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Results for “Signaling pathways”

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At least 109 records · Page 6Linked to original sources

PubMed2002

A new nuclear component of the Wnt signalling pathway.

The Wnt signalling pathway is pivotal in normal and malignant development. A key effector is Armadillo (Arm)/beta-catenin, which functions with TCF to transcribe Wnt target-genes. Here, we report the discovery of pygopus (pygo), whose mutant phenotypes specifically mimic loss-of-Wingless (Wg) signalling. pygo is required for dTCF-mediated transcription, but not for Wg-induced stabilization of Arm. Pygo is a nuclear protein that is found in a complex with Arm in vivo. Humans possess two Pygo proteins, both of which are required for TCF-mediated transcription in colorectal cancer cells. The presence of a PHD domain implicates Pygo proteins in a chromatin-related function, and we propose that they mediate chromatin access to TCF or Arm/beta-catenin.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Control of neural crest cell fate by the Wnt signalling pathway.

Environmental signals are important in the development of neural crest, during which process multipotent progenitor must choose from several fates. However, the nature of these environmental signals is unknown. A previous fate map of zebrafish cranial neural crest showed that lineage-restricted clones of pigment cells arise from medial cells near the neural keel, and that clones of neurons arise from lateral cells farther from the neural keel. Wnt-1 and Wnt-3a are candidate genes for influencing neural crest fate, as they are expressed next to medial, but not lateral, crest cells. Here we determine the role of Wnt signals in modulating the fate of neural crest by injecting messenger RNAs into single, premigratory neural crest cells of zebrafish. Lineage analysis of injected cells shows that activation of Wnt signalling by injection of mRNA encoding cytoplasmic beta-catenin promotes pigment-cell formation at the expense of neurons and glia. Conversely, inhibition of the Wnt pathway, by injection of mRNAs encoding either a truncated form of the transcription factor Tcf-3 or a dominant-negative Wnt, promotes neuronal fates at the expense of pigment cells. We conclude that endogenous Wnt signalling normally promotes pigment-cell formation by medial crest cells and thereby contributes to the diversity of neural crest cell fates.

Animals↗

PubMed2006

PfPKB, a protein kinase B-like enzyme from Plasmodium falciparum: II. Identification of calcium/calmodulin as its upstream activator and dissection of a novel signaling pathway.

Intracellular cell signaling cascades of protozoan parasite Plasmodium falciparum are not clearly understood. We have reported previously (Kumar, A., Vaid, A., Syin, C., and Sharma, P. (2004) J. Biol. Chem. 279, 24255-24264) the identification and characterization of a protein kinase B-like enzyme in P. falciparum (PfPKB). PfPKB lacks the phosphoinositide-interacting pleckstrin homology domain present in mammalian protein kinase B. Therefore, the mechanism of PfPKB regulation was expected to be different from that of the host and had remained unknown. We have identified calmodulin (CaM) as the regulator of PfPKB activity. A CaM binding domain was mapped in the N-terminal region of PfPKB. CaM, in a calcium-dependent manner, interacts with this domain and activates PfPKB. CaM associates with PfPKB in the parasite and regulates its activity. Furthermore phospholipase C acts as an upstream regulator of this cascade as it facilitates the release of calcium from intracellular stores. This is one of the first multicomponent signaling pathways to be dissected in the malaria parasite.

Amino Acid Sequence↗

PubMed2005

Biglycan is a new extracellular component of the Chordin-BMP4 signaling pathway.

The BMP4 signaling pathway plays key roles during early embryonic development and for maintenance of adult homeostasis. In the extracellular space, BMP4 activity is regulated by a group of interacting molecules including the BMP antagonist Chordin, the metalloproteinase Tolloid and Twisted gastrulation (Tsg). In this study, we identified Biglycan (Bgn), a member of the small leucine-rich proteoglycan family, as a new extracellular modulator of BMP4 signaling. Xenopus Bgn (xBgn) is expressed uniformly in the ectoderm and mesoderm and their derivatives during development. Microinjection of Bgn mRNA induced secondary axes, dorsalized the mesoderm and inhibited BMP4 activity in Xenopus embryos. Biochemical experiments showed that Bgn binds BMP4 and Chordin, interaction that increased binding of BMP4 to Chordin. Bgn was also able to improve the efficiency of Chordin-Tsg complexes to block BMP4 activity. Using antisense morpholinos, we demonstrated that Bgn required Chordin to induce double axes in Xenopus. This work unveiled a new function for Bgn, its ability to regulate BMP4 signaling through modulation of Chordin anti-BMP4 activity.

