TcR zeta/CD3 signal transduction in T-cells: downstream signalling via ZAP-70, SLP-76 and FYB.
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Adaptor Proteins, Signal Transducing↗
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Results for “Signal Transduction”
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Signal transduction. Are there close encounters between signaling pathways?
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Animals↗
[New mechanism of insulin signal transduction: participation of the adenylate cyclase signal system in growth stimulating insulin effect].
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Adenylyl Cyclases↗
Ste50p sustains mating pheromone-induced signal transduction in the yeast Saccharomyces cerevisiae.
In the yeast Saccharomyces cerevisiae, the heterotrimeric G protein transduces the mating pheromone signal from a cell-surface receptor. Free G beta gamma then activates a mitogen-activated protein (MAP) kinase cascade. STE50 has been shown to be involved in this pheromone signal-transduction pathway. In this study, we present a functional characterization of Ste50p, a protein that is required to sustain the pheromone-induced signal which leads cells to hormone-induced differentiation. Inactivation of STE50 leads to the attenuation of mating pheromone-induced signal transduction, and overexpression of STE50 intensifies the pheromone-induced signalling. By genetic analysis we have positioned the action of Ste50p downstream of the alpha-pheromone receptor (STE2), at the level of the heterotrimeric G protein, and upstream of STE5 and the kinase cascade of STE11 and STE7. In a two-hybrid assay Ste50p interacts weakly with the G protein and strongly with the MAPKKK Ste11p. The latter interaction is absent in the constitutive mutant Ste11pP279S. These data show that a new component, Ste50p, determines the extent and the duration of signal transduction by acting between the G protein and the MAP kinase complex in S. cerevisiae.
Alleles↗
Growth hormone receptor ubiquitination, endocytosis, and degradation are independent of signal transduction via Janus kinase 2.
The ubiquitin-proteasome system is required in growth hormone receptor (GHR) endocytosis. For cytokine receptors, which lack intrinsic tyrosine kinase activity, signal transduction is initiated by the activation of a member of the Janus kinase (JAK) family. Previously, we have shown that GHR and JAK2 tyrosine (de) phosphorylation are regulated via the ubiquitin system. In this study, we examined the role of JAK2-mediated signal transduction in GHR internalization and down-regulation. Mutation of the attachment site for JAK2, box-1, in the GHR cytoplasmic tail resulted in the complete absence of GHR and JAK2 phosphorylation. This modification did not alter the rate and extent of receptor-bound growth hormone internalization as compared with a functional GHR, nor did it change its turnover and transport to the plasma membrane. In addition, the receptor was still normally ubiquitinated and remained dependent on both an intact ubiquitin system and proteasomal action for its internalization. Thus, GHR ubiquitination, endocytosis, and degradation occur independently of GHR signal transduction via JAK2. We conclude that whereas endocytosis and degradation require the ubiquitin system, they are independent of GHR signal transduction.
Animals↗
mom identifies a receptor for the Drosophila JAK/STAT signal transduction pathway and encodes a protein distantly related to the mammalian cytokine receptor family.
The JAK/STAT signal transduction pathway controls numerous events in Drosophila melanogaster development. Receptors for the pathway have yet to be identified. Here we have identified a Drosophila gene that shows embryonic mutant phenotypes identical to those in the hopscotch (hop)/JAK kinase and marelle (mrl)/Stat92e mutations. We named this gene master of marelle (mom). Genetic analyses place mom's function between upd (the ligand) and hop. We further show that cultured cells transfected with the mom gene bind UPD and activate the HOP/STAT92E signal transduction pathway. mom encodes a protein distantly related to the mammalian cytokine receptor family. These data show that mom functions as a receptor of the Drosophila JAK/STAT signal transduction pathway.
Amino Acid Sequence↗
Downregulation of Lck-mediated signal transduction by tip of herpesvirus saimiri.
