SEARCH · PubMed Health

Results for “Signal Transduction”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 649 records · Page 36Linked to original sources

PubMed1996

Protein tyrosine phosphatases: their roles in signal transduction.

Protein tyrosine phosphatases play critical roles in a number of cellular signal transduction pathways. Receptor-like PTPases such as CD45 are essential for antigen-induced proliferative responses of T-cells. Intracellular PTPases have been shown to associate with specific growth factor receptors and this association has a dramatic effect on receptor signaling mechanisms. Other phosphatases (e.g., the product of the CDC25 gene) are essential for cell cycle progression. It appears that the cellular location of the intracellular PTPases plays an important role in defining the substrate specificity. Phosphatases are also present in both pathogenic bacteria and viruses. These PTPases most likely function to disrupt important signal transduction pathways present in the host. More than 30 different phosphatases have been cloned and characterized. A detailed understanding of their catalytic properties suggests that all PTPases use a common mechanism for removing phosphatase from various phosphoproteins. Two PTPase structures recently have been determined. The structural information along with biochemical and kinetic data provides a basis for understanding the catalytic properties of these enzymes.

Amino Acid Sequence↗

PubMed2004

The HAMP linker in histidine kinase dimeric receptors is critical for symmetric transmembrane signal transduction.

The HAMP linker, a common structural element between a sensor and a transmitter module in various sensor proteins, plays an essential role in signal transduction. Here, by in vivo complementation experiments with Tar-EnvZ hybrid receptor mutants in which the HAMP linker forms a heterodimer with Tar and EnvZ-type subunits, we found that mutations at one linker only affect the function of EnvZ in the same subunit. However, the same mutations affect the EnvZ function of both subunits when only a Tar or EnvZ-type HAMP linker is used. These results suggest that intersubunit interactions in the HAMP linker normally mediate signal transduction through both subunits in a sensor dimer, whereas the signal is asymmetrically transduced through the linker in a heterodimer. This is the first demonstration that two HAMP linkers in a sensor dimer are functionally coupled for normal signal transduction; however, this functional coupling can be reduced when the HAMP linkers lose their symmetric nature.

Bacterial Outer Membrane Proteins↗

PubMed2005

A VicRK signal transduction system in Streptococcus mutans affects gtfBCD, gbpB, and ftf expression, biofilm formation, and genetic competence development.

Bacteria exposed to transient host environments can elicit adaptive responses by triggering the differential expression of genes via two-component signal transduction systems. This study describes the vicRK signal transduction system in Streptococcus mutans. A vicK (putative histidine kinase) deletion mutant (SmuvicK) was isolated. However, a vicR (putative response regulator) null mutation was apparently lethal, since the only transformants isolated after attempted mutagenesis overexpressed all three genes in the vicRKX operon (Smuvic+). Compared with the wild-type UA159 strain, both mutants formed aberrant biofilms. Moreover, the vicK mutant biofilm formed in sucrose-supplemented medium was easily detachable relative to that of the parent. The rate of total dextran formation by this mutant was remarkably reduced compared to the wild type, whereas it was increased in Smuvic+. Based on real-time PCR, Smuvic+ showed increased gtfBCD, gbpB, and ftf expression, while a recombinant VicR fusion protein was shown to bind the promoter regions of the gtfB, gtfC, and ftf genes. Also, transformation efficiency in the presence or absence of the S. mutans competence-stimulating peptide was altered for the vic mutants. In vivo studies conducted using SmuvicK in a specific-pathogen-free rat model resulted in significantly increased smooth-surface dental plaque (Pearson-Filon statistic [PF], <0.001). While the absence of vicK did not alter the incidence of caries, a significant reduction in SmuvicK CFU counts was observed in plaque samples relative to that of the parent (PF, <0.001). Taken together, these findings support involvement of the vicRK signal transduction system in regulating several important physiological processes in S. mutans.

Animals↗

PubMed2002

Signal transduction in lemon seedlings in the hypersensitive response against Alternaria alternata: participation of calmodulin, G-protein and protein kinases.

