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At least 217 records · Page 12Linked to original sources

PubMed2006

Alternate recruitment of signal recognition particle and trigger factor to the signal sequence of a growing nascent polypeptide.

Different from cytoplasmic membrane proteins, presecretory proteins of bacteria usually do not require the signal recognition particle for targeting to the Sec translocon. Nevertheless signal sequences of presecretory proteins have been found in close proximity to signal recognition particle immediately after they have emerged from the ribosome. We show here that at the ribosome, the molecular environment of a signal sequence depends on the nature of downstream sequence elements that can cause an alternate recruitment of signal recognition particle and the ribosome-associated chaperone Trigger factor to a growing nascent chain. While signal recognition particle and Trigger factor might remain bound to the same ribosome, both ligands are clearly able to displace each other from a nascent chain. The data also imply that a signal sequence owes its molecular environment to the fact that it remains closely apposed to the ribosomal exit site during growth of a nascent secretory protein.

Adenosine Triphosphatases↗

PubMed1999

Interleukin 2 receptor signaling regulates the perforin gene through signal transducer and activator of transcription (Stat)5 activation of two enhancers.

Optimal T cell differentiation into effector cells with specialized functions requires the participation of cytokine receptor signals. In T helper cells, this process is controlled by chromatin changes and distal and proximal regulatory elements as well as specific transcription factors. Analogous events during cytotoxic T lymphocyte (CTL) differentiation remain to be identified. This process is known, however, to be crucially regulated by interleukin (IL)-2 receptor (R) signals. It is accompanied by the induction of perforin expression via a mechanism that does not entail proximal regulatory elements. In this report, transgenically expressed human perforin gene locus DNAs demonstrate that IL-2R signals target two IL-2-dependent enhancers approximately 15 and 1 kilobase upstream of the promoter. The most distal enhancer may also respond to TCR signals. In transient transfections, both enhancers required two identically spaced Stat-like elements for their activation, which was abolished by expression of a dominant negative signal transducer and activator of transcription (Stat)5 molecule, whereas a constitutively active Stat5 molecule bypassed the requirement for IL-2R signals. These results provide a molecular explanation for the activation of the perforin gene during CTL differentiation and complement the analysis of animals deficient in the activation of the IL-2R Stat signaling pathway by establishing perforin as a target gene.

Animals↗

PubMed2001

Dual involvement of coenzyme Q10 in redox signaling and inhibition of death signaling in the rat heart mitochondria.

Coenzyme Q10 (CoQ) has long been utilized as a cardioprotective agent in various heart diseases. One of the most important mechanisms by which CoQ exerts cardioprotection is aerobic ATP production as a mobile electron carrier in the mitochondrial electron transfer chain. The ability of CoQ to afford myocardial protection is also attributed to its antioxidant property. However, CoQ may also act as a pro-oxidant through the generation of reactive oxygen species. Although excess oxidative stress is known to induce death signaling via cytochrome c release from mitochondria, it is now apparent that a brief exposure to oxidative stress stimulates redox signaling for acquisition of tolerance to oxidative stress. Therefore, we have investigated dual involvement of CoQ in redox signaling generation through enhanced production of reactive oxygen species and death signaling inhibition through antioxidation. Mitochondria were isolated from the rat heart and incubated with CoQ (10 or 100 microM) or its vehicle HCO 60 for 1 h. H2O2 and cytochrome c release from respiring mitochondria were increased by antimycin A (2 microM), an inhibitor of complex III respiratory chain, or by high Ca2+ (10 microM). This enhanced release of H2O2 was associated with an increase in lipid peroxidation as measured with 4-hydroxy-2-nonenal-modified proteins and with large amplitude swelling of mitochondria. CoQ potentiated H2O2 release from antimycin A- or high Ca(2+)-treated mitochondria, but was capable of inhibiting lipid peroxidation and large amplitude swelling, and attenuated cytochrome c release from the mitochondria. In addition, CoQ increased ATP synthesis by mitochondria. These results suggest that CoQ plays dual roles in mitochondrial generation of intracellular signaling. CoQ acts as a pro-oxidant that participates in redox signaling. CoQ also acts as an antioxidant that inhibits permeability transition and cytochrome c release, and increases ATP synthesis, thereby attenuating death signaling toward apoptosis and necrosis.

