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Results for “Signal Transduction”

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At least 397 records · Page 22Linked to original sources

PubMed1998

Involvement of a putative G-protein-coupled receptor and a branching pathway in argipressin (4-8) signal transduction in rat hippocampus.

AIM: To study the signal transduction pathway induced by argipressin (4-8) (AVP4-8) in rat hippocampus. METHODS: Rat hippocampi were sectioned transversely at 300 microns with a tissue chopper and transferred to fresh incubation solution circulated with a humidified gas mixture of 95% O2 + 5% CO2 at 36 +/- 0.5 degrees C. After incubation with various drugs, MAP kinase (MAPK) activity and Ca2+/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation were measured. RESULTS: The main findings are: (1) The AVP4-8-stimulated MAPK activity and the CaMKII autophosphorylation were blocked by ZDC(C)PR, an antagonist of AVP4-8, and also completely inhibited by pertussis toxin, a selective inhibitor of the G-protein-coupled receptor (GPCR). But, AVP-induced MAPK activation was not sensitive to ZDC(C)PR or PTX. (2) Polymyxin B (PMB), an inhibitor of protein kinase C (PKC), markedly suppressed the peptide-activation of MAPK, but did not affect CaMKII autophosphorylation. Phorbol myristate acetate (TPA), an activator of PKC, elicited an increase of MAPK activity, but did not further influence the level of AVP4-8-enhanced MAPK activity; Nevertheless, the extent of CaMKII activation was attenuated by TPA. (3) The enhancement of MAPK activity was not reduced by KN-62, a specific inhibitor of CaMKII. (4) AVP4-8 did not show any influence on cAMP production. CONCLUSION: AVP4-8 stimulated signal transduction via a GPCR and a branching pathway in rat hippocampus.

Animals↗

PubMed2005

Involvement of a Che-like signal transduction cascade in regulating cyst cell development in Rhodospirillum centenum.

Homologues of the E. coli chemotaxis (Che) signal transduction pathway are present in nearly all motile bacteria. Although E. coli contains only one Che cascade, many other bacteria are known to possess multiple sets of che genes. The role of multiple che-like gene clusters could potentially code for parallel Che-like signal transduction pathways that have distinctly different input and output functions. In this study, we describe a che-like gene cluster in Rhodospirillum centenum that controls a developmental cycle. In-frame deletion mutants of homologues of CheW (DeltacheW(3a)and DeltacheW(3b)), CheR (DeltacheR(3)), CheA (DeltacheA(3)) and a methyl-accepting chemotaxis protein (Deltamcp(3)) are defective in starvation-induced formation of heat and desiccation resistant cyst cells. In contrast, mutants of homologues of CheY (DeltacheY(3)), CheB (DeltacheB(3)), and a second input kinase designated as CheS (DeltacheS(3)) result in cells that are derepressed in the formation of cysts. A model of signal transduction is presented in which there are three distinct Che-like signal transduction cascades; one that is involved in chemotaxis, one that is involved in flagella biosynthesis and the third that is involved in cyst development.

Bacterial Proteins↗

PubMed1998

Molecular aspects of adrenergic signal transduction in cardiac failure.

Abnormal beta-adrenergic signal transduction and intracellular Ca2+ handling appear to be a major cause of systolic and diastolic dysfunction in humans with heart failure. The precise mechanisms which cause an alteration in Ca2+ handling have been a subject of investigation in recent years. Several lines of evidence suggest that activation of neurohormonal systems plays a central role. Altered Ca2+-handling (increased diastolic concentrations, reduced systolic Ca2+ release) have a strong impact on diastolic and systolic performance of failing hearts. Sarcoplasmic reticulum Ca2+ ATPase is reduced in activity and in steady-state mRNA concentration. The Na+-Ca2+ exchanger is upregulated at the mRNA and protein levels. Phospholamban depends strongly on cAMP-dependent phosphorylation. A strong sympathetic activation has been shown to desensitize the cAMP system. At the receptor level, there is downregulation of beta1-adrenergic receptors. An uncoupling of beta2-adrenoceptors has been attributed to an increased activity and gene expression of beta-adrenergic receptor kinase in failing myocardium, leading to phosphorylation and uncoupling of receptors. Finally, recent evidence suggests that cAMP-dependent transcription mechanisms may play a role during beta-adrenergic stimulation and cardiomyopathy with heart failure - by means of altered actions of cAMP response element binding protein, the cAMP response element modulator, or the activating transcription factor 1. The exact characterization of signal transduction defects could offer novel approaches to the pharmacological treatment of heart failure.

