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)

Different types of plasma membrane receptors engage in various forms of cross-talk. We used cultures of rat renal mesangial cells to study the regulation of EGF receptors (EGFRs) by various endogenous G protein-coupled receptors (GPCRs). GPCRs (5-hydroxytryptamine(2A), lysophosphatidic acid, angiotensin AT(1), bradykinin B(2)) were shown to transactivate EGFRs through a protein kinase C-dependent pathway. This transactivation resulted in the initiation of multiple cellular signals (phosphorylation of the EGFRs and ERK and activation of cAMP-responsive element-binding protein (CREB), NF-kappaB, and E2F), as well as subsequent rapid down-regulation of cell-surface EGFRs and internalization and desensitization of the EGFRs without change in the total cellular complement of EGFRs. Internalization of the EGFRs and the down-regulation of cell-surface receptors in mesangial cells were blocked by pharmacological inhibitors of clathrin-mediated endocytosis and in HEK293 cells by transfection of cDNA constructs that encode dominant negative beta-arrestin-1 or dynamin. Whereas all of the effects of GPCRs on EGFRs were dependent to a great extent on protein kinase C, those initiated by EGF were not. These studies demonstrate that GPCRs can induce multiple signals through protein kinase C-dependent transactivation of EGFRs. Moreover, GPCRs induce profound desensitization of EGFRs by a process associated with the loss of cell-surface EGFRs through clathrin-mediated endocytosis.
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PMID:G protein-coupled receptors desensitize and down-regulate epidermal growth factor receptors in renal mesangial cells. 1137 70

Akt1/protein kinase B and the mitogen-activated protein (MAP) kinases extracellular signal-regulated kinase 1 (ERK1) and ERK2 have been shown to promote cell survival in a cell-specific manner. Since many receptors activate both pathways, inhibitors are commonly used to study the relative role of each pathway. In the present study, we examined the effects of PD098059 and U0126, two structurally dissimilar inhibitors of MAP kinase kinase (MEK1/2), on the activation of ERK and Akt stimulated by human 5-hydroxytryptamine(1B) (serotonin) (5-HT1B) receptors. Surprisingly, pathways for activation of both ERK and Akt were found to be sensitive to the two MEK inhibitors at concentrations commonly used to selectively inhibit the activation of ERK. Both compounds caused complete inhibition of phosphorylation of ERK and a maximal 60% inhibition of 5-HT1B receptor-mediated phosphorylation of Akt. Inhibition of Akt activation required almost complete inhibition of ERK. Transfection with cDNA for activated forms of MEK1/2 caused increased phosphorylation of ERK but not of Akt, demonstrating that independent activation of MEK/ERK was insufficient for activation of Akt. Therefore, it is not clear whether inhibition of activation of Akt resulted from selective inhibition of MEK or from additional actions on other unidentified common pathways. Nevertheless, our findings that PD098059 and U0126 inhibit activation of Akt at commonly used concentrations demonstrate that in at least some systems, these compounds inhibit activation of both ERK and Akt, and cannot be used to discern the relative roles of each pathway in mediating cellular responses.
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PMID:Activation of Akt1 by human 5-hydroxytryptamine (serotonin)1B receptors is sensitive to inhibitors of MEK. 1145 48

Serotonin (5-hydroxytryptamine (5-HT)) is a mitogen of pulmonary artery smooth muscle cells (PASMC) and plays an important role in the development of pulmonary hypertension. Signal transduction initiated by 5-HT involves serotonin transporter-dependent generation of reactive oxygen species and activation of the MEK-ERK pathway. However, the downstream transcriptional regulatory components have not been identified. In systemic smooth muscle cells, GATA-6 has been shown to regulate mitogenesis by driving cells into a quiescent state, and the down-regulation of GATA-6 induces mitogenesis. Thus, the present study tested the hypothesis that 5-HT induces mitogenesis of PASMC by down-regulating GATA-6. Quiescent bovine PASMC were treated with 5-HT, and the binding activity of nuclear extracts toward GATA DNA sequence was monitored. Surprisingly, PASMC express GATA-4, and 5-HT up-regulates the GATA DNA binding activity. Pretreatment of cells with inhibitors of serotonin transporter, reactive oxygen species, and MEK blocks GATA-4 activation by 5-HT. GATA-4 is not activated when the ERK phosphorylation site is mutated, indicating that 5-HT phosphorylates GATA-4 via the MEK/ERK pathway. GATA up-regulation is also induced by other mitogens of PASMC such as endothelin-1 and platelet-derived growth factor. Dominant negative mutants of GATA-4 suppress cyclin D2 expression and cell growth, indicating that GATA-4 activation regulates PASMC proliferation. Thus, GATA-4 mediates 5-HT-induced growth of PASMC and may be an important therapeutic target for the prevention of pulmonary hypertension.
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PMID:Activation of GATA-4 by serotonin in pulmonary artery smooth muscle cells. 1261 26

