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Results for “Signaling”

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At least 127 records · Page 7Linked to original sources

PubMed2005

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

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

Biological Clocks↗

PubMed1992

Functions of signal and signal-anchor sequences are determined by the balance between the hydrophobic segment and the N-terminal charge.

The signal sequence of secretory proteins and the signal-anchor sequence of type II membrane proteins initiate the translocation of the following polypeptide segments, whereas the signal-anchor sequence of cytochrome P-450-type membrane proteins mediates the membrane insertion of the polypeptide via a signal-recognition particle-dependent mechanism but does not lead to the translocation of the following C-terminal sequences. To establish the structural requirements for the function of signal and signal-anchor sequences, we constructed chimeric proteins containing artificial topogenic sequences in which the N-terminal net charge and the length of the hydrophobic segment were systematically altered. Utilizing an in vitro translation-translocation system, we found that hydrophobic segments consisting of 7-10 leucine residues functioned as signal sequences whereas segments with 12-15 leucine residues showed different topogenic functions, behaving as signal sequences or P-450-type signal-anchor sequences, depending on the N-terminal charge. From these observations, we propose that the function of N-terminal topogenic sequences depends on a balance between the N-terminal charge and the length of the following hydrophobic segment.

Base Sequence↗

PubMed1997

Tyrosine-dependent basolateral sorting signals are distinct from tyrosine-dependent internalization signals.

Converting cysteine 543 to tyrosine in the influenza virus hemagglutinin (HA) introduces both a basolateral sorting signal and an internalization signal into the HA cytoplasmic domain. Another HA mutant, HA+8, contains eight additional amino acids at the end of the cytoplasmic domain that include a powerful internalization signal. HA+8 was also sorted efficiently to the basolateral surface of Madin-Darby canine kidney cells. The simplest explanation for the observation that multiple sorting phenotypes depend upon the same small amino acid sequence is that certain tyrosine-based internalization signals might also function as basolateral sorting signals. To test this hypothesis, second-site mutations were introduced into HA C543Y or HA+8 to determine if the internalization and basolateral sorting functions can be separated. For HA C543Y, the same sequence positions were important for both basolateral sorting and internalization, but the two functions responded differently to individual amino acid replacements, indicating that they were distinct. For HA+8, the basolateral sorting signal required the same tyrosine as the internalization signal, but did not share any other characteristics. Thus, even when basolateral sorting signals that depend on tyrosine overlap or are co-linear with internalizations signals, the two sorting processes are sensitive to different characteristics of the sequence.

Amino Acid Sequence↗

PubMed2003

Basic amino acids in a distinct subset of signal peptides promote interaction with the signal recognition particle.

Previous studies have demonstrated that signal peptides bind to the signal recognition particle (SRP) primarily via hydrophobic interactions with the 54-kDa protein subunit. The crystal structure of the conserved SRP ribonucleoprotein core, however, raised the surprising possibility that electrostatic interactions between basic amino acids in signal peptides and the phosphate backbone of SRP RNA may also play a role in signal sequence recognition. To test this possibility we examined the degree to which basic amino acids in a signal peptide influence the targeting of two Escherichia coli proteins, maltose binding protein and OmpA. Whereas both proteins are normally targeted to the inner membrane by SecB, we found that replacement of their native signal peptides with another moderately hydrophobic but unusually basic signal peptide (DeltaEspP) rerouted them into the SRP pathway. Reduction in either the net positive charge or the hydrophobicity of the DeltaEspP signal peptide decreased the effectiveness of SRP recognition. A high degree of hydrophobicity, however, compensated for the loss of basic residues and restored SRP binding. Taken together, the data suggest that the formation of salt bridges between SRP RNA and basic amino acids facilitates the binding of a distinct subset of signal peptides whose hydrophobicity falls slightly below a threshold level.

Amino Acid Sequence↗

PubMed1999

Transduction of basolateral-to-apical signals across epithelial cells: ligand-stimulated transcytosis of the polymeric immunoglobulin receptor requires two signals.

