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Results for “Signal Transduction”

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At least 631 records · Page 35Linked to original sources

PubMed1994

Reversible uridylylation of the Escherichia coli PII signal transduction protein regulates its ability to stimulate the dephosphorylation of the transcription factor nitrogen regulator I (NRI or NtrC).

We have reconstituted the signal transduction system responsible for the negative regulation of the transcription of the Escherichia coli glnA gene, encoding glutamine synthetase, by glutamine. This signal transduction system consists of four proteins: the transcription factor NRI (NtrC), which activates glnA transcription when it is phosphorylated, the kinase/phosphatase protein NRII (NtrB) that directly controls the extent of NRI phosphorylation, the PII signal transduction protein that controls the phosphatase activity of NRII, and the uridylyltransferase/uridylyl-removing (UTase/UR) enzyme that is regulated by glutamine and controls the activity of PII. In the reconstituted system, the removal of uridylyl groups from the PII protein, catalyzed by the UTase/UR protein in the presence of glutamine, resulted in the stimulation of NRI approximately P dephosphorylation. In contrast, the uridylylated form of the PII protein had no discernible effect on NRI phosphorylation. The uridylylation of the trimeric PII protein by the monomeric UTase/UR protein is a non-cooperative reaction in which the partially modified species accumulated and were readily observed. Partially modified PII trimers were partially active in stimulating the dephosphorylation of NRI approximately P. Thus, both the PII-UTase/UR and PII-NRII interactions display the continuous variability characteristic of rheostats as opposed to the binary variability characteristic of toggle switches.

Bacterial Proteins↗

PubMed1994

The Drosophila rolled locus encodes a MAP kinase required in the sevenless signal transduction pathway.

Mitogen-activated protein (MAP) kinases have been proposed to play a critical role in receptor tyrosine kinase (RTK)-mediated signal transduction pathways. Although genetic and biochemical studies of RTK pathways in Caenorhabditis elegans, Drosophila melanogaster and mammals have revealed remarkable similarities, a genetic requirement for MAP kinases in RTK signaling has not been established. During retinal development in Drosophila, the sevenless (Sev) RTK is required for development of the R7 photoreceptor cell. Components of the signal transduction pathway activated by Sev in the R7 precursor include proteins encoded by the gap1, drk, Sos, ras1 and raf loci. In this report we present evidence that a Drosophila MAP kinase, ERK-A, is encoded by the rolled locus and is required downstream of raf in the Sev signal transduction pathway.

Animals↗

PubMed1994

Separation of oxidant-initiated and redox-regulated steps in the NF-kappa B signal transduction pathway.

Studies presented here show that overall NF-kappa B signal transduction begins with a parallel series of stimuli-specific pathways through which cytokines (tumor necrosis factor alpha), oxidants (hydrogen peroxide and mitomycin C), and phorbol ester (phorbol 12-myristate 13-acetate) individually initiate signaling. These initial pathways culminate in a common pathway through which all of the stimulating agents ultimately signal NF-kappa B activation. We distinguish the stimuli-specific pathways by showing that the oxidative stimuli trigger NF-kappa B activation in only one of two human T-cell lines (Wurzburg but not Jurkat), whereas tumor necrosis factor alpha and phorbol 12-myristate 13-acetate readily stimulate in both lines. We propose the common pathway as the simplest way of accounting for the common requirements and properties of the signaling pathway. We include a redox-regulatory mechanism(s) in this common pathway to account for the previously demonstrated redox regulation of NF-kappa B activation in Jurkat cells (in which oxidants don't activate NF-kappa B); we put tyrosine phosphorylation in the common pathway by showing that kinase activity (inhibitable by herbimycin A and tyrphostin 47) is required for NF-kappa B activation by all stimuli tested in both cell lines. Since internal sites of oxidant production have been shown to play a key role in the cytokine-stimulated activation of NF-kappa B, and since tyrosine kinase and phosphatase activities are known to be altered by oxidants, these findings suggest that intracellular redox status controls NF-kappa B activation by regulating tyrosine phosphorylation event(s) within the common step of the NF-kappa B signal transduction pathway.

Benzoquinones↗

PubMed2001

Signal transduction pathways activated by engaging immunoglobulin Fc receptors on chicken heterophils.