Animals↗

PubMed1998

Signal transduction pathways activated by the IL-1 receptor family: ancient signaling machinery in mammals, insects, and plants.

Interleukin-1 (IL-1) is a central regulator of the immune and inflammatory responses. Recently, significant advances have been made in the area of IL-1 receptors and IL-1 signal transduction. A family of proteins has been described that share significant homology in their signaling domains with the Type I IL-1 receptor (IL-1RI). These include the IL-1 receptor accessory protein (IL-1AcP), which does not bind IL-1 but is essential for IL-1 signaling; a Drosophila protein Toll; a number of human Toll-like receptors (hTLRs); the putative IL-18/IL-1-gamma receptor IL-1Rrp (IL-1 receptor-related protein); and a number of plant proteins. All appear to be involved in host responses to injury and infection. These homologies also extend to novel signaling proteins implicated in IL-1 action. Two IL-1 receptor-associated kinases, IRAK-1 and IRAK-2, which have homologs in Drosophila (Pelle) and plants (Pto), have been implicated in the activation of the transcription factor, nuclear factor kappaB (NF-kappaB). IRAK-1 has also been implicated in AP1 induction, Jun amino-terminal kinase (JNK) activation, and IL-2 induction. It recruits the adapter protein TRAF6 to the IL-1 receptor complex via an interaction with IL-1AcP. TRAF6 then relays the signal via NF-kappaB-inducing kinase (NIK) to two I-kappaB kinases (IKK-1 and -2), leading to NF-kappaB activation. Progress has also been made on other IL-1-responsive kinases, including JNK and p38 MAP kinase, with the latter having a role in multiple responses to IL-1. The remarkable conservation between diverse species indicates that the IL-1 system represents an ancient signaling machine critical for responses to environmental stresses and attack by pathogens.

Amino Acid Sequence↗

PubMed2005

Signal transduction pathway profiling of individual tumor samples.

BACKGROUND: Signal transduction pathways convey information from the outside of the cell to transcription factors, which in turn regulate gene expression. Our objective is to analyze tumor gene expression data from microarrays in the context of such pathways. RESULTS: We use pathways compiled from the TRANSPATH/TRANSFAC databases and the literature, and three publicly available cancer microarray data sets. Variation in pathway activity, across the samples, is gauged by the degree of correlation between downstream targets of a pathway. Two correlation scores are applied; one considers all pairs of downstream targets, and the other considers only pairs without common transcription factors. Several pathways are found to be differentially active in the data sets using these scores. Moreover, we devise a score for pathway activity in individual samples, based on the average expression value of the downstream targets. Statistical significance is assigned to the scores using permutation of genes as null model. Hence, for individual samples, the status of a pathway is given as a sign, + or -, and a p-value. This approach defines a projection of high-dimensional gene expression data onto low-dimensional pathway activity scores. For each dataset and many pathways we find a much larger number of significant samples than expected by chance. Finally, we find that several sample-wise pathway activities are significantly associated with clinical classifications of the samples. CONCLUSION: This study shows that it is feasible to infer signal transduction pathway activity, in individual samples, from gene expression data. Furthermore, these pathway activities are biologically relevant in the three cancer data sets.

Breast Neoplasms↗

PubMed1997

A system for simultaneous evaluation of the effect of signal transduction inhibitors on interleukin-2 synthesis and cell viability in a human T cell line.

BACKGROUND: The signal transduction pathways involved in interleukin-2 (IL-2) synthesis have become a focus of interest for pharmacological intervention. Regulation of synthesis of IL-2 requires costimulation of two cell surface receptors, the T cell receptor and an appropriate costimulatory receptor. Antibodies such as anti-CD3 to stimulate the T cell receptor and anti-CD28 can be used to induce this costimulation. Previous methodologies employed antibody coupled to polystyrene microtiter plates or solution phase stimulation. METHODS: Here, a method using magnetic beads to present anti-CD3 and anti-CD28, to the Jurkat T cell line was developed. Conditions were also developed for simultaneous analysis of the effect of test compounds on cell viability. The IL-2 synthesis methods and cell viability methods have been used to evaluate signal transduction inhibitors. RESULTS: This method was then employed to test the effects of various signal transduction inhibitors on IL-2 synthesis. Agents which increase cAMP, cyclosporin and inhibitors of calmodulin, tyrosine kinases/phosphatases, protein kinase C, and PC-PL-C decrease IL-2 synthesis at concentrations which do not affect cell viability. CONCLUSION: These results found with this novel system of stimulation with antibody to CD3 and CD28 compare favorably with activities reported in the literature thus validating this rapid facile system for evaluation of the effect of signal transduction inhibitors in IL-2 synthesis.