The development of an effective hypersensitive response (HR) in any plant system relies, not only in their gene composition and expression, but also on an effective and rapid signal transduction system. Lemon seedlings induce the phenylpropanoid pathway, which results in the de novo biosynthesis of the phytoalexin scoparone, as part of the hypersensitive response against Alternaria alternata. In order to elucidate some of the signaling elements that participate in the development of HR in lemon seedlings, we used several compounds that are known as activators or inhibitors of signal transduction elements in plants or in animal cells. Lemon seedlings treated either with cholera toxin or with phorbol 12-myristate 13-acetate (PMA), in the absence of A. alternata induced phenylalanine ammonia-lyase (PAL, E. C. 4.3.1.5) and the synthesis of scoparone, suggesting the participation of a G-protein and of a serine/threonine kinase, respectively, in signal transduction. The use of trifluoperazine (TFP), W-7, staurosporine, lavendustin A or 2,5-dihydroximethyl cinnamate (DHMC) prevented PAL induction as well as scoparone biosynthesis in response to the fungal inoculation, thus allowing us to infer the participation of Calmodulin (CaM), of serine/threonine and of tyrosine protein kinases (TPK) for signal transduction in Citrus limon in response to A. alternata.

Alternaria↗

PubMed2001

Redox signal transduction by the ArcB sensor kinase of Haemophilus influenzae lacking the PAS domain.

The Arc (anoxic redox control) two-component signal transduction system of Escherichia coli, which comprises the tripartite ArcB sensor kinase and the ArcA response regulator, modulates the expression of numerous operons in response to redox conditions of growth. We demonstrate that the arcA and arcB genes of Haemophilus influenzae specify a two-component system. The Arc proteins of the two bacterial species sufficiently resemble each other that they can participate in heterologous transphosphorylation in vitro. Moreover, the Arc system of H. influenzae mediates transcriptional control according to the redox condition of growth both autologously in its own host and homologously in E. coli, indicating a high degree of functional conservation of the signal transduction system. The H. influenzae ArcB, however, lacks the PAS domain present in the region of E. coli ArcB linking the transmembrane to the cytosolic catalytic domains. Because the PAS domain participates in signal reception in a variety of sensory proteins, including sensors of molecular oxygen and redox state, a similar role was previously ascribed to it in ArcB. Our results demonstrate that the ArcB protein of H. influenzae mediates signal transduction in response to redox conditions of growth despite the absence of the PAS domain.

Amino Acid Sequence↗

PubMed1995

Distinct regions of c-Mpl cytoplasmic domain are coupled to the JAK-STAT signal transduction pathway and Shc phosphorylation.

c-Mpl, a member of the hematopoietic cytokine receptor family, is the receptor for thrombopoietin. To investigate signal transduction by c-Mpl, a chimeric receptor, composed of the extracellular domain of human growth hormone receptor and the intracellular domain of c-Mpl, was introduced into the interleukin 3-dependent cell line Ba/F3. In response to growth hormone, this chimeric receptor induced growth in the absence of interleukin 3. Deletion analysis of the 123-amino acid intracellular domain indicated that the elements responsible for this effect are present within the 63 amino acids proximal to the transmembrane domain. Mutation of the recently described box 1 motif abrogated the proliferative response. Tyrosine phosphorylation of the tyrosine kinase JAK-2 and activation of STAT proteins were dependent on box 1 and sequences within 63 amino acids of the plasma membrane. STAT proteins activated by thrombopoietin in a megakaryocytic cell line were purified and shown to be STAT1 and STAT3. A separate region located at the C terminus of the c-Mpl intracellular domain was found to be required for induction of Shc phosphorylation and c-fos mRNA accumulation, suggesting involvement of the Ras signal transduction pathway. Thus, at least two distinct regions are involved in signal transduction by the c-Mpl.

Amino Acid Sequence↗

PubMed1997

Possible involvement of pertussis toxin-sensitive G protein in hepatocyte growth factor-induced signal transduction in cultured rat hepatocytes: pertussis toxin treatment inhibits activation of phospholipid signaling, calcium oscillation, and mitogen-activated protein kinase.

