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Results for “Signal Transduction”

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At least 613 records · Page 34Linked to original sources

PubMed1999

Agrin-independent activation of the agrin signal transduction pathway.

The neural factor agrin induces the aggregation of acetylcholine receptors (AChRs) and other synaptic molecules on cultured myotubes. This aggregating activity can be mimicked by experimental manipulations that include treatment with neuraminidase or elevated calcium. We report evidence that neuraminidase and calcium act through the agrin signal transduction pathway. The effects of neuraminidase and calcium on AChR clustering are additive with that of agrin at low concentrations and cosaturating at high concentrations. In addition, like agrin, both neuraminidase and calcium cause rapid tyrosine phosphorylation of the muscle-specific kinase (MuSK) and the AChR-beta subunit. Our results argue that all three agents act directly on components of the same signal transduction complex. We suggest that sialic acids on components of the complex inhibit interactions necessary for signal transduction and that disinhibition can result in activation. In such a model, agrin could activate signal transduction by disinhibition or by circumventing the inhibition.

Agrin↗

PubMed2002

The Raf/MEK/ERK signal transduction cascade as a target for chemotherapeutic intervention in leukemia.

The Raf/MEK/ERK (MAPK) signal transduction cascade is a vital mediator of a number of cellular fates including growth, proliferation and survival, among others. The focus of this review centers on the MAPK signal transduction pathway, its mechanisms of activation, downstream mediators of signaling, and the transcription factors that ultimately alter gene expression. Furthermore, negative regulators of this cascade, including phosphatases, are discussed with an emphasis placed upon chemotherapeutic intervention at various points along the pathway. In addition, mounting evidence suggests that the PI3K/Akt pathway may play a role in the effects elicited via MAPK signaling; as such, potential interactions and their possible cellular ramifications are discussed.

Animals↗

PubMed1992

Role of the carboxyl-terminal half of the extracellular domain of the human thyrotropin receptor in signal transduction.

We studied the role of the carboxyl-terminus of the extracellular region of the human TSH receptor in signal transduction (cAMP generation). For this purpose, we introduced homologous substitutions of smaller segments within amino acids 261-418 (domains D and E) of the TSH receptor with the corresponding amino acids of the rat LH/CG receptor. Amino acids 317-366 were not investigated in view of previous data indicating their noninvolvement. Mutant TSH receptor cDNAs, in a eukaryotic expression vector, were stably transfected into Chinese hamster ovary cells. Eight of nine plasmid constructs expressed TSH receptors that could be detected by radiolabeled TSH binding; six of these were of high affinity similar to the wild-type receptor and, therefore, provided informative data on signal transduction. Despite high affinity TSH binding, five of six TSH receptor mutants displayed a diminished cAMP response to TSH stimulation, suggesting the involvement of broad segments of domains DE in signal transduction. Amino acids 270-278 and 287-297 were particularly important in this respect. The conformation conferred by these segments of the TSH receptor, therefore, appears to be involved in transducing a signal from the extracellular to the intracellular region of the receptor.

Amino Acid Sequence↗

PubMed1992

Signal transduction by neutrophil immunoglobulin G Fc receptors. Dissociation of intracytoplasmic calcium concentration rise from inositol 1,4,5-trisphosphate.

