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Results for “Signal Transduction”

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PubMed1999

Insights into eukaryotic multistep phosphorelay signal transduction revealed by the crystal structure of Ypd1p from Saccharomyces cerevisiae.

"Two-component" phosphorelay signal transduction systems constitute a potential target for antibacterial and antifungal agents, since they are found exclusively in prokaryotes and lower eukaryotes (yeast, fungi, slime mold, and plants) but not in mammalian organisms. Saccharomyces cerevisiae Ypd1p, a key intermediate in the osmosensing multistep phosphorelay signal transduction, catalyzes the phosphoryl group transfer between response regulators. Its 1.8 A structure, representing the first example of a eukaryotic phosphorelay protein, contains a four-helix bundle as in the HPt domain of Escherichia coli ArcB sensor kinase. However, Ypd1p has a 44-residue insertion between the last two helices of the helix bundle. The side-chain of His64, the site of phosphorylation, protrudes into the solvent. The structural resemblance between Ypd1p and ArcB HPt domain suggests that both prokaryotes and lower eukaryotes utilize the same basic protein fold for phosphorelay signal transduction. This study sheds light on the best characterized eukaryotic phosphorelay system.

Amino Acid Sequence↗

PubMed1994

A limited cytoplasmic region of the prolactin receptor critical for signal transduction.

Prolactin receptors (PRL-R) are members of the cytokine receptor superfamily, which have in common, an absence of any known consensus sequence for signal transduction in their cytoplasmic domains. Four areas of high sequence homology have been identified in the cytoplasmic domains of PRL and growth hormone (GH) receptors, which may be important for signal transduction. The aim of this study was to investigate the role of these cytoplasmic regions in the functional activity of the PRL-R. Several mutant forms of PRL-R were constructed either by truncation or by deletion of the cDNA. Biological activities of these mutant receptors were assayed in CHO cells using a functional assay consisting in the co-transfection of PRL-R cDNA, along with a PRL responsive promoter fused to the coding sequence of the chloramphenicol acetyl transferase (CAT) gene. Progressive truncation of the cytoplasmic domain led to a progressive loss of ability to transactivate the CAT gene. Fully active PRL-R could be obtained when 217 of 358 aa of the cytoplasmic domain were present. Deletion of the first region of homology with the GH-R (residues 245-267) abolished the functional activity of PRL-R, whereas deletion of the second region of homology (residues 322-333) was without effect. These results indicate that a critical cytoplasmic region of 23 residues proximal to the transmembrane domain is essential for PRL signal transduction. There is strong homology within an 8-residue segment of this region with other members of the cytokine receptor superfamily, suggesting it contains a sequence necessary for signal transduction.

Amino Acid Sequence↗

PubMed1998

Lithium homeostasis in Xenopus oocytes: implications for the study of signal transduction.

The Xenopus oocyte has been shown to be a useful model for the study of signal transduction pathways. The present study investigated whether or not the oocyte could be used to study the effects of lithium on signal transduction mechanisms by comparing the dynamics of lithium homeostasis in the oocyte and a human immortalized hippocampal cell line using Flame Atomic Emission Spectroscopy (FAES). A biphasic pattern of lithium uptake was observed in the oocyte in the presence of 5 mM extracellular lithium. The late phase of lithium uptake, which started after 30 minutes of incubation time, was sensitive to phloretin, an inhibitor of Na+/Li+ counter-transport. Differences in lithium efflux kinetics further characterized the two observed phases of accumulation and also suggested that lithium might be distributed in different pools within the oocyte, including one sequestered in organelles or associated with cytosolic proteins. An analogous sequestered pool was not, however, observed in the hippocampal cell line indicating that lithium is distributed differently in these cell types. This suggests that the Xenopus oocyte might not be a suitable model for evaluating the effects of lithium on signal transduction pathways because of the unknown contribution of the sequestered pool on predicting relevant physiological effects.

Animals↗

PubMed2000

Two-component and phosphorelay signal transduction.

