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Results for “Signal Transduction”

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PubMed1996

[Receptor-mediated signal transduction].

The elucidation for the mechanism of receptor-mediated signal transduction has been the aim of our extensive studies. Cyclic AMP, which was controlled by membrane adenylyl cyclase, was an intracellular signal (the first second messenger in cells proposed by Sutherland) given by hormones and neurotransmitters. The GTP-binding (G) proteins play an important role in communication between membrane receptors and the adenylyl cyclase catalytic unit. One (Gs) of the G proteins is involved in the activation, while the other (Gi) is involved in the inhibition of adenylyl cyclase. Islet-activating protein (IAP, pertussis toxin, PTX) catalyses the transfer of the ADP-ribose moiety of NAD to the alpha subunit of Gi, resulting in a complete loss of the Gi functions. In some cases, arachidonic acid (AA) regulates cell functions as a second messenger. AA serves as a precursor to a number of biologically active lipids including prostaglandins and leukotrienes. Activation of cell surface receptors of many cell types results in the release of AA from membrane phospholipids by phospholipase A2 (PLA2). A new family of PLA2 has been discovered in the cytosol of various cells. The activation of receptor-mediated AA release by cytosolic PLA2 was also regulated by PTX-sensitive G proteins. PTX treatment inhibited cell growth of fibroblasts by serum and growth factors. G proteins have been involved in receptor-receptor interactions in neuronal cells. These findings suggest the regulatory roles of cell surface receptors-coupled G proteins in signal transductions and cell functions.

Adenylyl Cyclases↗

PubMed1999

Identification of a Wnt-responsive signal transduction pathway in primary endothelial cells.

The beta-catenin signal transduction pathway, which can be activated by secreted Wnt proteins, plays a key role in normal embryonic development and in malignant transformation of the mammary gland and colon. Here we demonstrate, for the first time, that Wnt and beta-catenin signaling also function in cells of the vasculature. RT-PCR analysis showed that primary endothelial and smooth muscle cell cultures, of both mouse and human origin, express members of the Wnt and Wnt receptor (Frizzled) gene families. Transfection of an expression vector for Wnt-1 into primary endothelial cells increased both the free pool of beta-catenin and the transcription from a Lef/tcf-dependent reporter gene construct. Expression of Wnt-1, but not Wnt-5a, also stimulated proliferation of primary endothelial cell cultures. These data show that Wnt and Frizzled proteins can regulate signal transduction, via beta-catenin, in endothelial cells. These findings suggest that Wnt signaling may feature in normal differentiation of the vasculature as well as in pathological settings where endothelial and smooth muscle proliferation is disturbed.

Animals↗

PubMed1993

Role of fatty acids in signal transduction: modulators and messengers.

Many of the steps involved in signal transduction are regulated positively or negatively by fatty acids (FA) per se. FA have been shown to act both as modulators and messengers, particularly of signals triggered at the level of cell membranes. Enzymes and proteins of the cyclic AMP and the protein kinase C signalling pathways and those involving ion fluxes and mobilization are both activated and/or inhibited by FA. FA can also participate in a feedback control mechanism since phospholipases are themselves modulated by FA. FA, particularly arachidonic acid liberated from membrane phospholipids, are also second messengers in signal transduction, and a good example is the activation of protein kinase C by FA. FA play an important role in regulating the transmission of signals from the extracellular environment by acting as modulators and messengers within the complex intracellular network of relays.

Animals↗

PubMed2001

[Influence of gravity change on EGF-induced signal transduction].

With the development of aerospace technology, biological effects induced by alteration of gravitation are drawing more and more attention. Among them the influence of alteration of gravitation on cytokine-induced signal transduction has been well studied recently. Epidermal growth factor (EGF)-induced signal transduction can activate increase of cell proliferation in most cell types, so it is always a hotspot in these years. Among the early effects evoked by EGF are receptor clustering, cell rounding, and early gene expression. After the study about the induction of EGF on human A431 cell line, it was observed that EGF-induced c-fos and c-jun expression decreased in microgravity. This was caused by alteration of the EGF receptor and protein kinase C-mediated signal transduction pathways. Meanwhile the key component of cytoskeleton, the actin microfilament system, was found to be linked to the EGF-induced signal transduction cascades either. So it seems reasonable to suggest that the cytoskeleton constitutes the gravity-sensitive cell component.

Actin Cytoskeleton↗

PubMed1994

Two different signal transduction pathways can be activated by transforming growth factor beta 1 in epithelial cells.