Animals↗

PubMed1996

Induction of mitogen-activated protein kinase phosphatase 1 by the stress-activated protein kinase signaling pathway but not by extracellular signal-regulated kinase in fibroblasts.

The intracellular mechanisms involved in the activation of extracellular signal-regulated kinase (ERK) are relatively well understood. However, the intracellular signaling pathways which regulate the termination of ERK activity remain to be elucidated. Mitogen-activated protein kinase phosphatase 1 (MKP-1) has been shown to dephosphorylate and inactivate ERK in vitro and in vivo. In the present study, we show in NIH3T3 fibroblasts that activation of the stress-activated protein kinase (SAPK) pathway by either specific extracellular stress stimuli or via induction of MEKK, an upstream kinase of SAPK, results in MKP-1 gene expression. In contrast, selective stimulation of the ERK pathway by 12-O-tetradecanoylphorbol-13-acetate or following expression of constitutively active MEK, the upstream dual specificity kinase of ERK did not induce the transcription of MKP-1. Hence, these findings demonstrate the existence of cross-talk between the ERK and SAPK signaling cascades since activation of SAPK induced the expression of MKP-1 that can inactivate ERK. This mechanism may modulate the cellular response to stimuli which employ the SAPK signal transduction pathway.

3T3 Cells↗

PubMed2005

The CRAL/TRIO and GOLD domain protein CGR-1 promotes induction of vulval cell fates in Caenorhabditis elegans and interacts genetically with the Ras signaling pathway.

Ras-mediated signaling is necessary for the induction of vulval cell fates during Caenorhabditis elegans development. We identified cgr-1 by screening for suppressors of the ectopic vulval cell fates caused by a gain-of-function mutation of the let-60 ras gene. Analysis of two cgr-1 loss-of-function mutations indicates that cgr-1 positively regulates induction of vulval cell fates. cgr-1 is likely to function at a step in the Ras signaling pathway that is downstream of let-60, which encodes Ras, and upstream of lin-1, which encodes a transcription factor, if these genes function in a linear signaling pathway. These genetic studies are also consistent with the model that cgr-1 functions in a parallel pathway that promotes vulval cell fates. Localized expression studies suggest that cgr-1 functions cell autonomously to affect vulval cell fates. cgr-1 also functions early in development, since cgr-1 is necessary for larval viability. CGR-1 contains a CRAL/TRIO domain likely to bind a small hydrophobic ligand and a GOLD domain that may mediate interactions with proteins. A bioinformatic analysis revealed that there is a conserved family of CRAL/TRIO and GOLD domain-containing proteins that includes members from vertebrates and Drosophila. The analysis of cgr-1 identifies a novel in vivo function for a member of this family and a potential new regulator of Ras-mediated signaling.

Amino Acid Sequence↗

PubMed2003

Overexpression of copper/zinc superoxide dismutase in transgenic mice protects against neuronal cell death after transient focal ischemia by blocking activation of the Bad cell death signaling pathway.

The Bad signaling pathway contributes to the regulation of apoptosis after a variety of cell death stimuli, and Bad plays a key role in determining cell death or survival. We have reported that overexpression of copper/zinc superoxide dismutase (SOD1) reduces apoptotic cell death after transient focal cerebral ischemia (tFCI). However, both the role of the Bad pathway after tFCI and the role of oxygen free radicals in the regulation of apoptosis remain unknown. To clarify these issues, we used an in vivo tFCI model of SOD1 transgenic mice and wild-type mice. Moreover, to examine the role of protein kinase A (PKA) in the Bad pathway after tFCI, we administered the PKA inhibitor, H89, into the mouse brain after tFCI. Immunohistochemistry and Western blot analysis showed that dephosphorylation and translocation of Bad were detected early after tFCI and that they were promoted by H89 treatment but prevented by SOD1. Coimmunoprecipitation revealed that the dimerization of Bad progressed with 14-3-3 (Bad/14-3-3) and with Bcl-x(L) (Bad/Bcl-x(L)) after tFCI. Moreover, Bad/14-3-3 was prevented by H89 treatment but promoted by SOD1. Bad/Bcl-x(L) was prevented by SOD1 but promoted by H89 treatment. A cell death assay revealed that apoptotic-related DNA fragmentation was aggravated by H89 treatment but reduced by SOD1. These results suggest that the Bad pathway mediated by PKA is involved in apoptotic cell death after tFCI and that overexpression of SOD1 may attenuate this apoptotic cell death.