Antibodies↗

PubMed1997

Signal transduction pathways for serotonin as an intestinal secretagogue.

This review presents a signal transduction pathways for serotonin (5-hydroxytryptamine, 5-HT) as an intestinal secretagogue and some recently published related findings. 5-HT is a secretagogue in the small and large intestine of all studied species including pig and man. 5-HT mediates intestinal secretion through activation of at least the epithelial 5-HT2, and neuronal 5-HT3, and 5-HT4 receptors in the submucosal plexus, including a reflex arc. 5-HT activates both a cholinergic and a non-cholinergic pathway in its secretory response. Intracellular mediators include at least eicosanoids (prostaglandin E2), calcium, phosphoinositols (1,4,5-inositol trisphosphate) and maybe nitric oxide and cyclic nucleotides. Pig small intestine appears to be an appropriate model for the human small intestine with respect to the signal transduction pathways for 5-HT as an intestinal secretagogue. Species and segmental differences in the signal transduction pathways for 5-HT as an intestinal secretagogues are discussed together with related news on 5-HT receptors, 5-HT antagonists in clinical use, the enteric nervous system, and intracellular mediators.

Animals↗

PubMed2003

Histidine kinases and histidine phosphorylated proteins in mammalian cell biology, signal transduction and cancer.

Intensive investigation of protein tyrosine, serine and threonine phosphorylation has lead to advances in signal transduction research and cancer treatment. This feature summarizes research on mammalian proteins exhibiting histidine phosphorylation. Histidine kinases are well known in prokaryotic and lower eukaryotic systems where they form the 'two-component' signal transduction system. The relative invisibility of histidine phosphorylation in mammalian cells may result from technical obstacles such as its acid lability, which precludes detection in electrophoretic systems, amino acid sequencing, etc. Emerging data have identified mammalian histidine kinases for the kinase suppressor of ras, a scaffold molecule for the Map kinase pathway, as well as histone H4, aldolase C and the beta-subunit of heterotrimeric G proteins. Additional mammalian proteins of interest to signal transduction and cancer research exhibit histidine phosphorylation, including P-selectin, annexin I and the 20S proteasome. Other candidate histidine phosphorylated proteins are identified. These data suggest the existence of another series of phosphorylation patterns in signal transduction.

Animals↗

PubMed1991

Inhibition of platelet-derived growth factor-mediated signal transduction by transforming ras. Suppression of receptor autophosphorylation.

The function of ras protein and its relationship to growth-factor mediated signal transduction remain unclear. The demonstration that the expression of transforming ras (v-ras) can block the stimulation of growth-related gene expression and cell division mediated by the platelet-derived growth factor (PDGF) may provide a model for the functional interation of ras with growth factor receptors. In the current studies, we have demonstrated that this blockade by v-ras of PDGF-BB signal transduction occurs very early in signal transduction, at the level of PDGF receptor autophosphorylation. Although the expression of PDGF receptor as detected by Western blot with anti-PDGF receptor antibody was not diminished in v-ras-transformed murine Balb/c 3T3 fibroblasts, the autophosphorylation of PDGF receptor in response to ligand (recombinant PDGF-BB homodimer) stimulation was profoundly suppressed. This same phenomenon of v-ras-mediated PDGF receptor autophosphorylation inhibition was also demonstrated in normal rat kidney fibroblasts. Further, factor(s) present in v-ras-expressing fibroblasts found in the membrane fractions of these cells can dominantly inhibit the autophosphorylation of the PDGF receptor obtained from normal fibroblasts. These findings suggest a role for ras in one of the earliest steps of the signal transduction pathway.

Animals↗

PubMed2000

A cellular automaton model of cellular signal transduction.