Signal transduction initiated by transforming growth factor beta 1 (TGF beta 1) was studied in two sublines of the same colon carcinoma cell line, which respond in opposite ways to TGF beta 1, by proliferation or by growth inhibition. TGF beta 1 activates ras proteins within 5 min of addition when it acts to inhibit growth but not when it acts as a mitogen. In both cases TGF beta 1 also rapidly modulates the activities of three protein kinases, detected by their in gel kinase activity on the mitogen-activated protein kinase (MAP kinase) substrate, myelin basic protein (MBP). When TGF beta 1 acts as a mitogen for U9 cells, it increases the activity of MBP kinases of 57, 105, and 130 kDa within 10 min of the addition without detectably activating ras proteins. When TGF beta 1 inhibits the growth of HD3 cells, it activates ras proteins and the 57-kDa MBP kinase within 5 min but inhibits the activity of the 105- and 130-kDa MBP kinases. In HD3 cells ras activation occurred in two signal transduction pathways, one from TGF beta 1 leading to growth inhibition and one from epidermal growth factor (EGF) leading to proliferation. In addition to ras proteins, EGF activates a different set of MBP kinases in HD3 cells than does TGF beta 1, MBP kinases of 85, 57, and 44 kDa. The latter is likely to be the 44-kDa MAP kinase extracellular signal-regulated kinase (erk) 1, because EGF treatment of HD3 cells activates erk1 by increasing its phosphotyrosine level. Therefore, in two closely related epithelial cell lines TGF beta 1 activates two different signal transduction pathways, one ras-dependent and one ras-independent, and modulates the activities of a set of MBP kinases.

Calcium-Calmodulin-Dependent Protein Kinases↗

PubMed2000

[RGS and the regulation of G protein signal transduction].

Regulators of G-protein signaling (RGSs) are recently identified negative regulator of G-protein signaling, most of the RGSs act as GTPase activating proteins (GAPs). RGSs can selectively act on Gas and their effects are scrupulously regulated in vivo. It is believed that we can learn more about regulation of signal transduction from the development of research on RGSs.

GTP Phosphohydrolases↗

PubMed1996

SPINDLY, a tetratricopeptide repeat protein involved in gibberellin signal transduction in Arabidopsis.

Gibberellins (GAs) are a major class of plant hormones that control many developmental processes, including seed development and germination, flower and fruit development, and flowering time. Genetic studies with Arabidopsis thaliana have identified two genes involved in GA perception or signal transduction. A semidominant mutation at the GIBBERELLIN INSENSITIVE (GAI) locus results in plants resembling GA-deficient mutants but exhibiting reduced sensitivity to GA. Recessive mutations at the SPINDLY (SPY) locus cause a phenotype that is consistent with constitutive activation of GA signal transduction. Here we show that a strong allele of spy is completely epistatic to gai, indicating that SPY acts downstream of GAI. We have cloned the SPY gene and shown that it encodes a new type of signal transduction protein, which contains a tetratricopeptide repeat region, likely serving as a protein interaction domain, and a novel C-terminal region. Mutations in both domains increase GA signal transduction. The presence of a similar gene in Caenorhabditis elegans suggests that SPY represents a class of signal transduction proteins that is present throughout the eukaryotes.

Alleles↗

PubMed1991

Signal transduction events and Fc gamma R engagement in human neutrophils stimulated with immune complexes.

Signal transduction events have been evaluated in human neutrophils stimulated with immune complexes consisting of polyclonal rabbit antibody complexed with BSA. Immune complexes induced dose-related O2- responses, but very small increases in intracellular calcium ([Ca2+]i) levels were observed, in contrast to FMLP-stimulated cells. Measurements employing [45Ca2+] demonstrated that calcium influx and efflux in cells stimulated with immune complexes was substantially less than fluxes found in FMLP-stimulated cells. With respect to inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) formation under conditions in which the O2- responses to immune complexes or FMLP were similar, the Ins(1,4,5)P3 response to immune complexes was much smaller (by 65%) as compared to that induced by FMLP. Although pertussis toxin-treated cells showed a greatly diminished O2- response (by 89%) to FMLP, the response to immune complexes was largely resistant (only 26% reduction) to the inhibitory effects of this toxin. Antibodies to Fc gamma R indicated that engagement of Fc gamma RII and Fc gamma RIII, but not Fc gamma RI, receptors was related to the O2- response of neutrophils to immune complexes. O2- formation occurred in neutrophils incubated with Staphylococcus aureus cell walls bearing antibodies to Fc gamma RII or Fc gamma RIII. These data indicate that, in human neutrophils stimulated with immune complexes, signal transduction events involve engagement of Fc gamma RII and Fc gamma RIII. The O2- response is largely pertussis-toxin insensitive, is not associated with a significant increase in levels of [Ca2+]i, and is associated with relatively little formation of Ins(1,4,5)P3. This is in contrast to cells stimulated with FMLP in which O2- responses are largely pertussis toxin-sensitive and associated with large increases in [Ca2+]i as well as formation of Ins(1,4,5)P3. Signal transduction events involving Fc gamma R appear to be quite different from those events related to engagement of FMLP receptors.