In the present studies, we initiated experiments to identify the signal transduction factors involved in activating phagocytosis, oxidative burst, and degranulation following the binding of IgG-opsonized SE to Fc receptors on the surface of avian heterophils. Peripheral blood heterophils were isolated and exposed to known inhibitors of signal transduction pathways for either 20min (chelerythine, genistein, or verapamil) or 120min (pertussis toxin) at 39 degrees C. The cells were then stimulated for 30min at 39 degrees C with SE opsonized with IgG purified from SE-immune chickens. Phagocytosis, luminol-dependent chemiluminescence (LDCL), and beta-D-glucuronidase release were then evaluated in vitro. The G-protein inhibitor, pertussis toxin, the protein kinase C inhibitor, chelerythine, and the Ca(++) channel blocker, verapamil, markedly reduced phagocytosis in a dose responsive manner. Genistein, a tyrosine kinase inhibitor, had no effect on the phagocytosis of the opsonized SE. Both pertussis toxin (66-98%) and verapamil (47-76%) had marked inhibitory effect on LDCL. Chelerythine (13-25%) and genistein (5-25%) had far less biologically significant effects on LDCL. Neither chelerythine nor genistein had a significant effect on degranulation. Verapamil (2-28%) and pertussis toxin (25-29%) had a moderate inhibitory effect on degranulation stimulated by IgG-opsonized SE. As was found with complement receptor mediated activation of heterophils, the binding of Fc receptors by the IgG-SE complex activated distinct signaling pathways that regulate the functional activities of avian heterophils. Pertussis toxin-sensitive, Ca(++)-dependent, G-proteins and protein kinase C-dependent protein phosphorylation play a major role in the phagocytosis of IgG-opsonized SE. Pertussis toxin-sensitive, Ca(++)-dependent, G-proteins appear to regulate LDCL following Fc receptor binding. The signal transduction inhibitors used in these studies did not affect Fc receptor mediated degranulation by avian heterophils.

Animals↗

PubMed2001

Protein kinase C epsilon-Src modules direct signal transduction in nitric oxide-induced cardioprotection: complex formation as a means for cardioprotective signaling.

An essential role for protein kinase C epsilon (PKCepsilon) has been shown in multiple forms of cardioprotection; however, there is a distinct paucity of information concerning the signaling architecture that is responsible for the manifestation of a protective phenotype. We and others have recently shown that signal transduction may proceed via the formation of signaling complexes (Circ Res. 2001;88:59-62). In order to understand if the assembly of multiprotein complexes is the manner by which signaling is conducted in cardioprotection, we designed a series of experiments to characterize the associations of Src tyrosine kinase with PKCepsilon in a conscious rabbit model of nitric oxide (NO)-induced late preconditioning. Our data demonstrate that PKCepsilon and Src can form functional signaling modules in vitro: PKCepsilon interacts with Src; the association with PKCepsilon activates Src; and adult cardiac cells receiving recombinant adenoviruses encoding PKCepsilon exhibit increased Src activity. Furthermore, our results show that NO-induced late preconditioning involved PKCepsilon-Src module formation and enhanced the enzymatic activity of PKCepsilon-associated Src. Inhibition of PKC blocked cardioprotection, module formation, and PKCepsilon-associated Src activity, providing direct evidence for a functional role of the PKCepsilon-Src module in the orchestration of NO-induced cardioprotection in conscious rabbits.

Animals↗

PubMed1996

SH2 domain function is essential for the role of the Lck tyrosine kinase in T cell receptor signal transduction.

Tyrosine kinase activity is required for signal transduction through the T cell antigen receptor (TCR). The Src family tyrosine kinase Lck appears to play a key role in the initiation of TCR signaling events. We have investigated the role of the phosphotyrosine-binding Src homology-2 (SH2), domain of Lck in TCR signaling. Lck containing a mutation in the phosphotyrosine binding pocket of the SH2 domain was expressed in an Lck-deficient cell line. We found that, in contrast to wild-type Lck, the SH2 domain mutant was unable to restore even the earliest TCR-mediated signaling events. To investigate the role of the Lck SH2 domain, we examined the association of tyrosine phosphoproteins with Lck. The predominant associated phosphoprotein was the ZAP-70 tyrosine kinase, which has also been implicated in the initiation of TCR signaling. In addition, the zeta subunit of the T cell receptor was found to weakly associate with Lck. Further analysis indicated that the SH2 domain of Lck can directly recognize both ZAP-70 and zeta in immunoprecipitates from TCR-stimulated cells. Our findings demonstrate that the SH2 domain of Lck is essential for the initiation of signaling events following TCR stimulation probably as a result of its ability to mediate an interaction between Lck and the ZAP-70 tyrosine kinase and/or the zeta subunit of the T cell receptor.

