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At least 415 records · Page 23Linked to original sources

PubMed2001

Why is DNA damage signaling so complicated? Chaos and molecular signaling.

Molecular signaling in eukaryotic cells is accomplished by complex and redundant pathways converging on key molecules that are allosterically controlled by a limited number of signaling proteins. The p53-signaling pathway is an example of a complicated sequence of signals produced in response to DNA damage. This pattern of signaling may arise from chance occurrences at the origin of life and the necessities imposed on a nanomolar system. From this viewpoint, chaos theory may explain the origin, complexity, and convergence of these pathways.

Animals↗

PubMed2002

MICA triggering signal for NK cell tumor lysis is counteracted by HLA-G1-mediated inhibitory signal.

MICA, a highly glycosylated membrane-anchored cell-surface MHC Class I-related chain, has recently been reported to activate NK cell cytolytic responses in epithelial tumors. Tumor cells may escape from NK lysis by counteracting NK cytotoxicity activating signals with inhibitory ones. Among the molecules that mediate an NK inhibitory signal, HLA-G1, a non-classical MHC Class I antigen, is of particular interest. HLA-G1 is ectopically expressed in various tumors, including melanoma and constitutes the major NK inhibitory ligand in the M8 melanoma cell line when coexpressed with HLA-A, -B, -C and -E molecules. We have evaluated the balance between 2 powerful signals that affect NK cell tumor lysis, one inhibitory and the other one activating, respectively HLA-G1 and MICA. For this purpose, we transfected the M8 melanoma cell line, which spontaneously expresses MICA, with HLA-G1 cDNA, using it as a target for the NKL effector. We carried out cytotoxicity assays, using antibodies that disrupt interactions between the MICA and HLA-G1 ligands and their respective NK effector counterparts, the NKG2D activating and ILT2 inhibitory receptors. Results showed that 1) MICA expressed in the M8 melanoma cell line triggered NK cell tumor lysis and 2) HLA-G1 coexpression mediated the inhibition of NK cytotoxicity by mitigating the MICA activating signal. HLA-G1 expression in a tumor cell line in which MICA is switched on would therefore appear to be a powerful way to turn off NK cells, supporting the emerging idea that the balance between positive and negative NK cytolysis signals critically influences tumor progression.

Animals↗

PubMed2004

Functional MRI using multiple receiver coils: BOLD signal changes and signal-to-noise ratio for three-dimensional-PRESTO vs. single shot EPI in comparison to a standard quadrature head coil.

PURPOSE: To compare the performance of single shot echo planar imaging (SSEPI) with three-dimensional-multishot echo-planar imaging (EPI) based on principles-of-echo-shifting-with-a-train-of-observations (PRESTO) in combination with a standard quadrature head coil and, as an alternative, a multiple receiver coil in intraoperative functional magnetic resonance imaging (fMRI). MATERIALS AND METHODS: Six healthy subjects underwent fMRI with visual stimulation using a SSEPI and a PRESTO-sequence with both coil systems. Statistical evaluation was done with a scanner-based post-processing software and SPM 99. The number of activated voxels in the visual cortex, the percent signal change between rest and activation, and finally the signal-to-noise ratio (SNR) during time course were measured and compared for both coil systems and both sequences, used in four different combinations. RESULTS: Blood oxygen level dependent (BOLD) signal changes were the lowest with PRESTO and standard head coil and the highest for SSEPI and phased array coil. For the latter combination, a significantly higher signal change and larger activation size was observed together with a better SNR. SSEPI yielded similar performance using both coils. CONCLUSION: SSEPI was superior due to its better SNR and a higher BOLD signal change in the defined settings, irrespective of the coil used. In a stereotactical setup the phased array coil can be used to generate fMRI data without loss of image quality.

Adult↗

PubMed1990

Can the topological distribution of membrane spanning amino acid residues be responsible for the recognition of signal peptides by signal peptide peptidases?

Signal peptides are selectively recognized and degraded by membrane associated proteases called as signal peptide peptidases. The hydrolysis of the signal peptide occurs only after its cleavage from the precursor. The possible reasons for this selectivity have been investigated. The results indicate that in signal peptides, leucine residues are clustered to a large extent on the same side of the membrane spanning alpha helix as the polar residues, but are distinctly separated along the length of the axis. Such topological differences in the distribution of amino acids on the surface of the membrane spanning alpha helix may play a crucial role in selective degradation of signal peptides.

Cell Membrane↗

PubMed1988

Signal processing strategies for enhancement of signal-to-noise ratio of thermodilution measurements.

Thermodilution measurements of clinically important cardiac parameters, such as cardiac output and stroke volume, are subject to many sources of error. The temperature fluctuations (thermal noise) normally found in the pulmonary artery constitute one of these sources of errors. To improve the signal-to-noise ratio of thermodilution flow measurements rather than increase the signal level, we investigated four signal processing strategies designed to reduce the thermal noise power. We applied the noise reduction strategies to thermal noise data, containing simulated thermodilution curves, obtained in a mock circulatory loop. We compared the accuracy and reproducibility of the curve area estimates produced by the algorithms to the area estimates obtained by numerical integration of the thermal signal. Our results show that a bandpass (BP) integration technique combined with a noise canceler can improve thermodilution curve area estimate reproducibility and accuracy. The BP integration technique improved the reproducibility of cardiac output measurements by roughly 16 dB and is directly applicable to most thermodilution hardware currently in use. The more accurate noise cancelers, combined with the BP integration technique, provided correspondingly improved signal-to-noise ratios, with the improvement ranging up to 50 dB.

Algorithms↗

PubMed1998

Spatial transformation of semicircular canal signals into abducens motor signals. A comparison between grass frogs and water frogs.

The spatial transformation of semicircular canal signals to extraocular motor signals was studied by recording abducens nerve responses in grass and water frogs. Both species have similar vestibular canal coordinates but dissimilar orientations of their optic axes. Before sinusoidal oscillation in darkness the static head position was systematically altered to determine the planes of head oscillation in pitch and roll associated with minimal abducens nerve responses. Measured data and known canal plane vectors were used to calculate the abducens response vector in canal coordinates. The abducens vector deviated from the horizontal canal plane vector in grass frogs by 15 degrees and in water frogs by 34 degrees but was aligned with the pulling direction of the lateral rectus muscle in each of the two species. Lesion experiments demonstrated the importance of convergent inputs from the contralateral horizontal and anterior semicircular canals for the orientation of the abducens response vector. Thus, the orientation of the optic axis and the pulling directions of extraocular muscles are taken into account by the central organization of vestibulo-ocular reflexes. Horizontal and vertical canal signals are combined species-specifically to transform the spatial coordinates of sensory signals into appropriate extraocular motor signals.

Abducens Nerve↗

PubMed2006

EGFR signaling pathway in breast cancers: from traditional signal transduction to direct nuclear translocalization.

Aberrant epidermal growth factor receptor (EGFR) signaling is a major characteristic of many human malignancies including breast cancer. Since the discovery of EGF in 1960's and its receptor in 1980's, our understanding of the EGF/EGFR pathway has been significantly advanced and consequently, EGFR is considered as a major oncogenic factor and an attractive therapeutic target. The well-established traditional function of EGFR is known to transmit extra-cellular mitogenic signals, such as EGF and transforming growth factor-alpha (TGF-alpha), through activating a number of downstream signaling cascades. These include signaling modules that involve phospholipase C-gamma, Ras, and phosphatidylinositol-3 kinase (PI-3K). In cancer cells, the common outcomes following the activation of the EGFR-mediated downstream pathways are altered gene activities, leading to un-controlled tumor proliferation and apoptosis. Interestingly, emerging evidences suggest the existence of a direct mode of the EGFR pathway that is distinct from the traditional transduction pathway. This new mode of EGFR signaling involves cellular transport of EGFR from the cell-surface to the cell nucleus, association of nuclear EGFR complex with gene promoters, and transcriptional regulation of the target genes. Although the nature and pathological consequences of the nuclear EGFR pathway remain elusive, accumulating evidences suggest its association with increased tumor cell proliferation and poor survival rate in breast cancer patients. While several anti-EGFR agents are being tested in breast cancer patients clinically and others under pre-clinical development, a better understanding of the traditional and the nuclear EGFR pathways will facilitate the identification of patients that are likely to respond to these agents as well as future development of more effective anti-EGFR therapeutic interventions.

Breast Neoplasms↗

PubMed1990

Molecular signals in B cell activation. II. IL-2-mediated signals are required in late G1 for transition to S phase after ionomycin and PMA treatment.

We report that sustained increase of intracellular calcium ion concentration and protein kinase C (PKC) activation maintained throughout the G1 phase of cell cycle do not provide sufficient signals to cause S-phase entry in rabbit B cells, and that additional signals transduced by IL-2 and IL-2 receptor interaction are essential for G1 to S transition. We have shown earlier that rabbit B cells can be activated to produce IL-2 and express functional IL-2 receptors after treatment with ionomycin and PMA. Herein we have compared the response of rabbit PBLs, which contain about 50% T cells, with those of purified B cells. After activation with ionomycin or PMA, comparable numbers of PBLs and B cells entered the cell cycle; but DNA synthesis by the PBL cultures was three to four times higher than that of cultures of purified B cells. Interestingly, IL-2 production by the PBL cultures was also three to four times higher than in B cell cultures, suggesting an involvement of IL-2 in inducing DNA synthesis in these cells. The hypothesis that IL-2, which is produced in early G1, acts in late G1 and is required for G1 to S transition in B cells was supported by the following observations: (i) IL-2 production by B cells was detected as early as 6 hr after activation and preceded DNA synthesis by at least 24 hr. (ii) B cell blasts in G1 (produced by treatment of resting B cells with ionomycin and PMA) showed DNA synthesis in response to IL-2, but showed very little DNA synthesis in response to restimulation with ionomycin and PMA. (iii) A polyclonal rabbit anti-human IL-2 antibody caused nearly complete inhibition of DNA synthesis by B cells activated by ionomycin and PMA. (iv) A PKC inhibitor, K252b, inhibited DNA synthesis in ionomycin and PMA-stimulated cells if added at the beginning of culture but was not inhibitory if added 16 hr later. We conclude that increased [Ca2+]i and PKC activation are not sufficient signals for G1 to S transition in B cells; entry into S is signaled by IL-2, and IL-2-mediated signal transduction probably does not involve increased [Ca2+]i or PKC activation.

Animals↗

PubMed2005

Identification of a basolateral sorting signal within the cytoplasmic domain of the interleukin-6 signal transducer gp130.

Interleukin-6-type cytokine receptors are expressed in polarized cells such as hepatocytes and intestinal cells. For the interleukin-6-receptor gp80 and its signal transducer gp130, a preferential basolateral localization was demonstrated in Madin-Darby canine kidney (MDCK) cells and two basolateral sorting signals were identified within the cytoplasmic domain of gp80. The cytoplasmic tail of gp130 is responsible for signaling via the Janus kinase/signal transducer and activator of transcription pathway. In addition, it mediates the internalization of the receptor complex which is dependent on a di-leucine motif. Truncated gp130 lacking the cytoplasmic domain is sorted apically in MDCK cells. For identification of the basolateral sorting signal(s) of gp130, a series of deletion mutants in the cytoplasmic domain of gp130 have been generated and stably expressed in MDCK cells. Biotinylation analyses of these mutants show that a ten amino acids sequence between amino acids 782 and 792 which contains the di-leucine internalization motif is also essential for a basolateral sorting. Accordingly, we detect apical delivery of a gp130 mutant in which the di-leucine motif has been exchanged by two alanines (gp130LL/AA). These findings indicate that the di-leucine motif which directs the internalization of the IL-6 receptor complex also mediates the basolateral sorting of the signal transducer gp130.

Amino Acid Motifs↗

PubMed2004

Global carbon/nitrogen control by PII signal transduction in cyanobacteria: from signals to targets.

PII signal transduction plays a pervasive role in microbial nitrogen control. Different phylogenetic lineages have developed various signal transduction schemes around the highly conserved core of the signalling system, which consists of the PII proteins. Among all various bacterial PII signalling systems, the one in cyanobacteria is so far unique: in unicellular strains, the mode of covalent modification is by serine phosphorylation and the interpretation of the cellular nitrogen status occurs by measuring the 2-oxoglutarate levels. Recent advances have been the identification of the phospho-PII phosphatase, the resolution of the crystal structure of PII proteins from Synechococcus and Synechocystis strains and the identification of novel functions of PII regulation in cyanobacteria, which highlight the central role of PII signalling for the acclimation to changing carbon-nitrogen regimes.

Bacterial Proteins↗

PubMed2006

Signal integration between IFNgamma and TLR signalling pathways in macrophages.

Macrophages are major effector cells of the innate immune system, and appropriate regulation of macrophage function requires the integration of multiple signalling inputs derived from the recognition of host factors (e.g. interferon-gamma/IFNgamma) and pathogen products (e.g. toll-like receptor/TLR agonists). The profound effects of IFNgamma pre-treatment ("priming") on TLR-induced macrophage activation have long been recognised, but many of the mechanisms underlying the priming phenotype have only recently been identified. This review summarises the known mechanisms of integration between the IFNgamma and TLR signalling pathways. Synergy occurs at multiple levels, ranging from signal recognition to convergence of signals at the promoters of target genes. In particular, the cross-talk between the IFNgamma, and LPS and CpG DNA signalling pathways is discussed.

Animals↗

PubMed2004

Turning off signal transducer and activator of transcription (STAT): the negative regulation of STAT signaling.

Signal transducer and activator of transcription (STAT) proteins are a group of transcription factors that transmit signals from the extracellular milieu of cells to the nucleus. They are crucial for the signaling of many cytokines that are mediators of allergic inflammation. Considerable information is known about the activation of STATs and their role in gene transcription; comparably much less is known about how STAT signaling is regulated. Because STATs are critical for the induction of many genes crucial for the allergic cascade and immune host defense, understanding the regulation of these molecules will provide novel insights into allergic and immunodeficiency disorders and will likely identify new targets for therapeutic interventions. This review will summarize the current understanding of the regulation of STAT signaling, emphasizing recent observations.

Animals↗

PubMed2001

A dual role of protein kinase C in insulin signal transduction via adenylyl cyclase signaling system in muscle tissues of vertebrates and invertebrates.

Further decoding of a novel adenylyl cyclase signaling mechanism (ACSM) of the action of insulin and related peptides detected earlier (Pertseva et al. Comp Biochem Physiol B Biochem Mol Biol 1995;112:689-95 and Pertseva et al. Biochem Pharmacol 1996;52:1867-74) was carried out with special attention given to the role of protein kinase C (PKC) in the ACSM. It was shown for the first time that transduction of the insulin signal via the ACSM followed by adenylyl cyclase (AC, EC 4.6.1.1) activation was blocked in the muscle tissues of rat and mollusc Anodonta cygnea in the presence of pertussis toxin, inducing the impairment of G(i)-protein function, wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3-K), and calphostin C, a blocker of PKC. The cholera toxin treatment of muscle membranes led to an increase in basal AC activity and a decrease in enzyme insulin reactivity. Phorbol ester and diacylglycerol activation of PKC (acute treatment) induced the inhibition of the insulin AC activating effect. This negative influence was also observed in the case of the AC system activated by biogenic amines. It was first concluded that the ACSM of insulin action involves the following signaling chain: receptor tyrosine kinase => G(i) (betagamma) => PI3-K => PKCzeta (?) => G(s) => AC => adenosine 3',5'-cyclic monophosphate. It was also concluded that the PKC system has a dual role in the ACSM: (1) a regulatory role (PKC sensitive to phorbol esters) that is manifested as a negative feedback modulation of insulin signal transduction via the ACSM; (2) a transductory role, which consists in direct participation of atypical PKC (PKCzeta) in the process of insulin signal transduction via the ACSM.

Adenylyl Cyclases↗

PubMed2003

Programming neural Hoxd10: in vivo evidence that early node-associated signals predominate over paraxial mesoderm signals at posterior spinal levels.

Studies of the programming of Hox patterns at anterior spinal levels suggest that these events are accomplished through an integration of Hensen's node-derived and paraxial mesoderm signaling. We have used in vivo tissue manipulation in the avian embryo to examine the respective roles of node- derived and other local signals in the programming of a Hox pattern at posterior spinal levels. Hoxd10 is highly expressed in the lumbosacral (LS) spinal cord and adjacent paraxial mesoderm. At stages of LS neural tube formation (stages 12-14), the tailbud contains the remnants of Hensen's node and the primitive streak. Hoxd10 expression was analyzed after transposition of LS neural segments with and without the tailbud, after isolation of normally positioned LS segments from the stage 13 tailbud, and after axial displacement of posterior paraxial mesoderm. Data suggest that inductive signals from the tailbud are primarily responsible for the programming of Hoxd10 at neural plate and the earliest neural tube stages. After these stages, the LS neural tube appears to differ from more anterior neural segments in its lack of dependence on Hox-inductive signals from local tissues, including paraxial mesoderm. Our data also suggest that a graded system of repressive signals for posterior Hox genes is present at cervical and thoracic levels and likely to originate from paraxial mesoderm.

Animals↗

PubMed2003

Systematic screening for signaling molecules expressed during somitogenesis by the signal sequence trap method.

We describe a systematic screening to search for molecules that act as an extracellular signal during somitogenesis in vertebrates. Somitogenesis, which gives rise to segmented structures of axial bones and muscles, is a consequence of cooperative morphogenetic movements caused by precisely regulated cell and tissue interactions. We employed a strategy that combined subtractive hybridization to enrich paraxial mesoderm/somite-specific cDNAs and the signal sequence trap method, which selects signal sequence-containing molecules. Ninety-two independent cDNAs found to possess a putative signal sequence or a transmembrane domain are presented with a data base accession number for each. These clones include cDNAs which were previously identified with a function characterized, cDNAs previously identified with an undetermined function, and also cDNAs with no similarity to known sequences. Among them, 16 clones exhibited peculiar patterns of expression in the presomitic mesoderm/somites revealed by whole-mount and section in situ hybridization techniques, with some clones also being expressed in the forming neural tube. This is the first report in which an elaborate strategy combining three different screening steps was employed to identify signaling molecules relevant to a particular morphogenetic process.

Animals↗

PubMed1983

A putative signal peptidase recognition site and sequence in eukaryotic and prokaryotic signal peptides.

Presecretory signal peptides of 39 proteins from diverse prokaryotic and eukaryotic sources have been compared. Although varying in length and amino acid composition, the labile peptides share a hydrophobic core of approximately 12 amino acids. A positively charged residue (Lys or Arg) usually precedes the hydrophobic core. Core termination is defined by the occurrence of a charged residue, a sequence of residues which may induce a beta-turn in a polypeptide, or an interruption in potential alpha-helix or beta-extended strand structure. The hydrophobic cores contain, by weight average, 37% Leu: 15% Ala: 10% Val: 10% Phe: 7% Ile plus 21% other hydrophobic amino acids arranged in a non-random sequence. Following the hydrophobic cores (aligned by their last residue) a highly non-random and localized distribution of Ala is apparent within the initial eight positions following the core: (formula; see text) Coincident with this observation, Ala-X-Ala is the most frequent sequence preceding signal peptidase cleavage. We propose the existence of a signal peptidase recognition sequence A-X-B with the preferred cleavage site located after the sixth amino acid following the core sequence. Twenty-two of the above 27 underlined Ala residues would participate as A or B in peptidase cleavage. Position A includes the larger aliphatic amino acids, Leu, Val and Ile, as well as the residues already found at B (principally Ala, Gly and Ser). Since a preferred cleavage site can be discerned from carboxyl and not amino terminal alignment of the hydrophobic cores it is proposed that the carboxyl ends are oriented inward toward the lumen of the endoplasmic reticulum where cleavage is thought to occur. This orientation coupled with the predicted beta-turn typically found between the core and the cleavage site implies reverse hairpin insertion of the signal sequence. The structural features which we describe should help identify signal peptides and cleavage sites in presumptive amino acid sequences derived from DNA sequences.

Amino Acid Sequence↗

PubMed2002

Macromolecular protein signaling complexes and mast cell responses: a view of the organization of IgE-dependent mast cell signaling.

The generation of signals following engagement of cell surface receptors is an ordered process that requires tight regulation as spurious signals could result in unwanted, and possibly deleterious, cellular responses. Like other cell surface receptors, stimulation of a mast cell via the high affinity IgE receptor (FcepsilonRI) causes multiple biochemical events that ultimately result in cell activation and effector responses. Recently, our knowledge of how these events are ordered has increased. We now have identified some of the molecules involved, how they are organized into macromolecular complexes by FcepsilonRI stimulation, and the role of some of the constituents of these macromolecular signaling complexes in mast cell effector responses. In brief, we review the knowledge on macromolecular signaling complexes used by FcepsilonRI in mast cell activation and provide our view on the regulation of signal generation and its effect on mast cell activation.

Animals↗

PubMed2002

Inhibition of somatostatin receptor 5-signaling by mammalian regulators of G-protein signaling (RGS) in yeast.

Regulators of G-protein signaling (RGSs) are negative regulators of G-protein coupled receptor (GPCR)-mediated signaling that function to limit the lifetime of receptor-activated G(alpha)-proteins. Here we show that four mammalian RGSs differentially inhibit the activation of a FUS1--LacZ reporter gene by the STE2 encoded GPCR in yeast. In order to examine the role of the GPCR in modulating RGS function, we functionally expressed the human somatostatin receptor 5 (SST(5)) in yeast. In the absence of RGSs, FUS1--LacZ activation in response to somatostatin increased in a dose-dependent manner in cells expressing SST(5). In contrast to the results obtained with Ste2p, all RGSs completely inhibited SST(5)-mediated signaling even at concentrations of agonist as high as 10(minus sign5) M. The ability of RGSs to inhibit SST(5) signaling was further assessed in cells expressing modified Gpa1 proteins. Even though SST(5)-mediated FUS1--LacZ activation was 5-fold more efficient with a Gpa1p/G(i3alpha) chimera, response to somatostatin was completely abolished by all four RGSs. Furthermore, we demonstrate that RGS1, RGS2 and RGS5 have reduced ability to inhibit SST(5)-mediated activation of the RGS-resistant Gpa1p(Gly302Ser) mutant suggesting that the ability to interact with the G(alpha)-protein is required for the inhibition of signaling. Taken together, our results indicate that RGSs serve as better GAPs for Gpa1p when activated by SST(5) than when this G-protein is activated by Ste2p.

Fungal Proteins↗