Adenosine Triphosphate↗

PubMed2000

Signal-exon trap: a novel method for the identification of signal sequences from genomic DNA.

We describe a genomic DNA-based signal sequence trap method, signal-exon trap (SET), for the identification of genes encoding secreted and membrane-bound proteins. SET is based on the coupling of an exon trap to the translation of captured exons, which allows screening of the exon-encoded polypeptides for signal peptide function. Since most signal sequences are expected to be located in the 5'-terminal exons of genes, we first demonstrate that trapping of these exons is feasible. To test the applicability of SET for the screening of complex genomic DNA, we evaluated two critical features of the method. Specificity was assessed by the analysis of random genomic DNA and efficiency was demonstrated by screening a 425 kb YAC known to contain the genes of four secretory or membrane-bound proteins. All trapped clones contained a translation initiation signal followed by a hydrophobic stretch of amino acids representing either a known signal peptide, transmembrane domain or novel sequence. Our results suggest that SET is a potentially useful method for the isolation of signal sequence-containing genes and may find application in the discovery of novel members of known secretory gene clusters, as well as in other positional cloning approaches.

Animals↗

PubMed1994

Different classes of volume transmission signals exist in the central nervous system and are affected by metabolic signals, temperature gradients and pressure waves.

Volume transmission (VT) is the mode of intercellular communication involving the diffusion of transmitters, via extracellular fluid (ECF) pathways, from nerve cells selectively capable of producing the signal (signal source) to nerve and glial cells selectively capable of recognizing it (signal target). The proposal is now put forward that at least two classes of VT signals can be distinguished: (a) the private-code signals, exemplified by neurotransmitters, which are released by a limited group of nerve cells and recognized, via high affinity G-protein coupled receptors or by cytosolic enzymes such as guanylate cyclase in the case of nitric oxide, by a specific group of cells; and (b) the accessible-code signals, such as the electrical signals that are released by all neuronal cells and decoded by almost every CNS cell. In the present paper, it will be underlined that carbon dioxide, hydrogen ions, temperature gradients and pressure waves may be regulators of wiring transmission and VT.

Animals↗

PubMed2004

Growth hormone-mediated janus associated kinase-signal transducers and activators of transcription signaling in the growth hormone-resistant potassium-deficient rat.

Potassium deficiency (KD) is associated with severe growth failure, in part caused by growth hormone (GH) resistance. This study set out to determine whether the resistance could be caused by a defect in GH-mediated janus associated kinase-signal transducers and activators of transcription (STAT) signaling as occurs in uremia. To this end, rats were fed a K-deficient diet for 8 d and pair-fed controls received a K-replete diet. Animals from each group received GH or vehicle, and during this period, KD rats were GH resistant; GH induced body and liver weight gain and linear body growth were severely attenuated in these rats. In addition, signal transduction was studied in the liver of rats that were killed 10 or 15 min after an intravenous GH bolus or vehicle. When the rats were killed, GH receptor mRNA and protein levels were similar in the two groups. The abundance of STAT5, STAT3, and STAT1, proteins that mediate GH signaling, was significantly increased by 40 to 130% in KD. Furthermore, GH induced a far greater increase in STAT5 and STAT3 phosphorylation in this group. STAT5 phosphorylation was enhanced fourfold even when normalized for total STAT5 content. Phosphorylated STAT5 and STAT3 proteins were also increased in nuclear extracts, suggesting normal nuclear translocation of the activated signaling proteins. DNA binding of nuclear STAT5 was unaltered. Thus, in KD, there is resistance to the growth-promoting action of GH despite hyperactivation of the janus associated kinase-STAT signaling pathway. This suggests the presence of a defect distal to the nuclear binding of STAT or, alternatively, a defect in a STAT-independent GH-activated signaling pathway.