Two-component and phosphorelay signal transduction systems are the major means by which bacteria recognize and respond to a variety of environmental stimuli. Recent results have implicated these systems in the regulation of a variety of essential processes including cell-cycle progression, pathogenicity, and developmental pathways. Elucidation of the structures of the interacting domains is leading to an understanding of the mechanisms of molecular recognition and phosphotransfer in these systems.

Bacteria↗

PubMed1998

Two-component signal transduction systems in eukaryotic microorganisms.

Conserved signal transduction pathways that use phosphorelay from histidine kinases through an intermediate transfer protein (H2) to response regulators have been found in a variety of eukaryotic microorganisms. Several of these pathways are linked to mitogen-activated protein kinase cascades. These networks control different physiological responses including osmoregulation, cAMP levels and cellular morphogenesis.

Amino Acid Sequence↗

PubMed1994

[TRH receptor-related signal transduction mechanism].

TRH receptor-related signal transduction mechanism in the pituitary cells and the central nervous system was reviewed. In pituitary cells, TRH binds to its specific receptor on the cell membrane, followed by hydrolysis of inositol phospholipids by activation of phospholipase C leading to an increase in inositol 1,4,5-trisphosphates (IP3) and diacylglycerol (DG). IP3 mobilizes intracellular Ca2+, which activates Ca2+ and Calmodulin dependent protein kinase (Ca-CaM kinase) and DG activates protein kinase C (PKC). Both Ca-CaM kinase and PKC phosphorylates several proteins in the nucleus, plasma membranes, and cytosol resulting in cell responses including hormone secretion and gene expression. Protein dephosphorylation is also involved in TRH action in the pituitary. In the central nervous system, TRH possesses different intracellular signaling systems, which vary with brain regions.

Animals↗

PubMed2005

[Progress in study on signal transduction of gametophytic self-incompatibility].

In nature, most self-incompatible flowering plants (angiosperms) show gametophytic self-incompatibility. Although gametophytic self-incompatibility functions can ultimately prevent self-fertilization, flowering plants have adopted different signal transduction pathways to reject self pollen. At present, there are mainly two pathways of signal transduction on gametophytic self-incompatibility. One is the S-RNase-based signal transduction in Solanaceae, Scrophulariaceae, and Rosaceae. The other is the cytosolic free Ca2+ acting as a second messenger in pollen of Papaveraceae. This review highlights the recent progress made towards understanding the signal transduction on gametophytic self-incompatibility.

Brassicaceae↗

PubMed2002

Salt and drought stress signal transduction in plants.

Salt and drought stress signal transduction consists of ionic and osmotic homeostasis signaling pathways, detoxification (i.e., damage control and repair) response pathways, and pathways for growth regulation. The ionic aspect of salt stress is signaled via the SOS pathway where a calcium-responsive SOS3-SOS2 protein kinase complex controls the expression and activity of ion transporters such as SOS1. Osmotic stress activates several protein kinases including mitogen-activated kinases, which may mediate osmotic homeostasis and/or detoxification responses. A number of phospholipid systems are activated by osmotic stress, generating a diverse array of messenger molecules, some of which may function upstream of the osmotic stress-activated protein kinases. Abscisic acid biosynthesis is regulated by osmotic stress at multiple steps. Both ABA-dependent and -independent osmotic stress signaling first modify constitutively expressed transcription factors, leading to the expression of early response transcriptional activators, which then activate downstream stress tolerance effector genes.

Abscisic Acid↗

PubMed2002

Age-dependent agonist-specific dysregulation of membrane-mediated signal transduction: emergence of the gate theory of aging.