14-3-3 Proteins↗

PubMed1993

Interaction between retinoic acid and vitamin D signaling pathways.

The nuclear signaling pathways for retinoids and vitamin D differ in the specificity of the respective receptors for response elements. Two pathways for the action of both retinoic acid receptors (RARs) and vitamin D receptors (VDRs) have been identified, one being retinoid X receptor (RXR)-dependent and the other being RXR-independent. Moreover, RXRs were found to function as homodimers. In several steps we converted the retinoid specific response element of the human retinoic acid receptor beta promoter into the vitamin D/retinoic acid response element of the human osteocalcin promoter. We found that VDR homodimers only bind to the motif RGGTGA. The extended osteocalcin element also contains an imperfect direct repeat based on the motif RGGTGA spaced by three nucleotides, which is bound by RXR homodimers and activated by 9-cis-retinoic acid. The responsiveness of the osteocalcin element to all-trans-retinoic acid is mediated neither by RAR homodimers nor by RAR-RXR heterodimers. However, a VDR-RAR heterodimer binds to the osteocalcin response element and mediates activation by all-trans-retinoic acid. This heterodimer also binds to pure retinoid response elements, but it does not mediate activation by vitamin D alone. In combination with all-trans-retinoic acid, however, vitamin D enhances VDR-RAR heterodimer-mediated gene expression. This finding suggests a direct interaction between nuclear signaling by retinoic acid and vitamin D increasing the combinatorial possibilities for gene regulation by the nuclear receptors involved.

Base Sequence↗

PubMed2003

[Role of Ski/SnoN protein in the regulation of TGF-beta signal pathway].

TGF-beta signal pathway plays an important role in the cell growth, differentiation, formation of extracellular matrix, embryo development and carcinogenesis, etc. However, the regulation of TGF-beta pathway is not totally understood. In 1999, three independent research groups found that Ski/SnoN protein could inhibit the TGF-beta mediated transcription by recruiting N-CoR, a transcription co-repressor. Later studies suggested that TGF-beta and SMADs degraded the Ski/SnoN protein by mediating ubiquitin linkage, showing negative feedback regulation. The important findings in Ski/SnoN laid the theoretical foundation for demonstrating the function of TGF-beta signal pathway.

Animals↗

PubMed2004

Genetically encoded optical probes for imaging cellular signaling pathways.

The intracellular signaling can be monitored in vivo in living cells by genetically encoded intracellular fluorescent and bioluminescent probes or indicators, which include second messengers, protein phosphorylation, protein conformational changes, protein-protein interactions, and protein localizations. These probes are of general use not only for fundamental biological studies, but also for assay and screening of possible pharmaceutical or toxic chemicals that inhibit or facilitate cellular signaling pathways. In this review, two examples of such indicators were briefly introduced. First, a genetically encoded fluorescent indicator was described for the detection and characterization of estrogen agonists and antagonists. The indicator was named SCCoR (single cell-coactivator recruitment). The high sensitivity of the present indicator made it possible to distinguish between estrogen strong and weak agonists in a dose-dependent fashion, immediately after adding a ligand to live cells. Discrimination of agonists from antagonists was efficiently achieved using the indicator. The approach described here can be applied to develop biosensors for other hormone receptors as well. Another example herein is a genetically encoded bioluminescent indicator for monitoring the nuclear trafficking of target proteins in vitro and in vivo. We demonstrated quantitative cell-based in vitro sensing of ligand-induced translocation of androgen receptor, which allowed high-throughput screening of exo- and endogenous agonists and antagonists. Furthermore, the indicator enabled noninvasive in vivo imaging of the androgen receptor translocation in the brains of living mice with a charge-coupled device imaging system. These rapid and quantitative analyses in vitro and in vivo provide a wide variety of applications for screening pharmacological or toxicological compounds and testing them in living animals.

Biosensing Techniques↗

PubMed1993

In vivo dissection of lymphocyte signaling pathways.

Attempts to dissect signaling pathways leading from the T cell antigen receptor to the cell interior rely primarily on careful biochemical analysis of changes in cellular metabolism provoked by ligand. An alternative approach tests hypotheses regarding the mechanism of T cell activation by altering the representation of putative signaling molecules in otherwise normal lymphocytes using gene manipulation techniques. Rigorous implementation of this strategy has defined crucial roles for two protein tyrosine kinases, p56lck and p59fyn, in T cell signaling pathways. Working from this strong foundation, a molecular description of the T cell activation sequence may now be achievable.

