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Results for “Signal Transduction”

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PubMed1997

Quantification of information transfer via cellular signal transduction pathways.

A conceptual framework is developed for the quantitative analysis of signal transfer through cellular signal transduction pathways and networks. This approach is referred to as signal transfer analysis and is based on formalisms that were first developed for the analysis of metabolic networks. Signal transduction is quantified as the sensitivity, known as the response coefficient of a target (e.g. an ion channel or transcription factor) to a signal (e.g. a hormone, growth factor or neurotransmitter). This response coefficient is defined in terms of the fractional change in the activated target brought about by a small fractional change in the signal. Quantifying the signal transduction in this way makes it possible to prove that for an idealized signaling cascade without feedback loops, the total response equals the product of all the local response coefficients, one for each level of the cascade. We show under which conditions merely having more levels in a cascade can boost the sensitivity of a target to a signal. If a signal propagates to a target through two different routes, these routes contribute independently to the total response, provided there is no feedback from the target. This independence makes the behavior of signaling cascades different from that of metabolic pathways, where different branches are connected through Kirchhoffs law. The relations between the total response and the local kinetics at each level are given for a number of network structures, such as branched signaling pathways and pathways with feedback. The formalism introduced here may provide a general approach to quantify cellular information transfer.

Cell Physiological Phenomena↗

PubMed2000

Activin signal transduction pathways.

Many of the signal transduction pathways required for mammalian endocrine cell function are conserved from flies and worms. These model organisms permitted the illumination of the biological properties of ligands and provided systems in which cellular coactivating molecules could be identified rapidly. Our knowledge about the activin signaling components has been advanced tremendously by the work carried out in these systems. Subsequent research is beginning to reveal the complex interactions that serve to regulate this signaling pathway.

Activins↗

PubMed2001

Exploration of signal transduction pathways in cerebellar long-term depression by kinetic simulation.

Because multiple molecular signal transduction pathways regulate cerebellar long-term depression (LTD), which is thought to be a possible molecular and cellular basis of cerebellar learning, the systematic relationship between cerebellar LTD and the currently known signal transduction pathways remains obscure. To address this issue, we built a new diagram of signal transduction pathways and developed a computational model of kinetic simulation for the phosphorylation of AMPA receptors, known as a key step for expressing cerebellar LTD. The phosphorylation of AMPA receptors in this model consists of an initial phase and an intermediate phase. We show that the initial phase is mediated by the activation of linear cascades of protein kinase C (PKC), whereas the intermediate phase is mediated by a mitogen-activated protein (MAP) kinase-dependent positive feedback loop pathway that is responsible for the transition from the transient phosphorylation of the AMPA receptors to the stable phosphorylation of the AMPA receptors. These phases are dually regulated by the PKC and protein phosphatase pathways. Both phases also require nitric oxide (NO), although NO per se does not show any ability to induce LTD; this is consistent with a permissive role as reported experimentally (Lev-Ram et al., 1997). Therefore, the kinetic simulation is a powerful tool for understanding and exploring the behaviors of complex signal transduction pathways involved in cerebellar LTD.

Cerebellum↗

PubMed2004

Ion condensation and signal transduction.

Many abiotic and other signals are transduced in eukaryotic cells by changes in the level of free calcium via pumps, channels and stores. We suggest here that ion condensation should also be taken into account. Calcium, like other counterions, is condensed onto linear polymers at a critical value of the charge density. Such condensation resembles a phase transition and has a topological basis in that it is promoted by linear as opposed to spherical assemblies of charges. Condensed counterions are delocalised and can diffuse in the so-called near region along the polymers. It is generally admitted that cytoskeletal filaments, proteins colocalised with these filaments, protein filaments distinct from cytoskeletal filaments, and filamentous assemblies of other macromolecules, constitute an intracellular macromolecular network. Here we draw attention to the fact that this network has physicochemical characteristics that enable counterion condensation. We then propose a model in which the feedback relationships between the condensation/decondensation of calcium and the activation of calcium-dependent kinases and phosphatases control the charge density of the filaments of the intracellular macromolecular network. We show how condensation might help mediate free levels of calcium both locally and globally. In this model, calcium condensation/decondensation on the macromolecular network creates coherent patterns of protein phosphorylation that integrate signals. This leads us to hypothesize that the process of ion condensation operates in signal transduction, that it can have an integrative role and that the macromolecular network serves as an integrative receptor.

Animals↗

PubMed1996

Structural aspects of signal transduction in B-cells.