Transcytosis of the polymeric immunoglobulin receptor (pIgR) is stimulated by binding of its ligand, dimeric IgA (dIgA). During this process, dIgA binding at the basolateral surface of the epithelial cell transmits a signal to the apical region of the cell, which in turn stimulates the transport of dIgA-pIgR complex from a postmicrotubule compartment to the apical surface. We have previously reported that the signal of stimulation was controlled by a protein-tyrosine kinase (PTK) activated upon dIgA binding. We now show that this signal of stimulation moves across the cell independently of pIgR movement or microtubules and acts through the tyrosine kinase activity by releasing Ca++ from inositol trisphosphate-sensitive intracellular stores. Surprisingly we have found that a second independent signal is required to achieve dIgA-stimulated transcytosis of pIgR. This second signal depends on dIgA binding to the pIgR solely at the basolateral surface and the ability of pIgR to dimerize. This enables pIgR molecules that have bound dIgA at the basolateral surface to respond to the signal of stimulation once they reach the postmicrotubule compartment. We propose that the use of two signals may be a general mechanism by which signaling receptors maintain specificity along their signaling and trafficking pathways.

Animals↗

PubMed1999

Polyisoprenyl phosphate (PIPP) signaling regulates phospholipase D activity: a 'stop' signaling switch for aspirin-triggered lipoxin A4.

It is of wide interest to understand how opposing extracellular signals (positive or negative) are translated into intracellular signaling events. Receptor-ligand interactions initiate the generation of bioactive lipids by human neutrophils (PMN), which serve as signals to orchestrate cellular responses important in host defense and inflammation. We recently identified a novel polyisoprenyl phosphate (PIPP) signaling pathway and found that one of its components, presqualene diphosphate (PSDP), is a potent negative intracellular signal in PMN that regulates superoxide anion generation by several stimuli, including phosphatidic acid. We determined intracellular PIPP signaling by autocoids with opposing actions on PMN: leukotriene B4 (LTB4), a potent chemoattractant, and lipoxin A4 (LXA4), a 'stop signal' for recruitment. LTB4 receptor activation initiated a rapid decrease in PSDP levels concurrent with activation of PLD and cellular responses. In sharp contrast, activation of the LXA4 receptor reversed LTB4-initiated PSDP remodeling, leading to an accumulation of PSDP and potent inhibition of both PLD and superoxide anion generation. Thus, an inverse relationship was established for PSDP levels and PLD activity with two PMN ligands that evoke opposing responses. In addition, PSDP directly inhibited both isolated human recombinant (Ki = 6 nM) and plant (Ki = 20 nM) PLD. Together, these findings link PIPP remodeling to intracellular regulation of PMN function and suggest a role for PIPPs as lipid repressors in signal transduction, a novel mechanism that may also explain aspirin's suppressive actions in vivo in cell signaling.

Aspirin↗

PubMed1996

Cyclosporin A inhibits the degradation of signal sequences after processing of presecretory proteins by signal peptidase.

Targeting of presecretory proteins to, and insertion into, the microsomal membrane are mediated by signal sequences. These signal sequences are removed from presecretory proteins by signal peptidase. We demonstrate that the signal sequence of preprolactin, after translocation into microsomes and cleavage by signal peptidase, is converted to an intermediate form. This intermediate was found outside the microsomes, where it was degraded in the presence of cytosol. Degradation of the signal sequence of another presecretory protein, preprocecropinA, occurred even in the absence of cytosol. The immunosuppressant cyclosporin A inhibited trimming of the preprolactin signal sequence and degradation of the preprocecropinA signal sequence. We observed by cross-linking studies that cleaved signal sequences are bound to two microsomal proteins prior to degradation.

Amino Acid Sequence↗

PubMed2001

Regulator of G protein signaling 4 suppresses basal and thyrotropin releasing-hormone (TRH)-stimulated signaling by two mouse TRH receptors, TRH-R(1) and TRH-R(2).

We cloned the mouse TRH receptor type 2 (mTRH-R2) gene, which is 92% identical with rat TRH-R2 and 50% identical with mTRH-R1 at the amino acid level, and identified an intron within the coding sequence that is not present in the TRH-R1 gene structure. Similar to its rat homolog, mTRH-R2 binds TRH with an affinity indistinguishable from mTRH-R1, signals via the phosphoinositide pathway like mTRH-R1, but exhibits a higher basal signaling activity than mTRH-R1. We found that regulator of G protein signaling 4 (RGS4), which differentially inhibits signaling by other receptors that couple to Gq, inhibits TRH-stimulated signaling via mTRH-R1 and mTRH-R2 to similar extents. In contrast, other RGS proteins including RGS7, RGS9, and GAIP had no effect on signaling by mTRH-R1 or mTRH-R2 demonstrating the specificity of RGS4 action. Interestingly, RGS4 markedly inhibited basal signaling by mTRH-R2. Inhibition of basal signaling of mTRH-R2 by RGS4 suggests that modulation of agonist-independent signaling may be an important mechanism of regulation of G protein-coupled receptor activity under normal physiologic circumstances.