Animals↗

PubMed1992

Adaptive filter for event-related bioelectric signals using an impulse correlated reference input: comparison with signal averaging techniques.

Many bioelectric signals result from the electrical response of physiological systems to an impulse that can be internal (ECG signals) or external (evoked potentials). In this paper an adaptive impulse correlated filter (AICF) for event-related signals that are time-locked to a stimulus is presented. This filter estimates the deterministic component of the signal and removes the noise uncorrelated with the stimulus, even if this noise is colored, as in the case of evoked potentials. The filter needs two inputs: the signal (primary input) and an impulse correlated with the deterministic component (reference input). We use the LMS algorithm to adjust the weights in the adaptive process. First, we show that the AICF is equivalent to exponentially weighted averaging (EWA) when using the LMS algorithm. A quantitative analysis of the signal-to-noise ratio improvement, convergence, and misadjustment error is presented. A comparison of the AICF with ensemble averaging (EA) and moving window averaging (MWA) techniques is also presented. The adaptive filter is applied to real high-resolution ECG signals and time-varying somatosensory evoked potentials.

Algorithms↗

PubMed1993

Waveform estimation from noisy signals with variable signal delay using bispectrum averaging.

A technique based on bispectrum averaging is described for generally recovering the signal waveform from a set of noisy signals with variable signal delay. The technique does not require explicit time alignment of signals and any initial estimate of signal. The technique, however, does not yield estimates of the signal position. A comparison is made of two algorithms for recovering the Fourier amplitude and the Fourier phase from an averaged bispectrum. These algorithms are the recursive method and the least squares method. The methods are numerically investigated using computer generated-data and a physiological signal and noise. The advantages and disadvantages of these different algorithms are discussed. Some experimental results for the evoked potential studies that demonstrate the technique are given. The results show the effectiveness of the technique: various potential applications of the technique might be expected.

Algorithms↗

PubMed2004

Chemical communication in proteobacteria: biochemical and structural studies of signal synthases and receptors required for intercellular signalling.

Cell-cell communication via the production and detection of chemical signal molecules has been the focus of a great deal of research over the past decade. One class of chemical signals widely used by proteobacteria consists of N-acyl-homoserine lactones, which are synthesized by proteins related to LuxI of Vibrio fischeri and are detected by proteins related to the V. fischeri LuxR protein. A related marine bacterium, Vibrio harveyi, communicates using two chemical signals, one of which, autoinducer-2 (AI-2), is a furanone borate diester that is synthesized by the LuxS protein and detected by a periplasmic protein called LuxP. Evidence from a number of laboratories suggests that AI-2 may be used as a signal by diverse groups of bacteria, and might permit intergeneric signalling. These two families of signalling systems have been studied from the perspectives of physiology, ecology, biochemistry, and more recently, structural biology. Here, we review the biochemistry and structural biology of both acyl-homoserine-lactone-dependent and AI-2-dependent signalling systems.

Bacterial Proteins↗

PubMed1992

Structure of yeast pGKL 128-kDa killer-toxin secretion signal sequence. Processing of the 128-kDa killer-toxin-secretion-signal-alpha-amylase fusion protein.