A protein, called tip, of herpesvirus saimiri associates with Lck in transformed T cells. To investigate the effects of complex formation on cellular signal transduction, we constructed human Jurkat-T-cell lines expressing tip. The expression of tip in Jurkat-T cells dramatically suppressed cellular tyrosine phosphorylation and surface expression of lymphocyte antigens. The expression of tip also blocked the induction of tyrosine phosphorylation by anti-CD3 stimulation. The expression of tip in fibroblast cells suppressed the transforming activity of oncogenic F505 Lck. Binding assays showed that the SH3 domain of Lck is sufficient to form a stable complex with tip in vitro. These results demonstrate that tip acts at an early stage of the T-cell signal transduction cascade by associating with Lck and downregulating Lck-mediated activation. Inhibition of Lck-mediated signal transduction by tip in T cells appears to be analogous to the inhibition of Lyn/Syk-mediated signal transduction in B cells by LMP2A of the B-cell-tropic Epstein-Barr virus.
Base Sequence↗
Integrated src kinase and costimulatory activity enhances signal transduction through single-chain chimeric receptors in T lymphocytes.
Adoptive immunotherapy using receptor-modified T lymphocytes has shown promise in preclinical studies for the treatment of infectious and malignant diseases. These modified T cells express chimeric receptors that link ligand recognition and signal transduction domains in a single gene product. Typically, a single chain Fv fragment is genetically attached to the cytoplasmic domain of the T-cell receptor (TCR) zeta chain. Modulating the signaling characteristics of chimeric receptors will be important for their application to human immunotherapy. It was hypothesized that linking coreceptor and costimulatory signaling motifs together with the zeta signaling domain will enhance receptor function. The present study compares signaling characteristics of 9 single-chain receptors consisting of the H-2K(b) extracellular and transmembrane domains and various combinations of T cell signal transduction domains. Signal transduction regions studied include the TCR zeta chain, the CD4 coreceptor, the lck protein tyrosine kinase, and the CD28 costimulatory receptor. Biochemical characteristics of the receptors, analyzed using calcium flux, receptor, and ZAP-70 phosphorylation, and lck association may be predicted from the known functions of receptor constituents. The combination of zeta together with coreceptor and costimulatory function in a single receptor maximizes chimeric receptor sensitivity and potency. Combining zeta with either the costimulatory or coreceptor function independently also enhances receptor function, though to a lesser extent. It is therefore possible to link TCR, coreceptor, and costimulatory activities in a single functional entity using modular domains. Such receptors demonstrate distinct signaling properties and should prove useful in the development of chimeric receptors for therapeutic purposes.
Amino Acid Sequence↗
The effect of purified extract of Fagopyrum esculentum (buckwheat) on protein kinases involved in signal transduction pathways.
The effect of a purified extract of the flowering herb of Fagopyrum esculentum (buckwheat) on various protein kinases involved in signal transduction was examined. We observed that buckwheat contains red fluorescent compounds having photosensitizing properties. Spectrophotometric analysis of the extract has indicated structural similarity to hypericin. Dose- and light-dependent inhibition of various protein kinases was observed. The purified buckwheat extract strongly inhibited two receptor-associated protein tyrosine kinases (EGF-R and Ins-R) and a Ser/Thr kinase (PK-C) at an ng/ml concentration range. Selectivity was exhibited as a decreased sensitivity to cytosolic PTKs and protein kinase CK-2. The protein kinases are important components of the signal transduction pathway. Aberration of signal transduction is a hallmark of several proliferative diseases. Our results indicate that photosensitizing compounds in buckwheat are potential antiproliferative agents.
3T3 Cells↗
Kinome profiling for studying lipopolysaccharide signal transduction in human peripheral blood mononuclear cells.