Animals↗

PubMed1999

ATP-induced inhibition of Na+, K+, Cl- cotransport in Madin-Darby canine kidney cells: lack of involvement of known purinoceptor-coupled signaling pathways.

P2U/2Y-receptors elicit multiple signaling in Madin-Darby canine kidney (MDCK) cells, including a transient increase of [Ca2+]i, activation of phospholipases C (PLC) and A2 (PLA2), protein kinase C (PKC) and mitogen-activated protein kinase (MAPK). This study examines the involvement of these signaling pathways in the inhibition of Na+,K+,Cl- cotransport in MDCK cells by ATP. The level of ATP-induced inhibition of this carrier ( approximately 50% of control values) was insensitive to cholera and pertussis toxins, to the PKC inhibitor calphostin C, to the cyclic nucleotide-dependent protein kinase inhibitors, H-89 and H-8 as well as to the inhibitor of serine-threonine type 1 and 2A phosphoprotein phosphatases okadaic acid. ATP led to a transient increase of [Ca2+]i that was abolished by a chelator of Ca2+i, BAPTA. However, neither BAPTA nor the Ca2+ ionophore A231287, or an inhibitor of endoplasmic reticulum Ca2+-pump, thapsigargin, modified ATP-induced inhibition of Na+,K+, Cl- cotransport. An inhibitor of PLC, U73122, and an inhibitor of MAPK kinase (MEK), PD98059, blocked ATP-induced inositol-1,4, 5-triphosphate production and MAPK phosphorylation, respectively. However, these compounds did not modify the effect of ATP on Na+,K+, Cl- cotransport activity. Inhibitors of PLA2 (AACOCF3), cycloxygenase (indomethacin) and lypoxygenase (NDGA) as well as exogenous arachidonic acid also did not affect ATP-induced inhibition of Na+,K+,Cl- cotransport. Inhibition of the carrier by ATP persisted in the presence of inhibitors of epithelial Na+ channels (amiloride), Cl- channels (NPPB) and Na+/H+ exchanger (EIPA) and was insensitive to cell volume modulation in anisosmotic media and to depletion of cells with monovalent ions, thus ruling out the role of other ion transporters in purinoceptor-induced inhibition of Na+,K+,Cl- cotransport. Our data demonstrate that none of the known purinoceptor-stimulated signaling pathways mediate ATP-induced inhibition of Na+,K+,Cl- cotransport and suggest the presence of a novel P2-receptor-coupled signaling mechanism.

Adenosine Triphosphate↗

PubMed2002

The Wnt signaling pathway in bipolar disorder.

The Wnt signaling pathway is a highly conserved pathway critical for proper embryonic development. However, recent evidence suggests that this pathway and one of its key enzymes, glycogen synthase kinase 3beta, may play important roles in regulating synaptic plasticity, cell survival, and circadian rhythms in the mature CNS-all of which have been implicated in the pathophysiology and treatment of bipolar disorder. Furthermore, two structurally highly dissimilar medications used to treat bipolar disorder, lithium and valproic acid, exert effects on components of the Wnt signaling pathway. Together, these data suggest that the Wnt signaling pathway may play an important role in the treatment of bipolar disorder. Here, the authors review the modulation of the Wnt/GSK-3beta signaling pathway by mood-stabilizing agents, focusing on two therapeutically relevant aspects: neuroprotection and modulation of circadian rhythms. The future development of selective GSK-3beta inhibitors may have considerable utility not only for the treatment of bipolar disorder but also for a variety of classical neurodegenerative disorders.

Animals↗

PubMed2005

Alternative signaling pathways: when, where and why?

Alternative cell signal transduction pathways have been demonstrated in some experimental systems. The importance of their existence has not been completely appreciated. In this review we present the cases of alternative pathways resulted from a survey of the available experimental data. The alternative pathways could show different relationships, i.e., synergistic, redundant, additive, opposite and competitive effects. They could have distinct time courses and cell, organ, sex or species specification. Further, they could happen during physiological or pathological situations, and display differentiated sensitivity. These case studies together imply that alternative signal pathways could be involved in the regulation of cell functions at the pathway level. In-depth understanding of the importance of the alternative pathways will rely on building and exploration of mathematical models.

Sensitivity and Specificity↗

PubMed1997

Cytoprotective effects of adrenomedullin in glomerular cell injury: central role of cAMP signaling pathway.