The linear double-stranded DNA plasmid pGKL1 in yeast encodes a killer toxin consisting of 97-kDa, 31-kDa and 28-kDa subunits. A 128-kDa protein precursor of the 97-kDa and 31-kDa subunits, was first synthesized with a 29-amino-acid extension at its NH2-terminus as a secretion signal sequence. In the present study, the property of this signal sequence was studied by the analysis of a fusion protein with mouse alpha-amylase. Using the secretion signal sequence of the killer protein, the mouse alpha-amylase was successfully secreted into the culture medium. An intracellular precursor form of alpha-amylase was identified and purified. Analysis of the NH2-terminal sequence of this precursor molecule indicated that it corresponded to the secretory intermediate (pro form) of alpha-amylase with the removal of the hydrophobic segment (Met1-Gly16) of the secretion signal. Both the secretion of alpha-amylase into the culture medium and the detection of the pro-alpha-amylase species in the cells were prohibited by a sec 11 mutation, or by the conversion of Gly to Val at the 16th position of the secretion signal. These results strongly suggest that the cleavage occurs between Gly16 and Leu17 by a signal peptidase, and that this cleavage is required for the secretion of alpha-amylase into the medium. Based on the data from the NH2-terminal amino acid sequences of secreted alpha-amylases, we conclude that the 29-amino-acid secretion signal present in the 128-kDa killer toxin precursor protein is a prepro structure.

Amino Acid Sequence↗

PubMed2006

Compartmentalization in T-cell signalling: membrane microdomains and polarity orchestrate signalling and morphology.

Lymphocyte function is regulated by complex signalling responses to diverse extracellular inputs, and a cell will often receive multiple, conflicting signals at one time. The mechanisms by which a lymphocyte integrates these signals into a single cellular response are not well understood. An important factor in the integration of signals likely involves the regulation of access of signalling molecules to cell surface receptors and of receptor signals to morphological determinants within the cell. Recent studies have led to important advances in our understanding of both the mechanisms by which signals are compartmentalized in T cells and the physiological role played by such compartmentalization. We review progress in the field, with a particular focus on membrane microdomains or lipid rafts and on cell polarity.

Cell Compartmentation↗

PubMed1993

Structural requirements of Bacillus subtilis alpha-amylase signal peptide for efficient processing: in vivo pulse-chase experiments with mutant signal peptides.

The Bacillus subtilis alpha-amylase signal peptide consists of 33 amino acids from its translation initiation site. To analyze the structural requirements for efficient processing of the signal peptide, single and repeated Ala-X-Ala sequences and their modifications were introduced into B. subtilis alpha-amylase signal peptides of different lengths and the mature thermostable alpha-amylase. Then the cleavage positions and processing rates of the signal peptides were analyzed by the NH2-terminal amino acid sequences of the exported thermostable alpha-amylases and by in vivo pulse-chase experiments. In B. subtilis, the most efficient cleavage site was located at the peptide bond between Ala-33 and amino acid X at position 34, even though Val-X-Ala and six repeating Ala-X-Ala sequences were present around the cleavage site. However, the cleavage site was shifted to the peptide bond between Ala-31 and amino acid X when Ala-33 was deleted, and it was also shifted to Ala-35 and X when Ala-33 was replaced with Val-33. The shorter signal peptide consisting of 31 amino acids reduced the processing rate and alpha-amylase production. In contrast, those signal peptides were cleaved preferentially at the peptide bond between Ala-31 and amino acid X in Escherichia coli. In addition to the presence of an Ala residue at the -1 amino acid position, the length of the signal peptide was another important requirement for efficient processing.

Alanine↗

PubMed1998

Signal peptidase cleavage at the flavivirus C-prM junction: dependence on the viral NS2B-3 protease for efficient processing requires determinants in C, the signal peptide, and prM.