The signal transduction mechanisms involved in the regulation of phagocytosis are largely unknown. We have recently shown that in neutrophils, when IgG-mediated phagocytosis is stimulated by formyl-methionyl-leucyl-phenyl-alanine (fMLP), the enhanced ingestion is dependent on the increase in [Ca2+]i which results from ligation of Fc receptors by the IgG-coated target (Rosales, C., and Brown, E. (1991) J. Immunol. 146, 3937-3944). Now, we have studied the mechanism by which this rise in [Ca2+]i occurs. Aggregated IgG, the monoclonal antibody 3G8 (which recognizes Fc receptor type III), and insoluble immune complexes caused an increase in [Ca2+]i. The rise in [Ca2+]i induced by Fc receptor ligation was resistant to pertussis toxin. In contrast, fMLP induced a rise in [Ca2+]i which was inhibited by pertussis toxin. fMLP-induced [Ca2+]i was accompanied by an accumulation of inositol 1,4,5-trisphosphate (IP3) which peaked by 15 s, and which was also abolished by pertussis toxin. IP3 accumulation after aggregated IgG, 3G8, or insoluble immune complexes was much less than after fMLP. Unlike [Ca2+]i rise induced by Fc receptor ligation, this small increase in IP3 was inhibited by pertussis toxin. These data demonstrated that the [Ca2+]i increase induced by Fc receptor ligation is not mediated by IP3. Immediate pretreatment of human polymorphonuclear neutrophils with optimal doses of fMLP also reduced subsequent increase in [Ca2+]i rise from thapsigargin, a sesquiterpene lactone tumor promoter that releases intracellular Ca2+ from IP3-sensitive stores without IP3 turnover. Similarly, to its effects on thapsigargin, fMLP inhibited the [Ca2+]i rise upon subsequent immune complex binding. Pretreatment of cells with immune complexes also prevented subsequent [Ca2+]i rise from thapsigargin and fMLP. These data demonstrate that IgG Fc receptor ligation and fMLP activation of human polymorphonuclear neutrophils use distinct signal transduction mechanisms to release Ca2+ from the same thapsigargin-sensitive intracellular pool. In contrast to fMLP, signal transduction for increased [Ca2+]i after Fc receptor stimulation does not involve a pertussis toxin-sensitive G protein, and is independent of IP3.

Adult↗

PubMed2004

[The effects of genistein on epidermal growth factor receptor mediated signal transduction pathway in human ovarian carcinoma cells lines SKOV3 and its xenograft in nude mice].

OBJECTIVE: It was reported previously that genistein could inhibit proliferation of human ovarian carcinoma cell line SKOV(3), but mechanism was not clear. There is a close relationship between EGFR mediated signal transduction pathway and the development of ovarian tumor. This study aimed to investigate the effects of genistein on the EGFR mediated signal transduction pathway and to clarify its mechanisms of proliferation inhibition on human ovarian carcinoma cell line SKOV(3) and its xenograft in nude mice. METHODS: The expression of c-erbB-2 protein was determined using immunocytochemistry. The expressions of c-jun and c-fos protein were determined using Western blotting. The expression of c-erbB-2, c-raf-1, c-jun and c-fos mRNA were tested by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The expression of c-erbB-2, c-raf-1 and its downstream gene c-jun and c-fos were decreased at mRNA level in the 20 micromol/L genistein group. The expression of c-erbB-2 protein were decreased, its average absorbency (A) were decreased after treatment of SKOV(3) with 20 micromol/L genistein for 48 h, reached at 0.42 +/- 0.02 (P < 0.05). Western blotting demonstrated that the expressions of c-jun and c-fos protein were decreased gradually after being treated with 20 micromol/L genistein for 12 - 72 h. CONCLUSIONS: Genistein could down-regulate the expression of two key genes, c-erbB-2 and c-raf-1 at mRNA and protein level in the EGFR mediated signal transduction pathway, and down-regulate the expression of its downstream nuclear transcription factors c-jun and c-fos at mRNA and protein level. It is suggested that interfering the expressions of some key signal molecules in EGFR mediated signal transduction system by genistein may account for its molecular foundation of proliferation inhibition in ovarian carcinoma.

Animals↗

PubMedDate not supplied

Hyperglycemia potentiates H(2)O(2) production in adipocytes and enhances insulin signal transduction: potential role for oxidative inhibition of thiol-sensitive protein-tyrosine phosphatases.

