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Results for “Signal Transduction”

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PubMed1997

The immunoreceptor tyrosine-based activation motif of Epstein-Barr virus LMP2A is essential for blocking BCR-mediated signal transduction.

The Epstein-Barr virus (EBV) latent membrane protein 2A (LMP2A) blocks B-cell receptor (BCR) signal transduction in EBV-immortalized B lymphocytes in vitro. The cytoplasmic amino-terminal domain of LMP2A contains an immunoreceptor tyrosine activation motif (ITAM). ITAMs consist of paired tyrosine and leucine residues and play a central role in signal transduction of the BCR and the T-cell receptor (TCR). To investigate the importance of the LMP2A ITAM, two EBV recombinants were constructed, each containing a tyrosine-to-phenylalanine point mutation at amino acid 74 or 85 within the ITAM of LMP2A. Tyrosine phosphorylation, calcium mobilization, and induction of BZLF1 expression were no longer blocked in the LMP2A ITAM mutant LCLs following BCR cross-linking. In addition, the Syk protein tyrosine kinase (PTK) was unable to bind LMP2A in unstimulated LCLs infected with either of the LMP2A ITAM mutants. Analysis of Syk phosphorylation before and after BCR cross-linking in the LMP2A mutant ITAM LCLs compared with wild-type EBV LCLs indicates a specific role of the LMP2A ITAM on the LMP2A-mediated negative effect on the Syk PTK. These data indicate the importance of the LMP2A ITAM motif in the LMP2A-mediated block on BCR signal transduction and position the role of the Syk PTK as being central to the function of LMP2A.

Amino Acid Sequence↗

PubMed1995

Two-component signal-transduction systems in budding yeast MAP a different pathway?

Until recently, two-component signal-transduction pathways were thought to be exclusively found in bacteria. Some eukaryotic examples have now been characterized but, at least in the budding yeast Saccharomyces cerevisiae, it appears that this type of signal-transduction pathway is not utilized as extensively as in bacteria. Further, the few eukaryotic examples described suggest that two-component signal-transduction pathways might not be freestanding, as in prokaryotes, but might effect gene expression by regulating eukaryotic mitogen-activated protein (MAP) kinase pathways.

Journal Article↗

PubMed2001

[Development of new antidiabetic drugs through the advanced knowledge of molecular biology in insulin signal transduction].

The advancement of molecular biology in the field of insulin signal transduction is remarkable and the knowledge acquired through the recent research can be applied to the development of new antidiabetic drugs. There are several serine-threonine kinases and tyrosine phosphatases which can decrease insulin action at the state of diabetes and adipocytokines, which are produced from enlarged adipocytes, may affect insulin signal transduction. To prevent these proteins and cytokines from suppressing insulin action, specific molecular targets could be identified and the new agents can be developed for the normal insulin signaling and the development of new antidiabetic drugs is ongoing at present time.

Adipocytes↗

PubMed1994

Signal transduction in host cells mediated by glycosylphosphatidylinositols of the parasitic protozoa, or why do the parasitic protozoa have so many GPI molecules?

Considerable circumstantial evidence indicates that glycosylphosphatidylinositol (GPI) molecules of mammalian origin are able to mediate signal transduction in lymphoid cells. For example, perturbation of GPI-anchored surface proteins, but not transmembrane forms of these molecules, can lead to the activation of T lymphocytes. GPIs appear also to be precursors of pharmacologically active phosphoinositol-glycans which mediate responses to hormones such as insulin, nerve growth factor and IL-2. Nonetheless, the biochemical mechanisms of signal transduction by GPIs remain obscure. We have shown that structurally defined GPIs of protozoal parasite origin are able to mediate signal transduction in host macrophages and lymphocytes, by substituting for the putative endogenous GPI-based signalling mechanisms of the host. Signalling by parasite GPIs appears to involve the activation of protein tyrosine kinase and protein kinase C. Evidence from other sources indicates that structurally variant GPIs may provide anergic signals to down-regulate host cell function. These phenomena may represent mechanisms by which eukaryotic parasites regulate host cell function, and can explain a variety of pathological and immunological features of protozoal infections. Furthermore, protozoal GPIs may prove to be an informative model system for the analysis of GPI-mediated signal transduction in lymphocytes and macrophages.