Antibodies, Monoclonal↗

PubMed1998

Signal decay through a reverse phosphorelay in the Arc two-component signal transduction system.

Escherichia coli senses and signals anoxic or low redox conditions in its growth environment by the Arc two-component system. Under those conditions, the tripartite sensor kinase ArcB undergoes autophosphorylation at the expense of ATP and subsequently transphosphorylates its cognate response regulator ArcA through a His --> Asp --> His --> Asp phosphorelay pathway. In this study we used various combinations of wild-type and mutant ArcB domains to analyze in vitro the pathway for signal decay. The results indicate that ArcA-P dephosphorylation does not occur by direct hydrolysis but by transfer of the phosphoryl group to the secondary transmitter and subsequently to the receiver domain of ArcB. This reverse phosphorelay involves both the conserved His-717 of the secondary transmitter domain and the conserved Asp-576 of the receiver domain of ArcB but not the conserved His-292 of its primary transmitter domain. This novel pathway for signal decay may generally apply to signal transduction systems with tripartite sensor kinases.

Bacterial Outer Membrane Proteins↗

PubMed2001

HstK, a cyanobacterial protein with both a serine/threonine kinase domain and a histidine kinase domain: implication for the mechanism of signal transduction.

Two distinct families of protein kinases are involved in signal transduction: Ser, Thr and Tyr kinases, which are predominantly found among eukaryotes, and His kinases, as part of bacterial two-component signalling systems. Genetic studies in Arabidopsis and Saccharomyces have demonstrated that bacterial-type two-component systems may act upstream of Ser/Thr kinases in the same signalling pathway, but how this coupling is accomplished remains unclear. In the present study, we report the characterization of a protein kinase, HstK, from the N(2)-fixing cyanobacterium Anabaena sp. PCC 7120, that possesses both a Ser/Thr kinase domain and a His kinase domain. Proteins with a structural architecture similar to that of HstK can be found in the eukaryote, Schizosaccharomyces pombe, and the bacterium, Rhodococcus sp. M5. HstK was present in cells grown with NH(4)(+) or N(2) as the nitrogen source, but was absent in cells grown with NO(3)(-). The hstK gene was inactivated and the mutant phenotype was characterized. The catalytic domain of the Ser/Thr kinase of HstK functionally replaced that of Hog1p, a well-characterized protein kinase required for the response to high osmolarity in the S. cerevisiae heterologous system. The unusual multidomain structure of HstK suggests that a two-component system could be directly coupled to Ser/Thr kinases in the same signal transduction pathway.

Amino Acid Sequence↗

PubMed2006

Signal transduction induced by opioids in immune cells: a review.

New data regarding signal transduction triggered by opioid ligands in immune cells are reviewed, and the signal transduction in neuronal cells is documented. Similar signaling pathways are induced by opioids in immune as well as neuronal cells. Opioids altered second messenger cAMP, intracellular calcium, and second messenger-induced kinases in immune cells. Met-enkephalin, preferentially delta-opioid, was bimodally regulated, while kappa-opioids inhibited these second messengers. delta-, kappa- and micro-opioids altered nitric oxide secretion, inducing cGMP as the second messenger in immune cells. Coupling of opioid agonists to opioid receptors activated mitogen-activated protein/extracellular signal-regulated protein kinases and various transcription factors in immune cells. Activator protein 1 (AP-1), c-fos, and nuclear factor-kappaB (NF-kappaB) are transcription factors shared by neuronal and immune cells. Delta-opioids activated AP-1, c-fos, activating transcription factor 2, Ikaros-1 and Ikaros-2 transcription factors in immune cells. Induction of kappa-opioid receptor gene by retinoic acid resulted in increased binding of Sp1 transcription factor to the promoter of the kappa-opioid receptor. Micro-opioids inhibited synthesis of common transcription factors AP-1, c-fos, NF-kappaB, and nuclear factor of activated T cells in activated or stimulated immune cells, whereas micro-opioids activated NF-kappaB, GATA-3, and Kruppel-like factor 7 transcription factors in non-stimulated immune cells.