The DNA array technique allows comprehensive analysis of the genome and transcriptome, but the high throughput array-based assessment of intracellular signal transduction remains troublesome. The goal of this study was to test a new peptide array technology for studying the activity of all kinases of whole cell lysates, the kinome. Cell lysates from human peripheral blood mononuclear cells before and after stimulation with lipopolysaccharide were used for in vitro phosphorylation with [gamma-33P]ATP arrays consisting of 192 peptides (substrates for kinases) spotted on glass. The usefulness of peptide arrays for studying signal transduction was demonstrated by the generation of the first comprehensive description of the temporal kinetics of phosphorylation events induced by lipopolysaccharide stimulation. Furthermore analysis of the signals obtained suggested activation of p21Ras by lipopolysaccharide, and this was confirmed by direct measurement of p21Ras GTP levels in lipopolysaccharide-stimulated human peripheral blood mononuclear cells, which represents the first direct demonstration of p21Ras activation by stimulation of a Toll receptor family member. Further confidence in the usefulness of peptide array technology for studying signal transduction came from Western blot analysis of lipopolysaccharide-stimulated cells, which corroborated the signals obtained using peptide arrays as well as from the demonstration that kinase inhibitors effected peptide array phosphorylation patterns consistent with the expected action of these inhibitors. We conclude that this first metabolic array is a useful method to determine the enzymatic activities of a large group of kinases, offering high throughput analysis of cellular metabolism and signal transduction.
Amino Acid Sequence↗
TRAF6 is required for TRAF2-dependent CD40 signal transduction in nonhemopoietic cells.
The emerging role of CD40, a tumor necrosis factor (TNF) receptor family member, in immune regulation, disease pathogenesis, and cancer therapy necessitates the analysis of CD40 signal transduction in a wide range of tissue types. In this study we present evidence that the CD40-interacting proteins TRAF2 and TRAF6 play an important physiological role in CD40 signaling in nonhemopoietic cells. Using mutational analysis of the CD40 cytoplasmic tail, we demonstrate that the specific binding of TRAF2 to CD40 is required for efficient signaling on the NF-kappaB, Jun N-terminal protein kinase (JNK), and p38 axis. In fibroblasts lacking TRAF2 or in carcinoma cells in which TRAF2 has been depleted by RNA interference, the CD40-mediated activation of NF-kappaB and JNK is significantly reduced, and the activation of p38 and Akt is severely impaired. Interestingly, whereas the TRAF6-interacting membrane-proximal domain of CD40 has a minor role in signal transduction, studies utilizing TRAF6 knockout fibroblasts and RNA interference in epithelial cells reveal that the CD40-induced activation of NF-kappaB, JNK, p38, and Akt requires the integrity of TRAF6. Furthermore, we provide evidence that TRAF6 regulates CD40 signal transduction not only through its direct binding to CD40 but also indirectly via its association with TRAF2. These observations provide novel insight into the mechanisms of CD40 signaling and the multiple roles played by TRAF6 in signal transduction.
CD40 Antigens↗
Recent progress in signal transduction research of the angiotensin II type-1 receptor: protein kinases, vascular dysfunction and structural requirement.
Accumulating evidence strongly implicates the critical roles of intracellular signaling of angiotensin II (AngII) in mediating cardiovascular diseases such as hypertension, atherosclerosis, and restenosis after vascular injury. The importance of AngII signals has also been reported in endothelial dysfunction and insulin resistance, two strong predictors of cardiovascular disease. Through its G protein-coupled AngII type-1 receptor (AT1), AngII activates various intracellular protein kinases, such as receptor or non-receptor tyrosine kinases and serine/threonine kinases. Activation of these kinases requires both G protein-dependent and independent pathways, reactive oxygen species and a metalloprotease, and each kinase could be involved specifically in mediating pathophysiological function of the AT1 receptor target organs. In fact, some of the kinases are indispensable for AngII-induced hypertrophy and migration. The role of these AT1-activated kinases in mediating vascular remodeling, vascular contractility, endothelial dysfunction, and insulin resistance will be discussed in this review. In addition, the AT1 receptor undergoes rapid phosphorylation, desensitization, and internalization upon AngII stimulation. Recent studies with site-directed mutagenesis of the AT1 receptor not only elucidated a G protein interaction and desensitization of the receptor, but also demonstrated a structural requirement of the receptor for downstream signal transduction. Thus, AT1 mutants have provided an excellent means to examine the mechanism of signal transduction and their significance in mediating AngII function. Taken together, in this review, we will focus our discussion on the recent findings of the signal transduction research elucidating novel signaling mechanisms of the AT1 receptor that are relevant to the vascular pathophysiology of AngII.