Signal peptidase cleavage at the C-prM junction in the flavivirus structural polyprotein is inefficient in the absence of the cytoplasmic viral protease, which catalyzes cleavage at the COOH terminus of the C protein. The signal peptidase cleavage occurs efficiently in circumstances where the C protein is deleted or if the viral protease complex is present. In this study, we used cDNA of Murray Valley encephalitis virus (MVE) to examine features of the structural polyprotein which allow this regulation of a luminal cleavage by a cytoplasmic protease. We found that the inefficiency of signal peptidase cleavage in the absence of the viral protease is not attributable solely to features of the C protein. Inhibition of cleavage still occurred when charged residues in C were mutated to uncharged residues or when an unrelated protein sequence (that of ubiquitin) was substituted for C. Also, fusion of the C protein did not inhibit processing of an alternative adjacent signal sequence. The cleavage region of the flavivirus prM translocation signal is unusually hydrophobic, and we established that altering this characteristic by making three point mutations near the signal peptidase cleavage site in MVE prM dramatically increased the extent of cleavage without requiring removal of the C protein. In addition, we demonstrated that luminal sequences downstream from the signal peptidase cleavage site contributed to the inefficiency of cleavage.

Amino Acid Sequence↗

PubMed2004

Modulation of T-cell receptor signal transduction by herpesvirus signaling adaptor protein.

Because of its central regulatory role, T-cell receptor (TCR) signal transduction is a common target of viruses. We report here the identification of a small signaling protein, ORF5, of the T-lymphotropic tumor virus herpesvirus saimiri (HVS). ORF5 is predicted to contain 89 to 91 amino acids with an amino-terminal myristoylation site and six SH2 binding motifs, showing structural similarity to cellular LAT (linker for activation of T cells). Sequence analysis showed that, despite extensive sequence variation, the myristoylation site and SH2 binding motifs were completely conserved among 13 different ORF5 isolates. Upon TCR stimulation, ORF5 was efficiently tyrosine phosphorylated and subsequently interacted with cellular SH2-containing signaling proteins Lck, Fyn, SLP-76, and p85 through its tyrosine residues. ORF5 expression resulted in the marked augmentation of TCR signal transduction activity, evidenced by increased cellular tyrosine phosphorylation, intracellular calcium mobilization, CD69 surface expression, interleukin-2 production, and activation of the NF-AT, NF-kappa B, and AP-1 transcription factors. Despite its structural similarity to cellular LAT, however, ORF5 could only partially substitute for LAT function in TCR signal transduction. These results demonstrate that HVS utilizes a novel signaling protein, ORF5, to activate TCR signal transduction. This activation probably facilitates viral gene expression and, thereby, persistent infection.

Alleles↗

PubMed2006

The sphingosine and diacylglycerol kinase superfamily of signaling kinases: localization as a key to signaling function.

The sphingosine and diacylglycerol kinases form a superfamily of structurally related lipid signaling kinases. One of the striking features of these kinases is that although they are clearly involved in agonist-mediated signaling, this signaling is accomplished with only a moderate (and sometimes no) increase in the enzymatic activity of the enzymes. Here, we summarize findings that indicate that signaling by these kinases is strongly dependent on their localization to specific intracellular sites rather than on increases in enzyme activity. Both the substrates and products of these enzymes are bioactive lipids. Moreover, many of the metabolic enzymes that act on these lipids are found in specific organelles. Therefore, changes in the membrane localization of these signaling kinases have profound effects not only on the production of signaling lipid phosphates but also on the metabolism of the upstream signaling lipids.

Animals↗

PubMed2004

The Fgf8 signal causes cerebellar differentiation by activating the Ras-ERK signaling pathway.