Analgesics, Opioid↗

PubMed1997

The state of the STATs: recent developments in the study of signal transduction to the nucleus.

The STATs (signal transducers and activators of transcription) are latent cytoplasmic proteins that, upon activation by cell surface bound polypeptide ligands, move to the nucleus to direct transcription. A variety of protein-protein interactions that affect the function of STATs has been recently recognized. It has become clear that the STATs are functional mosaics, or mixtures of signal transduction and transcription modules.

Animals↗

PubMed2003

Phosphotyrosyl mimetics in the development of signal transduction inhibitors.

Phosphotyrosyl (pTyr) residues play important roles in cellular signal transduction by facilitating recognition and binding necessary for critical protein-protein interactions, and for this reason pTyr motifs represent attractive starting points in the development of signaling antagonists. Although the pTyr phosphoryl moiety is central in these phenomena, its incorporation into signaling inhibitors is contraindicated due to enzymatic lability and limited bioavailability associated with phosphate esters. To address these limitations, an entire field of study has arisen devoted to the design and utilization of pTyr mimetics. This Account provides a perspective on the roles of pTyr residues in signal transduction and approaches to pTyr mimetic development.

Binding Sites↗

PubMed1999

TGF-beta family signal transduction in Drosophila development: from Mad to Smads.

The transforming growth factor-beta (TGF-beta) superfamily encompasses a large group of soluble extracellular proteins that are potent regulators of development in both vertebrates and invertebrates. Drosophila TGF-beta family members include three proteins with homology to vertebrate bone morphogenetic proteins (BMPs): Decapentaplegic (Dpp), Screw, and Glass bottom boat-60A. Genetic studies of Dpp signaling led to the identification of Smad proteins as central mediators of signal transduction by TGF-beta family members. Work in mammalian tissue culture has elucidated a biochemical model for signal transduction, in which activation of receptor serine-threonine kinase activity leads to phosphorylation of specific Smad proteins and translocation of heteromeric Smad protein complexes to the nucleus. Once in the nucleus Smad proteins interact with other DNA binding proteins to regulate transcription of specific target genes. Dissection of Dpp-response elements from genes expressed during embryonic mesoderm patterning and midgut morphogenesis provides important insights into the contributions of Smad proteins and tissue-specific transcription factors to spatial regulation of gene expression. Genetic studies in Drosophila are now expanding to include multiple BMP ligands and receptors and have uncovered activities not explained by the current signal transduction model. Identification of more ligand sequences and demonstration of a functional Drosophila activin-like signal transduction pathway suggest that all TGF-beta signal transduction pathways are present in flies.

Animals↗

PubMed2002

Signal transduction inhibitors as radiosensitizers.

DNA double strand breaks are the pivotal cellular damage induced by ionizing radiation. A plethora of molecular and cellular processes are activated as part of the cellular stress response that result in cell cycle arrest and induction of the DNA-repair machinery to restore the damage of DNA or to activate a cell death program. However ionizing radiation also initiates signal transduction cascades that are generated at cellular sites distant from and independent of DNA-damage. These signaling processes are similar to hormone activated growth factor receptor controlled signal transduction cascades and represent interesting targets for anticancer treatment modalities combining ionizing radiation with molecular defined pharmacological compounds. Activation of these signal transduction cascades upon irradiation or upregulation of growth factor mediated pathways due to oncogene-transformation often contribute to an acquired or inherent treatment resistance in malignant cells. Therefore pharmacological compounds inhibiting specific key-entities of these signal transduction cascades potentially sensitize for radiation induced cell death. Here we describe current preclinical concepts of combined treatment strategies with locoregional-applied ionizing radiation and molecular defined signal transduction inhibitors to overcome a high treatment threshold in tumor cells.

Animals↗

PubMed1994

Atrial natriuretic factor inhibits autophosphorylation of protein kinase C and A 240-kDa protein in plasma membranes of bovine adrenal glomerulosa cells: involvement of cGMP-dependent and independent signal transduction mechanisms.

