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Results for “Signaling”

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At least 289 records · Page 16Linked to original sources

PubMed2000

Galphas family G proteins activate IP(3)-Ca(2+) signaling via gbetagamma and transduce ventralizing signals in Xenopus.

During early embryonic development, IP(3)-Ca(2+) signaling transduces ventral signaling at the time of dorsoventral axis formation. To identify molecules functioning upstream in this signal pathway, we examined effects of a panel of inhibitory antibodies against Galphaq/11, Galphas/olf, or Galphai/o/t/z. While all these antibodies showed direct inhibition of their targets, their effects on redirection of the ventral mesoderm to a dorsal fate varied. Anti-Galphas/olf antibody showed strong induction of dorsal fate, anti-Galphai/o/t/z antibody did so weakly, and anti-Galphaq/11 antibody was without effect. Injection of betaARK, a Gbetagamma inhibitor, mimicked the dorsalizing effect of anti-Galphas/olf antibody, whereas injection of adenylyl cyclase inhibitors at a concentration which inhibited Galphas-coupled cAMP increase did not do so. The activation of Galphas-coupled receptor gave rise to Ca(2+) transients. All these results suggest that activation of the Galphas-coupled receptor relays dorsoventral signal to Gbetagamma, which then stimulates PLCbeta and then the IP(3)-Ca(2+) system. This signaling pathway may play a crucial role in transducing ventral signals.

Amino Acid Sequence↗

PubMed1995

Role of the time factor in signaling specificity: application to mitogenic and metabolic signaling by the insulin and insulin-like growth factor-I receptor tyrosine kinases.

The signal transduction pathways activated by hormones, growth factors, and cytokines show an extraordinary degree of cross-talk and redundancy. This review addresses the question of how the specificity conferred at the binding step is maintained through the signaling network despite the convergence of multiple signals on common efferent pathways such as mitogen-activated protein (MAP) kinase. The mechanism of receptor activation by ligand-induced dimerization provides a signaling device with both a switch and a timer. The role of the time factor, ie, of signaling kinetics, as a determinant of selectivity is discussed with emphasis on the receptor tyrosine kinases and cytokine receptors, and especially mitogenic versus metabolic signaling by insulin and insulin-like growth factor-I (IGF-I).

Animals↗

PubMed2006

The peptide Trp-Lys-Tyr-Met-Val-D-Met activates neutrophils through the formyl peptide receptor only when signaling through the formylpeptide receptor like 1 is blocked. A receptor switch with implications for signal transduction studies with inhibitors and receptor antagonists.

Neutrophils express the G protein-coupled N-formyl peptide receptor (FPR) and its homologue FPRL1. The hexapeptide Trp-Lys-Tyr-Met-Val-D-Met-NH2 (WKYMVm) activates HL-60 cells transfected either with FPRL1 or with FPR. The signaling through the stably expressed receptors was inhibited by specific receptor antagonists, cyclosporine H and WRWWWW (WRW4) for FPR and FPRL1, respectively. The neutrophil release of superoxide was used to determine receptor preference, when these cells were triggered with WKYMVm. The response was not affected by the FPR specific antagonist suggesting that no signals are transduced through this receptor. The response was only partly inhibited by WRW4, but this antagonist induced a receptor switch, perceptible as a change in sensitivity to the FPR antagonist. The activity remaining in the presence of WRW4 was inhibited by cyclosporine H. A cell permeable peptide (PBP10) corresponding to the phosphatidyl-inositol-bisphosphate binding region of gelsolin, inhibited the FPRL1-, but not the FPR-induced cellular response and induced the same type of receptor switch. We show that an agonist that has the potential to bind and activate neutrophils through FPRL1 as well as through FPR, uses the latter receptor and its signaling route, only when the activating signal generated through FPRL1 is blocked. The receptor switch is achieved when signaling through FPRL1 is inhibited both by a receptor antagonist, and by an inhibitor operating from the inside of the plasma membrane. The phenomenon described is of general importance for proper interpretation of results generated through the use of different "silencing technologies" in receptor operated signaling transduction research.

Chemotactic Factors↗

PubMed2005

Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway.