Insulin signal transduction in adipocytes is accompanied by a burst of cellular hydrogen peroxide (H(2)O(2)) that facilitates insulin signaling by inhibiting thiol-dependent protein-tyrosine phosphatases (PTPs) that are negative regulators of insulin action. As hyperglycemia is associated with increased cellular reactive oxygen species, we postulated that high glucose conditions might potentiate the H(2)O(2) generated by insulin and modulate insulin-stimulated protein phosphorylation. Basal H(2)O(2) generation was increased threefold in differentiated 3T3-L1 adipocytes by growth in 25 mM glucose versus 5 mM glucose. High glucose increased the sensitivity of the insulin-stimulated H(2)O(2) signal to lower concentrations of insulin. Basal endogenous total PTP activity and the activity of PTP1B, a PTP implicated in the negative regulation of insulin signaling, were reduced in high glucose conditions, and their further reduction by insulin stimulation was more enhanced in high versus low glucose medium. Phosphorylation of the insulin receptor, IRS-1, and Akt in response to insulin was also significantly enhanced in high glucose conditions, especially at submaximal insulin concentrations. In primary rat adipocytes, high glucose increased insulin-stimulated H(2)O(2) production and potentiated the oxidative inhibition of total PTP and PTP1B activity; however, insulin signaling was not enhanced in the primary cells in high glucose apparently due to cross-regulation of insulin-stimulated protein phosphorylation by activation of protein kinase C (PKC). These studies indicate that high glucose can enhance insulin stimulated H(2)O(2) generation and augment oxidative PTP inhibition in cultured and primary adipocytes, but the overall balance of insulin signal transduction is determined by additional signal effects in high glucose, including the activation of PKC.

Adipocytes↗

PubMed2000

Dengue virus nonstructural protein 1 is expressed in a glycosyl-phosphatidylinositol-linked form that is capable of signal transduction.

Dengue virus nonstructural protein 1 (NS1) is expressed on the surface of infected cells and is a target of human antibody responses to dengue virus infection. We show here that dengue virus uses the cellular glycosyl-phosphatidylinositol (GPI) linkage pathway to express a GPI-anchored form of NS1 and that GPI anchoring imparts a capacity for signal transduction in response to binding of NS1-specific antibody. This study is the first to identify GPI linkage of a virus-encoded protein. The GPI anchor addition signal for NS1 was identified, by transfection of HeLa cells with dengue cDNA constructs, as a downstream hydrophobic domain in NS2A. GPI linkage of NS1 in both transfected and infected cells was demonstrated by cleavage of NS1 from the surface by PI-specific phospholipase C and by metabolic incorporation of the GPI-specific components ethanolamine and inositol. In common with other GPI-anchored proteins, addition of specific antibody resulted in signal transduction, as evidenced by tyrosine phosphorylation of cellular proteins. Antibody-induced signal transduction by GPI-linked NS1 suggests a mechanism of cellular activation that may contribute to the pathogenesis of human dengue disease. Signal transduction by a GPI-anchored viral antigen interacting with a specific antibody that it induces is a new concept in the pathogenesis of viral disease.

Amino Acid Sequence↗

PubMed2002

Different signal transduction pathways are involved during human sperm capacitation induced by biological and pharmacological agents.

Human sperm capacitation involves complex signal transduction mechanisms during which double phosphorylation of the threonine-glutamine-tyrosine motif (P-Thr-Glu-Tyr-P) occurs in some sperm proteins. The objective of this study was to investigate the regulation of this process. Fetal cord serum ultrafiltrate (FCSu), follicular fluid ultrafiltrate (FFu), progesterone and a combination of N(6),2'-O-dibutyryl cAMP (dbcAMP; cell permeant analogue of cAMP) and 3-isobutyl-1-methylxanthine (IBMX; phosphodiesterase inhibitor) were used as inducers of capacitation alone or in combination with inhibitors of protein kinase A (H89), protein kinase C (chelerythrine), protein tyrosine kinase (tyrphostin A47, PP2) and of dual specificity kinase (MEK-like kinases; PD98059). The level of P-Thr-Glu-Tyr-P in sperm proteins of 80 and 105 kDa during capacitation induced by FCSu, FFu and progesterone was regulated by a similar signal transduction pathway and involved receptor type protein tyrosine kinase and dual specificity kinase (MEK or MEK-like) but not protein kinase A or C. However, the level of P-Thr-Glu-Tyr-P in these sperm proteins during capacitation induced by dbcAMP+IBMX was mainly mediated through protein kinase A and C and receptor type protein tyrosine kinase, but not by dual specificity kinase. In conclusion, human sperm capacitation induced by some biological and pharmacological agents is regulated through very different signal transduction pathways.

1-Methyl-3-isobutylxanthine↗

PubMed2006

Notch signal transduction induces a novel profile of Kaposi's sarcoma-associated herpesvirus gene expression.