Activation of cAMP signaling pathway was shown to inhibit some pathobiologic processes in mesangial cells (MC). We investigated whether adrenomedullin (ADM), a potent agonist of adenylate cyclase, is synthesized in MC and whether it can, via cAMP, suppress the generation of reactive oxygen metabolites (ROM) and proliferation of cells in glomeruli. With the use of an immunohistologic technique ADM was detected in mesangial and microvascular areas of rat glomeruli. MC grown in primary culture synthesized ADM, and the synthesis was stimulated by TNF alpha and IL-1 beta but not by PDGF and EGF. ADM inhibited ROM generation in MC dose-dependently and caused in situ activation of protein kinase A (PKA). In macrophages (cell line J774) ROM generation was about four times higher than in MC and was inhibited by ADM in a similar way as in MC. The rate of MC proliferation, measured by [3H]-incorporation, and the activity of mitogen-activated protein kinase (MAPK) stimulated by PDGF and EGF were dose-dependently inhibited by ADM; the maximum inhibition (at 10 nM ADM) was about -80%. Mitogenesis of MC and MAPK activity when stimulated to a similar extent by endothelin (ET-1) was inhibited by ADM to a significantly (P < 0.01) lesser degree (-30%). Further, ADM inhibited PDF-stimulated mitogenesis and activation of MAPK in cultured vascular smooth muscle cells (VSMC). The inhibition of PDGF-activated MAPK by ADM in VSMC was reversed by the protein kinase A (PKA) inhibitor, H89. Taken together, results indicate the adrenomedullin (ADM) generated in mesangial cells (MC) can suppress, via activation of the cAMP-protein kinase A (PKA) signaling pathway, reactive oxygen metabolites (ROM) generation in MC and infiltrating macrophages as well as mitogen-activated protein kinase (MAPK)-mediated mitogenesis in MC and vascular smooth muscle cells (VSMC). We suggest that introglomerular ADM may serve as a cytoprotective autoacoid that suppresses pathobiologic processes evoked by immuno-inflammatory injury of glomeruli.

Adrenomedullin↗

PubMed1992

CNTF and LIF act on neuronal cells via shared signaling pathways that involve the IL-6 signal transducing receptor component gp130.

Ciliary neurotrophic factor (CNTF) has a variety of actions within the nervous system. While some of the actions of leukemia inhibitory factor (LIF) on neurons resemble those of CNTF, LIF also has broad actions outside of the nervous system that in many cases mimic those of interleukin-6 (IL-6). Comparison of the tyrosine phosphorylations and gene activations induced by CNTF and LIF in neuron cell lines reveals that they are indistinguishable and also very similar to signaling events that characterize LIF and IL-6 responses in hematopoietic cells. We provide a basis for the overlapping actions of these three factors by demonstrating that the shared CNTF and LIF signaling pathways involve the IL-6 signal transducing receptor component gp130. Thus, the receptor system for CNTF is surprisingly unlike those used by the nerve growth factor family of neurotrophic factors, but is instead related to those used by a subclass of hematopoietic cytokines.

Animals↗

PubMed2004

Models of cell signaling pathways.

Cellular signaling circuits handle an enormous range of computations. Beyond the housekeeping, replicating and other functions of individual cells, signaling circuits must implement the immensely complex logic of development and function of multicellular organisms. Computer models are useful tools to understand this complexity. Recent studies have extended such models to include electrical, mechanical and spatial details of signaling, and to address the stochastic effects that arise when small numbers of molecules interact. Increasing numbers of models have been developed in close conjunction with experiments, and this interplay gives a deeper and more reliable insight into signaling function.

Cell Cycle↗

PubMed1997

Immunodeficiencies and haematological disorders--direct connections to cellular signalling pathways.

Extracellular signals, such as cytokines and foreign antigens, regulate the development and activation of haematopoietic cells through receptor-mediated transcriptional responses. Investigation of the biochemical events that transduce receptor activation to intracellular signal transduction have revealed a general mechanism for both the antigen receptor and the cytokine receptor nuclear signalling. Receptor stimulation is coupled to down-stream signalling cascades through activation of cytoplasmic tyrosine kinases but both receptor types utilize distinct signalling proteins. Antigen receptors employ protein tyrosine kinases of the Src, Syk, and Tec families which phosphorylate and activate cytoplasmic signalling proteins leading to activation of NF-AT, AP-1 and NF-kappaB transcription factors, while the principal signal transducers for cytokine receptors are the Jak tyrosine kinases and Stat transcription factors. The molecular basis for several immune and haematological disorders has been characterized during the last few years and they have been found to be caused by defects in various signalling proteins. In this review the aetiology of immune and haematological disorders is discussed in the light of the recent developments in signal transduction.

Antigens↗