Amino Acid Sequence↗

PubMed1997

Extracellular signal-regulated kinase-1 and -2 respond differently to mitogenic and differentiative signaling pathways in myoblasts.

In this report we show that extracellular signal-regulated kinase-1 and -2 (ERK-1 and -2) respond differently to signals that elicit proliferation and/or differentiation of myoblasts using the C2C12 cell line and nondifferentiating mutant NFB4 cells derived from them. Induction of differentiation by withdrawal of serum rendered ERKs in C2C12 myoblasts relatively insensitive to restimulation by serum. Instead, myogenic differentiation of C2C12 cells was associated with sustained activation of ERK-2 dependent on the insulin-like growth factor II (IGF-II) autocrine loop. By contrast, mutant NFB4 cells cultured under the same conditions remained proliferative and demonstrated robust activation of ERKs in response to serum. Similarly, a Gi-dependent signaling pathway induced activation of ERKs in NFB4 cells, but not in C2C12 cells, after stimulation by lysophosphatidic acid (LPA). In NFB4 cells partially rescued by prolonged IGF-I treatment, ERK activity remained responsive to Gi-dependent LPA stimulation, whereas rescue of NFB4 cells by constitutive expression of myogenin or MyoD, associated with activation of the IGF-II autocrine loop, rendered the Gi-signaling pathway refractory to LPA stimulation. Relatively high levels of G(alpha i2) were detected in NFB4 cells and IGF-I treated NFB4 cells, which correlated with responsive Gi signaling. Activation of the IGF-II autocrine loop in C2C12 and NFB4 myoblasts or treatment with IGF-II was associated with loss of G(alpha i2) and inhibition of Gi-dependent signaling. Thus, IGF-I and IGF-II activate distinct signaling cascades, with IGF-II eliciting a stronger differentiation effect correlated with down-regulation of G(alpha i2) protein. Short-term stimulation of NFB4 cells with IGF-I, a mitogenic signal for myoblasts, also induced ERK-1 and -2 activation. Transient stimulation of NFB4 cells with IGF-I while blocking activation of Gi-proteins is with pertussis toxin resulted in preferential activation of ERK-2 characteristic of differentiated C2C12 cells, suggesting that proliferation induced by IGF-I is Gi-dependent and separable from the IGF-I-signaling pathway that leads to differentiation.

Animals↗

PubMed1997

Cellular interpretation of multiple TGF-beta signals: intracellular antagonism between activin/BVg1 and BMP-2/4 signaling mediated by Smads.

During early embryogenesis of Xenopus, dorsoventral polarity of the mesoderm is established by dorsalizing and ventralizing agents, which are presumably mediated by the activity of an activin/BVg1-like protein and Bone Morphogenetic Proteins (BMP), respectively. Interestingly, these two TGF-beta subfamilies are found in overlapping regions during mesoderm patterning. This raises the question of how the presumptive mesodermal cells recognize the multiple TGF-beta signals and differentially interpret this information to assign a particular cell fate. In this study, we have exploited the well characterized model of Xenopus mesoderm induction to determine the intracellular interactions between BMP-2/4 and activin/BVg1 signaling cascades. Using a constitutively active BMP-2/4 receptor that transduces BMP-2/4 signals in a ligand-independent fashion, we demonstrate that signals provided by activin/BVg1 and BMP modulate each other's activity and that this crosstalk occurs through intracellular mechanisms. In assays using BMP-2/4 and activin/BVg1-specific reporters, we determined that the specificity of BMP-2/4 and activin/BVg1 signaling is mediated by Smad1 and Smad2, respectively. These Smads should be considered as the mediators of the intracellular antagonism between BMP-2/4 and activin/BVg1 signaling possibly through sequestration of a limited pool of Smad4. Consistent with such a mechanism, Smad4 interacts functionally with both Smad1 and -2 to potentiate their signaling activities, and a dominant negative variant of Smad4 can inhibit both activin/BVg1 and BMP-2/4 mediated signaling Finally, we demonstrate that an activin/BVg1-dependent transcriptional complex contains both Smad2 and Smad4 and thereby provides a physical basis for the functional involvement of both Smads in TGF-beta-dependent transcriptional regulation. Thus, Smad4 plays a central role in synergistically activating activin/BVg1 and BMP-dependent transcription and functions as an intracellular sensor for TGF-beta-related signals.