In the broadest sense, cellular stress describes conditions wherein cells encounter and react to a 'non-normal' state. Perturbations may originate through both extracellular and intracellular means. Whereas transient levels of stress are expected to occur on a regular basis, a series of checks and balances ensures that cells are well equipped to maintain a homeostatic state. In the case of supra-physiological stress signaling, cellular challenges are more severe, and programmed cell death may be the best option for the organism. The ability of a cell, and by extension, an organism, to adequately manage cellular stress is fundamental--a question of life or death. The endoplasmic reticulum (ER) is exquisitely poised to sense and respond to cellular stresses including those that result from metabolic and/or protein folding imbalances. In response to stress originating from within the ER, the PERK and Ire1 protein kinases, along with other proximal signaling molecules, initiate a program of transcriptional and translational regulation termed the unfolded protein response. A consequence of ER stress is the accumulation of reactive oxygen species that promotes a state of oxidative stress. PERK signaling, via activation of the Nrf2 and ATF4 transcription factors, coordinates the convergence of ER stress with oxidative stress signaling. Here we discuss progress regarding the signaling pathways involved in these cellular stresses and the implications of the intersection between the two signaling pathways.

Activating Transcription Factor 6↗

PubMed2005

The strength of receptor signaling is centrally controlled through a cooperative loop between Ca2+ and an oxidant signal.

Activation of cell-surface receptors stimulates generation of intracellular signals that, in turn, direct the cellular response. However, mechanisms that ensure combinatorial control of these signaling events are not well understood. We show here that the Ca2+ and reactive oxygen intermediates generated upon BCR activation rapidly engage in a cooperative interaction that acts in a feedback manner to amplify the early signal generated. This cooperativity acts by regulating the concentration of the oxidant produced. The latter exerts its influence through a pulsed inactivation of receptor-coupled phosphatases, where the amplitude of this pulse is determined by oxidant concentration. The extent of phosphatase inhibition, in turn, dictates what proportion of receptor-proximal kinases are activated and, as a result, the net strength of the initial signal. It is the strength of this initial signal that finally determines the eventual duration of BCR signaling and the rate of its transmission through downstream pathways.

Calcium↗

PubMed2004

Differential effects of regulator of G protein signaling (RGS) proteins on serotonin 5-HT1A, 5-HT2A, and dopamine D2 receptor-mediated signaling and adenylyl cyclase activity.

Regulator of G protein signaling (RGS) proteins function as GTPase accelerating proteins (GAP) for Galpha subunits, attenuating G-protein-coupled receptor signal transduction. The present study tested the ability of members of different subfamilies of RGS proteins to modulate both G-protein-dependent and -independent signaling in mammalian cells. RGS4, RGS10, and RGSZ1 significantly attenuated Galphai-mediated signaling by 5-HT1A, but not by dopamine D2, receptor-expressing cells. Additionally, RGS4 and RGS10 significantly inhibited forskolin-stimulated cAMP production in both cell lines. In contrast, RGS2, RGS7, and RGSZ1 had no effect on forskolin-stimulated cAMP production in these cells. RGS2 and RGS7 significantly decreased Galphaq-mediated signaling by 5-HT2A receptors, confirming that the RGS4 and RGS10 effects on forskolin-stimulated cAMP production were specific, and not simply due to overexpression. Interestingly, similar expression levels of RGS4 protein resulted in greater inhibition of G-protein-independent cAMP production compared to G-protein-dependent GAP activity. Our results suggest specificity and selectivity of RGS proteins on G-protein-dependent and -independent signaling in mammalian cells.

Adenylyl Cyclases↗

PubMed2005

Regulation of the extracellular signal-regulated kinase pathway in adult myocardium: differential roles of G(q/11), Gi and G(12/13) proteins in signalling by alpha1-adrenergic, endothelin-1 and thrombin-sensitive protease-activated receptors.

Using adenoviruses encoding RGS2, RGS4 and Lsc (regulator of G protein signalling (RGS) domain of p115 RhoGEF), we investigated the contributions of G(q/11), Gi and G(12/13) proteins to G protein-coupled receptor (GPCR)-mediated activation of the extracellular signal-regulated kinase (ERK) pathway in adult rat ventricular myocytes (ARVM). Exposure to phenylephrine, endothelin-1 (ET-1) or thrombin induced significant activation of ERK1/2 and their downstream target 90 kDa ribosomal S6 kinase (p90RSK), which was abolished by overexpression of RGS4 (inhibits signalling via G(q/11) and Gi) or RGS2 (inhibits signalling via G(q/11)). Pertussis toxin (inhibits signalling via Gi) only partially attenuated the activation of ERK1/2 and p90(RSK) by phenylephrine and ET-1, but abolished such activation by thrombin. Overexpression of Lsc (inhibits signalling via G(12/13)) did not affect the responses to phenylephrine and ET-1, but suppressed the activation of ERK1/2 and p90RSK by thrombin. We conclude that full activation of the ERK pathway in ARVM by alpha1-adrenergic, ET-1 and thrombin receptors requires the activation of distinct families of heterotrimeric G proteins.

