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Results for “Signal Transduction”

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PubMed1994

The relationship between 3',5'-cyclic adenosine monophosphate and calcium in mediating follicle-stimulating hormone signal transduction in Sertoli cells.

FSH signal transduction in Sertoli cells involves the generation of cAMP and calcium as second messengers; however, the relationship between these two signals is not clear. In order to determine whether these were serial or parallel signals, we studied cytosolic calcium levels in freshly isolated rat Sertoli cells using maneuvers to dissociate generation of endogenous cAMP from cytosolic calcium. Pretreatment with 1 mM MDL 12,330A, an adenylate cyclase inhibitor, reduced by greater than 90% increases in cytosolic calcium induced by FSH (97 +/- 6 vs. 213 +/- 16 nM), whereas, despite adenylate cyclase blockade, 1 mM (Bu)2cAMP continued to elevate cytosolic calcium (from 87 +/- 6 to 182 +/- 23 nM), indicating the involvement of adenylate cyclase in the FSH-induced rise of cytosolic calcium. A cAMP antagonist, 1 mM Rp-cAMP, reduced by 75% the FSH-induced rise of cytosolic calcium (115 +/- 14 vs. 213 +/- 16 nM), suggesting that endogenous cAMP levels generated by FSH are sufficient to activate the cytosolic calcium response to FSH. Pretreatment with pertussis toxin (1 mg/liter) to dissociate the FSH-receptor interaction from its G-protein-mediated linkage to adenylate cyclase also suppressed the FSH-induced rise in cytosolic calcium (97 +/- 11 vs. 213 +/- 16 nM). Sertoli cells preincubated with 1 mM staurosporine, an inhibitor of protein kinases, exhibited a reduced calcium response to FSH (125 +/- 14 vs. 213 +/- 16 nM), suggesting that FSH-induced calcium flux might be mediated by protein kinase, presumably cAMP-dependent protein kinase A. The present findings therefore strengthen the premise that the cytosolic calcium response to FSH in Sertoli cells is predominantly attributable to serial signaling after the generation of endogenous cAMP.

Adenylate Cyclase Toxin↗

PubMed1995

Phosphorylation in halobacterial signal transduction.

Regulated phosphorylation of proteins has been shown to be a hallmark of signal transduction mechanisms in both Eubacteria and Eukarya. Here we demonstrate that phosphorylation and dephosphorylation are also the underlying mechanism of chemo- and phototactic signal transduction in Archaea, the third branch of the living world. Cloning and sequencing of the region upstream of the cheA gene, known to be required for chemo- and phototaxis in Halobacterium salinarium, has identified cheY and cheB analogs which appear to form part of an operon which also includes cheA and the following open reading frame of 585 nucleotides. The CheY and CheB proteins have 31.3 and 37.5% sequence identity compared with the known signal transduction proteins CheY and CheB from Escherichia coli, respectively. The biochemical activities of both CheA and CheY were investigated following their expression in E.coli, isolation and renaturation. Wild-type CheA could be phosphorylated in a time-dependent manner in the presence of [gamma-32P]ATP and Mg2+, whereas the mutant CheA(H44Q) remained unlabeled. Phosphorylated CheA was dephosphorylated rapidly by the addition of wild-type CheY. The mutant CheY(D53A) had no effect on phosphorylated CheA. The mechanism of chemo- and phototactic signal transduction in the Archaeon H.salinarium, therefore, is similar to the two-component signaling system known from chemotaxis in the eubacterium E.coli.

Amino Acid Sequence↗

PubMed1997

Kinase-independent potentiation of B cell antigen receptor-mediated signal transduction by the protein tyrosine kinase Src.

Signal transduction mediated by the B cell Ag receptor involves the activation of multiple protein tyrosine kinases that are members of the Src family (i.e., Fyn, Lyn, Blk, Lck). To determine whether members of the Src family possess common physical and/or enzymatic properties that enable them to potentiate signal transduction via the B cell Ag receptor, we expressed the protein tyrosine kinase Src in the B lymphoma cell line K46-17 mu m lambda. Based on coprecipitation analysis and two-color immunofluorescence, this heterologous Src family kinase was observed to physically associate with the B cell Ag receptor. Additional experiments demonstrated that B cell Ag receptor cross-linking results in increased tyrosine phosphorylation and activation of Src. Several parameters of B cell activation, including tyrosine phosphorylation of intracellular substrates, calcium mobilization, and transcription factor activation, were potentiated in cells that expressed Src when compared with control cells. To determine whether potentiation of Ag receptor-mediated signaling by Src was dependent on its catalytic activity, a kinase-deficient form of Src was expressed in K46-17 mu m lambda cells. Transfectants expressing kinase-deficient Src exhibited an enhanced responsiveness to stimulation through the B cell Ag receptor that was comparable with transfectants expressing wild-type Src. Additionally, kinase-deficient Src was observed to associate with the endogenous kinase Lyn in an activation-dependent manner. These findings indicate that members of the Src family may potentiate Ag receptor-mediated signaling via a kinase-independent mechanism(s) that involves amplification of kinase recruitment to the Ag receptor activation complex.