Animals↗

PubMed1998

Activation of p21ras/MAPK signal transduction molecules decreases with age in mitogen-stimulated T cells from rats.

Signal transduction is ubiquitously involved in the initiation of physiological signals that lead to growth and proliferation of cells. The signaling cascade mediated by the mitogen-activated protein kinase (MAPK) is considered essential for T cell growth and function. Therefore, it was of interest to determine the influence of age on the induction of MAPK in mitogen-activated T cells. T cells from young (4-6 months) and old (24-26 months) rats responded to concanavalin A (Con A) stimulation by increasing MAPK, c-jun amino terminal kinase (JNK), and p21ras activities. The time course of induction of MAPK/JNK and p21ras activities was similar in T cells isolated from young and old rats. The induction of JNK activity did not change significantly with age; however, the induction of MAPK and p21ras activities was significantly less (50 to 65%) in T cells from old rats than in T cells from young rats. Although the relative protein levels of p42 and p44 MAPK did not change with age, the proportion of the phosphorylated p44 MAPK decreased with age. In addition, it was found that the in vitro kinase activities of the T cell receptor-associated protein tyrosine kinase Lck (p56Lck) and ZAP-70 but not Fyn (p59Fyn) were lower in T cells from old rats than in T cells from young rats. The decline in activities of these signaling molecules with age was not associated with changes in their corresponding protein levels. Thus, our results demonstrate that aging alters the activation of the signal transduction cascade that leads to T cell activation.

Aging↗

PubMed1999

Impaired integrin-mediated signal transduction, altered cytoskeletal structure and reduced motility in Hck/Fgr deficient macrophages.

Integrin-mediated adhesion of monocytes and macrophages initiates a signal transduction pathway that leads to actin cytoskeletal reorganization, cell migration and immunologic activation. This signaling pathway is critically dependent on tyrosine kinases. To investigate the role of the Src-family of tyrosine kinases in integrin signal transduction, we have examined the adhesive properties of macrophages isolated from hck-/-fgr-/- double knockout mice which lack two of the three predominant Src-family kinases expressed in myeloid cells. Previous examination of polymorphonuclear leukocytes from these animals indicated that these kinases were critical in initiating the actin cytoskeletal rearrangements that lead to respiratory burst and granule secretion following integrin ligation. Double mutant peritoneal exudate macrophages demonstrated markedly reduced tyrosine phosphorylation responses compared to wild-type cells following plating on fibronectin, collagen or vitronectin-coated surfaces. Tyrosine phosphorylation of several actin-associated proteins (cortactin, paxillin, and tensin), as well as the Syk and Pyk2 tyrosine kinases, were all significantly reduced in double mutant cells. The subcellular localization of focal-adhesion associated proteins was also dramatically altered in mutant macrophages cultured on fibronectin-coated surfaces. In wild-type cells, filamentous actin, paxillin, and talin were concentrated along leading edges of the plasma membrane, suggesting that these proteins contribute to cellular polarization during migration in culture. Double mutant cells failed to show the polarized subcellular localization of these proteins. Likewise, double mutant macrophages failed to form normal filopodia under standard culture conditions. Together, these signaling and cytoskeletal defects may contribute to the reduced motility observed in in vitro assays. These data provide biochemical and morphological evidence that the Src-family kinases Hck and Fgr are required for normal integrin-mediated signal transduction in murine macrophages.

Actins↗

PubMed2006

On the role of galectins in signal transduction.

Galectins are a family of proteins that bind to beta-galactoside carbohydrate structure through their carbohydrate recognition domains (CRDs). These proteins have been shown to be involved in multiple biological functions such as cell-matrix and cell-cell interactions, cell proliferation, cell differentiation, cellular transformation, or apoptosis mainly through their binding properties to specific ligands. Signal transduction should be dramatically affected and changed in the process of those biological functions; namely, galectins can also be involved in several signal transduction pathways. This chapter discusses the role of galectins in signal transduction, dividing into extracellular and intracellular galectins. In addition, we will indicate the methods to identify the interactions of galectins in signal transduction.

Animals↗

PubMed2002

A signal transduction system in Streptomyces coelicolor that activates the expression of a putative cell wall glycan operon in response to vancomycin and other cell wall-specific antibiotics.