Adenoviridae↗

PubMed2006

Analytically exact correction scheme for signal extraction from noisy magnitude MR signals.

An analytically exact method is proposed to extract the signal intensity and the noise variance simultaneously from noisy magnitude MR signals. This method relies on a fixed point formula of signal-to-noise ratio (SNR) and a correction factor. The correction factor, which is a function of SNR, establishes a fundamental link between the variance of the magnitude MR signal and the variance of the underlying Gaussian noise in the two quadrature channels. A more general but very similar method is developed for parallel signal acquisitions with multiple receiver coils. In the context of MR imaging, the proposed method can be carried out on a pixel-by-pixel basis if the mean and the standard deviation of the magnitude signal are available.

Algorithms↗

PubMed2006

A modified Zeeman model for producing HRV signals and its application to ECG signal generation.

Developing a mathematical model for the artificial generation of electrocardiogram (ECG) signals is a subject that has been widely investigated. One of the challenges is to generate ECG signals with a wide range of waveforms, power spectra and variations in heart rate variability (HRV)--all of which are important indexes of human heart functions. In this paper we present a comprehensive model for generating such artificial ECG signals. We incorporate into our model the effects of respiratory sinus arrhythmia, Mayer waves and the important very low-frequency component in the power spectrum of HRV. We use a new modified Zeeman model for generating the time series for HRV, and a single cycle of ECG is produced by using a simple neural network. The importance of the work is the model's ability to produce artificial ECG signals that resemble experimental recordings under various physiological conditions. As such the model provides a useful tool to simulate and analyse the main characteristics of ECG, such as its power spectrum and HRV under different conditions. Potential applications of this model include using the generated ECG as a flexible signal source to assess the effectiveness of a diagnostic ECG signal-processing device.

Arrhythmia, Sinus↗

PubMed2003

Ephrin signaling: One raft to rule them all? One raft to sort them? One raft to spread their call and in signaling bind them?

The Eph receptor tyrosine kinases (RTK) and their membrane-bound ligands, the ephrins, mediate cell-contact-dependent signaling events that control multiple aspects of metazoan embryonic development. The ephrins and their receptors regulate cell movement that is essential for forming and stabilizing the spatial organization of tissues and cell types. This includes the guidance of migrating cells or neuronal growth cones to specific targets. Although the biological responses mediated by the ephrin-Eph system were thought to be imparted by the Eph receptor via 'classical' RTK signaling pathways, there is now accumulating evidence that the ephrins are not merely ligands but have biological activity independent of the kinase activity of their cognate Eph receptor. This activity is commonly referred to as 'reverse' or 'bi-directional' signaling. Furthermore, ephrin-mediated signaling is restricted to specific membrane microdomains known as 'lipid rafts', which we believe imparts specificity to the extracellular signal. This review highlights the current data to support a role for lipid rafts in regulating aspects of ephrin-mediated signaling.

Animals↗

PubMed2005

Involvement of extracellular signal-regulated kinases 1/2 and (phosphoinositide 3-kinase)/Akt signal pathways in acquired resistance against neurotoxin of 6-hydroxydopamine in SH-SY5Y cells following cell-cell interaction with astrocytes.

Glial cells interact with neurons and play important roles in the development, differentiation, maintenance and repair of the nervous system. Human neuroblastoma cells (SH-SY5Y) became dramatically resistant to neurotoxin 6-hydroxydopamine (6-OHDA), when co-cultured with mouse astrocytes. In order to further delineate the molecular mechanism involved in the neuroprotection in this selective cell-cell interaction, we assessed the activation of two signal pathways, namely, the MAP kinases (extracellular signal-regulated kinases, ERK1/2) and phosphoinositide 3-kinase (PI3-K)/Akt signal pathways in response to 6-OHDA insult and subsequent neuronal survival. Western blot revealed that 6-OHDA significantly increased the phosphorylation of ERK1/2 and Akt in mono-cultured SH-SY5Y cells. However, the increase in ERK1/2 in SH-SY5Y cells after co-cultured with astrocytes occurred as early as 3 h after 6-OHDA treatment in oppose to the increase after 12 h in monocultures. The phosphorylation of Akt in the co-cultured SH-SY5Y cells was much pronounced 3 h after 6-OHDA treatment compared with that in the mono-cultured cells. The anti-apoptotic protein bcl-2 was also increased in the co-cultured SH-SY5Y cells 3 h after treatment with 6-OHDA. Selective inhibitor of PI3-K/Akt signal pathway blocked the acquired resistance to 6-OHDA in SH-SY5Y cells following interaction with astrocytes. Inhibition of ERK1/2 signal pathway did not affect the cell survival. Our data suggest that PI3-K/Akt signal pathway, but not ERK1/2, is involved the acquired resistance in SH-SY5Y cells following cell-cell interaction with astrocytes against the neurotoxic 6-OHDA insult.