Adjuvants, Immunologic↗

PubMed2002

Antioxidants and oxidants regulated signal transduction pathways.

Many drugs and xenobiotics induce signal transduction events leading to gene expression of either pharmacologically beneficial effects, or unwanted side effects such as cytotoxicity which can compromise drug therapy. Using dietary chemopreventive compounds (isothiocyanates and green tea polyphenols), which are effective against various chemically-induced carcinogenesis models in animals studies, we studied the signal transduction events and gene expression profiles. These compounds have typically generated cellular "oxidative stress" and modulated gene expression including phase II detoxifying enzymes GST and QR as well as cellular defensive enzymes, heme oxygenase 1 (HO-1) and GST via the antioxidant/electrophile response element (ARE/EpRE). Members of the bZIP transcription factor, Nrf2 which heterodimerizes with Maf G/K, were found to bind to ARE, and transcriptionally activate ARE. Additionally the mitogen-activated protein kinases (MAPK; ERK, JNK and p38) were differentially activated by these compounds, and involved in the transcriptional activation of ARE-mediated reporter gene. Transfection studies with various cDNA encoding for wild-type of MAPK and Nrf2 showed synergistic response during co-transfection and to these agents. However, by increasing the concentrations of these xenobiotics, caspase activities and apoptosis were observed which were preceded by mitochondria damage and cytochrome c mitochondria release. Further, increased concentrations led to rapid cell necrosis. [corrected] Thus, we have proposed a model, that at low concentrations, these compounds activate MAPK pathway leading to activation of Nrf2 and ARE with subsequent induction of phase II and other defensive genes which protect cells against toxic insults thereby enhancing cell survival, a beneficial homeostatic response. At higher concentrations, these agents activate the caspase pathways, leading to apoptosis, a potential cytotoxic effect if it occurred in normal cells. The studies of these signaling pathways may yield important insights into the pharmacodynamic and toxicodynamic effects of drugs and xenobiotics during pharmaceutical drug discovery and development.

Animals↗

PubMed1998

[Signal transduction of alpha 1-adrenoceptors].

alpha 1-adrenoceptors activate multiple signal transduction pathways. In addition to the classic inositol phosphates-Ca2+ system and diacylglycerol-protein kinase C system, the phospholipase A2-arachidonic acid system, the tyrosine kinase phosphorylation system, the adenylate cyclase-cAMP system etc. were also involved. These signal transduction cascades interact complicatedly with each other as a network. The activation of one signal system can initiate, potentiate or inhibit other systems. They play pivotal role in diversified physiological and pathophysiological processes. Different alpha 1-adrenoceptor subtypes activate different signal transduction pathways. In some experiments, however, the differences are due to the different tissues or cells used.

Calcium↗

PubMed2006

Molecular chaperones in signal transduction.

Many cellular signaling molecules exist in different conformations corresponding to active and inactive states. Transition between these states is regulated by reversible modifications, such as phosphorylation, or by binding of nucleotide triphosphates, their regulated hydrolysis to diphosphates, and their exchange against fresh triphosphates. Specificity and efficiency of cellular signaling is further maintained by regulated subcellular localization of signaling molecules as well as regulated protein-protein interaction. Hence, it is not surprising that molecular chaperones--proteins that are able to specifically interact with distinct conformations of other proteins--could per se interfere with cellular signaling. Hence, it is not surprising that chaperones have co-evolved as integral components of signaling networks where they can function in the maturation as well as in regulating the transition between active and inactive state of signaling molecules, such as receptors, transcriptional regulators and protein kinases. Furthermore, new classes of specific chaperones are emerging and their role in histone-mediated chromatin remodeling and RNA folding are under investigation.

Animals↗

PubMed1994

Cytokines and signal transduction.

Cytokines are signaling molecules that coordinate cellular interactions in immune and hematopoietic systems. During the past 5 years many cytokines and their receptors have been identified and cloned. With a few exceptions, cytokine receptors do not contain any known signaling domains and therefore, in order to trigger a specific cellular response, new and unusual features of signaling pathways must be assumed. A major advance in the field has come with the discovery of new family of cytoplasmic protein tyrosine kinases that associate with occupied cytokine receptors and make them competent for intracellular signal generation. This review describes some general characteristics of cytokine signaling.

Cytokines↗

PubMed1995

Integrins: emerging paradigms of signal transduction.

Integrins receive signals from other receptors that lead to activation of ligand binding (inside-out signaling) and matrix assembly. Upon binding ligands, they also activate intracellular signaling pathways. These signals converse with pathways that are initiated by soluble ligands to regulate cell functions. In this way, cell adhesion is coordinated with other events to orchestrate complex cellular behavior.

Animals↗

PubMed2000

Diffusion control of protein phosphorylation in signal transduction pathways.

Multiple signalling proteins are phosphorylated and dephosphorylated at separate cellular locations, which potentially causes spatial gradients of phospho-proteins within the cell. We have derived relationships that enable us to estimate the extent to which a protein kinase, a phosphatase and the diffusion of signalling proteins control the protein phosphorylation flux and the phospho-protein gradient. Two different cellular geometries were analysed: (1) the kinase is located on one planar membrane and the phosphatase on a second parallel planar membrane, and (2) the kinase is located on the plasma membrane of a spherical cell and the phosphatase is distributed homogeneously in the cytoplasm. We demonstrate that the control contribution of protein diffusion is potentially significant, given the measured rates for protein kinases, phosphatases and diffusion. If the distance between the membranes is 1 microm or greater, the control by diffusion can reach 33% or more, with the rest of the control (67%) shared by the kinase and the phosphatase. At distances of less than 0.1 microm, diffusion does not limit protein phosphorylation. For a spherical cell of radius 10 microm, a protein diffusion coefficient of 10(-8) cm(2). s(-1) and rate constants for the kinase and the phosphatase of approx. 1 s(-1), control over the phosphorylation flux resides mainly with the phosphatase and protein diffusion, with approximately equal contributions of each of these. The ratio of phospho-protein concentrations at the cell membrane and the cell centre (the dynamic compartmentation of the phospho-protein) is shown to be controlled by the rates of the protein phosphatase and of diffusion. The kinase can contribute significantly to the control of the absolute value of the phospho-protein gradient.

Cell Membrane↗

PubMed1991

Interleukin 1 signal transduction.

Interleukin 1 signals through an 80kDa receptor to change protein kinase activity in fibroblasts. Two increases in protein phosphorylation have been identified: the EGF receptor and the small heat shock protein (hsp 27). Both involve serine and are similarly transient (maximal 5-15 minutes). The kinase activity differs from PKA or C. Hsp 27 can be used for its assay in extracts of stimulated cells.

Animals↗

PubMed1991

Suppression of lymphocyte signal transduction by murine mastocytoma ascites.

The lymphocyte signal transduction, as determined by intracellular free Ca2+ mobilization of concanavalin A-stimulated T lymphocytes and of anti-immunoglobulin mu chain antibody-stimulated B lymphocytes, was suppressed in spleen cells from mice injected with murine P1.HTR mastocytoma-induced ascites and in spleen cells treated with the ascites in vitro. The suppression was observed both at the peak level and in the reactive pattern of Ca2+ influx. In the suppression, the ascites were replaceable with tumor culture supernatants or tumor homogenates. Correspondingly, primary and secondary cytotoxic T lymphocyte (CTL) responses of DBA/2 mice to allogeneic antigen were also significantly suppressed by injection of the syngeneic P1.HTR tumor-derived ascites. This new finding suggested that the mechanism of the tumorous ascites or of the tumor-derived factor-mediated immunosuppression involves at least in part the suppression of the early event of the signal transduction for lymphocyte activation.

Animals↗

PubMed2006

Effects of sequestration on signal transduction cascades.