Calcium↗

PubMed1998

An essential, multicomponent signal transduction pathway required for cell cycle regulation in Caulobacter.

Cell differentiation and division in Caulobacter crescentus are regulated by a signal transduction pathway mediated by the histidine kinase DivJ and the essential response regulator DivK. Here we report genetic and biochemical evidence that the DivJ and DivK proteins function to control the activity of CtrA, a response regulator required for multiple cell cycle events, including flagellum biosynthesis, DNA replication, and cell division. Temperature-sensitive sokA (suppressor of divK) alleles were isolated as extragenic suppressors of a cold-sensitive divK mutation and mapped to the C terminus of the CtrA protein. The sokA alleles also suppress the lethal phenotype of a divK gene disruption and the cold-sensitive cell division phenotype of divJ mutants. The relationship between these signal transduction components and their target was further defined by demonstrating that the purified DivJ kinase phosphorylates CtrA, as well as DivK. Our studies also showed that phospho-CtrA activates transcription in vitro from the class II flagellar genes and that their promoters are recognized by the principal C. crescentus sigma factor sigma73. We propose that an essential signal transduction pathway mediated by DivJ, DivK, and CtrA coordinates cell cycle and developmental events in C. crescentus by regulating the level of CtrA phosphorylation and transcription from sigma73-dependent class II gene promoters. Our results suggest that an unidentified phosphotransfer protein or kinase (X) is responsible for phosphoryl group transfer to CtrA in the proposed DivJ --> DivK --> X --> CtrA phosphorelay pathway.

Alleles↗

PubMed2005

Colored Petri net modeling and simulation of signal transduction pathways.

Presented herein is a methodology for quantitatively analyzing the complex signaling network by resorting to colored Petri nets (CPN). The mathematical as well as Petri net models for two basic reaction types were established, followed by the extension to a large signal transduction system stimulated by epidermal growth factor (EGF) in an application study. The CPN models based on the Petri net representation and the conservation and kinetic equations were used to examine the dynamic behavior of the EGF signaling pathway. The usefulness of Petri nets is demonstrated for the quantitative analysis of the signal transduction pathway. Moreover, the trade-offs between modeling capability and simulation efficiency of this pathway are explored, suggesting that the Petri net model can be invaluable in the initial stage of building a dynamic model.

Algorithms↗

PubMed2002

Signal transduction abnormalities in schizophrenia: the cAMP system.

Understanding the neurochemistry of schizophrenia involves the study, not only of neurotransmitters and their receptors, but also of the signal transduction systems that translate their actions into neural activity. Of particular interest is the signal transduction system involving the second messenger cyclic adenosine monophosphate (cAMP), as all dopamine receptors are either positively or negatively coupled to this system. Studies in blood platelets, cerebrospinal fluid, or postmortem brains of patients with schizophrenia demonstrate abnormalities of stimulated cAMP production. Neuroleptic administration in animal models results in altered cAMP metabolism in a pattern opposite to that seen in schizophrenic patients. These studies suggest that abnormal signal transduction may be involved in the pathogenesis of schizophrenia and that the normalization of this defect may be one mechanism of action of neuroleptic drugs.

Animals↗

PubMed2001

Signal transduction pathways through TRK-A and TRK-B receptors in human neuroblastoma cells.