Signal transduction in hematopoietic cells is a highly specific process. The stimulation of B cell receptor following antigen binding triggers, as a first step, phosphorylation of the cytoplasmic immunoreceptor tyrosine-based activation motifs (ITAMs). Src family tyrosine kinases Blk, Fyn, Lck, and Lyn as well as spleen kinase, Syk, are activated to transmit the signal further. In this review the signaling events are discussed in structural terms. The factors related to B cell maturation and their targeted mutations are reviewed. During the last 2 years plenty of structural information concerning signaling molecules in B cells has been obtained by using X-ray crystallography, NMR spectroscopy, molecular modeling, and mutational analysis. The molecules discussed include Src family kinases, Syk, Grb2 adaptor protein, and Tec family kinases Bmx and Btk. The structure, function, and interactions of these signaling compounds are described in atomic detail.

Adaptor Proteins, Signal Transducing↗

PubMed2007

[Correlation of p38 mitogen-activated protein kinase signal transduction pathway to uPA expression in breast cancer].

BACKGROUND & OBJECTIVE: p38 mitogen-activated protein kinase (p38MAPK) signal transduction pathway regulates the expression of various metastasis-related genes. Urokinase-type plasminogen activator (uPA) plays an important role in cancer invasion and metastasis. This study was to explore the correlation of p38MAPK signal transduction pathway to uPA expression in breast cancer. METHODS: SP immunohistochemistry was used to test the expression of p-p38, p-Akt, p-Erk, and uPA in 60 specimens of breast cancer. Western blot was used to detect the protein levels of p-p38 and uPA in breast cancer MDA-MB-231 and MCF-7 cells and the protein level of uPA in MDA-MB-231 cells after blocking p38MAPK signal transduction pathway by SB203580, a specific inhibitor of p38MAPK. The correlations of p-p38, p-Akt, p-Erk, and uPA expression to the clinicopathologic characteristics of breast cancer, and the correlations of p-p38, p-Akt, and p-Erk expression to uPA expression were analyzed. The mechanism of p38MAPK signal transduction pathway regulating the protein expression of uPA in breast cancer cells was investigated. The correlation of p-p38 and uPA expression to prognosis of breast cancer was analyzed. RESULTS: The positive rates of p-p38, p-Akt, p-Erk, and uPA proteins in breast cancer tissues were 56.7%, 95.0%, 93.3%, and 60.0%, respectively. The expression of p-p38 was positively correlated to the expression of uPA (r=0.316, P<0.05), while the expression of p-Akt and p-Erk was not related to uPA expression. The expression of p-p38 and uPA was correlated to lymph node metastasis and TNM stage (P<0.05), but not to patients' age and tumor size (P>0.05). The expression of p-Akt and p-Erk were correlated to lymph node metastasis (P<0.05), but not to TNM stage, patients' age, and tumor size (P>0.05). The protein levels of p-p38 and uPA in MDA-MB-231 cells were higher than that in MCF-7 cells. SB203580 concentration-dependently inhibited p38MAPK pathway and induced uPA protein expression. The expression of p-p38 and uPA was negatively correlated to prognosis of breast cancer (log-rank=4.98, 5.40, P=0.026, 0.020). CONCLUSIONS: p38MAPK signal transduction pathway might improve breast cancer progression by up-regulating uPA expression, and might be an important route in invasion and metastasis of breast cancer. p-p38 and uPA might help to evaluate prognosis of breast cancer.

Adult↗

PubMed1990

Src homology region 2 domains direct protein-protein interactions in signal transduction.

Cytoplasmic proteins that regulate signal transduction or induce cellular transformation, including cytoplasmic protein-tyrosine kinases, p21ras GTPase-activating protein (GAP), phospholipase C gamma, and the v-crk oncoprotein, possess one or two copies of a conserved noncatalytic domain, Src homology region 2 (SH2). Here we provide direct evidence that SH2 domains can mediate the interactions of these diverse signaling proteins with a related set of phosphotyrosine ligands, including the epidermal growth factor (EGF) receptor. In src-transformed cells GAP forms heteromeric complexes, notably with a highly tyrosine phosphorylated 62-kDa protein (p62). The stable association between GAP and p62 can be specifically reconstituted in vitro by using a bacterial polypeptide containing only the N-terminal GAP SH2 domain. The efficient phosphorylation of p62 by the v-Src or v-Fps tyrosine kinases depends, in turn, on their SH2 domains and correlates with their transforming activity. In lysates of EGF-stimulated cells, the N-terminal GAP SH2 domain binds to both the EGF receptor and p62. Fusion proteins containing GAP or v-Crk SH2 domains complex with similar phosphotyrosine proteins from src-transformed or EGF-stimulated cells but with different efficiencies. SH2 sequences, therefore, form autonomous domains that direct signaling proteins, such as GAP, to bind specific phosphotyrosine-containing polypeptides. By promoting the formation of these complexes, SH2 domains are ideally suited to regulate the activation of intracellular signaling pathways by growth factors.

