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At least 523 records · Page 29Linked to original sources

PubMed2006

Modulation of TLR4 signaling by a novel adaptor protein signal-transducing adaptor protein-2 in macrophages.

Signal-transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein that contains pleckstrin and Src homology 2-like domains as well as a YXXQ motif in its C-terminal region. Our previous studies have demonstrated that STAP-2 binds to STAT3 and STAT5, and regulates their signaling pathways. In the present study, STAP-2 was found to positively regulate LPS/TLR4-mediated signals in macrophages. Disruption of STAP-2 resulted in impaired LPS/TLR4-induced cytokine production and NF-kappaB activation. Conversely, overexpression of STAP-2 enhanced these LPS/TLR4-induced biological activities. STAP-2, particularly its Src homology 2-like domain, bound to both MyD88 and IkappaB kinase (IKK)-alphabeta, but not TNFR-associated factor 6 or IL-1R-associated kinase 1, and formed a functional complex composed of MyD88-STAP-2-IKK-alphabeta. These interactions augmented MyD88- and/or IKK-alphabeta-dependent signals, leading to enhancement of the NF-kappaB activity. These results demonstrate that STAP-2 may constitute an alternative LPS/TLR4 pathway for NF-kappaB activation instead of the TNFR-associated factor 6-IL-1R-associated kinase 1 pathway.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Focal adhesion kinase enhances signaling through the Shc/extracellular signal-regulated kinase pathway in anaplastic astrocytoma tumor biopsy samples.

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that on activation generates signals that can modulate crucial cell functions, including cell proliferation, migration, and survival. In vitro, overexpression of FAK has been shown to promote cell proliferation by signaling through the Ras/mitogen-activated protein kinase cascade in several cell types. We have shown previously that overexpression of exogenous FAK lacking alternative splicing in malignant astrocytoma clones injected intracerebrally into SCID mouse brains promotes tumor cell proliferation. Here, we show that in anaplastic astrocytoma biopsy samples, FAK is expressed as an unspliced variant and migrates with a faster mobility similar to that observed in embryonic brain. Compared with nonneoplastic adult brain biopsies, the levels of FAK protein are elevated as are its levels of activation as assessed by autophosphorylation and overall tyrosine phosphorylation. The activity of Src kinase in these tumors is also elevated, as well as the activity of Src kinase associated with FAK; the latter may result in enhanced Src kinase phosphorylation of FAK. Phosphorylated Shc is associated with FAK in the anaplastic astrocytoma biopsy samples and in astrocytoma cells overexpressing FAK in vitro but not in nonneoplastic brain biopsy samples. Elevated extracellular signal-regulated kinase-2 activation and elevated expression of cyclins D and E are also found in anaplastic astrocytoma biopsy samples. These data provide evidence that the increased FAK activity in these tumors contributes to phosphorylation of Shc and likely to the promotion of Ras activity, extracellular signal-regulated kinase-2 activation, and cell proliferation in vivo.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Compensatory effect of the minor Streptomyces lividans type I signal peptidases on the SipY major signal peptidase deficiency as determined by extracellular proteome analysis.

The developmentally complex bacterium Streptomyces lividans has the ability to produce and secrete a significant amount of protein and possesses four different type I signal peptidase genes (sipW, sipX, sipY and sipZ) that are unusually clustered in its chromosome. 2-DE and subsequent MS of extracellular proteins showed that proteins with typical export signals for type I and type II signal peptidases are the main components of the S. lividans secretome. Secretion of extracellular proteins is severely reduced in a strain deficient in the major type I signal peptidase (SipY). This deficiency was efficiently compensated by complementation with any of the other three signal peptidases as deduced from a comparison of the corresponding 2-D PAGE patterns with that of the wild-type strain.

Amino Acid Sequence↗

PubMed2002

Extracellular signal-regulated kinase transmits palytoxin-stimulated signals leading to altered gene expression in mouse keratinocytes.

We have been probing the molecular mechanisms of tumor promoters that stimulate distinct initial signals to define critical downstream biochemical events in carcinogenesis. The action of the novel skin tumor promoter palytoxin on signaling and gene expression in keratinocytes, the primary target cells of tumor promoters, was therefore investigated. Palytoxin stimulated an increase in mRNA for matrix metalloproteinase-13 (MMP-13), an enzyme implicated in carcinogenesis, in a keratinocyte cell line derived from initiated mouse skin (308). Palytoxin stimulated an increase in c-Fos binding to the activator protein-1 (AP-1) site present in the promoter of the mouse MMP-13 gene. This effect was specific because palytoxin had little effect on c-Jun, JunB, JunD, FosB, Fra-1, or Fra-2 binding or on overall levels of transcription factor binding. The increase in c-Fos binding corresponded to a palytoxin-stimulated increase in c-Fos protein levels. Palytoxin stimulated the activation of the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase, and p38. The MAPK kinase inhibitor PD 98059 blocked palytoxin-stimulated ERK activation. PD 98059 also blocked the palytoxin-stimulated increases in c-Fos protein levels, c-Fos binding to the AP-1 site, and MMP-13 mRNA. These studies identify important differences between palytoxin-stimulated signaling in keratinocytes derived from initiated mouse skin, the biologically relevant cell type, and other cell lines. Specifically, our data suggest that, in keratinocytes derived from initiated mouse skin, ERK plays an important role in transmitting palytoxin-stimulated signals to three downstream targets that are likely to affect carcinogenesis: c-Fos, AP-1, and MMP-13.

Acrylamides↗

PubMed1986

The effect of Cl- depletion and X- reconstitution on the oxygen-evolution rate, the yield of the multiline manganese EPR signal and EPR signal II in the isolated Photosystem-II complex.

The role of Cl- in photosynthetic O2 evolution has been investigated by measurement of the steady-state O2 rate and EPR of the electron donors responsible for the S2 multiline signal and Signal IIs upon Cl- depletion and substitution in Photosystem II membranes. Cl- removal has three effects upon the donor side of Photosystem II. (1) It abolishes O2 evolution reversibly, while decreasing the yield of the S2 multiline signal indicative of the manganese site of the O2-evolving complex in the S2 oxidation state. This decrease is brought about by (2) the reversible disconnection of the manganese complex from the reaction center; and by (3) deactivation of S1 centers having reduced primary acceptor QA to form SO centers having a reduced Signal IIs species. Reactivation of O2 evolution by anions confirms earlier work showing a requirement for a univalent anion of optimum charge density. The observed order of reactivation is Cl- greater than Br- approximately NO3- much greater than OH- approximately F-. Reactivation of the S2 multiline signal follows Cl- approximately Br- greater than NO3- approximately OH- greater than F-, in near correspondence with reactivation of O2-evolution rates. Cl- titrations of F- -inhibited samples reveal two binding sites for Cl- which differ in binding affinity by 11-fold. The higher-affinity site reactivates the S1----S2 light reaction, while the lower-affinity site reactivates the S3----S0 light reaction. The high affinity site is located within the O2-evolving complex at an undetermined site, while the lower-affinity site functions in coupling the reaction center photochemistry to the O2-evolving complex. The results are compared with Cl-/F- exchange equilibria for Mn3+ in solution. A model for the lower S-state transitions is presented in which specific oxidation state assignments are made for some of the donors and acceptors of Photosystem II.

Chlorides↗

PubMed1989

The effect of context change on long-term habituation of the skin conductance response to signal and non-signal stimuli in humans.

The present experiment investigated the role of contextual cues in long-term habituation of the skin conductance response. Subjects (N = 65) first underwent a habituation training session in which they received 15 presentations each of a signal and a non-signal stimulus. Signal value was induced by a motor response requirement to stimulus offset. In a test session one week later, the effect of context change on long-term habituation was examined by presenting the habituation stimuli in either the same or in a changed context. Although both short-term (within-session) and long-term (between-session) habituation were demonstrated, the results provided no evidence for context-dependency of long-term habituation. Moreover, there was no evidence of differential long-term habituation as a function of signal value in either the same- or changed-context conditions. The data are discussed in terms of Wagner's (1978) priming theory, and the methodological implications of the experimental manipulations of context change and signal value induction are explored.

Adolescent↗

PubMed1996

MRI evidence of high signal intensity and temporomandibular arthralgia and relating pain. Does the high signal correlate to the pain?

In order to investigate the relationship between various temporomandibular joint (TMJ) pain levels and the detection of high signal intensity (joint effusion) on T2 weighted magnetic resonance imaging (MRI), 19 consecutive patients who complained of unilateral painful TMJ hypomobility (closed locking) were involved in this study. All patients were clinically examined in a routine manner, and all patients rated their pain levels by a visual analogue scale and eight pain questionnaire prior MRI study. T1 and T2 weighted MRI was taken in sagittal section at unilateral affected joint side. The presence or absence of a high signal intensity spot within the TMJ compartment were judged by three examiners. The high signal intensity was detected in 10 joints, but not in 9 joints. In between these two groups, the pain ratio was calculated and compared. The data showed that there was no significant statistical correlation between pain levels and the presence of high signals. This study disclosed that the MRI detection of high signal intensity in the closed locking TMJ did not directly relate to the presence of TMJ pain nor the increased pain level. These indicate the need of further larger studies.

Adolescent↗

PubMed1989

Identification of signalling and non-signalling binding contributions to enzyme reactivity. Alternative combinations of binding interactions provide for change in transition-state geometry in reactions of papain.

1. 2-(N'-Acetyl-L-phenylalanyl)hydroxyethyl 2'-pyridyl disulphide (compound V) was synthesized, and a study of the pH-dependence of the second-order rate constant (k) for its reaction with the catalytic-site thiol group of papain (EC 3.4.22.2) was used to evaluate the consequences for transition-state geometry of the presence of a hydrophobic occupant for the S2 subsite of the enzyme in the absence of the N-H component of the P1-P2 amide bond. 2. Comparison of the pH-dependences of K for reactions of compound (V), 2-(acetamido)ethyl 2'-pyridyl disulphide (compound I) and 2-(acetoxy)ethyl 2'-pyridyl disulphide (compound III) with the cysteine-proteinase minimal catalytic-site model, benzimidazol-2-ylmethanethiol, established the activation of all of these pyridyl disulphides by hydronation and that their reactivities are relatively insensitive to structural change in the non-pyridyl part of the molecule. The marked differences in their reactivities towards papain therefore derive from binding, either directly, or indirectly via signalling mechanisms. 3. Comparison of the kinetic data for the reaction of papain with compound (V) with those for analogous reactions with reactivity probes that provide opportunities for a variety of binding interactions in the S1-S2 intersubsite region and in the S2 subsite itself lead to the following conclusions: (a) the (Gly-66) N-H...O = C less than (P1-P2 ester) interaction of papain with compound (III) provides for better binding relative to that for a probe with a simple hydrocarbon side chain, but no signalling to the catalytic site to provide a (His-159)-ImH+-assisted transition state; (b) when this interaction is augmented either by a (P1-P2 amide) N-H...O = C less than (Asp-158) interaction (compound I) or hydrophobic P2/S2 contacts (compound V), signalling to the catalytic region occurs to provide the assisted transition state; (c) when both the P2/S2 contacts and the interaction involving Gly-66 exist, provision additionally of the (P1-P2 amide) N-H...O = C less than (Asp-158) interaction [as in 2-(N'-acetyl-L-phenylalanylamino)ethyl 2'-pyridyl disulphide] serves only to assist the binding without an additional signalling effect. 4. Such studies promise to allow binding interactions that merely locate substrates in appropriate enzyme loci to be distinguished from those that transmit signals with a chemical consequence to catalytic sites.

Animals↗

PubMed1999

The catalytic mechanism of endoplasmic reticulum signal peptidase appears to be distinct from most eubacterial signal peptidases.

Many type I signal peptidases from eubacterial cells appear to contain a serine/lysine catalytic dyad. In contrast, our data show that the signal peptidase complex from the endoplasmic reticulum lacks an apparent catalytic lysine. Instead, a serine, histidine, and two aspartic acids are important for signal peptidase activity by the Sec11p subunit of the yeast signal peptidase complex. Amino acids critical to the eubacterial signal peptidases and Sec11p are, however, positioned similarly along their primary sequences, suggesting the presence of a common structural element(s) near the catalytic sites of these enzymes.

Amino Acid Sequence↗

PubMed1987

Synergistic signals in the mechanism of antigen-induced exocytosis in 2H3 cells: evidence for an unidentified signal required for histamine release.

The aim of this study was to determine whether the increase in cytosolic free Ca2+ concentration ([Ca2+]i) in response to antigen (aggregated ovalbumin) on IgE-primed 2H3 cells was sufficient to account for exocytosis. When the [Ca2+]i responses to antigen and the Ca2+ ionophore A23187 were compared, A23187 was much less effective at releasing histamine at equivalent [Ca2+]i increases, and little or no stimulated histamine release occurred with A23187 concentrations that matched the [Ca2+]i response to antigen concentrations that stimulated maximal histamine release. The [Ca2+]i response to antigen is not, therefore, sufficient to account for exocytosis, although extracellular Ca2+ is necessary to initiate both the [Ca2+]i response and histamine release: the antigen must generate an additional, unidentified, signal that is required for exocytosis. To determine whether this signal was the activation of protein kinase C, the effects of the phorbol ester 12-0-tetradecanoyl phorbol 13-acetate (TPA) on the responses to antigen were examined. TPA blocked the antigen-induced [Ca2+]i response and the release of inositol phosphates but had little effect on histamine release and did not stimulate exocytosis by itself. The unidentified signal from the antigen is therefore distinct from the activation of protein kinase C and is generated independently of the [Ca2+]i response or the release of inositol phosphates. Taken together with other data that imply that there is very little activation of protein kinase C by antigen when the rate of histamine release is maximal, it is concluded that the normal exocytotic response to antigen requires the synergistic action of the [Ca2+]i signal together with an unidentified signal that is not mediated by protein kinase C.

Antigens↗

PubMed1995

Cross-linking of the TCR-CD3 complex with CD4, CD8 or LFA-1 induces an anti-apoptotic signal in thymocytes: the signal is canceled by FK506.

The immunosuppressant FK506 did not block differentiation of double-negative thymocytes into double-positive (DP) cells, but interfered with differentiation of DP cells into mature single-positive cells in a fetal thymus organ culture system, suggesting that FK506 inhibits positive selection. The drug also reduced the number of DP cells recovered after the culture. As positive selection depends on the inhibition of thymocyte apoptosis at its DP stage by signaling through the TCR-CD3 complex and some of the accessory molecules, including CD4, CD8 and LFA-1, we studied the possibility that FK506 enhanced apoptosis by itself or canceled the inhibition of apoptosis. The results indicated that FK506 was hardly toxic or hardly affected anti-CD3-induced DNA fragmentation in isolated thymocytes in vitro. On the other hand, upon cross-linking TCR-CD3 together with CD4, CD8 or LFA-1, FK506 markedly enhanced DNA fragmentation and cytolysis. The drug, however, hardly or only slightly enhanced these responses upon cross-linking TCR-CD3 together with CD2, CD28, Thy-1 or H-2Kd. Cross-linking of TCR-CD3 together with CD4, CD8 or LFA-1 markedly inhibited glucocorticoid-induced death and the inhibition was canceled by FK506. Furthermore, cross-linking of TCR-CD3 together with LFA-1 potentially induces both an apoptosis-inducing signal and an FK506-sensitive anti-apoptotic signal, and that the latter signal may be related to an essential signal for positive selection.

Animals↗

PubMed1992

DnaG-dependent priming signals can substitute for the two essential DNA initiation signals in oriV of the broad host-range plasmid RSF1010.

Broad host-range plasmid RSF1010 contains in the oriV region two DNA initiation signals, ssiA(RSF1010) and ssiB(RSF1010), which are essential for plasmid replication. Each of ssiA and ssiB could be substituted functionally by either of the two G4-type (DnaG-dependent) priming signals, the oric of bacteriophage G4 and an ssi signal from plasmid pSY343 (an R1 plasmid derivative). Functions of the chimeric oriVs of RSF1010 thus constructed were dependent on the RSF1010-specific replication proteins, RepA, RepB' and RepC. When both of ssiA and ssiB were replaced by the G4-type ssi signals, functions of the chimeric oriVs were no longer dependent on RepB' (RSF1010-specific DNA primase). The replication activities of the chimeric oriVs of RSF1010 were not influenced markedly by the type of heterologous priming signals they contained. It is conceivable that DNA replication of RSF1010 does not need the priming mechanism for lagging strand synthesis and proceeds by the strand displacement mechanism.

Bacterial Proteins↗

PubMed2004

P signalling in unicellular cyanobacteria: analysis of redox-signals and energy charge.

This communication presents a short outline of the current knowledge on the molecular basis of P(II) signal transduction in unicellular cyanobacteria with respect to the perception of environmental stimuli. First, the general characteristics of the P(II) signalling system in unicellular cyanobacteria are presented, the hallmark of which is modification by serine-phosphorylation, as compared to the paradigmatic P(II) signal transduction system in proteobacteria, which is based on tyrosyl-uridylylation. Then, the focus is turned on the signals controlling P(II) phosphorylation state. Recently, the cellular phosphatase (termed PphA), which specifically dephosphorylates phosphorylated P(II) (P(II)-P) was identified in Synechocystis sp. strain PCC 6803. With the availability of a PphA-deficient mutant and the purified components for in vitro assay of PphA mediated P(II)-P dephosphorylation, novel insights into the signals, to which P(II)-P dephosphorylation responds, can be obtained. Here we present an investigation of the response of P(II)-P dephosphorylation towards treatments that affect the redox-balance of the cells. Furthermore, a possible role of varying ATP/ADP ratios on P(II)-P dephosphorylation was examined. From these studies, together with previous investigations, we conclude that P(II)-P dephosphorylation specifically responds to changes in the levels of central metabolites of carbon metabolism, in particular 2-oxoglutarate.

Journal Article↗

PubMed1995

Modulation of the platelet-derived-growth-factor-induced calcium signal by extracellular/intracellular pH in Syrian hamster embryo cells. Implications for the role of calcium in mitogenic signalling.

Studies have been performed to understand the interactions and the role which intracellular calcium and intracellular pH have in mediating mitogen-stimulated cellular proliferation. Stimulation of Syrian hamster embryo (SHE) cells with the mitogen platelet-derived growth factor A/B (PDGF) results in intracellular acidification and capacitative calcium entry involving the intracellular release of calcium via the inositol trisphosphate gamma receptor calcium channel, followed by an extracellular influx of calcium through a dihydropyridine-sensitive plasma membrane calcium channel. Chronic extracellular/intracellular acidification results in the inactivation of both these calcium channels due to slowly reversible protein alterations. Paradoxically, transient intracellular acidification, like that following PDGF stimulation, could not stimulate the activation of either calcium channel. In addition, even though intracellular calcium fluxes by themselves could intiate intracellular acidification, loss of the PDGF-induced calcium signal did not result in the loss of the PDGF-induced transient intracellular acidification. Importantly with regard to the role intracellular calcium and pH have in mediating the mitogenic signal leading to cellular proliferation, chronic extracellular/intracellular acidification, which leads to a complete loss of the PDGF-induced calcium signal, did not result in the loss of PDGF-induced mitogenesis. These results indicate that the PDGF-induced calcium signal is not essential for PDGF-stimulated mitogenesis in Syrian hamster embryo cells. In contrast, blocking the PDGF-induced transient intracellular acidification completely blocks PDGF-induced mitogenesis, indicating that the mitogen-induced transient intracellular acidification, unlike the intracellular calcium ion signal, is indispensible for cellular proliferation in Syrian hamster embryo cells.

Animals↗

PubMed2004

Signal crimes and signal disorders: notes on deviance as communicative action.

In this paper a 'signal crimes' perspective is outlined in an effort to unpack the relationships between experiences of crime and disorder, and perceptions of criminogenic risk. Grounded in symbolic interactionist sociology, and developing a social semiotic understanding of risk perception, it is a perspective that focuses upon processes of social reaction and the ways in which people interpret and define threats to their security. It is proposed that people interpret the occurrence of certain incidents as 'warning signals' about the levels of risk to which they are either actually or potentially exposed. These signals tend to take the form of signal crimes and/or signal disorders and are important in terms of how social space is symbolically constructed.

Crime↗

PubMed1980

Detection of signals with identical energy spectra but different waveforms under conditions of signal uncertainty.

Previous research has shown that a signal which may be one of two pure tones will be less detectable than a signal that is of constant, known frequency. In the present study, the effect of waveform uncertainty was evaluated by using pulse-train signals with identical power spectra but different phase spectra. Results for a group of 11 listeners suggest that when differences in the energy spectra of signals are eliminated, signal uncertainty has, at best, a small effect on detection performance.

Acoustic Stimulation↗

PubMed2000

Contributions of suppression and excitation to simultaneous masking: effects of signal frequency and masker-signal frequency relation.

This study investigated the contributions of suppression and excitation to simultaneous masking for a range of masker frequencies both below and above three different signal frequencies (750, 2000, and 4850 Hz). A two-stage experiment was employed. In stage I, the level of each off-frequency simultaneous masker necessary to mask a signal at 10 or 30 dB sensation level was determined. In stage II, three different forward-masking conditions were tested: (1) an on-frequency condition, in which the signals in stage I were used to mask probes of the same frequency; (2) an off-frequency condition, in which the off-frequency maskers (at the levels determined in stage I) were used to mask the probes; and (3) a combined condition, in which the on- and off-frequency maskers were combined to mask the probes. If the off-frequency maskers simultaneously masked the signal via spread of excitation in stage I, then the off-frequency and combined maskers should produce considerable forward masking in stage II. If, on the other hand, they masked via suppression, they should produce little or no forward masking. The contribution of suppression was found to increase with increasing signal frequency; it was absent at 750 Hz, but dominant at 4850 Hz. These results have implications for excitation pattern analyses and are consistent with stronger nonlinear processing at high rather than at low frequencies.

Acoustic Stimulation↗

PubMed1983

Feedback suppression of ACTH secretion by cortisol in dogs: lags after large signals equal those following very small signals.

Previously, low stepwise infusions of cortisol in resting adrenalectomized dogs (plateaux less than or equal to 6 micrograms/dL) were shown to reduce ACTH secretion only after 20 min. In the present study, large, steep-sloped cortisol signals were used to try to evoke faster feedback. Adrenalectomized male mongrel dogs were maintained on exogenous steroids until 48 h before the experiment. Of the 23 experiments on 15 dogs (under light pentobarbital anesthesia), 12 were on resting dogs, 7 on dogs stressed by variable insulin infusion (keeping plasma glucose at 18-40 mg/dL), and 4 stressed as above but with 4 h of low cortisol infusion (plasma congruent to 5 micrograms/dL) before applying the feedback signal. After a 50-min control period, a 30-min feedback period was initiated by one of two i.v. cortisol signals: (a) injection of 0.3 mg/kg or (b) infusion of 46 micrograms kg-1 min-1. Both raised plasma cortisol above physiological limits (within 2 and 6 min, respectively). In each experiment, 23 timed venous blood samples were assayed for plasma ACTH and cortisol. ACTH secretion rates were calculated continuously using a validated single-compartment method. Results from both types of cortisol signals were indistinguishable, and were thus pooled. In the unstressed dogs, control-period ACTH secretion of 0.97 +/- 0.12 mU kg-1 min-1 showed no significant decline due to the feedback signal for 20.3 +/- 1.4 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenalectomy↗