Angiotensin II↗
The genetics of signal transduction and the outcome of diagnostic tests in growth retardation.
The effects of 'normal' genetic variability of signal transduction on endocrine function may be more evident during stimulation tests than is observed in basal states, thereby contributing to a greater understanding of the possible role of signal transduction genetics in the pathogenesis of endocrine disorders. In the present study, we have studied the outcome of growth hormone (GH) stimulation testing by insulin in growth-retarded children in relation to the genotype of ACP1 (acid phosphatase locus 1; also referred to as cLMWPTP, cytosolic low molecular weight phosphotyrosine phosphatase). ACP1 is an enzyme, expressed as two distinct isoforms designated F and S, that down-regulates insulin receptor signal transduction and which shows a genetic polymorphism with strong quantitative enzymatic differences among genotypes. In this study, we examined 116 growth-retarded children of which 101 were genotyped for ACP1. We found that the basal level of GH is higher in ACP1 genotypes with low concentrations of the S isoform than in genotypes with high S isoform concentrations (P<0.02). Additionally, during GH stimulation with insulin, the genotypes with low S isoform concentrations were found to perform better (P<0.005) and to react more promptly than the genotypes with high S isoform concentrations (P<0.05). These findings suggest that high S isoform ACP1 activity slows down the effect of insulin, resulting in a retardation of its metabolic effect.
Acid Phosphatase↗
Organized endothelial cell surface signal transduction in caveolae distinct from glycosylphosphatidylinositol-anchored protein microdomains.
Regulated signal transduction in discrete microdomains of the cell surface is an attractive hypothesis for achieving spatial and temporal specificity in signaling. A procedure for purifying caveolae separately from other similarly buoyant microdomains including those rich in glycosylphosphatidylinositol-anchored proteins has been developed (Schnitzer, J. E., McIntosh, D. P., Dvorak, A. M., Liu, J., and Oh, P. (1995) Science 269, 1435-1439) and used here to show that caveolae contain many signaling molecules including select kinases (platelet-derived growth factor (PDGF) receptors, protein kinase C, phosphatidylinositol 3-kinase, and Src-like kinases), phospholipase C, sphingomyelin, and even phosphoinositides. More importantly, two different techniques reveal that caveolae function as signal transducing subcompartments of the plasma membrane. PDGF rapidly induces phosphorylation of endothelial cell plasmalemmal proteins residing in caveolae as detected by membrane subfractionation and confocal immunofluorescence microscopy. This PDGF signaling cascade is halted when the caveolar compartment is disassembled by filipin. Finally, in vitro kinase assays show that caveolae contain most of the intrinsic tyrosine kinase activity of the plasma membrane. As signal transducing organelles, caveolae organize a distinct set of signaling molecules to permit direct regionalized signal transduction within their boundaries.
Animals↗
Function of a heterologous muscarinic receptor in T cell antigen receptor signal transduction mutants.
Previously we have described a system of somatic cell genetics (J.CaM1 and J.CaM2) for analyzing signal transduction via the T cell antigen receptor complex (CD3/Ti). Here we describe a third mutant, J.CaM3, which also expresses high levels of receptors that are functionally impaired. Like J.CaM1, J.CaM3 demonstrates partial signal transduction via CD3/Ti to only certain stimuli. J.CaM1, J.CaM2, and J.CaM3 define three non-Ti complementation groups involved in receptor function. To evaluate the mutations further we have introduced a heterologous receptor, the human muscarinic receptor 1 (HM1), into the parental Jurkat and mutant cell lines. This receptor demonstrates signal transduction competence in all these hosts, indicating that 1) T cells express the necessary apparatus for the coupling of HM1 to second messenger generation and 2) the mutations in the J.CaM family all affect molecules that are specific to CD3/Ti, and not HM1, function. Finally, the HM1 receptor exhibits partial sensitivity to cholera toxin in Jurkat cells, in contrast to the virtually complete sensitivity of CD3/Ti to cholera toxin.