Adrenergic Agents↗

PubMed2003

Insulin and leptin revisited: adiposity signals with overlapping physiological and intracellular signaling capabilities.

The adipocyte-derived hormone leptin and the pancreatic beta cell-derived hormone insulin each function as afferent signals to the hypothalamus in an endocrine feedback loop that regulates body adiposity. Although these two hormones, and the receptors on which they act, are unrelated and structurally distinct, they exert overlapping effects in the arcuate nucleus, a key hypothalamic area involved in energy homeostasis. Defects in either insulin or leptin signaling in the brain result in hyperphagia, disordered glucose homeostasis, and reproductive dysfunction. To explain this striking physiological overlap, we hypothesize that hypothalamic insulin and leptin signaling converge upon a single intracellular signal transduction pathway, known as the insulin-receptor-substrate phosphatidylinositol 3-kinase pathway. Here we synthesize data from a variety of model systems in which such "cross-talk" between insulin and leptin signal transduction has either been observed or can be inferred, discuss our own data demonstrating that insulin and leptin both activate hypothalamic phosphatidylinositol 3-kinase signaling, and discuss the significance of such convergence with respect to neuronal function in normal individuals and in pathological states such as obesity. Identification of the key early molecular events mediating the action of both insulin and leptin in hypothalamic neurons promises new insight into the regulation of these neurons in health and disease.

Animals↗

PubMed2003

Regulators of G-protein signalling: multifunctional proteins with impact on signalling in the cardiovascular system.

Regulator of G-protein signalling (RGS) proteins form a superfamily of at least 25 proteins, which are highly diverse in structure, expression patterns, and function. They share a 120 amino acid homology domain (RGS domain), which exhibits GTPase accelerating activity for alpha-subunits of heterotrimeric G-proteins, and thus, are negative regulators of G-protein-mediated signalling. Based on the organisation of the Rgs genes, structural similarities, and differences in functions, they can be divided into at least six subfamilies of RGS proteins and three more families of RGS-like proteins. Many of these proteins regulate signalling processes within cells, not only via interaction with G-protein alpha-subunits, but are G-protein-regulated effectors, Gbetagamma scavenger, or scaffolding proteins in signal transduction complexes as well. The expression of at least 16 different RGS proteins in the mammalian or human myocardium have been described. A subgroup of at least eight was detected in a single atrial myocyte. The exact functions of these proteins remain mostly elusive, but RGS proteins such as RGS4 are involved in the regulation of G(i)-protein betagamma-subunit-gated K(+) channels. An up-regulation of RGS4 expression has been consistently found in human heart failure and some animal models. Evidence is increasing that the enhanced RGS4 expression counter-regulates the G(q/11)-induced signalling caused by hypertrophic stimuli. In the vascular system, RGS5 seems to be an important signalling regulator. It is expressed in vascular endothelial cells, but not in cultured smooth muscle cells. Its down-regulation, both in a model of capillary morphogenesis and in an animal model of stroke, render it a candidate gene, which may be involved in the regulation of capillary growth, angiogenesis, and in the pathophysiology of stroke.

Animals↗

PubMed2001

NGF signaling from clathrin-coated vesicles: evidence that signaling endosomes serve as a platform for the Ras-MAPK pathway.

The target-derived neurotrophic factor "nerve growth factor" (NGF) signals through TrkA to promote the survival, differentiation, and maintenance of neurons. How the NGF signal in axon terminals is conveyed to the cell body is unknown. The "signaling endosome hypothesis" envisions that NGF-TrkA complexes are internalized at the axon terminal and retrogradely transported to the cell body. Following NGF treatment, we found that clathrin-coated vesicles contained NGF bound to TrkA together with activated signaling proteins of the Ras-MAP kinase pathway. Evidence that these vesicles could signal was their ability in vitro to activate Elk, a downstream target of Erk1/2. Our results point to the existence of a population of signaling endosomes derived from clathrin-coated membranes in NGF-treated cells.