Kaposi's sarcoma-associated herpesvirus (KSHV) RTA transcription factor is recruited to its responsive elements through interaction with RBP-Jkappa that is a downstream transcription factor of the Notch signaling pathway that is important in development and cell fate determination. This suggests that KSHV RTA mimics cellular Notch signal transduction to activate viral lytic gene expression. Here, I demonstrated that unlike other B lymphoma cells, KSHV-infected primary effusion lymphoma BCBL1 cells displayed the constitutive activation of ligand-mediated Notch signal transduction, evidenced by the Jagged ligand expression and the complete proteolytic process of Notch receptor I. In order to investigate the effect of Notch signal transduction on KSHV gene expression, human Notch intracellular (hNIC) domain that constitutively activates RBP-Jkappa transcription factor activity was expressed in BCBL1 cells, TRExBCBL1-hNIC, in a tetracycline inducible manner. Gene expression profiling showed that like RTA, hNIC robustly induced expression of a number of viral genes including K5 immune modulatory gene resulting in downregulation of MHC I and CD54 surface expression. Finally, the genetic analysis of KSHV genome demonstrated that the hNIC-mediated expression of K5 during viral latency consequently conferred the downregulation of MHC I and CD54 surface expression. These results indicate that cellular Notch signal transduction provides a novel expression profiling of KSHV immune deregulatory gene that consequently confers the escape of host immune surveillance during viral latency.

Antigens, Surface↗

PubMed2000

Mitogen-activated protein kinase and abscisic acid signal transduction.

The phytohormone abscisic acid (ABA) is a classical plant hormone, responsible for regulation of abscission, diverse aspects of plant and seed development, stress responses and germination. It was found that ABA signal transduction in plants can involve the activity of type 2C-phosphatases (PP2C), calcium, potassium, pH and a transient activation of MAP kinase. The ABA signal transduction cascades have been shown to be tissue-specific, the transient activation of MAP kinase has until now only been found in barley aleurone cells. However, type 2C phosphatases are involved in the induction of most ABA responses, as shown by the PP2C-deficient abi-mutants. These phosphatases show high homology with phosphatases that regulate MAP kinase activity in yeast. In addition, the role of farnesyl transferase as a negative regulator of ABA responses also indicates towards involvement of MAP kinase in ABA signal transduction. Farnesyl transferase is known to regulate Ras proteins, Ras proteins in turn are known to regulate MAP kinase activation. Interestingly, Ras-like proteins were detected in barley aleurone cells. Further establishment of the involvement of MAP kinase in ABA signal transduction and its role therein, still awaits more study.

Abscisic Acid↗

PubMed2000

Signal transduction to the Azotobacter vinelandii NIFL-NIFA regulatory system is influenced directly by interaction with 2-oxoglutarate and the PII regulatory protein.

PII-like signal transduction proteins, which respond to the nitrogen status via covalent modification and signal the carbon status through the binding of 2-oxoglutarate, have been implicated in the regulation of nitrogen fixation in several diazotrophs. The NIFL-NIFA two-component regulatory system, which integrates metabolic signals to fine-tune regulation of nitrogenase synthesis in Azotobacter vinelandii, is a potential target for PII-mediated signal transduction. Here we demonstrate that the inhibitory activity of the A.vinelandii NIFL protein is stimulated by interaction with the non-uridylylated form of PII-like regulatory proteins. We also observe that the NIFL-NIFA system is directly responsive to 2-oxoglutarate. We propose that the PII protein signals the nitrogen status by interaction with the NIFL-NIFA system under conditions of nitrogen excess, and that the inhibitory activity of NIFL is relieved by elevated levels of 2-oxoglutarate when PII is uridylylated under conditions of nitrogen limitation. Our observations suggest a model for signal transduction to the NIFL-NIFA system in response to carbon and nitrogen status which is clearly distinct from that suggested from studies on other diazotrophs.

Adenine Nucleotides↗

PubMed2001

[Signal transduction inhibitor].