Although a general mechanism for the limited responsiveness of senescent cells has yet to be established, reduced responsiveness may in part be ascribed to deficits in the apparatus required for cell surface receptor-mediated signal transduction. Age-related changes of receptor-mediated signal transduction occur at many levels, and are known to include quantitative and qualitative changes in growth factor receptors, G-protein coupled receptors, and many other downstream signaling molecules. Here, we emphasize the prime role of the cellular surface in the perception and transmission of external stimuli in response to the aging process. As major means of cellular signal transduction, the receptor tyrosine kinase (RTK) system and the G protein-coupled receptor (GPCR) system of senescent cells were investigated. We observed that the RTK system was severely damaged, while the GPCR system was only partially inactivated by aging. These results suggest that the agonist-dependent dysregulation of and imbalance of signal transduction pathways might be responsible for the functional deterioration of senescent cells, and indicate a possibility of the functional recovery of senescent cells through agonist-specific signal system activation. Moreover, those data evoke the emerging concept that the senescent phenotype may be modulated by the membrance-associated signal system, implying the gate theory of aging.

Aging↗

PubMed2004

A subset of hypersensitive response marker genes, including HSR203J, is the downstream target of a spermine signal transduction pathway in tobacco.

A cellular signal transduction pathway induced by the polyamine, spermine (Spm), and transmitted by mitochondrial dysfunction is proposed in tobacco. In this investigation, we further resolve the pathway by identifying a subset of hypersensitive response (HR) marker genes as downstream components. In a previous report, we identified harpin-induced 1 (HIN1) and two closely related genes as responsive to Spm. Other HR marker genes, HSR203J, HMGR, HSR201, and HSR515, are also Spm-responsive. Induction of these HR marker genes, including HIN1, by Spm was suppressed by pre-treatment with antioxidants, calcium channel blockers, inhibitor of mitochondrial permeability transition pore openings, and blockers of amine oxidase/polyamine oxidase. Such quenching is also observed for Spm-induced activation of two mitogen-activated protein kinases (MAPKs), salicylic acid-induced protein kinase (SIPK), and wound-induced protein kinase (WIPK), and upregulation of the WIPK gene, suggesting that all these components are part of the same signaling pathway. Furthermore, gain-of-function and loss-of-function studies on MAPK cascade members reveal that the expression of Spm-induced HR marker genes varies with respect to involvement of SIPK/WIPK activation.

Antioxidants↗

PubMed2000

SOCS3 exerts its inhibitory function on interleukin-6 signal transduction through the SHP2 recruitment site of gp130.

Interleukin-6 is involved in the regulation of many biological activities such as gene expression, cell proliferation, and differentiation. The control of the termination of cytokine signaling is as important as the regulation of initiation of signal transduction pathways. Three families of proteins involved in the down-regulation of cytokine signaling have been described recently: (i) SH2 domain-containing protein-tyrosine phosphatases (SHP), (ii) suppressors of cytokine signaling (SOCS), and (iii) protein inhibitors of activated STATs (PIAS). We have analyzed the interplay of two inhibitors in the signal transduction pathway of interleukin-6 and demonstrate that the tyrosine phosphatase SHP2 and SOCS3 do not act independently but are functionally linked. The activation of one inhibitor modulates the activity of the other; Inhibition of SHP2 activation leads to increased SOCS3-mRNA levels, whereas increased expression of SOCS3 results in a reduction of SHP2 phosphorylation after activation of the interleukin-6 signal transduction pathway. Furthermore, we show that tyrosine 759 in gp130 is essential for both SHP2 and SOCS3 but not for SOCS1 to exert their inhibitory activities on interleukin-6 signal transduction. Besides SHP2, SOCS3 also interacts with the Tyr(P)-759 peptide of gp130. Taken together, our results suggest differences in the function of SOCS1 and SOCS3 and a link between SHP2 and SOCS3.

Antigens, CD↗

PubMed2006

Modeling regulatory mechanisms in IL-6 signal transduction in hepatocytes.