We have investigated a signal transduction system proposed to allow Streptomyces coelicolor to sense and respond to changes in the integrity of its cell envelope. The system consists of four proteins, encoded in an operon: sigmaE, an RNA polymerase factor; CseA (formerly ORF202), a protein of unknown function; CseB, a response regulator; and CseC, a sensor histidine protein kinase with two predicted transmembrane helices (Cse stands for control of sigma E). To develop a sensitive bioassay for inducers of the sigE system, the promoter of the sigE operon (sigEp) was fused to a reporter gene conferring resistance to kanamycin. Antibiotics that acted as inducers of the sigE signal transduction system were all inhibitors of intermediate and late steps in peptidoglycan biosynthesis, including ramoplanin, moenomycin A, bacitracin, several glycopeptides and some beta-lactams. The cell wall hydrolytic enzyme lysozyme also acted as an inducer. These data suggest that the CseB-CseC signal transduction system may be activated by the accumulation of an intermediate in peptidoglycan biosynthesis or degradationa. A computer-based searching method was used to identify a sigmaE target operon of 12 genes (the cwg operon), predicted to specify the biosynthesis of a cell wall glycan. In low-Mg(2+) medium, transcription of the cwg operon was induced by vancomycin in a sigE-dependent manner but, in high-Mg(2+) medium, there was substantial cwg transcription in a sigE null mutant, and this sigE-independent activity was also induced by vancomycin. Based on these data, we propose a model for the regulation and function of the sigmaE signal transduction system.

Anti-Bacterial Agents↗

PubMed1997

UV and blue light signal transduction in Arabidopsis.

The application of genetic and biochemical approaches in Arabidopsis has generated new insights into the photoreceptors and signal transduction processes that mediate the effects of UV and blue light on gene expression and development. Biochemical studies with an Arabidopsis cell culture have provided information on the signal transduction events that couple UV-B and UV-A/blue light perception to transcription of the chalcone synthase (CHS) gene. Interactions between UV-B and both UV-A and blue light signalling pathways enhance the level of CHS transcription. Mutants which identify negative regulators of CHS transcription in response to UV and blue light have been isolated. The integration of biochemical and genetic approaches will further advance understanding of UV and blue light perception and signal transduction.

Acyltransferases↗

PubMed1996

An effect of K-ras gene mutation on epidermal growth factor receptor signal transduction in PANC-1 pancreatic carcinoma cells.

The Ras protein is involved in tyrosine kinase signal transduction pathway steps such as EGFR signalling. Most human pancreatic carcinomas harbor a point mutation of K-ras oncogene and overexpress transforming TGF-alpha. We studied how K-ras gene mutation could influence the EGFR signal transduction mechanism and the autonomous proliferation of pancreatic carcinoma cells, using PANC-1 human pancreatic carcinoma line and W1-38 normal human fibroblast cell line as a control. PANC-1 cells responded to neither EGF nor exogenous TGF-alpha, although anti-TGF-alpha MAb suppressed their growth. Expression of TGF-alpha mRNA was detected only in PANC-1 cells, which confirmed EGFR being within an autocrine loop. Ras protein and MAP kinase were constitutively activated in PANC-1 cells so that the cells did not respond to treatment with staurosporine or herbimycin A, and exhibited slight response to EGF stimulation. PANC-1 cells harbored K-ras gene mutation in codon 12. In contrast, EGF stimulation induced an elevation of GTP-bound ratio to Ras protein and an activation of MAP kinase with accelerated growth in W1-38 cells. From these findings, we concluded that K-ras gene mutation possibly plays an important role in the autonomous proliferation of PANC-1 pancreatic carcinoma cells, and that an autocrine loop represented by TGF-alpha and EGFR may further accelerate the growth of PANC-1 cells.

Antibodies, Monoclonal↗

PubMed1999

Growth factor-induced signal transduction in adherent mammalian cells is sensitive to gravity.

Epidermal growth factor (EGF) activates a well-characterized signal transduction cascade in a wide variety of cells. This activation leads to increased cell proliferation in most cell types. Among the early effects evoked by EGF are receptor clustering, cell rounding, and early gene expression. The influence of gravity on EGF-induced EGF receptor clustering and gene expression as well as on actin polymerization and cell rounding have been investigated in adherent A431 epithelial cells with the use of sounding rockets to create microgravity conditions. EGF-induced c-fos and c-jun expression decreased in microgravity. This was caused by alteration of the EGF receptor and protein kinase C-mediated signal transduction pathways. In contrast, neither the binding of EGF to the receptor nor the receptor clustering were changed under microgravity conditions. Because cell morphology was also modulated under microgravity conditions, and the growth factor-induced signal transduction cascades have been demonstrated to be linked to the actin microfilament system, it is tempting to suggest that the actin microfilament system constitutes the gravity-sensitive cell component.