Treatment of primary cultured rat hepatocytes with hepatocyte growth factor (HGF) gives rise to inositol phosphate formation, cytosolic calcium oscillation, activation of mitogen-activated protein (MAP) kinase and phospholipase D (PLD), and arachidonic acid release, leading to DNA synthesis. Pretreatment of cultured hepatocytes with pertussis toxin (PT), which is known to adenosine diphosphate-ribosylate Gi and Go guanine nucleotide -binding proteins and to inhibit their functions, partially inhibited HGF-induced [3H]thymidine incorporation in a concentration-dependent manner. These results suggest that HGF-mediated DNA synthesis of hepatocytes is partly regulated via PT-sensitive guanine nucleotide-binding protein. Therefore, the effects of PT treatment on HGF-induced signal-transduction pathways were investigated. HGF-induced MAP kinase activation and arachidonic acid release were decreased by PT treatment, whereas PLD activation was diminished by PT to the level of unstimulated control. PT also interfered with HGF-induced inositol phosphate formation and cytosolic calcium oscillation. These results suggest that both PT-sensitive and PT-insensitive pathways are involved in HGF-induced signaling.

Animals↗

PubMed2005

A census of membrane-bound and intracellular signal transduction proteins in bacteria: bacterial IQ, extroverts and introverts.

BACKGROUND: Analysis of complete microbial genomes showed that intracellular parasites and other microorganisms that inhabit stable ecological niches encode relatively primitive signaling systems, whereas environmental microorganisms typically have sophisticated systems of environmental sensing and signal transduction. RESULTS: This paper presents results of a comprehensive census of signal transduction proteins--histidine kinases, methyl-accepting chemotaxis receptors, Ser/Thr/Tyr protein kinases, adenylate and diguanylate cyclases and c-di-GMP phosphodiesterases--encoded in 167 bacterial and archaeal genomes, sequenced by the end of 2004. The data have been manually checked to avoid false-negative and false-positive hits that commonly arise during large-scale automated analyses and compared against other available resources. The census data show uneven distribution of most signaling proteins among bacterial and archaeal phyla. The total number of signal transduction proteins grows approximately as a square of genome size. While histidine kinases are found in representatives of all phyla and are distributed according to the power law, other signal transducers are abundant in certain phylogenetic groups but virtually absent in others. CONCLUSION: The complexity of signaling systems differs even among closely related organisms. Still, it usually can be correlated with the phylogenetic position of the organism, its lifestyle, and typical environmental challenges it encounters. The number of encoded signal transducers (or their fraction in the total protein set) can be used as a measure of the organism's ability to adapt to diverse conditions, the 'bacterial IQ', while the ratio of transmembrane receptors to intracellular sensors can be used to define whether the organism is an 'extrovert', actively sensing the environmental parameters, or an 'introvert', more concerned about its internal homeostasis. Some of the microorganisms with the highest IQ, including the current leader Wolinella succinogenes, are found among the poorly studied beta-, delta- and epsilon-proteobacteria. Among all bacterial phyla, only cyanobacteria appear to be true introverts, probably due to their capacity to conduct oxygenic photosynthesis, using a complex system of intracellular membranes. The census data, available at http://www.ncbi.nlm.nih.gov/Complete_Genomes/SignalCensus.html, can be used to get an insight into metabolic and behavioral propensities of each given organism and improve prediction of the organism's properties based solely on its genome sequence.

Acclimatization↗

PubMed2006

Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transduction.

Noonan syndrome is a relatively common, genetically heterogeneous Mendelian trait with a pleiomorphic phenotype. Prior to the period covered in this review, missense mutations in PTPN11 had been found to account for nearly 50% of Noonan syndrome cases. That gene encodes SHP-2, a protein tyrosine kinase that plays diverse roles in signal transduction including signaling via the RAS-mitogen activated protein kinase (MAPK) pathway. Noonan syndrome-associated PTPN11 mutations are gain-of-function, with most disrupting SHP-2's activation-inactivation mechanism. Here, we review recent information that has elucidated further the types and effects of PTPN11 defects in Noonan syndrome and compare them to the related, but specific, missense PTPN11 mutations causing other diseases including LEOPARD syndrome and leukemias. These new data derive from biochemical and cell biological studies as well as animal modeling with fruit flies and chick embryos. The discovery of KRAS missense mutation as a minor cause of Noonan syndrome and the pathogenetic mechanisms of those mutants is discussed. Finally, the elucidation of gene defects underlying two phenotypically related disorders, Costello and cardio-facio-cutaneous syndromes is also reviewed. As these genes also encode proteins relevant for RAS-MAPK signal transduction, all of the syndromes discussed in this article now can be understood to constitute a class of disorders caused by dysregulated RAS-MAPK signaling.