Little is known about the signal transduction pathways of TRK family receptors in neuroblastoma (NB) cells. In this study, an NB cell line, designated MP-N-TS, was established from an adrenal tumor taken from a 2-year-old boy. This cell line expressed both TRK-A and TRK-B receptors, which is rare in a single NB cell line. Therefore, the MP-N-TS cell line was used to determine whether the signal transduction through these constitutive receptors is functional. Three neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-4 / 5 (NT-4 / 5), induced tyrosine phosphorylation of panTRK, and BDNF and NT-4 / 5 induced tyrosine phosphorylation of TRK-B. Tyrosine phosphorylation of panTRK and / or TRK-B by the neurotrophins was inhibited in the presence of a tyrosine kinase inhibitor K252a. Tyrosine phosphorylation of Src homologous and collagen (Shc), extracellular signal-regulated kinase (ERK)-1 and ERK-2, and phospholipase C-gamma1 (PLC-gamma1) was increased by the three neurotrophins and the increase was inhibited in the presence of K252a. Activation of Ras, detected as the GTP-bound form of Ras, was induced by the three neurotrophins. The neurotrophins did not modulate the expressions of TRK-A or TRK-B mRNA, but they did induce the expression of c-fos mRNA. Exogenous NGF induced weak neurite outgrowth, whereas exogenous BDNF and NT-4 / 5 induced distinct neurite outgrowth. Exogenous BDNF and NT-4 / 5 increased the number of viable cells, while NGF did not. Our results demonstrate that the signal transduction pathways through TRK-A and TRK-B in MP-N-TS cells are functional and similar, and the main downstream signaling pathways from the three neurotrophins are mitogen-activated protein kinase (MAPK) cascades through Shc, activated Ras, ERK-1 and ERK-2, and the transduction pathway through PLC-gamma1. Further, BDNF and NT-4 / 5 increased cell viability. The MP-N-TS cell line should be useful for clarifying the TRK-A and TRK-B signaling pathways responsible for the different prognoses in patients with NB.

Adrenal Gland Neoplasms↗

PubMed2001

14-3-3 is involved in p75 neurotrophin receptor-mediated signal transduction.

The low affinity neurotrophin receptor (p75NTR) has been shown to mediate the apoptosis signaling to neural cells. However, the specific mechanisms of intracellular signal transduction of this process are largely unknown. To understand p75NTR-mediated signal transduction, we previously identified a protein that interacts with the intracellular domain of p75NTR, and we named it p75NTR-associated cell death executor (NADE). To elucidate further the signaling mechanisms utilized by p75NTR and NADE, we screened for NADE-binding protein(s) with the yeast two-hybrid method, and we identified 14-3-3epsilon as a NADE-binding protein in vivo. To examine whether 14-3-3epsilon affects the induction of p75NTR-mediated apoptosis, wild type or various deletion mutant forms of 14-3-3epsilon were co-expressed in HEK293, PC12nnr5, and oligodendrocytes. Interestingly, transient expression of the mutant form of 14-3-3epsilon lacking the 208-255 amino acid region blocked nerve growth factor-dependent p75NTR/NADE-mediated apoptosis, although this mutant form of 14-3-3epsilon continued to associate with NADE. These results suggest that 14-3-3epsilon plays an important role in the modulation of nerve growth factor-dependent p75NTR/NADE-mediated apoptosis.

14-3-3 Proteins↗

PubMed2000

Impaired leptin signal transduction with age-related obesity.

Leptin contributes to the regulation of both food intake and energy expenditure. We previously demonstrated that the F-344xBN rat, a rodent model for late-onset obesity, is leptin resistant, suggesting that leptin signal transduction may be impaired in these aged, overweight rats. To test this hypothesis, we examined the in vivo dose-response and time-course response of leptin-induced STAT3 activation (phosphorylation and binding activity to the SIE M67 oligonucleotide) in the hypothalamus of young rats along with the dose-response leptin-induced STAT3 phosphorylation (P-STAT3) and maximum increase in binding activity in young and aged rats. In young rats there was a dose (0-1 mg, iv) and time dependent increase in P-STAT3 and in P-STAT3 binding activity. P-STAT3 paralleled the rise and fall in serum leptin levels with P-STAT3 elevated for at least 4 h with return to basal levels by 14 h after 1 mg leptin. The maximum level of leptin-induced P-STAT3 was unchanged with age, but the dose for half maximal phosphorylation was greater in aged (138 microg) compared with young (26 microg) rats. In addition, the leptin-induced increase in P-STAT3 transcription factor binding was diminished in aged rats. These data suggest that leptin signal transduction, in vivo, demonstrate a time and dose response increase paralleling the rise and fall in serum leptin, suggesting that serum leptin levels are the most important factor in determining leptin-induced phosphorylation of STAT3 in the hypothalamus. In addition, aged, overweight rats demonstrate reduced signal transduction in response to leptin, with reduced sensitivity for STAT3 phosphorylation and diminished leptin-induced P-STAT3 transcription factor binding. This impaired leptin signal transduction may be due to either the elevated obesity with age or due to age itself or both.