Smooth muscle cell proliferation around small pulmonary vessels is essential to the pathogenesis of pulmonary hypertension. Here we describe a molecular mechanism and animal model for this vascular pathology. Rodents engineered to express angiopoietin 1 (Ang-1) constitutively in the lung develop severe pulmonary hypertension. These animals manifest diffuse medial thickening in small pulmonary vessels, resulting from smooth muscle cell hyperplasia. This pathology is common to all forms of human pulmonary hypertension. We demonstrate that Ang-1 stimulates pulmonary arteriolar endothelial cells through a TIE2 (receptor with tyrosine kinase activity containing IgG-like loops and epidermal growth factor homology domains) pathway to produce and secrete serotonin (5-hydroxytryptamine), a potent smooth muscle mitogen, and find that high levels of serotonin are present both in human and rodent pulmonary hypertensive lung tissue. These results suggest that pulmonary hypertensive vasculopathy occurs through an Ang-1/TIE2/serotonin paracrine pathway and imply that these signaling molecules may be targets for strategies to treat this disease.
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PMID:Induction of pulmonary hypertension by an angiopoietin 1/TIE2/serotonin pathway. 1451 15

Previously, it has been shown that oocytes of marine nemertean worms resume meiosis and undergo germinal vesicle breakdown (GVBD) following treatment with either natural seawater (NSW), or the neurohormone serotonin (5-hydroxytryptamine or 5-HT). In this investigation of the nemerteans Cerebratulus lacteus and Cerebratulus sp., immunoblots and kinase assays were used to compare the roles of two regulatory kinases: mitogen-activated protein kinase (MAPK) and Cdc2/cyclin B (referred to as maturation promoting factor or MPF). Based on such analyses, an ERK (extracellular signal regulated kinase) type of MAPK was found to be activated concurrently with Cdc2/cyclin B during NSW- and 5-HT-induced maturation. MAPK activation occurred prior to GVBD and seemed to be controlled primarily by phosphorylation rather than de novo protein synthesis. Inhibition of MAPK signaling by U0126 was capable of delaying but not permanently blocking Cdc2/cyclin B activation and GVBD in 5-HT treated oocytes and subsets of NSW-treated oocytes. Collectively such data indicated that GVBD is not fully dependent on MAPK activation, since Cdc2/cyclin B can apparently be activated by MAPK-independent mechanism(s) in maturing nemertean oocytes.
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PMID:Germinal vesicle breakdown is not fully dependent on MAPK activation in maturing oocytes of marine nemertean worms. 1551 58

The purpose of this study was to elucidate the mechanism of 5-hydroxytryptamine (5-HT, serotonin) action on migration of vascular smooth muscle cells. Migration of cultured human aortic smooth muscle cells (HASMCs), evaluated using time-lapse microscopy, was significantly enhanced by 5-HT at concentrations of 1-100 nM. The enhancing effect of 5-HT on cell migration was markedly inhibited in the presence of ketanserin, a 5-HT2 receptor antagonist, but not by GR 55562, a 5-HT1 receptor antagonist. Activities of RhoA and ERK were increased by 5-HT, and the increase in cell migration by 5-HT was abolished in the presence of U0126, a MEK1/2 inhibitor, or Y-27632, a Rho-kinase inhibitor. Activation of ERK was strongly inhibited by Y-27632. 5-HT-induced formation of stress fiber and detachment of uropod (trailing edge) were abolished by Y-27632. Thus, 5-HT has a potent enhancing action on migration of HASMCs due to an increase in stress fiber formation by 5-HT2 receptor stimulation followed by activation of the Rho-kinase and ERK pathways.
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PMID:5-Hydroxytryptamine augments migration of human aortic smooth muscle cells through activation of RhoA and ERK. 1621 95

The purpose of the present study was to investigate whether 5-hydroxytryptamine (5-HT, serotonin) affects migration of vascular endothelial cells. 5-HT significantly enhanced migration of human aortic endothelial cells (HAECs), and this enhancement was completely inhibited by GR 55562, a 5-HT1 receptor antagonist, and fluoxetine, a 5-HT transporter inhibitor, but was not affected by ketanserin, a 5-HT2 receptor antagonist. 5-HT stimulation increased RhoA and ERK activity of HAECs, and inhibitors of RhoA (Y-27632 and H-1152) and inhibitors of MEK (U0126 and PD98059) abolished the 5-HT-induced increase in migration velocity. Inhibition of Rho kinase by Y-27632 blocked stress fiber formation and rear release of HAECs. Thus, 5-HT has a potent enhancing action on migration of HAECs through activating the RhoA and ERK pathways following 5-HT1 receptor stimulation.
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PMID:5-Hydroxytryptamine as a potent migration enhancer of human aortic endothelial cells. 1631 Jul 80