Actins↗

PubMed2002

Dual coupling of MT(1) and MT(2) melatonin receptors to cyclic AMP and phosphoinositide signal transduction cascades and their regulation following melatonin exposure.

In this investigation, we wanted to determine whether MT(1) or MT(2) melatonin receptors are capable of coupling to the phosphoinositide (PI) signal transduction cascade. In addition, we wanted to assess the effects of chronic melatonin exposure on MT(1) and MT(2) melatonin receptor-mediated stimulation of PI hydrolysis. We also assessed the effects of chronic melatonin exposure on other parameters of the MT(2) melatonin receptor function including total specific 2-[125I]-iodomelatonin binding, the affinity of melatonin for the receptor, and melatonin (1nM)-mediated inhibition of cyclic 3',5'-adenosine monophosphate (cAMP) accumulation. Investigation of the PI signal transduction cascade activated by either the MT(1) or MT(2) melatonin receptor expressed in Chinese hamster ovary (CHO) cells showed that melatonin (1pM to 1mM) was able to stimulate the formation of PIs to approximately 40-60% over basal [EC(50): MT(1)=29nM (2-300nM) and MT(2)=1.1nM (0.32-3.5nM), N=5]. This response was mediated via receptors based upon the findings that melatonin did not stimulate the formation of PIs in CHO cells devoid of receptor and that antagonism of MT(2) melatonin receptors by 4P-PDOT (AH 024; 4-phenyl-2-propionamidotetralin) attenuated melatonin-mediated stimulation of PI hydrolysis in CHO cells expressing the MT(2) melatonin receptor. The consequence of chronic melatonin exposure on MT(1) and MT(2) receptor function was also examined. Pretreatment of either MT(1)- or MT(2)-CHO cells with melatonin (1 microM for 5hr) resulted in: (a) a complete loss of melatonin-mediated stimulation of PI hydrolysis, and (b) an attenuation of melatonin (1nM)-mediated inhibition of forskolin-induced cAMP accumulation by approximately 20-40%. The desensitization of the PI hydrolysis signal transduction cascades coupled to either MT(1) or MT(2) melatonin receptors following chronic melatonin exposure was not due to depleted phospholipid pools, to elevated basal levels, or to decreases in receptor affinity and density. This dual coupling of melatonin receptors to different signal transduction cascades may contribute to the diversity of melatonin receptor function in vivo.

Analysis of Variance↗

PubMed1993

Desipramine desensitizes beta-adrenergic signal transduction in salivary glands: differential regulation with age.

We previously reported that the tricyclic antidepressant, desipramine desensitizes beta-adrenergic signal transduction in parotid and submandibular salivary glands. To determine the consequences of repeated desipramine administration on beta-adrenergic signal transduction in salivary glands from aged rats and whether the recovery after drug withdrawal is impaired, we assessed the effects of 28-day desipramine administration and the reversibility of this treatment following a 15-day washout period on beta-adrenoceptors and adenylyl cyclase activity in parotid and submandibular glands from F-344 rats of 6, 12 and 24 months of age. beta-Adrenoceptors were also assessed in the cerebral cortex. Desipramine administration down-regulated receptor number and attenuated isoproterenol-stimulated adenylyl cyclase activity in all three ages of rats. However, the reduction in isoproterenol-stimulated adenylyl cyclase activity was greater than the loss of receptor number. Desipramine administration attenuated the efficacy of NaF-stimulated activity with no change in forskolin-stimulated adenylyl cyclase activity. These data suggest that in addition to desensitizing beta-adrenergic-mediated signal transduction, desipramine impaired G-protein-mediated adenylyl cyclase stimulation. The recovery from desipramine desensitization was age dependent. beta-Adrenoceptor density recovered more slowly in the cerebral cortex and the submandibular gland in 24-month-old rats than in 6-month-old rats. In contrast, in 12-month-old rats, there was a receptor up-regulation and adenylyl cyclase supersensitivity. These data indicate that the capacity for receptor modulation is age dependent and suggest that desipramine treatment may down-regulate stimulatory G protein.