Numerous molecular targets for cancer chemotherapy have been identified based on the progress made in molecular biology, and new categories of anticancer drugs have been developed. They are variously called target-based drugs, non-cytotoxic drugs and cytostatic drugs. These include inhibitors of signal transduction, cyclin-dependent kinase, angiogenesis, and matrix metalloproteinases. Other new therapies include gene therapy and immunotherapy. There are multiple steps in the signal transduction cascade. Growth factor binds to its cognate receptor tyrosine kinase and the phosphotyrosines on the receptor serve as attachment sites for substrates or adapter molecules. Grb2 functions by directly coupling activated receptor tyrosine kinases to the Ras-activating nucleotide exchange factor SOS. Activation of Ras or Ras family members leads to activation of the mitogen-activated protein kinase (MAPK) cascade pathway. This has been implicated as a necessary component of intracellular signaling to elicit a range of cellular responses including mitogenesis, differentiation, and cell survival. We introduce signal transduction inhibitors including, Ras inhibitors, protein kinase C inhibitors, and MAPK cascade inhibitors. Recently, these drugs have been used in clinical trials and some of them have an antitumor effect. In the near future these drugs may play an important role in cancer chemotherapy. However, these drugs are thought to induce a non-cytotoxic effect different from cytotoxic drugs. Therefore correct and efficient clinical evaluation of these drugs is needed. We look forward to developments from future research on signal transduction inhibitors.

Alkyl and Aryl Transferases↗

PubMed1999

[The signal transduction of cell activation by LPS: the studies from CD14 to p38 MAPK].

Recently there have been some substantial progresses in signal transduction of cell activation by lipopolysaccharide (LPS). After binding with LBP in the plasma, LPS is transported to the cell membrane surface of monocytes, then binds with membrane CD14 to induce cell activation. Mitogen-activated protein kinases (MAPKs) take part in the signal transduction of LPS stimulated cell activation to produce bioactive substances including tumor necrosis factor. p38 MAPK is an important regulator for TNF-alpha expression. It is possible to provide new theory and idea for the treatment of septic shock from the studies of signal transduction of cell activation by LPS.

Animals↗

PubMed1996

Two mutations of the lutropin/choriogonadotropin receptor that impair signal transduction also interfere with receptor-mediated endocytosis.

The experiments presented herein were designed to probe a potential role for the activation of the LH/CG receptor (LHR) on the receptor-mediated endocytosis of human CG (hCG). Two mutants of the rat LHR (rLHR) that bind the hormone with high affinity but are deficient in signal transduction were prepared by mutating highly conserved residues that have been previously shown to be important in signal transduction in other members of the G protein-coupled receptor family. Mutation of a highly conserved aspartic acid in the second transmembrane domain of the rLHR (designated rLHR-D383N) does not affect hCG binding but impairs signal transduction. When compared with cells expressing an equivalent density of wild type rLHR (rLHR-wt), concentration-response curves for the hCG-stimulated cAMP accumulation in cells expressing rLRH-D383N- are characterized by an 18-fold increase in the EC50 but no change in the maximal response. Cells expressing rLHR-D383N also display a 4- to 5-fold increase in the half-life of internalization of hCG. Mutation of a highly conserved arginine in the second intracellular loop of the rLHR (designated rLHR-R442H) also does not affect hCG binding but impairs signal transduction. When compared with cells expressing an equivalent density of rLHR-wt, concentration-response curves for the hCG-stimulated cAMP accumulation in cells expressing rLHR-R442H are characterized by a 7-fold increase in the EC50 and a 6- to 10-fold decrease in the maximal response. Cells expressing rLHR-R442H also display a 1.5- to 2-fold increase in the half-life of internalization of hCG. These results, together with the finding that an antagonist of hCG is internalized more slowly than hCG, suggest that the activation of the LHR is needed for the efficient endocytosis of the bound hCG.

Arginine↗

PubMed2006

Genetic reconstitution of bone marrow for the study of signal transduction ex vivo.

Introducing genes into cells by retroviral transduction has greatly increased the ability to study signal transduction pathways in primary cells. Retroviral transduction has proven to be an efficient method to express genes of interest in cells that are difficult to manipulate using standard transfection techniques. This technology also can be coupled with classic protocols for generating bone marrow chimeras. Murine bone marrow cells can be infected with a retrovirus expressing wild-type or mutant forms of a gene of interest and subsequently transplanted into irradiated recipient hosts. The requirement for a gene of interest in hematopoietic cell development, as well as its role in specific signal transduction pathways, can then be studied. This chapter provides protocols for the production of high-titer replication-incompetent retrovirus, retroviral infection of murine bone marrow, the generation of bone marrow chimeras, and analysis of chimeras by flow cytometry.