Animals↗

PubMed2000

[Signal transduction and biological function of IL-6 in a human myeloma cell line-XG-7].

OBJECTIVE: To investigate the relationship between IL-6 signal transduction and its biological function on a human IL-6-dependent myeloma cell line-XG-7. METHODS: Electrophoretic mobility shift (EMSA) and immunopeipitation were used respectively to detect the activation of transcription factors (STAT3 and NF-IL-6) and protein kinases (JAK1 and ERK) in the two IL-6 signal transduction pathways by IL-6 in XG-7 cells. Then the cells were transfected with the sense or anti-sense expression plasmids of the transcription factors, which could up- or down-regulate the activation of the signal transduction pathways specially, the changes of the biological function of IL-6 on XG-7 cells was shown by cell number counting and MTT. RESULTS: IL-6 can promote the proliferation of XG-7 cells and activate one of the IL-6 signal transduction pathway-Ras/NF-IL-6; but Jak/STAT signal transduction pathway was not activated at the same conditions. When the activation of Ras/NF-IL-6 pathway was up- or down-regulated, the growth effect of IL-6 on XG-7 cells was strongthened or weakened. CONCLUSIONS: The proliferation of XG-7 cells in the presence of IL-6 is mediated by the activation of Ras/NF-IL-6 signal transduction pathway.

Cell Division↗

PubMed2005

Signal transduction pathways implicated in neural recognition molecule L1 triggered neuroprotection and neuritogenesis.

The signal transduction pathways involved in adhesion molecule L1-triggered neuritogenesis and neuroprotection were investigated using the extracellular domain of mouse or human L1 in fusion with the Fc portion of human immunoglobulin G or L1 purified from mouse brain by affinity chromatography. Substrate L1-triggered neuritogenesis and neuroprotection depended on distinct but also overlapping signal transduction pathways and on the expression of L1 at the neuronal cell surface. PI3 kinase inhibitors, Src family kinase inhibitors as well as mitogen-activated protein kinase kinase inhibitors reduced both L1-triggered neuritogenesis and neuroprotection. In contrast, fibroblast growth factor receptor inhibitors, a protein kinase A inhibitor, and an inhibitor of cAMP-mediated signal transduction pathways, blocked neuritogenesis, but did not affect L1-triggered neuroprotection. Proteolytic cleavage of L1 or its interaction partners is necessary for both L1-mediated neuritogensis and neuroprotection. Furthermore, L1-triggered neuroprotection was found to be associated with increased phosphorylation of extracellular signal-regulated kinases 1/2, Akt and Bad, and inhibition of caspases. These observations suggest possibilities of differentially targeting signal transduction pathways for L1-dependent neuritogenesis and neuroprotection.

Animals↗

PubMed2007

Design principles of the proteolytic cascade governing the sigmaE-mediated envelope stress response in Escherichia coli: keys to graded, buffered, and rapid signal transduction.

Proteolytic cascades often transduce signals between cellular compartments, but the features of these cascades that permit efficient conversion of a biological signal into a transcriptional output are not well elucidated. sigma(E) mediates an envelope stress response in Escherichia coli, and its activity is controlled by regulated degradation of RseA, a membrane-spanning anti-sigma factor. Examination of the individual steps in this protease cascade reveals that the initial, signal-sensing cleavage step is rate-limiting; that multiple ATP-dependent proteases degrade the cytoplasmic fragment of RseA and that dissociation of sigma(E) from RseA is so slow that most free sigma(E) must be generated by the active degradation of RseA. As a consequence, the degradation rate of RseA is set by the amount of inducing signal, and insulated from the "load" on and activity of the cytoplasmic proteases. Additionally, changes in RseA degradation rate are rapidly reflected in altered sigma(E) activity. These design features are attractive as general components of signal transduction pathways governed by unstable negative regulators.

Adaptation, Physiological↗

PubMed1995

Sphingosine-1-phosphate inhibits PDGF-induced chemotaxis of human arterial smooth muscle cells: spatial and temporal modulation of PDGF chemotactic signal transduction.