Adenylyl Cyclases↗

PubMed1993

[Alterations in receptor status and signal transduction mechanisms in pituitary tumors].

Recently evidence has been accumulating that important abnormalities in the receptor status and postreceptor signal transduction frequently occurred in human pituitary tumors. Several in vivo and in vitro studies suggest that during tumoral expansion, pituitary cells acquire functionally active receptors and respond to a variety of hypothalamic hormones. Alterations in proteins responsible for signal transduction have been reported. Somatic mutations of the alpha chain of Gs, the stimulatory regulatory protein of adenylate cyclase (AC), causing constitutive activation of AC have been identified in a subset of human GH-secreting adenomas. Alterations in receptor and signal transduction mechanisms in pituitary tumors triggered by hypothalamic hormones may result in amplification of stimulatory inputs and impairment of inhibitory inputs.

Adenylyl Cyclases↗

PubMed2005

Identification of Drosophila genes modulating Janus kinase/signal transducer and activator of transcription signal transduction.

The JAK/STAT pathway was first identified in mammals as a signaling mechanism central to hematopoiesis and has since been shown to exert a wide range of pleiotropic effects on multiple developmental processes. Its inappropriate activation is also implicated in the development of numerous human malignancies, especially those derived from hematopoietic lineages. The JAK/STAT signaling cascade has been conserved through evolution and although the pathway identified in Drosophila has been closely examined, the full complement of genes required to correctly transduce signaling in vivo remains to be identified. We have used a dosage-sensitive dominant eye overgrowth phenotype caused by ectopic activation of the JAK/STAT pathway to screen 2267 independent, newly generated mutagenic P-element insertions. After multiple rounds of retesting, 23 interacting loci that represent genes not previously known to interact with JAK/STAT signaling have been identified. Analysis of these genes has identified three signal transduction pathways, seven potential components of the pathway itself, and six putative downstream pathway target genes. The use of forward genetics to identify loci and reverse genetic approaches to characterize them has allowed us to assemble a collection of genes whose products represent novel components and regulators of this important signal transduction cascade.

Animals↗

PubMed1992

Yeast pheromone receptor endocytosis and hyperphosphorylation are independent of G protein-mediated signal transduction.

When alpha factor binds to the yeast alpha factor receptor a signal is transmitted via a tripartite G protein that prepares the cell for conjugation. As a result of alpha factor binding the receptor also undergoes a regulated internalization and hyperphosphorylation. Using cells that lack activity of this tripartite G protein, we show that G protein-mediated pheromone signal transduction is not necessary for regulation of receptor internalization or hyperphosphorylation. Therefore, the processes of signal transduction and down regulation can be uncoupled. We propose that binding of alpha factor to its receptor results in a receptor conformation change that permits receptor hyperphosphorylation and interaction with the endocytic machinery.

Down-Regulation↗

PubMed1997

Modeling signal transduction in normal and cancer cells using complex adaptive systems.

As a first approximation, organisms can be defined by the complement of cell types that they possess. Each cell type is defined by its specific collection of signal transduction pathways. While many pathways are common to most cell types (e.g. glycolysis), others are specific to a particular cell type and serve to characterized that cell. Many diseases, including cancer, are characterized by aberrations in general and specific signal-transduction pathways. These pathways are generally intricate and not easily modeled. The formalism of complex adaptive system theory, however, provides the tools by which these pathways can be investigated. By modeling signal-transduction pathways from the viewpoint of complex adaptive systems, a deeper understanding of their intricacies may result. This could eventually lead to novel methods of therapeutic intervention in diseases that arise from aberrant signal transduction.

Adaptation, Physiological↗

PubMed2005

Modulation of host cell signal transduction pathways by Helicobacter pylori infection.

Bacterial pathogens modulate host cell signal transduction responses to establish infection and cause disease. The purpose of the present summary, first presented at the Canadian Helicobacter Study Group meeting, is to discuss current knowledge of specific Helicobacter pylori factors, including the vacuolating cytotoxin, cytotoxin-associated gene A and the type four secretion system encoded by the cytotoxin-associated gene pathogenicity island and review the host cell signal transduction cascades that they modulate.

Antigens, Bacterial↗