To clarify the intracellular signalling mechanisms of atrial natriuretic factor (ANF), we studied its effect on protein phosphorylation in plasma membranes of bovine adrenal cortical cells. ANF (1 x 10(-7) M) inhibited phosphorylation of the 78-kDa protein kinase C (PKC) and a 240-kDa protein in specific manner. In parallel experiments, cGMP (0.5 mM) inhibited phosphorylation of only the 78-kDa PKC but it did not affect phosphorylation of the 240-kDa protein. Phosphorylation of the 78-kDa PKC was enhanced in a Ca(2+)-/phospholipid-dependent manner. However, after prolonged preincubation of plasma membranes with Ca2+ (0.5 mM), the incorporation of 32P-radioactivity rapidly decreased in the 78-kDa PKC and subsequently increased in the 45- and 48-kDa protein bands due to Ca(2+)-dependent proteolytic degradation of 78-kDa PKC. Polyclonal antibodies against brain PKC were used to immunoblot and immunoprecipitate the 78-kDa PKC. Preincubation of plasma membranes with Ca2+ for varying times, followed by immunoblotting revealed a gradual loss of the immunoreactive 78-kDa PKC band in a time-dependent manner. Immunoprecipitation of phosphorylated 78-kDa PKC in plasma membranes showed that its phosphorylation was significantly inhibited in the presence of ANF as compared to control membranes, phosphorylated in the absence of ANF. The results in this present study document a new signal transduction mechanism of ANF at molecular level which possibly involves dephosphorylation of the 78-kDa PKC and a 240-kDa protein in a cGMP-dependent and -independent manner in bovine adrenal glomerulosa cell membranes.

Animals↗

PubMed1992

Signal transduction within the nucleus by mitogen-activated protein kinase.

The nucleus is an important target of signal transduction by growth factor receptors that stimulate mitogen-activated protein (MAP) kinases. We tested the hypothesis that MAP kinases have a signaling role within the nucleus by examining the effect of the expression of a human MAP kinase isoform (p41mapk) in tissue culture cells. The expressed p41mapk was found to be localized in both the cytoplasmic and nuclear compartments of the cells. Significantly, the expression of p41mapk caused an increase in the phosphorylation of a nuclear substrate: Ser62 of c-Myc. Phosphorylation at Ser62 stimulated the activity of the NH2-terminal transactivation domain of c-Myc. Thus, p41mapk causes the phosphorylation and regulation of a physiologically significant nuclear target of signal transduction. These data establish that at least one MAP kinase isoform has a nuclear role during signal transduction.

Amino Acid Sequence↗

PubMed1998

Effect of ligand conformation on melanoma cell alpha3beta1 integrin-mediated signal transduction events: implications for a collagen structural modulation mechanism of tumor cell invasion.

The importance of three-dimensional interactions between receptors with their respective ligands has been extensively explored during the binding process, but considerably less so for postbinding events such as induction of signaling pathways. Tumor cell receptor association with basement membrane proteins is believed to facilitate the metastatic process. Melanoma and ovarian carcinoma cells have been shown to utilize the alpha3beta1 integrin to bind to models of the alpha1(IV)531-543 sequence from basement membrane (type IV) collagen [Miles, A. J., et al. (1994) J. Biol. Chem. 269, 30939-30945; Miles, A. J., et al. (1995) J. Biol. Chem. 270, 29047-29050]. In the present study, the effects of ligand three-dimensional structure on possible signal transduction pathways induced by alpha3beta1 integrin binding have been evaluated. Human melanoma cell binding to type IV collagen resulted in Tyr phosphorylation of p125(FAK), consistent with prior studies correlating beta1 integrin subunit binding to collagen and p125(FAK) Tyr phosphorylation. Cross-linking of an anti-alpha3 integrin subunit monoclonal antibody also induced p125(FAK) Tyr phosphorylation. Incubation of melanoma cells with single-stranded or triple-helical peptide models of alpha1(IV)531-543 induced Tyr phosphorylation of intracellular proteins. Immunoprecipitation analysis identified one of these proteins as pp125(FAK). Induction of p125(FAK) Tyr phosphorylation was enhanced and the time of induction was shortened when the ligand was used in triple-helical conformation. Subsequent clustering of either the single-stranded or the triple-helical ligand also increased the level of p125(FAK) phosphorylation compared to unclustered ligand. The clustered triple-helical peptide ligand induced more rapid paxillin Tyr phosphorylation than the single-stranded ligand. In addition, the induction of activated proteases was found to be more rapid due to ligand triple helicity. Overall, these studies have shown that (i) a model of an isolated sequence from type IV collagen, alpha1(IV)531-543, can induce alpha3beta1 integrin-mediated signal transduction in melanoma cells and (ii) ligand conformation (secondary, tertiary, and/or quaternary structure) can directly influence several alpha3beta1 integrin-mediated signal transduction events. The effects of ligand conformation suggest that a "collagen structural modulation" mechanism may exist for tumor cell invasion, whereby triple-helical collagen promotes cell binding and induction of signal transduction, subsequently leading to collagen dissolution by proteases, decreased signal transduction, and enhanced tumor cell motility.

Cell Adhesion↗