (PKB) acted as a previously unknown, potent inhibitor of integrin function and mediator of the disruptive effects of c-erbB2 on adhesion and morphogenesis. The integrin-linked kinase, previously identified as a PKB coactivator, was also found to be required for integrin inactivation by c-erbB2. In addition, the PI3K-dependent mTOR/S6 kinase pathway was shown to mediate c-erbB2-induced inhibition of adhesion (but not spreading) independently of PKB. Overexpression of MEK1 or PKB suppressed adhesion without requirement for c-erbB2 activation, suggesting that these two pathways partake in integrin inhibition by targeting common downstream effectors. These results demonstrate a major novel role for PI3K and PKB in regulation of integrin function.
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PMID:c-erbB2-induced disruption of matrix adhesion and morphogenesis reveals a novel role for protein kinase B as a negative regulator of alpha(2)beta(1) integrin function. 1218 54

Hereditary sensory and autonomic neuropathy type IV (HSAN-IV) and type V (HSAN-V) are autosomal recessive genetic disorders, both characterized by a lack of pain sensation. We report a girl with clinical and neurophysiological findings consistent with a diagnosis of HSAN-V. We sequenced her TRKA gene, encoding a receptor tyrosine kinase for nerve growth factor and responsible for HSAN-IV, but we could not detect any mutation. These data indicate that a gene (or genes) other than TRKA is probably responsible for HSAN-V in some patients.
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PMID:No mutation in the TRKA (NTRK1) gene encoding a receptor tyrosine kinase for nerve growth factor in a patient with hereditary sensory and autonomic neuropathy type V. 1260 14

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.
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PMID:4-Methylcatechol stimulates phosphorylation of Trk family neurotrophin receptors and MAP kinases in cultured rat cortical neurons. 1239 93

It is well known that dichlorodiphenyltrichloroethane (DDT) is used as an insecticide and prevents many people in the tropical zone from devastating malaria. On the other hand, a number of reports have indicated that it may act as an endocrine disruptor and also has possible carcinogenic effects. However, the effects of DDT on the neural cells remain to be investigated. In this study, therefore, we observed the effects of p,p'-DDT, o,p'-DDT and its major metabolite p,p'-DDE on the differentiation and survival of PC12 pheochromocytoma cells. After stimulation with nerve growth factor, PC12 cells exhibited remarkable neurite outgrowth, suggesting that neuronal differentiation was induced by this growth factor. p,p'-DDT and o,p'-DDT suppressed this neurite outgrowth dose dependently, and p,p'-DDE also revealed a similar effect but to a lesser extent. Apoptotic cell death was induced within 3-6 h after treatment with p,p'-DDT and o,p'-DDT. Again p,p'-DDE showed a weaker apoptosis-inducing effect. In the organochlorine-treated PC12 cells phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) was upregulated, whereas phosphorylation bands were not detected in any kinases of other MAPK groups such as p38 MAPK and SAPK/JNK. A kinase assay on p44/42 MAPK revealed that the extent of phosphorylation of Elk-1 substrates well correlated with the suppressive effect on neuronal differentiation and apoptosis-inducing activity. These results suggest that p,p'-DDT and o,p'-DDT exerted their effects on neuronal cells by the stimulation of p44/42 MAPK, and p,p'-DDE had less effects than the other two organochlorines.
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PMID:Dichlorodiphenyltrichloroethane suppresses neurite outgrowth and induces apoptosis in PC12 pheochromocytoma cells. 1252 60

The c-fes protooncogene encodes a non-receptor protein-tyrosine kinase (Fes) that has been implicated in the differentiation of myeloid haematopoietic cells. Fes is also expressed in several neuronal cell types and the vascular endothelium, suggestive of a more general function in development. To examine the role of Fes in neuronal differentiation, we investigated the effect of Fes expression on process outgrowth in PC12 cells following stimulation with nerve growth factor (NGF). PC12 cells expressing wild-type and activated mutants of Fes extended processes faster and of greater length than control cells. In contrast, expression of kinase-inactive Fes was without effect, indicating that cooperation with NGF requires Fes kinase activity. Short-term treatment of PC12-Fes cells with NGF enhanced tyrosine phosphorylation of Fes, suggesting upstream regulation by the NGF receptor. Fes-mediated acceleration of neurite outgrowth was blocked by wortmannin and LY294002, implicating phosphatidylinositol 3-kinase (PI3K) activation in the Fes-induced response. In contrast, the MEK inhibitor PD98059 was without effect, suggesting that the Ras-Erk pathway is not involved. These data provide the first evidence that Fes may contribute to morphological differentiation of neuronal cells by enhancing NGF signalling through the PI3K pathway.
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PMID:The c-Fes protein-tyrosine kinase accelerates NGF-induced differentiation of PC12 cells through a PI3K-dependent mechanism. 1253 26

This study was designed to examine the effects of bone marrow stromal cells (MSCs) cultured in vitro with or without neurotrophic factors transplanted into adult male Wistar rats after traumatic brain injury (TBI). MSCs harvested from donor Wistar rats were cultured with either the culture medium containing brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) or the same culture media without these factors. Control and experimental animals were then traumatized by a controlled cortical impact. One day after the impact, either the placebo or the washed MSCs (1 x 10(6)) cultured with or without NGF and BDNF were transplanted adjacent to the site of injury. In addition, a nontreated group of rats was employed. Motor function of the animals was evaluated by the Rotarod test both before and after the injury. All animals were sacrificed 8 days after TBI, and the brain sections were stained by H&E as well as for immunohistochemistry. MSCs survived and migrated toward the injury site. The group treated with MSCs cultured with BDNF and NGF had a significantly higher number of engrafted cells than the group treated with MSCs cultured without BDNF and NGF (6.3 x 10(4) +/- 4250 compared to 4.1 x 10(4) +/- 3684; p < 0.05). In both groups, some transplanted MSCs showed positive staining for astrocytic (GFAP) and neuronal markers (Neu N and MAP-2). The groups treated with MSCs had better motor function than the groups receiving no treatment or receiving the placebo (PBS; p < 0.05); however, the improvement reached statistical significance only in the group treated with MSCs cultured with neurotrophic factors. These data suggest that more robust motor function described in rats subjected to TBI and treated with intracerebral transplantation of MSCs was achieved by the use of MSCs cultured with neurotrophic factors.
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PMID:Intracerebral transplantation of marrow stromal cells cultured with neurotrophic factors promotes functional recovery in adult rats subjected to traumatic brain injury. 1254 61

