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Results for “Signal Transduction”

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At least 19 recordsLinked to original sources
PubMed2006

Hedgehog signal transduction: signal integration and cross talk in development and cancer.

Hedgehog (HH) signaling regulates a diversity of processes involved in developmental patterning, stem cell growth and maintenance, and cancer etiology. Despite its biological importance, the HH signal transduction pathway remains largely mysterious. Our past understanding of the HH pathway signaling components and mechanisms came from groundbreaking genetic and biochemical studies in the fruit fly Drosophila melanogaster. Some of these mechanisms are strikingly conserved in vertebrates, although some specific aspects are clearly divergent. In this article, we discuss recent findings for cross talk in HH signal transduction with PI3K signaling through Akt, and with PKC-delta signaling through MEK-1, indicating that these pathways converge to control the Gli transcription factor. The integration of these convergent pathways on the regulation of mammalian Sonic Hedgehog signaling highlights their potential involvement in the control of HH-dependent events in development and tumorigenesis.

Amino Acid Sequence↗
PubMed2006

New paradigms in signal transduction.

Signal transduction is a dynamic field in which established pathways evolve and new pathways emerge. The purpose of this commentary is to highlight new paradigms of signal transduction that have developed over the past few years. This discussion proposes a third member of the generic models of membrane receptors in addition to the 7-transmembrane pass receptor and the enzyme-linked receptor: the non-enzymatic nucleating receptor. Also discussed are the new paradigms of signal transduction by proteolysis which includes signaling by Notch, signaling through the Hedgehog and Wnt pathways, signaling through histidine phosphorylation, and reactive oxygen species in signal transduction.

Animals↗
PubMed2003

Protein complexes involved in heptahelical receptor-mediated signal transduction.

Signal transduction mediated by heterotrimeric G proteins that couple to heptahelical receptors requires the involvement of many different proteins. Although some of the early evidence suggested that signal transduction components were assembled into complexes, much of the data supported an alternative hypothesis positing that the process involved transient interactions driven by random collision events. However, recent data indicate that many of the components involved in signal transduction do indeed form complexes. Here we review the evidence for these complexes and how they contribute to the specificity and efficiency of signaling in cells that must manage numerous signal transduction pathways.

Animals↗
PubMed2000

Interaction of dishevelled and Xenopus axin-related protein is required for wnt signal transduction.

Signaling by the Wnt family of secreted proteins plays an important role in animal development and is often misregulated in carcinogenesis. Wnt signal transduction is controlled by the rate of degradation of beta-catenin by a complex of proteins including glycogen synthase kinase 3 (GSK3), adenomatous polyposis coli, and Axin. Dishevelled is required for Wnt signal transduction, and its activation results in stabilization of beta-catenin. However, the biochemical events underlying this process remain largely unclear. Here we show that Xenopus Dishevelled (Xdsh) interacts with a Xenopus Axin-related protein (XARP). This interaction depends on the presence of the Dishevelled-Axin (DIX) domains in both XARP and Xdsh. Moreover, the same domains are essential for signal transduction through Xdsh. Finally, our data point to a possible mechanism for signal transduction, in which Xdsh prevents beta-catenin degradation by displacing GSK3 from its complex with XARP.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Proteomic analysis of phosphorylation, oxidation and nitrosylation in signal transduction.

Signal transduction pathways control cell fate, survival and function. They are organized as intricate biochemical networks which enable biochemical protein activities, crosstalk and subcellular localization to be integrated and tuned to produce highly specific biological responses in a robust and reproducible manner. Post translational Modifications (PTMs) play major roles in regulating these processes through a wide variety of mechanisms that include changes in protein activities, interactions, and subcellular localizations. Determining and analyzing PTMs poses enormous challenges. Recent progress in mass spectrometry (MS) based proteomics have enhanced our capability to map and identify many PTMs. Here we review the current state of proteomic PTM analysis relevant for signal transduction research, focusing on two areas: phosphorylation, which is well established as a widespread key regulator of signal transduction; and oxidative modifications, which from being primarily viewed as protein damage now start to emerge as important regulatory mechanisms.

Animals↗
PubMed1995

The GS domain of the transforming growth factor-beta type I receptor is important in signal transduction.

Signal transduction by transforming growth factor-beta (TGF-beta) involves the formation of a heteromeric complex of two transmembrane serine/threonine kinase receptors, type I (T beta R-I) and type II (T beta R-II). In the region preceeding the kinase domain of T beta R-I there is a glycine- and serine-rich sequence, termed the GS domain, which has been shown to be phosphorylated by T beta R-II. In order to determine the importance of the serine residues in this domain, receptor mutants with one or more serine residues mutated were analyzed. All the mutants of T beta R-I were able to bind ligand and their kinase activity was not abolished by the mutations. The receptor mutants with single mutated serine residues mediated transcriptional responses to TGF-beta with similar efficiency as the wild type receptor, whereas those with two or three of the serine residues mutated showed only weak transcriptional responses. These results suggest that serine residues in the GS domain are important for signal transduction by T beta R-I; however, the signaling activity of T beta R-I does not depend on any particular serine residue in the GS domain, but rather on how many of the serine residues in the region are intact.

Activin Receptors, