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Results for “Signal Transduction”

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At least 73 records · Page 4Linked to original sources

PubMed1993

Immobilization of Fc epsilon receptors by wheat germ agglutinin. Receptor dynamics in IgE-mediated signal transduction.

Transmembrane signaling initiated by the receptor with high affinity for Fc stem of IgE(Fc epsilon RI) requires the diffusion-dependent cross-linkage and persistent aggregation of the Fc epsilon RI. Disruption or prevention of receptor cross-links at any time during the secretory response quickly terminates secretion. We found that in the rat basophilic leukemia mast cell line, addition of wheat germ agglutinin, a lectin that binds to the Fc epsilon RI alpha subunit, caused a precipitous decline in the lateral diffusional and electrokinetic mobilities of the Fc epsilon RI. Both the unoccupied Fc epsilon RI and IgE-Fc epsilon RI complexes became immobilized, as determined from in situ electromigration and postelectric field relaxation. Immobilization of the Fc epsilon RI by wheat germ agglutinin was accompanied by a ligand-reversible association of 125I-IgE-Fc epsilon RI complexes with the Triton X-100-insoluble cytoskeletal fraction. Wheat germ agglutinin rapidly inhibited Fc epsilon RI-mediated signal transduction and secretion, whether cross-linkage was initiated by multivalent antigen, covalent IgE oligomers, anti-IgE, or anti-Fc epsilon RI antibody. Inhibition of signaling and secretion occurred on simultaneous addition of wheat germ agglutinin and antigen, and also when wheat germ agglutinin was added at increasing times after induction of Fc epsilon RI cross-linkage. Wheat germ agglutinin neither reduced the affinity of anti-DNP IgE for haptenic DNP-lysine nor reversed the binding of IgE to the Fc epsilon RI. Although wheat germ agglutinin caused internalization of the Fc epsilon RI, the onset of inhibition preceded and its extent exceeded that of internalization. Wheat germ agglutinin did not interfere with the secretory apparatus, as indicated by its lack of inhibition of secretion elicited by calcium ionophores. These findings suggest that inhibition of signal transduction is secondary to an initial event linked to immobilization of the Fc epsilon RI. Implications of these results are discussed with respect to the dynamics of Fc epsilon RI aggregation on rat basophilic leukemia cells.

Animals↗

PubMed1993

The T cell receptor associated CD3-epsilon protein is phosphorylated upon T cell activation in the two tyrosine residues of a conserved signal transduction motif.

Signal transduction through the T cell receptor for antigen, the TcR/CD3 complex, involves phosphorylation of tyrosine residues in the CD3-zeta chain. Since both CD3-epsilon and the zeta chain contain a tyrosine-based signaling motif, we examine phosphorylation of CD3-epsilon in human T cells. Engagement of the TcR/CD3 complex induced tyrosine phosphorylation of CD3-epsilon in vivo. Induction of CD3-epsilon phosphorylation followed similar kinetics to that of the zeta chain phosphorylation. In contrast to zeta, CD3-epsilon phosphorylation was strictly dependent upon cell surface expression of this member of the TcR/CD3 complex. Chemical and proteolytic cleavage combined with peptide-specific Western blotting established that CD3-epsilon phosphorylation occurred in the two tyrosine residues located in the signal transduction motif in the C-terminal portion of the molecule. Taken together, these data indicated that phosphorylation of CD3-epsilon by tyrosine protein kinases may serve to couple the TcR/CD3 complex to other effector molecules in the signaling cascade.

CD3 Complex↗

PubMed2000

PAT1, a new member of the GRAS family, is involved in phytochrome A signal transduction.

Light signaling via the phytochrome A (phyA) photoreceptor controls basic plant developmental processes including de-etiolation and hypocotyl elongation. We have identified a new Arabidopsis mutant, pat (phytochrome A signal transduction)1-1, which shows strongly reduced responses in continuous far-red light. Physiological and molecular data indicate that this mutant is disrupted at an early step of phyA signal transduction. The PAT1 gene encodes a cytoplasmic protein of 490 amino acids with sequence homologies to the plant-specific GRAS regulatory protein family. In the pat1-1 mutant, a T-DNA insertion introduces a premature stop codon, which likely results in the production of a truncated PAT1 protein of 341 amino acids. The semidominant phenotype of this mutant can be recapitulated by overexpression of an appropriately truncated PAT1 gene in the wild type. The results indicate that the truncated PAT1 protein acts in a dominant-negative fashion to inhibit phyA signaling.

Amino Acid Motifs↗

PubMed2006

Knockout mouse models to study Wnt signal transduction.

Wnt signal transduction is crucial for maintaining the balance between proliferation and differentiation throughout embryogenesis and postnatal life. Here, we provide a comprehensive overview of the conventional knockout mouse studies of both the canonical and the noncanonical Wnt pathways during mammalian development. Many of these knockout mice display early embryonic lethality, underscoring the fundamental importance of Wnt signal transduction, but precluding functional analyses at later stages. Use of conditional or inducible mouse models will enable us to study the role of Wnt signaling during later stages of development and adult life. Furthermore, genomic-scale approaches and advanced imaging techniques could provide a means to start dissecting the mechanism behind the observed phenotypes.

Alleles↗

PubMed1994

Lipopolysaccharide-induced cytokine production in human monocytes: role of tyrosine phosphorylation in transmembrane signal transduction.

The signal transduction events that follow the binding of lipopolysaccharide (LPS) to the macrophage cell surface are not well defined. In the current studies LPS was found to induce alterations in phosphorylation of monocyte proteins on tyrosine. Herbimycin A and genistein, inhibitors of tyrosine kinases, markedly attenuated LPS-induced tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) protein and mRNA production. Reciprocally, the tyrosine phosphatase inhibitor sodium orthovanadate enhanced LPS-induced production of TNF-alpha. LPS induced a concentration-dependent increase in tyrosine phosphorylation of several proteins, which paralleled and preceded the onset of LPS-induced TNF-alpha production. LPS stimulation had different but reproducible effects on three members of the src family of tyrosine kinases. Both Hck and Lyn kinase activity increased before the onset of TNF-alpha production, consistent with their participation in the observed LPS-induced tyrosine phosphoprotein accumulation. In contrast, Yes kinase activity was not affected. These observations were made at concentrations of LPS that required serum rich in LPS-binding protein and the monocyte surface antigen CD14 for TNF-alpha production. These data indicate that tyrosine kinases and phosphatases are involved in the signal transduction cascade by which LPS induces production of TNF-alpha and IL-6 by human monocytes, and suggest that Lyn and Hck are candidate participants in this process.

Acute-Phase Proteins↗

PubMed1995

Interleukin-13 signal transduction in lymphohemopoietic cells. Similarities and differences in signal transduction with interleukin-4 and insulin.

Interleukin-13 (IL-13) and interleukin-4 (IL-4) are related in structure and function and are thought to share a common receptor component. We have investigated the signal transduction pathways activated by these two growth factors, as well as insulin, in cell-lines and primary cells of lymphohemopoietic origin. All three factors induced the tyrosine phosphorylation of a protein of 170 kDa (p170), which coimmunoprecipitated with the p85 subunit of P13'-kinase, via high affinity interactions mediated by the SH2 domains of p85. Antibodies raised against the entire insulin-receptor substrate-1 (IRS-1) protein immunoprecipitated p170 much less efficiently than they did IRS-1 from 3T3 cells. However, antibodies directed against the conserved pleckstrin homology domain of IRS-1 immunoprecipitated both p170 and IRS-1 with similar efficiency, suggesting they share structural similarities in this region. In lymphohemopoietic cells, IL-13, IL-4, and insulin failed to induce increased tyrosine phosphorylation of Shc, or its association with grb2, modification of Sos1, or activation of erk-1 and erk-2 mitogen-activated protein kinases, suggesting that p170 mediates downstream pathways distinct from those mediated by IRS-1. Both IL-13 and IL-4 induced low levels of tyrosine phosphorylation of Tyk-2 and Jak-1. IL-4 also activated the Jak-3-kinase, but, despite other similarities, IL-13 did not. Insulin failed to activate any of the known members of the Janus family of kinases. In that Jak-3 is reported to associate with the IL-2 gamma c chain, these data suggest that the IL-13 receptor does not utilize this subunit. However, both IL-13 and IL-4 induced tyrosine phosphorylation of the IL-4-140 kDa receptor chain, suggesting that this is a component of both receptors in these cells and accounts for the similarities in signaling pathways shared by IL-13 and IL-4.

3T3 Cells↗

PubMed1998

Heterologous desensitization in neoplastic thyroid cells: influence of the phospholipase C signal transduction system on the thyrotropin-adenylate cyclase signal transduction system.

Desensitization is defined as a decreased functional response after continuous or repetitive stimulation of a receptor with its agonist. Thyrotropin (TSH) increases cAMP levels in normal and neoplastic thyroid tissue. The tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) activates protein kinase C (PKC). The aim was to determine whether TPA induces heterologous desensitization of the TSH-adenylate cyclase (AC) signal transduction system. Three human thyroid neoplasms in culture for 6 months or longer (one papillary carcinoma, one Hurthle cell carcinoma, one follicular adenoma) were incubated with TSH (10 mU/ml) and TPA (1.6 x 10(-8) M) separately and together for various time periods (from 10 minutes to 24 hours). The mixture was subsequently incubated for 30 minutes with TSH. TPA alone had no effect on cAMP levels, but co-incubation of TPA and TSH caused a significant reduction in cAMP response when compared to the cAMP response that resulted after stimulation with only TSH (p < 0.001). cAMP levels in response to TSH decreased by 31%, 44%, and 57% after preincubation with TSH for 10 minutes, 4 hours, and 24 hours, respectively (p < 0.01; ANOVA). Co-incubation of cells with TPA and staurosporine (10 ng/ml), a PKC inhibitor, prevented the effect of TPA on desensitization at 10 minutes and blunted the effect at 4 hours. This is the first demonstration in human neoplastic thyroid cells that TPA induced heterologous desensitization of the cAMP response to TSH. This TPA-induced effect appears to involve PKC activation, as it can be blocked by staurosporine.

Adenylyl Cyclases↗

PubMed1993

The CD19 signal transduction complex of B lymphocytes. Deletion of the CD19 cytoplasmic domain alters signal transduction but not complex formation with TAPA-1 and Leu 13.

CD19 expressed on the surface of B lymphocytes is a key member of a cell surface signal transduction complex that includes TAPA-1, Leu 13 and CD21. The human CD19 protein is composed of 540 amino acids with a cytoplasmic domain of 242 amino acids. Although the cytoplasmic domain of CD19 has no sequence homology with other proteins, the cytoplasmic domain of human, mouse, and guinea pig CD19 is highly conserved suggesting that this region of CD19 is at least partially responsible for signaling activity. In this study, the regions of CD19 required for intermolecular associations and signal transduction were determined by comparing a series of carboxyl-terminal cytoplasmic tail deletion mutants and a CD19/L-selectin chimera with native CD19. CD19 expressed in the human Rex T cell line and the K562 erythroleukemia cell line generated transmembrane signals and also associated with endogenous TAPA-1. Deletion of 95% of the CD19 cytoplasmic domain did not affect the ability of CD19 to be expressed or to associate with TAPA-1. However, replacement of the CD19 transmembrane and cytoplasmic domains with those of L-selectin (CD19-LAM) resulted in the loss of CD19 complex formation, suggesting that the membrane spanning domain is critical for this association. Similarly, the induction of homotypic adhesion through CD19 or truncated CD19 was equivalent, whereas homotypic adhesion was not induced via the CD19-LAM chimera. In addition, the cytoplasmic domain was not necessary for CD19 mAb-mediated growth inhibition or internalization. In contrast, the CD19 cytoplasmic domain was required for optimal mAb-induced increases in [Ca2+]i in CD19 cDNA-transfected Rex cells. Thus, the CD19 cytoplasmic domain is responsible for the induction of increased [Ca2+]i, and the transmembrane region is required for cell surface associations with the other members of the CD19 complex and most signaling events. Therefore, mAb binding to CD19 is likely to initiate multiple intracellular signal transduction cascades either through CD19 directly, or through other members of the CD19 complex.

Antigens, CD↗

PubMed1993

Signal transduction through extracellular signal-regulated kinase-like pp57 blocked in differentiated colon carcinoma cells having low levels of c-src kinase.

Basic fibroblast growth factor (FGF) induced a rapid increase in tyrosine phosphorylation of a 57-kDa cytoplasmic protein with functional myelin basic protein kinase activity and antigenic properties common to mitogen-activated kinases or extracellular signal-regulated kinases. Basic and acidic FGFs and the diacylglycerol diolein used the same signal transduction pathway to activate pp57. These FGFs, like diolein (Lee, H., Ghose-Dastidar, J., Winawer, S., and Friedman, E. (1993) J. Biol. Chem., 268, 5255-5263), increased the cellular concentration of long-chain diacylglycerols within the same short time period as they increased pp57 tyrosine phosphorylation. Both FGF and diolein increased phosphorylation of pp57 on the same V8 protease-generated fragments, suggesting a common pathway for the phosphorylation of pp57. FGF-induced signal transduction through pp57 mitogen-activated kinase led to cell growth in two undifferentiated colon carcinoma cell lines. In contrast, basic FGF neither increased tyrosine phosphorylation of pp57 nor increased cell growth in two colon goblet cell differentiated lines derived from the same parental line as the undifferentiated cells. Both goblet cell lines exhibited levels of protein-tyrosine kinase activity about one-fifth that of the undifferentiated lines. The decrease in tyrosine kinase activity was not due to down-regulation of FGF receptors or their tyrosine kinase activities. c-src kinase-specific activity was decreased 4-5-fold in both goblet cell lines, suggesting a role for c-src in pp57-mediated signal transduction.

CSK Tyrosine-Protein Kinase↗

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↗

PubMed1998

Usage of activating mutations in the analysis of cytokine signal transduction pathways.

Cytokine signal transduction pathways are highly redundant and complex. The analysis of the structure and function of signal transduction molecules was conventionally done by using mutated or truncated receptors, dominant negative molecules, and knockout mice. These methods are designed to look at the result of a subtraction of a part of the whole signal transduction pathway. In contrast, analysis using activating mutations of a signal transduction molecule is designed to look at the downstream result of one pathway which originated from the pertinent molecule. This method is less influenced by other signal transduction molecules which may have an overlapping effect on the downstream molecules. By combining both the subtraction and activating methods, we can gain more insight into the complex interactions between signal transduction molecules. An activating mutation of a signal transduction molecule is usually found as an oncogene. However, known oncogenes are not always the molecules of interest. In this review, several methods to create activating mutations of a target molecule are discussed.

Animals↗

PubMed2001

Continuous recycling: a mechanism for modulatory signal transduction.

Modulatory signal transduction commonly requires efficient "on demand" assembly of specific multicomponent cellular machines that convert signals to cellular actions. This article suggests that for these signaling machines to detect and respond to fluctuations in signal strength, they must be continuously disassembled in an energy-dependent process that probably involves molecular chaperones.

Animals↗

PubMed2006

Anchored cAMP signaling: onward and upward - a short history of compartmentalized cAMP signal transduction.

Intracellular signal transduction pathways require a high degree of spatial and temporal resolution in order to deliver the appropriate outputs. Specific signaling mediated by the ubiquitous second messenger cAMP and its effector, the cAMP-dependent protein kinase (PKA), is governed by the spatial organization of different pathway components by A-kinase anchoring proteins (AKAPs). This review discusses the history and future of anchored cAMP signaling pathways.

Adaptor Proteins, Signal Transducing↗

PubMed2003

The role of MyD88-like adapters in Toll-like receptor signal transduction.

Signal-transduction pathways activated by Toll-like receptors (TLRs) have been the subject of intense investigation because of the key role played by TLRs in the recognition and elimination of microbes. Signalling is initiated by a domain termed the Toll/interleukin-1 (IL-1) receptor (TIR) domain that occurs on the cytosolic face of TLRs. This recruits, via homotypic interactions, adapter proteins that contain TIR domains. Three such adapter proteins have been discovered to date, and have been named MyD88, Mal [MyD88 adapter-like; also known as TIRAP (TIR domain-containing adapter protein)] and Trif (TIR-domain-containing adapter inducing interferon-beta). Differences are emerging between TLRs in terms of which adapter is recruited by which TLR. This may lead to specificities in TLR signalling, with pathways being triggered that are specific for the elimination of the invading microbe. However, signals that separate Mal from MyD88 have yet to emerge, although biochemical differences between the two proteins imply that each will have a specific function.

Adaptor Proteins, Signal Transducing↗

PubMed2004

A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway.

Signal transduction pathways are modular composites of functionally interdependent sets of proteins that act in a coordinated fashion to transform environmental information into a phenotypic response. The pro-inflammatory cytokine tumour necrosis factor (TNF)-alpha triggers a signalling cascade, converging on the activation of the transcription factor NF-kappa B, which forms the basis for numerous physiological and pathological processes. Here we report the mapping of a protein interaction network around 32 known and candidate TNF-alpha/NF-kappa B pathway components by using an integrated approach comprising tandem affinity purification, liquid-chromatography tandem mass spectrometry, network analysis and directed functional perturbation studies using RNA interference. We identified 221 molecular associations and 80 previously unknown interactors, including 10 new functional modulators of the pathway. This systems approach provides significant insight into the logic of the TNF-alpha/NF-kappa B pathway and is generally applicable to other pathways relevant to human disease.