On the basis of cellular automata models, a software specifically tailored to model biochemical reactions involved in cellular signal transduction was implemented on a personal computer. Recent data regarding desensitization processes in mouse Leydig cells are used to simulate the underlying reactions of signal transduction. Pretreatment of real Leydig cells with different molecules results in a modification of the signal transduction cascade leading to a diminished response of the cells during subsequent stimulations. The model is capable of simulating the complex behavior of this intracellular second messenger production in a qualitative and semi-quantitative way. The results indicate that quantitative simulations on a molecular level will be possible once appropriate computer hardware is available. The simulations and results of the cellular automaton presented are easily described and comprehended, which make it a useful tool that will facilitate research in cellular signal transduction and other fields covering complex reaction networks.

Adenylyl Cyclases↗

PubMed2003

[Insulin signal transduction disorder and development of insulin resistance].

Insulin action is initiated through the binding to its cell-surface receptor, stiring up a series of signal transduction and eventually reach various effectors which produce various physiological effects. Insulin signal transduction is crucial to insulin action. Impairment of insulin signal transduction results in attenuation of insulin action and finally leads to insulin resistance. This article reviewed the function of insulin signal transduction disorder in the development of insulin resistance.

Animals↗

PubMed2003

An integrated model of epidermal growth factor receptor trafficking and signal transduction.

Endocytic trafficking of many types of receptors can have profound effects on subsequent signaling events. Quantitative models of these processes, however, have usually considered trafficking and signaling independently. Here, we present an integrated model of both the trafficking and signaling pathway of the epidermal growth factor receptor (EGFR) using a probability weighted-dynamic Monte Carlo simulation. Our model consists of hundreds of distinct endocytic compartments and approximately 13,000 reactions/events that occur over a broad spatio-temporal range. By using a realistic multicompartment model, we can investigate the distribution of the receptors among cellular compartments as well as their potential signal transduction characteristics. Our new model also allows the incorporation of physiochemical aspects of ligand-receptor interactions, such as pH-dependent binding in different endosomal compartments. To determine the utility of this approach, we simulated the differential activation of the EGFR by two of its ligands, epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-alpha). Our simulations predict that when EGFR is activated with TGF-alpha, receptor activation is biased toward the cell surface whereas EGF produces a signaling bias toward the endosomal compartment. Experiments confirm these predictions from our model and simulations. Our model accurately predicts the kinetics and extent of receptor downregulation induced by either EGF or TGF-alpha. Our results suggest that receptor trafficking controls the compartmental bias of signal transduction, rather than simply modulating signal magnitude. Our model provides a new approach to evaluating the complex effect of receptor trafficking on signal transduction. Importantly, the stochastic and compartmental nature of the simulation allows these models to be directly tested by high-throughput approaches, such as quantitative image analysis.

Cell Line↗

PubMed2000

LDL-receptor-related proteins in Wnt signal transduction.

The Wnt family of secreted signalling molecules are essential in embryo development and tumour formation. The Frizzled (Fz) family of serpentine receptors function as Wnt receptors, but how Fz proteins transduce signalling is not understood. In Drosophila, arrow phenocopies the wingless (DWnt-1) phenotype, and encodes a transmembrane protein that is homologous to two members of the mammalian low-density lipoprotein receptor (LDLR)-related protein (LRP) family, LRP5 and LRP6 (refs 12-15). Here we report that LRP6 functions as a co-receptor for Wnt signal transduction. In Xenopus embryos, LRP6 activated Wnt-Fz signalling, and induced Wnt responsive genes, dorsal axis duplication and neural crest formation. An LRP6 mutant lacking the carboxyl intracellular domain blocked signalling by Wnt or Wnt-Fz, but not by Dishevelled or beta-catenin, and inhibited neural crest development. The extracellular domain of LRP6 bound Wnt-1 and associated with Fz in a Wnt-dependent manner. Our results indicate that LRP6 may be a component of the Wnt receptor complex.

Animals↗

PubMed1995

Membrane alterations as causes of impaired signal transduction in Alzheimer's disease and aging.

Changes in cell-membrane composition in normal aging and in Alzheimer's and other age-related diseases appear to result in impaired neurotransmitter-triggered signal transduction. The impaired signal transduction seems to be related to dysfunctions in the coupling of G proteins to their receptors and effectors. Direct demonstration of altered physiochemical properties of brain tissue of patients with Alzheimer's disease has been achieved by small-angle X-ray diffraction. In this disease, thinner membranes correlate with a 30% decrease in moles of cholesterol:phospholipid. Such changes can affect directly the coupling and uncoupling properties of G proteins, and can account for signal transduction deficits. These findings offer a complementary alternative to the beta-amyloid hypothesis, and an opportunity to consider new types of therapeutic interventions.