Animals↗

PubMed1995

A role for Hsp90 in retinoid receptor signal transduction.

The ubiquitous heat shock protein Hsp90 appears to participate directly in the function of a broad range of cellular signal transduction components, including steroid hormone receptors; however, an evolutionarily related subclass of intracellular receptors, exemplified by the retinoid receptors RAR and RXR, had been inferred from biochemical studies to function independently of Hsp90. To examine this issue genetically, we measured mammalian and avian retinoid receptor activity in a Saccharomyces cerevisiae strain in which the expression of the yeast Hsp90 homologue could be conditionally repressed approximately 20-fold relative to wild type. We tested transcriptional activation by RAR or RXR-RAR, from two types of retinoic acid response elements, triggered by three different agonist ligands. In every condition, we found that activation was severely compromised under conditions of low Hsp90 expression. We showed that the defect was in signal transduction rather than transcription activation per se, and that high affinity hormone binding was abolished in extracts of cells producing low levels of Hsp90. We suggest that Hsp90 may function in at least one step of signal transduction by all members of the intracellular receptor superfamily.

Animals↗

PubMed1995

Early activation signal transduction pathways of Th1 and Th2 cell clones stimulated with anti-CD3. Roles of protein tyrosine kinases in the signal for IL-2 and IL-4 production.

In the present experiments, TCR-CD3-associated early activation signal transduction pathways were examined in Th1 and Th2 clones by the stimulation with soluble monovalent anti-CD3 which resulted in efficient production of IL-2 and IL-4 in Th1 and Th2 cells, respectively. Although protein tyrosine kinases such as Fyn and ZAP-70 were activated in Th1 clones shortly after stimulation, these kinases in Th2 clones were not activated; but, their activity in resting conditions was shown to be decreased by the stimulation. In accordance with these findings, neither phospholipase C-gamma 1 activation nor phosphatidyl inositol-4,5-bisphosphate breakdown was induced in Th2 clones, in contrast to positive responses in Th1 clones. The oscillation of intracellular free Ca2+ concentration ([Ca2+]i) was a common signal for the activation of both Th1 and Th2 clones; however, the [Ca2+]i elevation in Th1 clones was herbimycin A sensitive, whereas that in Th2 was clone resistant, suggesting that the mechanism of the [Ca2+]i elevation in Th2 cells is different from that in Th1 cells in terms of the participation of protein tyrosine kinases. The anti-CD3 stimulation did not cause Lck activation in either the Th1 or Th2 clone, although remarkable activation was induced in both clones following anti-CD4 stimulation, indicating that Lck activation was not required for either IL-2 or IL-4 production of Th cells. Taken together, these results indicate that Th1 and Th2 cells are different from each other in early activation signal transduction pathways, especially in the role of protein tyrosine kinases.

Animals↗

PubMed2006

Differential changes in beta-adrenoceptor signal transduction in left and right ventricles of infarcted rats.

Although different experimental and clinical studies have revealed varying degrees of defects in beta-adrenoceptors (beta-ARs) during the development of heart failure, the mechanisms for differences in beta-AR signal transduction between the left (LV) and right ventricle (RV) are not understood. Because biochemical alterations in the myocardium depend on the stage of heart disease, this study was undertaken to assess the status of beta-ARs in the LV and RV at different stages of heart failure. Myocardial infarction was induced in rats by occluding the left coronary artery for 8 and 24 weeks. The beta-AR signal transduction was monitored by measuring beta1-AR density, the isoproterenol-induced positive inotropic effect, the increase in [Ca2+]i in cardiomyocytes, and the activation of adenylyl cyclase. The beta-AR signal transduction parameters in the 8- and 24-week failing LV were depressed, whereas the RV showed upregulation at 8 weeks and downregulation at 24 weeks of these mechanisms. These results suggest that beta-AR-mediated signal transduction in the LV and RV are differentially regulated and are dependent upon the stage of development of congestive heart failure due to myocardial infarction.

Adenylyl Cyclases↗