Cytokines like interleukin-6 (IL-6) play an important role in triggering the acute phase response of the body to injury or inflammation. Signaling by IL-6 involves two pathways: Janus-associated kinases (JAK) and signal transducers and activators of transcription (STAT 3) are activated in the first pathway while the second pathway involves the activation of mitogen-activated protein kinases (MAPK). While it is recognized that both pathways play a major role in IL-6 signal transduction, a majority of studies have focused on signaling through either one of the pathways. However, simultaneous signaling through both JAK/STAT and MAPK pathways is still poorly understood. In this work, a mathematical model has been developed that integrates signaling through both the JAK/STAT and the MAPK pathway. The presented model is used to analyze the effect of three molecules that are involved in the regulation of IL-6 signaling-SHP-2 (domain containing tyrosine phosphatase 2), SOCS3 (suppressor of cytokine signaling 3), and a STAT3 nuclear phosphatase (PP2)-on the dynamics of IL-6 signal transduction in hepatocytes. The obtained results suggest that interactions between SHP-2 and SOCS3 influence signaling through the JAK/STAT and the MAPK pathways. It is shown that SHP-2 and SOCS3 do not just regulate the pathway that they are known to be associated with, (SHP-2 with MAPK and SOCS3 with JAK/STAT), but also have a strong effect on the other pathway. Several simulations with SOCS3, SHP-2, and PP2 knockout cells, that is, where the signaling pathway is unable to produce these proteins, have been performed to characterize the effect of these regulatory proteins on IL-6 signal transduction in hepatocytes.

Hepatocytes↗

PubMedDate not supplied

[Contractile proteins in chemical signal transduction in plant microspores].

Involvement of contractile components in chemical signal transduction from the cell surface to the organelles was studied using unicellular systems. Neurotransmitters dopamine and serotonin as well as active forms of oxygen hydrogen peroxide and tert-butyl peroxide were used as chemical signals. Experiments were carried out on vegetative microspores of field horsetail Equisetum arvense and generative microspores (pollen) of amaryllis Hippeastrum hybridum treated with cytochalasin B (an inhibitor of actin polymerization in microfilaments), colchicine, and vinblastine (inhibitors of tubulin polymerization in microtubules). Both types of thus treated microspores demonstrated suppressed development, particularly, for cytochalasin B treatment. At the same time, an increased typical blue fluorescence of certain cell regions (along the cell wall and around nuclei and chloroplasts) where the corresponding contractile proteins could reside was observed. In contrast to anticontractile agents, dopamine, serotonin B, and the peroxides stimulated microspore germination. Microspore pretreatment with cytochalasin B and colchicine followed by the treatment with serotonin, dopamine, or the peroxides decreased the germination rate. Involvement of actin and tubulin in chemical signal transduction from the cell surface to the nucleus is proposed.

Actins↗

PubMed2004

Ethylene signal transduction in Arabidopsis.

It has been more than a centaury since the identification of ethylene as a gaseous plant hormone, and the effects of ethylene on plants have enabled broad applications in agriculture. Efforts had been made to understand ethylene signal transduction in plants, but it had not been successful until the identification and cloning of the first plant hormone receptor gene, ETR1, in Arabidopsis a decade ago. Comprehensive genetic studies allow the dissecting of the signaling pathway to reveal the components involved, which makes the studies of ethylene signal transduction become one the most-understood signal transduction pathways in plants. The identification of the signaling components and the genetic model of ethylene signal transduction pathway are described in this review.

Arabidopsis↗

PubMed1996

MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway.

The p38 mitogen-activated protein (MAP) kinase signal transduction pathway is activated by proinflammatory cytokines and environmental stress. The detection of p38 MAP kinase in the nucleus of activated cells suggests that p38 MAP kinase can mediate signaling to the nucleus. To test this hypothesis, we constructed expression vectors for activated MKK3 and MKK6, two MAP kinase kinases that phosphorylate and activate p38 MAP kinase. Expression of activated MKK3 and MKK6 in cultured cells caused a selective increase in p38 MAP kinase activity. Cotransfection experiments demonstrated that p38 MAP kinase activation causes increased reporter gene expression mediated by the transcription factors ATF2 and Elk-1. These data demonstrate that the nucleus is one target of the p38 MAP kinase signal transduction pathway.