Animals↗

PubMed1999

Implications for Src kinases in hematopoiesis: signal transduction therapeutics.

Signal transduction therapeutics is now the dominant theme of drug discovery, and its most immediate impact will be in cancer therapeutics. Blood cell proliferation, differentiation, and activation are controlled by cytokines, whose receptors contain tyrosine kinase catalytic domains or recruit cytosolic tyrosine kinases. Among the most important cytosolic protein tyrosine kinases are the Src and Jak families. Receptor or cytosolic protein tyrosine kinases activate a similar set of intracellular signaling molecules. In blood cells, excessive tyrosine kinase activity is associated with either cancer or autoreactive diseases. Therefore, tyrosine kinases and their substrates serve as excellent candidates for drug intervention. Herceptin has been approved for use in breast cancer. Other agents, such as SU101 and CGP 57418B, are well into phase I-III trials. Newer, more selective tyrosine kinase inhibitors are being evaluated for future use in the treatment of hematologic and solid tumors as well as a wide range of inflammatory or autoimmune diseases.

Animals↗

PubMed1998

Repression of c-fos and c-jun gene expression is not part of AT2 receptor coupled signal transduction.

The signal transduction mechanism coupled to angiotensin AT2 receptors is still a matter of debate. Based on the findings that AT2 receptor stimulation causes inhibition of proliferation, and that other antiproliferative agents such as transforming growth factor-beta, retinoic acid, and MyoD act via repression of immediate early gene (IEG) expression, this study was aimed at elucidating whether downregulation of IEG expression is also part of the AT2 receptor coupled signaling mechanism. Stimulation of angiotensin AT2 receptors in the rat pheochromocytoma cell line PC12 W following pretreatment with growth factors was able to counteract growth factor induced proliferation but not to repress growth factor induced c-fos and c-jun expression; neither did AT2 receptor stimulation cause an induction of c-fos expression. We conclude that, in contrast to other growth-inhibiting agents, the antiproliferative effect of angiotensin II via the AT2 receptor is not mediated by repression of the immediate early genes c-fos and c-jun.

Angiotensin II↗

PubMed2002

The role of Grp 78 in alpha 2-macroglobulin-induced signal transduction. Evidence from RNA interference that the low density lipoprotein receptor-related protein is associated with, but not necessary for, GRP 78-mediated signal transduction.

The low density lipoprotein receptor-related protein (LRP) is a scavenger receptor that binds to many proteins, some of which trigger signal transduction. Receptor-recognized forms of alpha(2)-Macroglobulin (alpha(2)M*) bind to LRP, but the pattern of signal transduction differs significantly from that observed with other LRP ligands. For example, neither Ni(2+) nor the receptor-associated protein, which blocks binding of all known ligands to LRP, block alpha(2)M*-induced signal transduction. In the current study, we employed alpha(2)-macroglobulin (alpha(2)M)-agarose column chromatography to purify cell surface membrane binding proteins from 1-LN human prostate cancer cells and murine macrophages. The predominant binding protein purified from 1-LN prostate cancer cells was Grp 78 with small amounts of LRP, a fact that is consistent with our previous observations that there is little LRP present on the surface of these cells. The ratio of LRP:Grp 78 is much higher in macrophages. Flow cytometry was employed to demonstrate the presence of Grp 78 on the cell surface of 1-LN cells. Purified Grp 78 binds to alpha(2)M* with high affinity (K(d) approximately 150 pm). A monoclonal antibody directed against Grp 78 both abolished alpha(2)M*-induced signal transduction and co-precipitated LRP. Ligand blotting with alpha(2)M* showed binding to both Grp 78 and LRP heavy chains in these preparations. Use of RNA interference to silence LRP expression had no effect on alpha(2)M*-mediated signaling. We conclude that Grp 78 is essential for alpha(2)M*-induced signal transduction and that a "co-receptor" relationship exists with LRP like that seen with several other ligands and receptors such as the uPA/uPAR (urinary type plasminogen activator or urokinase/uPA receptor) system.

Animals↗