Antibodies, Monoclonal↗
Amino acid-dependent signal transduction and insulin sensitivity.
Recent developments indicate that amino acids, in addition to their function as substrates for many metabolic pathways, can stimulate a signal transduction pathway that shares components with insulin-stimulated signalling cascades. Insulin sensitivity is dependent on the ambient amino acid concentration. Amino acid-dependent signal transduction is present in all insulin-sensitive tissues and in pancreatic beta cells. A defect in amino acid-dependent signal transduction may result in phenomena similar to those found in diabetes mellitus.
Amino Acids↗
Signal transduction in vertebrate growth cones navigating in vivo.
Navigating growth cones need signal transduction machinery to amplify and transmit the effects of extracellular signals throughout the growth cone. In culture, many drugs that affect second messengers are known to modulate neurite extension (with different effects on different neurons), and gradients of calcium influx and cyclic nucleotide analogs can cause growth cones to turn. However, it is not clear which of these responses are physiologically relevant, as axons grow through much more complex environments in vivo. The "exposed brain" preparation in Xenopus embryos provides an experimentally tractable system in which it is possible to study growth, pathfinding, and target recognition of retinal growth cones in vivo, while pharmacologically manipulating their signal transduction systems. These growth cones can also be easily studied in explant culture. We describe preliminary results of parallel in vivo and in vitro experiments using an array of drugs that perturb transduction molecules. Surprisingly, calcium ionophores and cyclic nucleotide analogs have no significant effect on retinal axon growth or pathfinding. Several agents including herbimycin A, ML-7, mastoparan, and RHC80267 inhibit retinal axon growth, both in vivo and in vitro, suggesting that tyrosine kinases, myosin, heterotrimeric G-proteins, and diacylglycerol lipase are important for retinal growth cones navigating in the optic pathway.
Animals↗
[Research progress of ethylene signal transduction in plants].
During the past decade, molecular genetic studies on the model plant Arabidopsis have established a largely linear signal transduction pathway for the response to ethylene gas. Ethylene response occurs by receptors binding ethylene and signaling along a linear signal transduction pathway comprising of MAPK and transcriptional cascades. Ethylene receptor family in Arabidopsis consists of five components, ETR1, ERS1, ETR2, ERS2 and EIN4. Each receptor contains an amino-terminal ethylene-binding domain (also called the sensor domain). Some receptors contain a well-conserved carboxy terminal histidine (His) kinase domain and some have an additional receiver domain. Some contain a degenerate His-kinase-like domain that lacks one or more elements and some lack the receiver domain. The ETR1 localizing to endoplasmic reticulum and activating CTR1 negatively regulates the ethylene response as an inhibitive ETR-CTR1 complex. ENI2, EIN3, ERF in turn act downstream of CTR1 and positively regulate the ethylene response. EIN3/EIL, members of regulative protein family activating transcription factor, is posttranscriptionally regulated and stabilized by ethylene. F box protein EBF1/EBF2 accelerate the EIN3 degeneration. ERF1, one of transcription factor family, also called ethylene response element binding protein, is the direct target of EIN3. The biochemical mechanisms of components interaction with each other in the signal transduction pathway are still unknown and largely further research are needed. The signaling pathway is possibly a network consisting of many branches, in which various ethylene-dependent and independent signaling factors cooperate with each other, and complete the specific regulation of different species, developmental stages and tissues response to ethylene.
Ethylenes↗