Activation of the PDGF receptor on human arterial smooth muscle cells (SMC) induces migration and proliferation via separable signal transduction pathways. Sphingosine-1-phosphate (Sph-1-P) can be formed following PDGF receptor activation and therefore may be implicated in PDGF-receptor signal transduction. Here we show that Sph-1-P does not significantly affect PDGF-induced DNA synthesis, proliferation, or activation of mitogenic signal transduction pathways, such as the mitogen-activated protein (MAP) kinase cascade and PI 3-kinase, in human arterial SMC. On the other hand, Sph-1-P strongly mimics PDGF receptor-induced chemotactic signal transduction favoring actin filament disassembly. Although Sph-1-P mimics PDGF, exogenously added Sph-1-P induces more prolonged and quantitatively greater PIP2 hydrolysis compared to PDGF-BB, a markedly stronger calcium mobilization and a subsequent increase in cyclic AMP levels and activation of cAMP-dependent protein kinase. This excessive and prolonged signaling favors actin filament disassembly by Sph-1-P, and results in inhibition of actin nucleation, actin filament assembly and formation of focal adhesion sites. Sph-1-P-induced interference with the dynamics of PDGF-stimulated actin filament disassembly and assembly results in a marked inhibition of cell spreading, of extension of the leading lamellae toward PDGF, and of chemotaxis toward PDGF. The results suggest that spatial and temporal changes in phosphatidylinositol turnover, calcium mobilization and actin filament disassembly may be critical to PDGF-induced chemotaxis and suggest a possible role for endogenous Sph-1-P in the regulation of PDGF receptor chemotactic signal transduction.

Actin Cytoskeleton↗

PubMed2002

A RIP tide in neuronal signal transduction.

The generation of nuclear signaling proteins by regulated intramembrane proteolysis (RIP) is a new paradigm of signal transduction. Mammalian proteins that are processed by RIP include SREBP-1, Notch-1, amyloid precursor protein (APP), and ErbB-4. Intramembranous gamma-secretase cleavage of APP plays a central role in Alzheimer's disease by generating the amyloid beta protein. An intriguing possibility is that the cognate C-terminal fragment generated by gamma-secretase cleavage could also play a role through the regulation of nuclear signaling events. Thus, RIP may contribute to both brain development and degeneration and may provide unexpected diversity to the signaling repertoire of a cell.

Active Transport, Cell Nucleus↗

PubMed1994

Age-related changes in signal transduction. Implications for neuronal transmission and potential for drug intervention.

Problems associated with aging will become one of the leading health dilemmas of the next century. Age-associated diseases, including those affecting the neuronal system, are increasing in frequency. Age-related deficiencies in the brain result in impaired motor functions, sleep, behaviour and cognitive functions. Good functioning of the brain is based on the communication between neurons, by means of signal sending and processing. Neuronal transmission is a very complex phenomenon which involves neuromediator receptors, ion channels and various signal transduction systems. Aging is associated with modification of many brain neurotransmitter and second messenger systems directly involved in signal transduction. Thus, signal transduction events that are deficient in the aged include calcium mobilisation, phosphatidylinositol breakdown, cyclic nucleotides formation, accumulation of proto-oncogene transcripts and synthesis of new proteins, such as certain neurotransmitters. Other events in signal transduction, such as protein tyrosine kinase activity, G-protein structure and function and receptor-G-protein coupling, have not been studied in great detail as yet. Alterations in these various intracellular signalling events may fundamentally influence the functional activity of neurons, and, in consequence, play an important role in the age-dependent alterations of brain functions. Future studies are needed to better understand the molecular basis and the importance of signal transduction changes with aging. Such knowledge will certainly lead to design of better drugs for the prevention or treatment of age-related deficiencies or diseases, such as Parkinson's disease or Alzheimer's disease.

Aging↗

PubMed2005

Re-evaluating the role of Frat in Wnt-signal transduction.

Frat proteins are potent activators of canonical Wnt-signal transduction. By binding to GSK3, Frat prevents the phosphorylation and concomitant degradation of beta-catenin and allows the activation of downstream target genes by beta-catenin/TCF complexes. The identification of the Xenopus Frat homologue GBP as an essential component of the maternal Wnt-pathway during embryonic axis formation suggested that Frat might fulfill a similar role in higher vertebrates. As a result most, if not all, studies addressing Frat function have focused on its ability to bind GSK3 and induce signaling through beta-catenin/TCF. Consequently, Frat has been advocated as the "missing link" that bridged signaling from Dishevelled to GSK3 in the canonical Wnt-pathway. Recent mouse-knockout studies however, call for a reevaluation of the physiological role of Frat. Mice that lack all Frat-family members appear to be normal and display no obvious defects in beta-catenin/TCF signaling. This observation reopens the question as to how GSK3 activity is controlled in vertebrate canonical Wnt-signal transduction in view of the apparent dispensability of Frat. Here we will review the studies that have been conducted on Frat proteins to date, with a specific focus on those that implicate a role for Frat in Wnt-signal transduction. In addition, we will discuss potential alternatives for the endogenous function of Frat.