Animals↗

PubMed2002

Fused-dependent Hedgehog signal transduction is required for somatic cell differentiation during Drosophila egg chamber formation.

The fused gene encodes a serine/threonine kinase involved in Hedgehog signal transduction during Drosophila embryo and larval imaginal disc development. Additionally, fused mutant females exhibit reduced fecundity that we report here to be associated with defects in three aspects of egg chamber formation: encapsulation of germline cysts by prefollicular cells in the germarium, interfollicular stalk morphogenesis and oocyte posterior positioning. Using clonal analysis we show that fused is required cell autonomously in prefollicular and pre-stalk cells to control their participation in these aspects of egg chamber formation. In contrast to what has been found for Hedgehog and other known components of Hedgehog signal transduction, we show that fused does not play a role in the regulation of somatic stem cell proliferation. However, genetic interaction studies, as well as the analysis of the effects of a partial reduction in Hedgehog signaling in the ovary, indicate that fused acts in the classical genetic pathway for Hedgehog signal transduction which is necessary for somatic cell differentiation during egg chamber formation. Therefore, we propose a model in which Hedgehog signals at least twice in germarial somatic cells: first, through a fused-independent pathway to control somatic stem cell proliferation; and second, through a classical fused-dependent pathway to regulate prefollicular cell differentiation.

Animals↗

PubMed2002

Activation of the Syk tyrosine kinase is insufficient for downstream signal transduction in B lymphocytes.

BACKGROUND: Immature B lymphocytes and certain B cell lymphomas undergo apoptotic cell death following activation of the B cell antigen receptor (BCR) signal transduction pathway. Several biochemical changes occur in response to BCR engagement, including activation of the Syk tyrosine kinase. Although Syk activation appears to be necessary for some downstream biochemical and cellular responses, the signaling events that precede Syk activation remain ill defined. In addition, the requirements for complete activation of the Syk-dependent signaling step remain to be elucidated. RESULTS: A mutant form of Syk carrying a combination of a K395A substitution in the kinase domain and substitutions of three phenylalanines (3F) for the three C-terminal tyrosines was expressed in a murine B cell lymphoma cell line, BCL1.3B3 to interfere with normal Syk regulation as a means to examine the Syk activation step in BCR signaling. Introduction of this kinase-inactive mutant led to the constitutive activation of the endogenous wildtype Syk enzyme in the absence of receptor engagement through a 'dominant-positive' effect. Under these conditions, Syk kinase activation occurred in the absence of phosphorylation on Syk tyrosine residues. Although Syk appears to be required for BCR-induced apoptosis in several systems, no increase in spontaneous cell death was observed in these cells. Surprisingly, although the endogenous Syk kinase was enzymatically active, no enhancement in the phosphorylation of cytoplasmic proteins, including phospholipase Cgamma2 (PLCgamma2), a direct Syk target, was observed. CONCLUSION: These data indicate that activation of Syk kinase enzymatic activity is insufficient for Syk-dependent signal transduction. This observation suggests that other events are required for efficient signaling. We speculate that localization of the active enzyme to a receptor complex specifically assembled for signal transduction may be the missing event.

Amino Acid Substitution↗

PubMed2002

A dispersion model for cellular signal transduction cascades.