Amino Acid Sequence↗

PubMed2003

Novel agents for the prevention of breast cancer: targeting transcription factors and signal transduction pathways.

Transformation of breast cells occurs through loss or mutation of tumor suppressor genes, or activation or amplification of oncogenes, leading to deregulation of signal transduction pathways, abnormal amplification of growth signals, and aberrant expression of genes that ultimately transform the cells into invasive cancer. The goal of cancer preventive therapy, or "chemoprevention," is to eliminate premalignant cells or to block the progression of normal cells into cancer. Multiple alterations in signal pathways and transcription factors are observed in mammary gland tumorigenesis. In particular, estrogen receptor (ER) deregulation plays a critical role in breast cancer development and progress, and targeting ER with selective ER modulators (SERMs) has achieved significant reduction of breast cancer incidence in women at high risk for breast cancer. However, not all breast cancer is prevented by SERMs, because 30-40% of the tumors are ER-negative. Other receptors for retinoids, vitamin D analogs and peroxisome proliferator-activiator, along with transcription factors such as AP-1, NF-kappaB, and STATs (signal transducers and activators of transcription) affect breast tumorigenesis. This is also true for the signal transduction pathways, for example cyclooxygenase 2 (Cox-2), HER2/neu, mitogen-activated protein kinase (MAPK), and PI3K/Akt. Therefore, proteins in pathways that are altered during the process of mammary tumorigenesis may be promising targets of future chemopreventive drugs. Many newly-developed synthetic or natural compounds/agents are now under testing in preclinical studies and clinical trials. Receptor selective retinoids, receptor tyrosine kinase inhibitors (TKIs), SERMs, Cox-2 inhibitors, and others are some of the promising novel agents for the prevention of breast cancer. The chemopreventive activity of these agents and other novel signal transduction inhibitors are discussed in this chapter.

Anticarcinogenic Agents↗

PubMed1997

Expression and chromosomal localization of the human alpha 4/IGBP1 gene, the structure of which is closely related to the yeast TAP42 protein of the rapamycin-sensitive signal transduction pathway.

To study the function of the B cell signal transduction molecule alpha 4 (IGBP1), we isolated a human alpha 4 (IGBP1) gene that has sequence similarity to the yeast protein (TAP42) involved in the rapamycin-sensitive signal transduction pathway. The human alpha 4 has sequence identities with murine alpha 4 of 83.4% nucleotide and 82.9% amino acid sequence, and a stretch of consensus motifs in the carboxyl terminal is conserved among the related genes of human, mouse, yeast, and rice. The gene is expressed as a 1.4-kb mRNA in the spleen, lymph node, thymus, appendix, peripheral blood leukocytes, bone marrow, fetal liver, heart, brain, placenta, skeletal muscle, kidney, and pancreas. The anti-human alpha 4 antibody detected a 45-kDa protein in human lymphoid cell lines. Moreover, human alpha 4 (IGBP1) gene is located at q13.1-q13.3 on chromosome X.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Tandem DNA recognition by PhoB, a two-component signal transduction transcriptional activator.

PhoB is a signal transduction response regulator that activates nearly 40 genes in phosphate depletion conditions in E. coli and closely related bacteria. The structure of the PhoB effector domain in complex with its target DNA sequence, or pho box, reveals a novel tandem arrangement in which several monomers bind head to tail to successive 11-base pair direct-repeat sequences, coating one face of a smoothly bent double helix. The protein has a winged helix fold in which the DNA recognition elements comprise helix alpha 3, penetrating the major groove, and a beta hairpin wing interacting with a compressed minor groove via Arg219, tightly sandwiched between the DNA sugar backbones. The transactivation loops protrude laterally in an appropriate orientation to interact with the RNA polymerase sigma(70) subunit, which triggers transcription initiation.

Amino Acid Sequence↗