Adaptor Proteins, Signal Transducing↗

PubMed1999

Leptin receptor activation of SH2 domain containing protein tyrosine phosphatase 2 modulates Ob receptor signal transduction.

Leptin exerts its weight-reducing effects by binding to its receptor and activating signal transduction in hypothalamic neurons and other cell types. To identify the components of the leptin signal transduction pathway, an approach was developed in which bacterially expressed phosphorylated fragments of Ob receptor b (Ob-Rb) were used as affinity agents. Leptin binding to the Ob-Rb form of the leptin receptor leads to tyrosyl phosphorylation of the cytoplasmic domain of its receptor. Two of the three cytoplasmic tyrosines of Ob-Rb, at positions 985 and 1138, are phosphorylated after leptin treatment. Affinity chromatography using a tyrosine-phosphorylated fragment spanning Tyr 985 of Ob-Rb was used to identify proteins that bind to this site. The SH2 domain containing protein tyrosine phosphatase 2 (SHP-2) was isolated from bovine and mouse hypothalamus by using this method. After cotransfection of Ob-Rb, Janus kinase 2 (JAK2), and SHP-2 into 293T cells, leptin results in direct binding of SHP-2 to the phosphorylated Tyr 985. The bound SHP-2 is itself tyrosine phosphorylated after leptin treatment. SHP-2 is not phosphorylated after leptin treatment when a Y-->F 985 receptor mutant is cotransfected. In the absence of SHP-2 phosphorylation, the level of JAK2 phosphorylation was increased. Tyrosyl phosphorylation of the leptin receptor and signal transducer and activater of transcription 3 (STAT3) are not affected by phosphorylation of SHP-2. These data suggest that activation of SHP-2 by the leptin receptor results in a decreased phosphorylation of JAK2 and may act to attenuate leptin signal transduction. The method used in this report can in principle be used to isolate additional components of the leptin, or other, signal transduction pathway.

Amino Acid Sequence↗

PubMed2001

Signal transduction pathways and cell-wall construction in Candida albicans.

Signal transduction pathways are the molecular mechanisms responsible for detecting and transmitting changes in the surrounding environment to the nucleus where appropriate responses are generated. The cell wall is the most external structure of the fungal cell and, in pathogenic fungi, is responsible for specifically interacting with the mammalian host cell in a highly dynamic interplay. Recent work has shown the role that some signal transduction pathways, involving members of the MAP kinase family, have in this process in the nonpathogenic model organism Saccharomyces cerevisiae. However, as yet little is known about these phenomena in pathogenic fungi. The aim of this review is to characterize the existing signal transduction pathways in Candida albicans and their relationship with the cell-wall construction.

Candida albicans↗

PubMed1991

Signal transduction and gene control.

Extracellular signals regulate gene expression by triggering signal transduction cascades that result in the modulation of transcription factor activity. This is most commonly achieved by changes in the phosphorylation state of these nuclear proteins. Phosphorylation affects transcription factor activity at several distinct levels. It can modulate their intracellular localization by controlling the association with other proteins, have both negative and positive effects on their DNA-binding activity, and modulate the activity of their transcriptional activation domains. In addition to phosphorylation, protein-protein interactions also have an important role in mediating a crosstalk at the nuclear level between different signalling pathways.

Animals↗

PubMed2006

Two-component signal transduction in human fungal pathogens.

Signal transduction pathways provide mechanisms for adaptation to stress conditions. One of the most studied of these pathways is the HOG1 MAP kinase pathway that in Saccharomyces cerevisiae is used to adapt cells to osmostress. The HOG1 MAPK has also been studied in Candida albicans, and more recently observations on the Hog1p functions have been described in two other human pathogens, Aspergillus fumigatus and Cryptococcus neoformans. The important, but not surprising, concept is that this pathway is used for different yet similar functions in each of these fungi, given their need to adapt to different environmental signals. Current studies of C. albicans focus upon the identification of two-component signal proteins that, in both C. albicans and S. cerevisiae, regulate the HOG1 MAPK. In C. albicans, these proteins regulate cell wall biosynthesis (and, therefore, adherence to host cells), osmotic and oxidant adaptation, white-opaque switching, morphogenesis, and virulence of the organism.

Adaptation, Physiological↗