Aging↗

PubMed1988

Aspects of signal transduction in stimulus exocytosis-coupling in Paramecium.

This paper deals with the detailed mechanisms of signal transduction that lead to exocytosis during regulative secretion induced by specific secretagogues in a eukaryotic cell, Paramecium tetraurelia. There are at least three cellular compartments involved in the process: I) the plasma membrane, which contains secretagogue receptors and other transmembrane proteins, II) the cytoplasms, particularly in the region between the cell and secretory vesicle membranes, where molecules may influence interactions of the membranes, and III) the secretory vesicle itself. The ciliated protozoan Paramecium tetraurelia is very well suited for the study of signal transduction events associated with exocytosis because this eukaryotic cell contains thousands of docked secretory vesicles (trichocysts) below the cell membrane which can be induced to release synchronously when triggered with secretagogue. This ensures a high signal-to-noise ratio for events associated with this process. Upon release the trichocyst membrane fuses with the cell membrane and the trichocyst content undergoes a Ca2+-dependent irreversible expansion. Secretory mutants are available which are blocked at different points in the signal transduction pathway. Aspects of the three components mentioned above that will be discussed here include a) the properties of the vesicle content, its pH, and its membrane; b) the role of phosphorylation/dephosphorylation of a cytosolic 63-kilodalton (kDa)Mr protein in membrane fusion; and c) how influx of extracellular Ca2+ required for exocytosis may take place via exocytic Ca2+ channels which may be associated with specific membrane microdomains (fusion rosettes).

Animals↗

PubMed1997

Signal transduction via glycosyl phosphatidylinositol-anchored proteins in T cells is inhibited by lowering cellular cholesterol.

Glycosylphosphatidylinositol (GPI)-anchored proteins can deliver costimulatory signals to lymphocytes, but the exact pathway of signal transduction involved is not yet characterized. GPI-anchored proteins are fixed to the cell surface solely by a phospholipid moiety and are clustered in distinct membrane domains that are formed by an unique lipid composition requiring cholesterol. To elucidate the role of membrane lipids for signal transduction via GPI-anchored proteins, we studied the influence of reduced cellular cholesterol content on calcium signaling via GPI-anchored CD59 and CD48 in Jurkat T cells. Lowering cholesterol by different inhibitors of cellular cholesterol synthesis suppressed calcium response via GPI-anchored proteins by about 50%, whereas stimulation via CD3 was only minimally affected (<10%). The decrease in overall calcium response via GPI-anchored proteins was reflected by inhibition of calcium release from intracellular stores. Cell surface expression of GPI-anchored proteins was not changed quantitatively by lowering cellular cholesterol, and neither was the pattern of immunofluorescence in microscopic examination. In addition, the distribution of GPI-anchored proteins in detergent-insoluble complexes remained unaltered. These results suggest that cellular cholesterol is an important prerequisite for signal transduction via GPI-anchored proteins beyond formation of membrane domains.

CD59 Antigens↗

PubMed1997

Surface expression of hemopoietic cell phosphatase fails to complement CD45 deficiency and inhibits TCR-mediated signal transduction in a Jurkat T cell clone.

Previous studies have shown that the protein tyrosine phosphatase CD45 is required for initiation of signal transduction through several lymphoid receptors. In contrast, there is increasing evidence that another protein tyrosine phosphatase, hemopoietic cell phosphatase (known as HCP, SHP, PTP1C, SHPTP-1, or PTPN6), is a negative regulator of signaling in hemopoietic cells. To determine the effect of HCP on signal transduction through the TCR, HCP was expressed as a chimeric molecule with extracellular and transmembrane domains of the HLA-A2 molecule (A2/HCP) on wild-type Jurkat T cells and the CD45-deficient variant, J45.01. In this report, we show that expression of A2/HCP, unlike A2 chimeras containing the enzymatic regions of CD45, fails to rescue TCR-mediated signal transduction in J45.01. Furthermore, expression of A2/HCP on wild-type Jurkat T cells results in diminished inositol phosphate production following TCR ligation as well as markedly diminished nuclear factor of activated T cells promoter activity. Surprisingly, however, TCR-mediated tyrosine phosphorylation of phospholipase C gamma 1 remains intact in the Jurkat cells expressing the A2/HCP chimera. These experiments provide further evidence that HCP can serve a negative regulatory role in receptor-mediated signaling in immune cells. Additionally, our studies suggest that surface expression of HCP in T cells may provide a means to identify phosphotyrosine-containing proteins that are required for coupling signaling pathways initiated by ligation of the T cell Ag receptor.