Synaptic neurotransmission in the central nervous system (CNS) requires the precise control of the duration and the magnitude of neurotransmitter action at specific molecular targets. At the molecular level, neurotransmitter signaling is dynamically regulated by a diverse set of macromolecules including biosynthetic enzymes, secretory proteins, ion channels, pre- and postsynaptic receptors and transporters. Monoamines, 5-hydroxytryptamine or serotonin (5-HT), norepinephrine (NE), and dopamine (DA) play an important modulatory role in the CNS and are involved in numerous physiological functions and pathological conditions. Presynaptic plasma membrane transporters for 5-HT (SERT), NE (NET), and DA (DAT), respectively, control synaptic actions of these monoamines by rapidly clearing the released amine. Monoamine transporters are the sites of action for widely used antidepressants and are high affinity molecular targets for drugs of abuse including cocaine, amphetamine, and 3,4-methylenedioxymetamphetamine (MDMA) "Ecstasy." Monoamine transporters also serve as molecular gateways for neurotoxins. Emerging evidence indicates that regulation of transporter function and surface expression can be rapidly modulated by "intrinsic" transporter activity itself, and antidepressant and psychostimulant drugs that block monoamine transport have a profound effect on transporter regulation. Therefore, disregulations in the functioning of monoamine transporters may underlie many disorders of transmitter imbalance such as depression, attention deficit hyperactivity disorder, and schizophrenia. This review integrates recent progress in understanding the molecular mechanisms of monoamine transporter regulation, in particular, posttranscriptional regulation by phosphorylation and trafficking linked to cellular protein kinases, protein phosphatases, and transporter interacting proteins. The review also discusses the possible role of psychostimulants and antidepressants in influencing monoamine transport regulation.
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PMID:Regulation of monoamine transporters: influence of psychostimulants and therapeutic antidepressants. 1635 49

We report a binary targeted enzymatic system that is composed of two covalent monoclonal antibody conjugates for specific labeling of cellular targets in vivo. The system utilizes low-molecular weight peroxidase-reducing substrates synthesized by linking 5-hydroxytryptamine (serotonin) with DTPA (5HT-DTPA) for magnetic resonance and radionuclide imaging or with Cy5.5 for near-infrared optical imaging. Initially, the conjugation reaction conditions were optimized to achieve a low level of antiepidermal growth factor receptor (EGFR) antibody (EMD 72000) modification with the N-hydroxysuccinimide ester of 4-hydrazinonicotinate acetone hydrazone (SANH), yielding mAb-HNH conjugate. The resultant modified antibodies were incubated with the periodate-oxidized peroxidase (HRP) or 4-formylbenzoyl-conjugated glucose oxidase (GO), followed by the purification of the resultant mAb-enzyme conjugates by size-exclusion HPLC. The conjugates were further characterized by electrophoresis and were tested by cross-titration on A431 EGFR+ squamous carcinoma or SW620 adenocarcinoma cells (negative control). The conjugates at the optimized concentration ratios were further tested using near-infrared fluorescence microscopy in the presence of Cy5.5 monocarboxy-5-hydroxytryptamide. Further in vitro experiments demonstrated that (1) antibody binding was specific and could be inhibited by free antibody; (2) both antibody conjugates exhibited high enzymatic activity after the binding to the cells; (3) 111In-labeled 5-HT-DTPA was avidly binding to EGFR-positive cells only if both HRP- and GO-conjugates were bound to the cells. The conjugates were tested in vivo using a SPECT imaging experiment, which demonstrated the accumulation of 111In-labeled 5-HT-DTPA substrate at the site containing both conjugates.
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PMID:Synthesis and testing of a binary catalytic system for imaging of signal amplification in vivo. 1750 10

Staphylococcal enterotoxins (SEs) produced by Staphylococcus aureus are the most recognizable bacterial superantigenic toxins causing food poisoning in humans throughout the world. However, it remains unclear how SEs induce emesis and its emetic signal pathway. We investigated a mechanism of SEA-induced emesis using a small emetic animal model, house musk shrew. SEA-induced emesis in the animals was inhibited by a 5-hydroxytryptamine (5-HT) synthesis inhibitor and a 5-HT(3) receptor antagonist. SEA could increase 5-HT release in the small intestine. Pre-treatment with 5,7-dihydroxytryptamine (5,7-DHT) markedly inhibited SEA-induced emesis. SEA-induced emesis was also abolished by surgical vagotomy. Furthermore, cannabinoid (CB) receptor agonists inhibited SEA-induced emesis, and the action was reversed by a CB1 antagonist. Both 5-HT release and CB1 receptor expression were found in the mucosal and myenteric plexus of the intestine. Moreover, a CB1 receptor agonist significantly decreased the 5-HT release in the intestine. These results demonstrate that SEA induces 5-HT release in intestine, rather than in brain, and that the 5-HT(3) receptors on vagal afferent neurons are essential for SEA-stimulated emesis. In addition, SEA-induced emesis is downregulated by the CB system through decreasing 5-HT release in intestine.
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PMID:Staphylococcal enterotoxin induces emesis through increasing serotonin release in intestine and it is downregulated by cannabinoid receptor 1. 1751 65


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