Activins↗

PubMed1996

Visual signal detection in structured backgrounds. I. Effect of number of possible spatial locations and signal contrast.

Several studies have investigated the effect of signal location uncertainty on the detectability of simple visual signals in uncorrelated Gaussian noise with a deterministic background. For this case, human performance in locating a signal in a forced-choice experiment has been successfully predicted for 2-1800 alternative locations with the use of signal detection theory and the usual assumption that the observer's internal response is Gaussian distributed. Gaussian uncorrelated noise is far from realistic medical image noise, which includes not only fluctuations in intensity of quantum origin but also other anatomical objects lying in the x-ray path (structured backgrounds). Our goal is to determine whether signal detection theory with the Gaussian assumption is adequate for the case of structured backgrounds, or whether other more complex models need to be developed to predict human performance as a function of the number of possible signal locations in structured backgrounds. We present experimental data suggesting that an assumed Gaussian internal response accurately predicts the decrease in observer performance as the number of alternative locations is increased. The one exception is a lower-than-predicted performance for the detection of low-contrast signals for two alternative locations. Performance as measured by the index of detectability d' is also found to be linear with signal contrast. Together these findings extend the applicability of signal detection theory with Gaussian internal response functions to the case of complex structured backgrounds.

Computer Simulation↗

PubMed2003

NF-kappaB as an integrator of diverse signaling pathways: the heart of myocardial signaling?

NF-kappaB is a pleiotropic transcription factor implicated in the regulation of diverse biological phenomena, including apoptosis, cell survival, cell growth, cell division, innate immunity, cellular differentiation, and the cellular responses to stress, hypoxia, stretch and ischemia. In the heart, NF-kappaB has been shown to be activated in atherosclerosis, myocarditis, in association with angina, during transplant rejection, after ischemia/reperfusion, in congestive heart failure, dilated cardiomyopathy, after ischemic and pharmacological preconditioning, heat shock, burn trauma, and in hypertrophy of isolated cardiomyocytes. Regulation of NF-kappaB is complicated; in addition to being activated by canonical cytokine-mediated pathways, NF-kappaB is activated by many of the signal transduction cascades associated with the development of cardiac hypertrophy and response to oxidative stress. Many of these signaling cascades activate NF-kappaB by activating the IkappaB kinase (IKK) complex a major component of the canonical pathway. These signaling interactions occur largely via signaling crosstalk involving the mitogen-activated protein kinase/extracellular signalregulated kinase kinases (MEKKs) that are components of mitogen activated protein kinase (MAPK) signaling pathways. Additionally, there are other signaling factors that act more directly to activate NF-kappaB via IkappaB or by direct phosphorylation of NF-kappaB subunits. Finally, there are combinatorial interactions at the level of the promoter between NF-kappaB, its coactivators, and other transcription factors, several of which are activated by MAPK and cytokine signaling pathways. Thus, in addition to being a major mediator of cytokine effects in the heart, NF-kappaB is positioned as a signaling integrator. As such, NF-kappaB functions as a key regulator of cardiac gene expression programs downstream of multiple signal transduction cascades in a variety of physiological and pathophysiological states. We show that genetic blockade of NF-kappaB reduces infarct size in the murine heart after ischemia/reperfusion (I/R), implicating NF-kappaB as a major determinant of cell death after I/R. These results support the concept that NF-kappaB may be an important therapeutic target for specific cardiovascular diseases.

Animals↗

PubMed1999

Role of cytokine signaling molecules in erythroid differentiation of mouse fetal liver hematopoietic cells: functional analysis of signaling molecules by retrovirus-mediated expression.

Erythropoietin (EPO) and its cell surface receptor (EPOR) play a central role in proliferation, differentiation, and survival of erythroid progenitors. Signals induced by EPO have been studied extensively by using erythroid as well as nonerythroid cell lines, and various controversial results have been reported as to the role of signaling molecules in erythroid differentiation. Here we describe a novel approach to analyze the EPO signaling by using primary mouse fetal liver hematopoietic cells to avoid possible artifacts due to established cell lines. Our strategy is based on high-titer retrovirus vectors with a bicistronic expression system consisting of an internal ribosome entry site (IRES) and green fluorescent protein (GFP). By placing the cDNA for a signaling molecule in front of IRES-GFP, virus-infected cells can be viably sorted by fluorescence-activated cell sorter, and the effect of expression of the signaling molecule can be assessed. By using this system, expression of cell-survival genes such as Bcl-2 and Bcl-XL was found to enhance erythroid colony formation from colony-forming unit-erythroid (CFU-E) in response to EPO. However, their expression was not sufficient for erythroid colony formation from CFU-E alone, indicating that EPO induces signals for erythroid differentiation. To examine the role of EPOR tyrosine residues in erythroid differentiation, we introduced a chimeric EGFR-EPOR receptor, which has the extracellular domain of the EGF receptor and the intracellular domain of the EPOR, as well as a mutant EGFR-EPOR in which all the cytoplasmic tyrosine residues are replaced with phenylalanine, and found that tyrosine residues of EPOR are essential for erythroid colony formation from CFU-E. We further analyzed the function of the downstream signaling molecules by expressing modified signaling molecules and found that both JAK2/STAT5 and Ras, two major signaling pathways activated by EPOR, are involved in full erythroid differentiation.