PURPOSE: The purpose of this study was to evaluate the ability of the dispersion model to describe pharmacokinetic-pharmacodynamic data containing contributions from signal transduction cascades. METHODS: The partial differential equations and appropriate boundary conditions describing the dispersion model for signal transduction were obtained. Explicit analytical solutions to the dispersion equation were not available, and a numerical approach was necessary. Solutions were obtained by numerical inversion of the output Laplace transform. Generalized least square fitting was used to obtain parameter estimates for a variety of experimental data sets. RESULTS: The parameters of the dispersion model estimate the relative roles of diffusion, convection, and chemical reaction in signal transduction. The model is capable of describing messenger RNA and protein expression kinetics induced by drug action. CONCLUSIONS: The dispersion model may find potential applications in pharmacokinetic-pharmacodynamic models involving delayed drug effects mediated by transcriptional changes.

Models, Biological↗

PubMed2001

Transactivation of the epidermal growth factor receptor is involved in 12-O-tetradecanoylphorbol-13-acetate-induced signal transduction.

The mechanism of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced tumor promotion is still not well understood even though it is thought to be related to the protein kinase C/mitogen-activated protein kinase/AP-1 pathway. Recently, TPA was also found to induce epidermal growth factor receptor (EGFR) activity. Here, we investigated whether the EGFR is a necessary component for TPA-induced signal transduction associated with tumor promotion. We demonstrated that potent inhibitors of the EGFR, PD153035 and AG1478, blocked TPA-induced phosphorylation of extracellular signal-regulated kinases (ERKs), AP-1 activity, and cell transformation. Egfr gene deficiency blocked TPA-induced ERK activity and AP-1 binding activity. The blocking of the ectodomain of the EGFR by a monoclonal antibody depressed TPA-induced ERK activity and AP-1 DNA binding activity. The use of a neutralizing antibody for heparin-binding EGF, one of the ligands of EGFR, blocked TPA-induced phosphorylation of ERKs. BB-94, a potent inhibitor of matrix metalloproteinases, which are activators of ectodomain shedding of EGFR ligands, also blocked TPA-induced ERK activity, AP-1 DNA binding, and cell transformation but had no effect on EGF-induced signal transduction. Anti-EGFR, anti-heparin-binding EGF, and BB-94 each blocked TPA-induced EGFR phosphorylation, but only anti-EGFR could block EGF-induced EGFR phosphorylation. Based on these results, we conclude that the EGFR is required for mediating TPA-induced signal transduction. EGFR transactivation induced by TPA is a mechanism by which the EGFR mediates TPA-induced tumor promotion-related signal transduction.

Animals↗

PubMed1998

CD38: a new paradigm in lymphocyte activation and signal transduction.

CD38 is a type II transmembrane glycoprotein that is extensively expressed on cells of hematopoietic and non-hematopoietic lineage. Although the intracellular domain of CD38 is not homologous to any known proteins, the extracellular domain of CD38 is structurally related to enzymes in the ADP-ribosyl cyclase family. The structural homology between CD38 and the cyclase family members extends to functional homology, as the extracellular domain of CD38 can mediate the catalysis of beta-NAD+ into nicotinamide, ADP-ribose (ADPR) and, to a lesser extent, into cyclic ADPR-ribose (cADPR). Extensive investigation in other systems has shown that cADPR is an important regulator of intracellular Ca2+ release. Since engagement of CD38 on hematopoietic cells with anti-CD38 Abs has been shown to have potent effects on a number of in vitro cellular responses, we have speculated that cADPR might control CD38-mediated signal transduction. However, it has been difficult to understand how a mediator which is typically an intracellular signaling molecule could potentiate its effects from an extracellular location, thus posing a dilemma which pertains to all ecto-enzymes and the mechanisms by which they regulate signal transduction and cellular processes. This review describes the biologic properties of murine CD38, its role in humoral immunity, and its signal transduction properties in B lymphocytes. We suggest that signaling through CD38 represents a new paradigm in lymphocyte signal transduction and is predicated upon extracellular, rather than intracellular, crosstalk.

ADP-ribosyl Cyclase↗

PubMed1999

Propofol inhibits muscarinic acetylcholine receptor-mediated signal transduction in Xenopus Oocytes expressing the rat M1 receptor.