We have analyzed signaling pathways involved in neurotrophic factor (NTF)-induced upregulation of nociceptive properties, specifically vanilloid receptor type 1 (VR1), by adult rat dorsal root ganglion neurons. Upregulation of VR1 by nerve growth factor and glial cell line-derived neurotrophic factor is partially blocked by a MEK inhibitor. Dominant negative Ras, but not Rap, blocks NTF-induced ERK activation and VR1 upregulation. Activated Ras mimics NTF-mediated induction of VR1 in dorsal root ganglion neurons. An inhibitor of phosphatidylinositol 3-kinase, LY294002, also inhibited NTF-induced VR1 upregulation. However, this may at least in part be due to a block of NTF-induced ERK activation. Constitutive simultaneous stimulation of both ERK and phosphatidylinositol 3-kinase is not sufficient for VR1 upregulation. Together, the data suggest that VR1 expression by dorsal root ganglion neurons is regulated by common Ras-dependent pathways.
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PMID:Activation of Ras is necessary and sufficient for upregulation of vanilloid receptor type 1 in sensory neurons by neurotrophic factors. 1259 44

PC12 cells have been used as a model system for neuronal differentiation due to their ability to alter their phenotype to a sympathetic neuron-like cell in response to nerve growth factor or fibroblast growth factor. Under some conditions, epidermal growth factor (EGF) can also induce PC12 cells to differentiate. To study signaling from the EGF receptor without the confounding effects of endogenous EGF receptors we generated a chimeric receptor comprised of the ectodomain of platelet-derived growth factor (PDGF) receptor in-frame with the transmembrane and cytoplasmic domains of EGF receptor, termed PER. Expression of PER in PC12 cells confers the ability of PDGF to induce differentiation whereas PDGF has no effect on untransfected PC12 cells. This response is kinase activity-dependent since a kinase-deficient mutant (K721M) fails to induce differentiation in response to PDGF. Mutation of five tyrosine residues that are autophosphorylated in response to EGF either individually or in combination had minimal effects on the ability of these receptors to induce morphological PC12 cell differentiation. The PER mutant with all five autophosphorylation sites mutated to phenylalanine (5YF) was equivalently capable of interacting with several important signaling molecules, including Shc, Grb2, Gab1, phospholipase Cgamma, and Cbl. Furthermore, both the phosphatidylinositol 3-kinase (PI3K)/Akt and Ras/Erk pathways were activated in a sustained manner when PER or 5YF-expressing cells were stimulated with PDGF. Our results show that the five autophosphorylation sites in the extra-kinase C-terminal domain of EGFR are not required for the ability of EGFR to induce morphological differentiation of PC12 cells.
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PMID:PC12 cell activation by epidermal growth factor receptor: role of autophosphorylation sites. 1261 82

The molecular mechanisms by which neurotrophins such as nerve growth factor (NGF) induce neurite outgrowth and differentiation remain unclear, although multiple intracellular signaling pathways are known to participate. Recent studies have shown that nuclear transcription factors play an important role in NGF-stimulated neuritic outgrowth in PC12 cells. We investigated whether FAC1, a novel transcriptional regulator that exhibits altered subcellular distribution during brain development, is responsive to NGF-induced neurite outgrowth of PC12 cells. Our studies demonstrate that NGF induces a rapid, transient increase in FACI mRNA that is dependent upon ERK activation, and that FAC1 protein exhibits altered subcellular distribution during neurite outgrowth. These findings suggest that FAC1 expression and subcellular localization are regulated by NGF signaling pathways during neurite outgrowth.
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PMID:Altered expression and distribution of FAC1 during NGF-induced neurite outgrowth of PC12 cells. 1263 1

The present study was undertaken to examine the factors that regulate rat serum (RS)- and nerve growth factor (NGF)-induced differentiation in a rat parotid acinar cell line. RS elicited extracellular signal-regulated kinase (ERK1/ERK2) activation within 5min, while cyclic AMP (cAMP) levels transiently rose after 6hr. RS also elicited a rise in amylase mRNA levels within 30min, which preceded the rise in amylase protein levels. A possible role for NGF was suggested by the findings that parotid cells express both TrkA and p75 receptors. The immunoreactivity of these NGF receptors was reduced during exposure to RS. Following prolonged incubation in RS when ERK activity subsided to near basal levels, NGF restored ERK1/ERK2 activity to the elevated level initially observed in RS. NGF was ineffective when cells were incubated in fetal bovine serum. NGF, when incubated in combination with the cAMP-generating neuropeptides, calcitonin gene-related peptide and vasoactive intestinal peptide, markedly enhanced the cellular amylase content produced by RS. We conclude that parotid cell differentiation arises from an activation of cell surface receptors by humoral factors in combination with NGF and cAMP-generating neuropeptides.
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PMID:Role of nerve growth factor in the regulation of parotid cell differentiation induced by rat serum. 1273 63


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