The building blocks of most signal transduction pathways are pairs of enzymes, such as kinases and phosphatases, that control the activity of protein targets by covalent modification. It has previously been shown [Goldbeter A & Koshland DE (1981) Proc Natl Acad Sci USA 78, 6840-6844] that these systems can be highly sensitive to changes in stimuli if their catalysing enzymes are saturated with their target protein substrates. This mechanism, termed zero-order ultrasensitivity, may set thresholds that filter out subthreshold stimuli. Experimental data on protein abundance suggest that the enzymes and their target proteins are present in comparable concentrations. Under these conditions a large fraction of the target protein may be sequestrated by the enzymes. This causes a reduction in ultrasensitivity so that the proposed mechanism is unlikely to account for ultrasensitivity under the conditions present in most in vivo signalling cascades. Furthermore, we show that sequestration changes the dynamics of a covalent modification cycle and may account for signal termination and a sign-sensitive delay. Finally, we analyse the effect of sequestration on the dynamics of a complex signal transduction cascade: the mitogen-activated protein kinase (MAPK) cascade with negative feedback. We show that sequestration limits ultrasensitivity in this cascade and may thereby abolish the potential for oscillations induced by negative feedback.

MAP Kinase Signaling System↗

PubMed2005

Signal transduction in a coupled hormone system: selective explicit internal signal stochastic resonance and its control.

Cooperative interactions of signal transduction and environmental noise are investigated with a coupled hormone system, in which selective explicit internal signal stochastic resonance (EISSR) is observed. More specifically, the large peak of a period-2 oscillation (i.e., a strong signal) is greatly amplified by the environmental noise while the small peak (i.e., a weak signal) does not exhibit cooperative interactions with noise. The EISSR phenomenon could be controlled by adjusting the frequency or amplitude of an external signal and a critical amplitude for external signal is found. Significantly, the maximal signal-to-noise ratio increases almost linearly with the increment of control parameter, despite that the magnitude of the large peak is decreased. In addition, the noise does not alter the fundamental frequencies of the strong signal and the weak signal, which implicates that the system can keep its intrinsic oscillatory state and resist the effect of environmental fluctuations.

Biological Clocks↗

PubMed1995

Vav: Captain Hook for signal transduction?

The binding of growth factors to membrane receptors leads to transmission of signals through the cytoplasm and into the nucleus. One of the proteins that is involved in linking tyrosine phosphorylation and subsequent signal transduction events is proto-vav. Vav was first identified as a transforming gene by the use of the nude mice tumorigenicity assay. The vav protooncogene encodes a protein with motifs usually found in nucleotide exchange factors, as well as those found in substrates of signal transduction (Src Homology 2-SH2 and Src Homology 3-SH3). Based on the transforming potential of vav, its exclusive expression in hematopoietic cells and its encoded protein structure, it is suggested that the vav protooncogene functions as an important mediator in hematopoietic signal transduction, resulting in cell growth and/or differentiation. In this review I discuss the evidence that proto-vav acts as one of the most pivotal hook elements for signal transduction in the hemopoietic system.

Animals↗

PubMed2005

Gravity signal transduction in primary roots.

AIMS: The molecular mechanisms that correlate with gravity perception and signal transduction in the tip of angiosperm primary roots are discussed. SCOPE: Gravity provides a cue for downward orientation of plant roots, allowing anchorage of the plant and uptake of the water and nutrients needed for growth and development. Root gravitropism involves a succession of physiological steps: gravity perception and signal transduction (mainly mediated by the columella cells of the root cap); signal transmission to the elongation zone; and curvature response. Interesting new insights into gravity perception and signal transduction within the root tip have accumulated recently by use of a wide range of experimental approaches in physiology, biochemistry, genetics, genomics, proteomics and cell biology. The data suggest a network of signal transduction pathways leading to a lateral redistribution of auxin across the root cap and a possible involvement of cytokinin in initial phases of gravicurvature. CONCLUSION: These new discoveries illustrate the complexity of a highly redundant gravity-signalling process in roots, and help to elucidate the global mechanisms that govern auxin transport and morphogenetic regulation in roots.

Gravitropism↗

PubMed2000

Modification of beta-adrenoceptor signal transduction pathway by genetic manipulation and heart failure.