The mes/metencephalic boundary (isthmus) is an organizing center for the optic tectum and cerebellum. Fgf8 is accepted as a crucial organizing signal. Previously, we reported that Fgf8b could induce cerebellum in the mesencephalon, while Fgf8a transformed the presumptive diencephalon into mesencephalon. Since lower doses of Fgf8b exerted similar effects to those of Fgf8a, the type difference could be attributed to the difference in the strength of the signal. It is of great interest to uncover mechanisms of signal transduction pathways downstream of the Fgf8 signal in tectal and cerebellar development, and in this report we have concentrated on the Ras-ERK pathway. In normal embryos, extracellular-signal-regulated kinase (ERK) is activated at the site where Fgf8 mRNA is expressed. Fgf8b activated ERK while Fgf8a or a lower dose of Fgf8b did not activate ERK in the mes/metencephalon. Disruption of the Ras-ERK signaling pathway by a dominant negative form of Ras (RasS17N) changed the fate of the metencephalic alar plate from cerebellum to tectum. RasS17N canceled the effects of Fgf8b, while co-transfection of Fgf8a and RasS17N exerted additive effects. Disruption of Fgf8b, not Fgf8a, by siRNA resulted in posterior extension of the Otx2 expression domain. Our results indicate that the presumptive metencephalon receives a strong Fgf8 signal that activates the Ras-ERK pathway and differentiates into the cerebellum.

Animals↗

PubMed2005

Stress signaling: coregulation of hemoglobin and male sex determination through a terpenoid signaling pathway in a crustacean.

Environmental signals can activate neuro-endocrine cascades that regulate various physiological processes. In the present study, we demonstrate that two responses to environmental stress signaling in the crustacean Daphnia magna--hemoglobin accumulation and male offspring production--are co-elevated by the crustacean terpenoid hormone methyl farnesoate and several synthetic analogs. Potency of the hormones with respect to the induction of both hemoglobin and male offspring was highly correlated, suggesting that both processes are regulated by the same terpenoid signaling pathway. Six clones of the D. pulex/pulicaria species complex that were previously characterized as unable to produce male offspring and five clones that were capable of producing males were evaluated for both hemoglobin induction and male offspring production in response to methyl farnesoate. Four of the five male-producing clones produced both hemoglobin and male offspring in response to the hormone. Five of the six non-male-producing clones produced neither hemoglobin nor males in response to the hormone. These results provide additional evidence that both physiological processes are regulated by the same signaling pathway. Furthermore, the results indicate that the non-male-producing clones are largely defective in some methyl farnesoate signaling component, downstream from methyl farnesoate synthesis but upstream from the genes regulated by the hormone. A likely candidate for the site of the defect is the methyl farnesoate receptor. As a consequence of this defect, non-male-producing clones have lost their responsiveness to environmental signals that are transduced by this endocrine pathway. This defect in signaling would be likely to enhance population growth in stable environments due to the elimination of males from the population, assuming that other processes critical to population growth are not also compromised by this defect.

Analysis of Variance↗

PubMed2004

Extracellular signal-regulated kinase 1/2 signaling pathway in solitary nucleus mediates cholecystokinin-induced suppression of food intake in rats.

Increased food intake is a major factor in the development of obesity, and the control of meal size is a valid approach to reduce food intake in humans. Meal termination, or satiety, is thought to be organized within the caudal brainstem where direct signals from the food handling alimentary canal and long-term signals from the forebrain converge in the solitary nucleus. Cholecystokinin (CCK) released from the gut after ingestion of food has been strongly implicated in nucleus tractus solitarius (NTS)-mediated satiation, but the exact cellular and intracellular signaling events are not understood. Using Western blotting and immunohistochemistry with phosphospecific antibodies, we demonstrate here that peripheral administration of CCK in rats leads to rapid activation of the extracellular signal-regulated kinase (ERK) signaling cascade in NTS neurons and that blockade of ERK signaling with microinfusion of a selective mitogen-activated ERK kinase inhibitor into the fourth ventricle attenuates the capacity of CCK to suppress food intake. In addition, we show that CCK-induced activation of ERK results in phosphorylation of the voltage-dependent potassium channel Kv4.2 and the nuclear transcription factor CREB (cAMP response element-binding protein). The results demonstrate that ERK signaling is necessary for exogenous CCK to suppress food intake in deprived rats and suggest that this pathway may also be involved in natural satiation and the period of satiety between meals through coupling of ERK activation to both cytosolic and nuclear effector mechanisms that have the potential to confer acute and long-term changes in neuronal functioning.

Animals↗