Animals↗

PubMed2006

The mAKAP signaling complex: integration of cAMP, calcium, and MAP kinase signaling pathways.

Following its production by adenylyl cyclases, the second messenger cAMP is in involved in pleiotrophic signal transduction. The effectors of cAMP include the cAMP-dependent protein kinase (PKA), the guanine nucleotide exchange factor Epac (exchange protein activated by cAMP), and cAMP-dependent ion channels. In turn, cAMP signaling is attenuated by phosphodiesterase-catalyzed degradation. The association of cAMP effectors and the enzymes that regulate cAMP concentration into signaling complexes helps to explain the differential signaling initiated by members of the G(s)-protein coupled receptor family. The signal transduction complex formed by the scaffold protein mAKAP (muscle A kinase-anchoring protein) at the nuclear envelope of both striated myocytes and neurons contains three cAMP-binding proteins, PKA, Epac1, and the phosphodiesterase PDE4D3. In addition, the mAKAP complex also contains components of the ERK5 MAP kinase signaling pathway, the calcium release channel ryanodine receptor and the phosphatases PP2A as well as calcineurin. Analysis of the mAKAP complex illustrates how a macromolecular complex can serve as a node in the intracellular signaling network of cardiac myocytes to integrate multiple cAMP signals with those of calcium and MAP kinases to regulate the hypertrophic actions of several hormones.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2004

Feedback inhibition of leptin receptor/Jak2 signaling via Tyr1138 of the leptin receptor and suppressor of cytokine signaling 3.

Leptin is an adipocyte-derived hormone that communicates the status of body energy stores to the brain to regulate feeding and energy balance. The inability of elevated leptin levels to adequately suppress feeding in obesity suggests attenuation of leptin action under these conditions; the activation of feedback circuits due to high leptin levels could contribute to this leptin resistance. Using cultured cells exogenously expressing the long form of the leptin receptor (LRb) or an erythropoietin receptor/LRb chimera, we show that chronic stimulation results in the attenuation of LRb signaling and the establishment of a state in which the receptor is refractory to reactivation. Mutation of LRb Tyr1138 (the site that recruits signal transducer and activator of transcription 3) alleviated this feedback inhibition, suggesting that signal transducer and activator of transcription 3 mediates the induction of a feedback inhibitor, such as suppressor of cytokine signaling 3 (SOCS3), during chronic LRb stimulation. Indeed, manipulation of the expression or activity of the LRb-binding tyrosine phosphatase, SH2-domain containing phosphatase-2, by overexpression of wild-type and dominant negative isoforms or RNA interference-mediated knockdown did not alter the attenuation of LRb signals. In contrast, SOCS3 overexpression repressed LRb signaling, whereas RNA interference-mediated knockdown of SOCS3 resulted in increased LRb signaling that was not attenuated during chronic ligand stimulation. These data suggest that Tyr1138 of LRb and SOCS3 represent major effector pathways for the feedback inhibition of LRb signaling. Furthermore, we show that mice expressing an LRb isoform mutant for Tyr1138 display increased activity of the leptin-dependent growth and immune axes, suggesting that Tyr1138-mediated feedback inhibition may regulate leptin sensitivity in vivo.

Animals↗

PubMed2001

gamma-Interferon signaling in pancreatic beta-cells is persistent but can be terminated by overexpression of suppressor of cytokine signaling-1.