The beta-adrenoceptor (beta-AR) mediated signal transduction pathway in cardiomyocytes is known to involve beta1- and beta2-ARs, stimulatory (Gs) and inhibitory (Gi) guanine nucleotide binding proteins, adenylyl cyclase (AC) and cAMP-dependent protein kinase (PKA). The activation of beta1- and beta2-ARs has been shown to increase heart function by increasing Ca2+ -movements across the sarcolemmal membrane and sarcoplasmic reticulum through the stimulation of Gs-proteins, activation of AC and PKA enzymes and phosphorylation of the target sites. The activation of PKA has also been reported to increase phosphorylation of some myofibrillar proteins (for promoting cardiac relaxation) and nuclear proteins (for cardiac hypertrophy). The activation of beta2-AR has also been shown to affect Gi-proteins, stimulate mitogen activated protein kinase and increase protein synthesis by enhancing gene expression. Beta1- and beta2-ARs as well as AC are considered to be regulated by PKA- and protein kinase C (PKC)-mediated phosphorylations directly; both PKA and PKC also regulate beta-AR indirectly through the involvement of beta-AR kinase (betaARK), beta-arrestins and Gbeta gamma-protein subunits. Genetic manipulation of different components and regulators of beta-AR signal transduction pathway by employing transgenic and knockout mouse models has provided insight into their functional and regulatory characteristics in cardiomyocytes. The genetic studies have also helped in understanding the pathophysiological role of PARK in heart dysfunction and therapeutic role of betaARK inhibitors in the treatment of heart failure. Varying degrees of defects in the beta-AR signal transduction system have been identified in different types of heart failure to explain the attenuated response of the failing heart to sympathetic stimulation or catecholamine infusion. A decrease in beta1-AR density, an increase in the level of G1-proteins and overexpression of betaARK are usually associated with heart failure; however, these attenuations have been shown to be dependent upon the type and stage of heart failure as well as region of the heart. Both local and circulating renin-angiotensin systems, sympathetic nervous system and endothelial cell function appears to regulate the status of beta-AR signal transduction pathway in the failing heart. Thus different components and regulators of the beta-AR signal transduction pathway appears to represent important targets for the development of therapeutic interventions for the treatment of heart failure.

Adenylyl Cyclases↗

PubMed1996

Aspartyl-phosphate phosphatases deactivate the response regulator components of the sporulation signal transduction system in Bacillus subtilis.

Bacteria use two-component signal transduction systems to sense and respond to their environment. A sensor kinase and a response-regulator transcription factor work in concert by phosphorylation/dephosphorylation through kinase and phosphatase activities to maintain a level of phosphorylated response regulator commensurate with the level of signal input. Signal input can be accommodated through stimulation of the kinase activity or the phosphatase activity of the two-component system. With some notable exceptions, the sensor kinases recognize a single stimulatory ligand. A new dimension in the regulation of two-component signal transduction systems was discovered in the Rap phosphatases which dephosphorylate the SpoOF response-regulator of Bacillus subtilis independent of the sensor kinases. This family of phosphatases is encoded by at least six chromosomal genes. Although not all of the phosphatases of the family have activity on phosphorylated SpoOF, the two best-characterized members, RapA and RapB, prevent sporulation by dephosphorylating this response regulator component of the phosphorelay. Phosphatase activity of RapA is regulated by a gene, phrA, in the same transcriptional unit, that encodes a peptide secreted from the cell which may serve as a quorum sensor. Most of the Rap phosphatase operons have a gene coding for a protein with some similarity to PhrA in their transcription units, but it is uncertain whether all of these play a role in regulation. The Rap phosphatases are postulated to be a mechanism for allowing signals other than those that affect the sensor kinases to regulate the signal transduction pathway. They may have been recruited to help regulate sporulation because the multiple signals regulating this process may outstrip the recognition capacity of the kinases.

ATP-Binding Cassette Transporters↗

PubMed1997

Cyclic-AMP modulates downstream events in CD40-mediated signal transduction, but inhibition of protein kinase A has no direct effect on CD40 signaling.

The role of cAMP/protein kinase A (PKA) in CD40 signal transduction is controversial, with evidence both for and against its importance. In this study we have used a tetracycline-repressible expression system to reversibly express a dominant-negative form of the PKA regulatory subunit type I (PKA-R(G324D)) in a B lymphoma line, M12. Expression of PKA-R(G324D) in M12 lymphomas inhibits both cAMP-mediated growth inhibition and cAMP-mediated induction of B7-2. This inhibition is reversed by tetracycline treatment of the cells to turn off inhibitor expression. In contrast, the expression of the PKA-R(G324D) subunit has no effect on CD40-mediated growth inhibition in M12 cells, nor on CD40-mediated induction of B7-1, CD23, Fas, ICAM-1, or LFA-1. Thus, our data do not support a direct role for cAMP/PKA in CD40-mediated signal transduction. However, we do observe that cAMP can regulate CD40 signaling both positively and negatively. Cyclic-AMP synergizes with CD40-mediated B7-1 induction in M12 lymphomas, while inhibiting CD40-mediated CD23, Fas, and ICAM-1 induction.

Adjuvants, Immunologic↗