The effects of propofol, 2,6-diisopropylphenol, an intravenous general anesthetic, on signal transduction mediated by the rat M1 muscarinic acetylcholine (ACh) receptor (M1 receptor) were examined in electrophysiological studies by analyzing receptor-stimulated, Ca2+-activated Cl--current responses in the Xenopus oocyte expression system. In oocytes expressing the M1 receptor, ACh induced the Ca2+-activated C1- current, in a dose-dependent manner (EC50= 114 nM). Propofol (5-50 microM) reversibly and dose-dependently inhibited induction of the Ca2+-activated Cl- current by ACh (100 nM) (IC50=5.6 microM). To determine a possible site affected by propofol in this signal transduction, we tested the effects of this anesthetic (10 microM) on the activation of current by injection of CaCl2 and aluminum fluoride (AlF4-). Propofol did not affect activation of the current by the intracellular injected Ca2+, or activation of the current by the intracellular injected AlF4-. These results indicate that propofol does not affect G protein, the inositol phosphate turnover, release of Ca2+ from Ca2+ store or the Ca2+-activated Cl- channel. Propofol apparently inhibits the M1 receptor-mediated signal transduction at the receptor site and/or the site of interaction between the receptor and associated G protein.

Acetylcholine↗

PubMed2000

Signal transduction and biochemical targeting of ovarian carcinoma.

UNLABELLED: The purpose was to identify novel targets for the chemotherapy of ovarian carcinoma. METHODS: Assays were worked out to measure the activities of P1 kinase, PIP kinase and PLC in ovarian carcinoma samples and in OVCAR-5 cells and to compare the activities to those in normal ovaries. A method was also designed for measuring the concentration of the end product of signal transduction, IP3. RESULTS AND DISCUSSION: Signal transduction activity was markedly increased in ovarian cancer cells as shown by the increased steady-state activities of the three enzymes and the elevated concentrations of IP3. Inhibitors blocked activities of PI kinase (quercetin), PIP kinase (genistein), and lowered GTP concentration required for PLC (tiazofurin). Combinations of tiazofurin with quercetin, tiazofurin with genistein, and quercetin with genistein yielded a synergistic kill of ovarian cancer cells. Tiazofurin, quercetin and genistein are in various stages of clinical trials. CONCLUSION: The increased signal transduction activity provides novel, sensitive targets to chemotherapy in ovarian cancer cells.

Cell Survival↗

PubMed1992

Intracellular signal transduction in proliferation of synovial cells.

We investigated some steps in the signal transduction pathway leading to the proliferation of synovial cells. 12-o-tetradecanoyl phorbol-13-acetate (TPA) which is known to stimulate phospholipid- and Ca(2+)-dependent protein kinase (C-kinase) enhanced the proliferation of synovial cells. The proliferation of synovial cells induced by interleukin-1 beta. Tumour necrosis factor alpha and granulocytes/macrophages colony stimulating factor, was inhibited by a potent C-kinase inhibitor, H7. These findings strongly suggested that the signal transduction pathway leading to proliferation of synovial cells is transmitted via C-kinase activation. Prostaglandin E2, which is known to stimulate adenylate cyclase, leading to the elevation of intracellular c-AMP level, inhibited the proliferation of synovial cells. This effect could also be mimicked by the addition of a cell permeable c-AMP analog, dibutyryl c-AMP or theophylline. Studies suggest that the feedback signal for proliferation of synovial cells was transmitted through c-AMP. We therefore conclude that signals for stimulation and inhibition of synovial cell proliferation are transmitted through different pathways.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1995

Noise-induced enhancement of signal transduction across voltage-dependent ion channels.

The presence of noise in a signal transduction system usually interferes with its ability to transfer information reliably. But many nonlinear systems can use noise to enhance performance, and this phenomenon, called stochastic resonance, may underlie the extraordinary ability of some biological systems to detect and amplify small signals in noisy environments. Previous work has demonstrated the occurrence of stochastic resonance in a complex system of biological transducers and neural signal pathways, but the possibility that it could occur at the sub-cellular level has remained open. Here we report the observation of stochastic resonance in a system of voltage-dependent ion channels formed by the peptide alamethicin. A hundred-fold increase in signal transduction induced by external noise is accompanied by a growth in the output signal-to-noise ratio. The system of ion channels considered here represents the simplest biological system yet known to exhibit stochastic resonance.

Alamethicin↗