Proinflammatory cytokines, including gamma-interferon (IFN-gamma), have been implicated in the destruction of beta-cells in autoimmune diabetes. IFN-gamma signaling is transient in some cell types, but there is indirect evidence that it may be prolonged in beta-cells. In this study, we have shown that IFN-gamma signaling, measured by signal transducer and activator of transcription-1 (STAT1) activation and the expression of IFN-gamma-responsive genes, is persistent in beta-cells for as long as the cytokine is present. Because members of the suppressor of cytokine signaling (SOCS) family may regulate the duration of IFN-gamma signaling, their expression was investigated in beta-cells. We found that cytokine-inducible SH2-containing protein, SOCS-1, and SOCS-2 are expressed in primary islets and NIT-1 insulinoma cells, both at the mRNA and protein levels, after treatment with IFN-gamma and other proinflammatory cytokines. Transfected SOCS-1 was found to inhibit responses to IFN-gamma in NIT-1 insulinoma cells, including STAT1 activation, class I major histocompatibility complex upregulation, and IFN-gamma-induced cell death, but only when expressed at levels higher than those found in untransfected cells. Consistent with this, IFN-gamma signaling was not affected in SOCS-1-deficient beta-cells. Therefore, persistent IFN-gamma signaling in beta-cells is associated with SOCS-1 expression that is not sufficient to terminate signaling. Because overexpression of SOCS-1 can suppress responses to IFN-gamma, this may be a useful strategy for protecting beta-cells from cytotoxicity mediated by IFN-gamma and possibly other proinflammatory cytokines.

Animals↗

PubMed2001

Cooperation of Toll-like receptor 2 and 6 for cellular activation by soluble tuberculosis factor and Borrelia burgdorferi outer surface protein A lipoprotein: role of Toll-interacting protein and IL-1 receptor signaling molecules in Toll-like receptor 2 signaling.

Toll-like receptor 2 (TLR2) and TLR4 play important roles in innate immune responses to various microbial agents. We have previously shown that human dermal endothelial cells (HMEC) express TLR4, but very little TLR2, and respond to LPS, but not to Mycobacterium tuberculosis 19-kDa lipoprotein, unless transfected with TLR2. Here we report that HMEC are unresponsive to several additional biologically relevant TLR2 ligands, including, phenol-soluble modulin (PSM), a complex of three small secreted polypeptides from the skin commensal Staphylococcus epidermidis, soluble tuberculosis factor (STF), and Borrelia burgdorferi outer surface protein A lipoprotein (OspA-L). Expression of TLR2 renders HMEC responsive to all these ligands. We further characterized the signaling pathway in response to STF, OspA-L, and PSM in TLR2-transfected HMEC. The TLR2 signaling pathway for NF-kappaB trans-activation shares the IL-1R signaling molecules. Dominant negative constructs of TLR2 or TLR6 inhibit the responses of STF and OspA-L as well as PSM in TLR2-transfected HMEC, supporting the concept of functional cooperation between TLR2 and TLR6 for all these TLR2 ligands. Moreover, we show that Toll-interacting protein (Tollip) coimmunoprecipitates with TLR2 and TLR4 using HEK 293 cells, and overexpression of Tollip inhibits NF-kappaB activation in response to TLR2 and TLR4 signaling. Collectively, these findings suggest that there is functional interaction between TLR2 and TLR6 in the cellular response to STF and OspA-L in addition to S. epidermidis (PSM) Ags, and that engagement of TLR2 triggers a signaling cascade, which shares the IL-1R signaling molecules, similar to the TLR4-LPS signaling cascade. Our data also suggest that Tollip may be an important constituent of both the TLR2 and TLR4 signaling pathways.

Adaptor Proteins, Signal Transducing↗

PubMed1991

Visually induced signal-locked neuronal activity changes in precentral motor areas of the monkey: hierarchical progression of signal processing.

In the precuing paradigm, two successive visual signals were presented to trained monkeys. The first one, the preparatory signal, provided complete, partial or no prior information about parameters, such as direction and extent of the forthcoming wrist movement. After a delay, the illumination of a second visual signal, the response signal, called for execution of the movement and indicated the target. Signal-locked neuronal activity changes, i.e. those which occurred time-locked to the signal onset, were recorded in the premotor cortex and the primary motor cortex of the monkey and classified as selective or non-selective. Selective neurons were defined as those responding to particular information, for instance information about movement direction, provided by the signal, while non-selective neurons responded to all signals irrespective of any contained information. Clear latency differences according to both the selectivity of the neuronal response and the area in which the neuron was recorded could be discerned. The mean latency of non-selective activity changes was significantly shorter than that of selective activity changes. Furthermore, the mean latency of premotor cortical responses was significantly shorter than that of primary motor cortical responses. The data indicate the existence of distinct levels of signal processing from the very general to the highly specific.

Action Potentials↗