Aging↗

PubMed1995

Endosomes, receptor tyrosine kinase internalization and signal transduction.

Upon the binding of insulin or epidermal growth factor to their cognate receptors on the liver parenchymal plasmalemma, signal transduction and receptor internalization are near co-incident. Indeed, the rapidity and extent of ligand mediated receptor internalization into endosomes in liver as well as other organs predicts that signal transduction is regulated at this intracellular locus. Although internalization has been thought as a mechanism to attenuate ligand mediated signal transduction responses, detailed studies of internalized receptors in isolated liver endosomes suggest an alternative scenario whereby selective signal transduction pathways can be accessed at this locus.

Animals↗

PubMed2000

A positive role for the PP2A catalytic subunit in Wnt signal transduction.

Protein phosphatase-2A (PP2A) is a multisubunit serine/threonine phosphatase involved in intracellular signaling, gene regulation, and cell cycle progression. Different subunits of PP2A bind to Axin and Adenomatous Polyposis Coli, components of the Wnt signal transduction pathway. Using early Xenopus embryos, we studied how PP2A functions in Wnt signal transduction. The catalytic subunit of PP2A (PP2A-C) potentiated secondary axis induction and Siamois reporter gene activation by Dishevelled, a component of the Wnt pathway, indicating a positive regulatory role of this enzyme in Wnt signaling. In contrast, small t antigen, an antagonist of PP2A-C, inhibited Dishevelled-mediated signal transduction, as did the regulatory PP2A-B'epsilon subunit, consistent with the requirement of PP2A function in this pathway. Although Wnt signaling is thought to occur via regulation of beta-catenin degradation, PP2A-C did not significantly affect beta-catenin stability. Moreover, the pathway activated by a stabilized form of beta-catenin was sensitive to PP2A-C and its inhibitors, suggesting that PP2A-C acts downstream of beta-catenin. Because previous work has suggested that PP2A can act upstream of beta-catenin, we propose that PP2A regulates the Wnt pathway at multiple levels.

Adaptor Proteins, Signal Transducing↗

PubMed1995

Lipopolysaccharide (LPS) signal transduction and clearance. Dual roles for LPS binding protein and membrane CD14.

Under physiological conditions, lipopolysaccharide (LPS) activation of cells involves the LPS binding protein (LBP) and either membrane or soluble CD14. We find LPS forms a ternary complex with LBP and membrane CD14 (mCD14). Subsequent to complex formation and distinct from signal transduction, LBP and LPS internalize. Internalization can be separated from signal transduction with the anti-LBP antibody 18G4 and the anti-CD14 antibody 18E12. 18G4 inhibits LBP binding to mCD14 without blocking signal transduction or LPS transfer to soluble CD14; 18E12 inhibits signal transduction without affecting LPS binding and uptake. These data show that while LPS signal transduction and LPS clearance utilize both LBP and mCD14, the pathways bifurcate after LPS binding to mCD14.

Acute-Phase Proteins↗

PubMed1992

Two different signal transductions of neuropeptide Y1 receptor in SK-N-MC cells.

The signal transduction systems of the neuropeptide Y (NPY) Y1 receptor were studied in SK-N-MC human neuroblastoma cells. NPY induced an increase in intracellular calcium ion concentration ([Ca2+]i) and inhibition of forskolin-stimulated cyclic AMP accumulation, which were mediated through Y1 receptors. One-min preincubation of cells with phorbol 12-myristate 13-acetate (PMA) inhibited both signal transductions dose-dependently, but its effect on [Ca2+]i was about 100-fold more potent than that on cyclic AMP. PMA had no effect on [125I]BH-NPY binding in SK-N-MC cells and hardly inhibited the endothelin-1-induced increase in [Ca2+]i. Pertussis toxin also inhibited the NPY-induced [Ca2+]i increase 30-fold more effectively than the NPY-mediated inhibition of cyclic AMP accumulation. These results indicate that Y1 receptors in SK-N-MC cells couple to two signal transduction systems that have different sensitivities to phorbol ester and pertussis toxin treatments.

Alkaloids↗