Calcium↗

PubMed2000

The suppression of small GTPase rho signal transduction pathway inhibits angiogenesis in vitro and in vivo.

Angiogenesis consists of multistep pathways such as the degradation of the matrix, proliferation of the endothelial cells, motility of the endothelial cells, formation of the cord structure and network formation of microvessels. The small GTPase Rho participates in cell motility through actin fiber polymerization. The role of the small GTPase Rho signal transduction pathway in regulating angiogenesis, however, is still unknown. In this study, we investigated the role of the small GTPase Rho signal transduction pathway in angiogenesis in vitro and in vivo using the exoenzyme, Clostridium botulinum C3 transferase, which specifically suppresses Rho and a compound, Y-27632, which suppresses p160ROCK (Rho-associated coiled-coil containing protein kinase). In this paper, we showed that the small GTPase Rho-p160ROCK signal transduction pathway played an important role in angiogenesis both in vitro and in vivo. These results suggest that inhibition of the small GTPase Rho signal transduction pathway by the p160ROCK inhibitor could be a possible new strategy for angiogenic diseases.

Amides↗

PubMed2006

Beyond microarrays: find key transcription factors controlling signal transduction pathways.

BACKGROUND: Massive gene expression changes in different cellular states measured by microarrays, in fact, reflect just an "echo" of real molecular processes in the cells. Transcription factors constitute a class of the regulatory molecules that typically require posttranscriptional modifications or ligand binding in order to exert their function. Therefore, such important functional changes of transcription factors are not directly visible in the microarray experiments. RESULTS: We developed a novel approach to find key transcription factors that may explain concerted expression changes of specific components of the signal transduction network. The approach aims at revealing evidence of positive feedback loops in the signal transduction circuits through activation of pathway-specific transcription factors. We demonstrate that promoters of genes encoding components of many known signal transduction pathways are enriched by binding sites of those transcription factors that are endpoints of the considered pathways. Application of the approach to the microarray gene expression data on TNF-alpha stimulated primary human endothelial cells helped to reveal novel key transcription factors potentially involved in the regulation of the signal transduction pathways of the cells. CONCLUSION: We developed a novel computational approach for revealing key transcription factors by knowledge-based analysis of gene expression data with the help of databases on gene regulatory networks (TRANSFAC and TRANSPATH. The corresponding software and databases are available at http://www.gene-regulation.com.

Binding Sites↗

PubMed1994

Signal transduction by lymphocyte antigen receptors.

Despite the differences in the antigens that they recognize and in the effector functions they carry out, B and T lymphocytes utilize remarkably similar signal transduction components to initiate responses. They both use oligomeric receptors that contain distinct recognition and signal transduction subunits. Antigen receptors on both cells interact with at least two distinct families of PTKs via common sequence motifs, ARAMs, in the cytoplasmic tails of their invariant chains, which have likely evolved from a common evolutionary precursor. Coreceptors appear to serve to increase the sensitivity of both of these receptor systems through events that influence ligand binding and signal transduction. The critical role of tyrosine phosphorylation of downstream signaling components, such as phospholipase C, is the net result of changes in the balance of the action of antigen receptor-regulated PTKs and PTPases. The identification of downstream effectors, including calcineurin and Ras, that regulate cellular responses, such as lymphokine gene expression, promises the future possibility of connecting the complex pathway from the plasma membrane to the nucleus in lymphocytes. Insight gained from studies of the signaling pathways downstream of TCR and BCR stimulation is likely to contribute significantly to future understanding of mechanisms responsible for lymphocyte differentiation and for the discrimination of self from nonself in developing and mature cells.

Amino Acid Sequence↗