Animals↗

PubMed2001

The somatostatin analogue TT-232 induces apoptosis in A431 cells: sustained activation of stress-activated kinases and inhibition of signalling to extracellular signal-regulated kinases.

TT-232 is a somatostatin analogue containing a five-residue ring structure. The present report describes TT-232-induced signalling events in A431 cells, where a 4-h preincubation with the peptide irreversibly induced a cell death program, which involves DNA-laddering and the appearance of shrunken nuclei, but is unrelated to somatostatin signalling. Early intracellular signals of TT-232 include a transient two-fold activation of the extracellular signal-regulated kinase (ERK2) and a strong and sustained activation of the stress-activated protein kinases c-Jun NH(2)-terminal kinase (JNK)/SAPK and p38MAPK. Blocking the signalling to ERK or p38MAPK activation had no effect on the TT-232-induced cell killing. At the commitment time for inducing cell death, TT-232 decreased EGFR-tyrosine phosphorylation and prevented epidermial growth factor (EGF)-induced events like cRaf-1 and ERK2 activation. Signalling to ERK activation by FCS, phorbol 12-myristate 13-acetate (PMA) and platelet-derived growth factor (PDGF) was similarly blocked. Our data suggest that TT-232 triggers an apoptotic type of cell death, concomitant with a strong activation of JNK and a blockade of cellular ERK2 activation pathways.

Antineoplastic Agents↗

PubMed2002

Requirements of high levels of Hedgehog signaling activity for medial-region cell fate determination in Drosophila legs: identification of pxb, a putative Hedgehog signaling attenuator gene repressed along the anterior-posterior compartment boundary.

We show that high levels of Hedgehog signaling activity are essential for medial-region patterning in Drosophila legs. In mid-to-late third instar leg discs, high levels of Hedgehog signals repress the transcription of pxb, a newly identified gene encoding a transmembrane protein expressed specifically in the anterior compartment. Misexpression experiments indicate that Pxb may serve as a Hedgehog signaling attenuator capable of acting prior to Hedgehog-Patched interactions, suggesting that Hedgehog signaling in leg discs includes a pxb-repression-mediated positive feedback loop. RNA interference and clonal analysis show that neither Wingless nor Decapentaplegic signaling is required for pxb repression but high levels of Wingless signaling activity are essential for patterning in the leg ventral medial region.

Amino Acid Sequence↗

PubMed1999

Direct regulation of the Xenopus engrailed-2 promoter by the Wnt signaling pathway, and a molecular screen for Wnt-responsive genes, confirm a role for Wnt signaling during neural patterning in Xenopus.

The co-activation of Wnt signaling and concomitant inhibition of BMP signaling has previously been implicated in vertebrate neural patterning, as evidenced by the combinatorial induction of engrailed-2 and krox-20 in Xenopus. However, screens have not previously been conducted to identify additional potential target genes. Using a PCR-based screening method we determined that XA-1, xCRISP, UVS.2, two UVS.2-related genes, and xONR1 are induced in response to Xwnt-3a and a BMP-antagonist, noggin. Two additional genes, connexin 30 and retinoic acid receptor gamma were induced by Xwnt-3a alone. To determine whether any of the induced genes are direct targets of Wnt signaling, we focussed on engrailed-2. In the present study we show that the Xenopus engrailed-2 promoter contains three consensus binding sites for LEF/TCF, which are HMG box transcription factors which bind to beta-catenin in response to activation of the Wnt- 1 signaling pathway. An engrailed-2 promoter luciferase reporter construct containing these LEF/TCF sites is induced in embryo explant assays by the combination of Xwnt-3a or beta-catenin and noggin. These LEF/TCF sites are required for expression of engrailed-2, as a dominant negative Xtcf-3 blocks expression of endogenous engrailed-2 as well as expression of the reporter construct. Moreover, mutation of these three LEF/TCF sites abrogates expression of the reporter construct in response to noggin and Xwnt-3a or beta-catenin. We conclude that the engrailed-2 gene is a direct target of the Wnt signaling pathway, and that Wnt signaling works with BMP antagonists to regulate gene expression during patterning of the developing nervous system of Xenopus.

Animals↗

PubMed1998

Specificity in signaling pathways: assembly into multimolecular signaling complexes.

A critical issue in the field of signal transduction is how signaling molecules are organized into different pathways within the same cell. The importance of assembling signaling molecules into architecturally defined complexes is emerging as an essential cellular strategy to ensure specificity and selectivity of signaling. Scaffold proteins function as the pillars of these transduction complexes, bringing together a diversity of signaling components into defined ultramicrodomains of signaling.

Animals↗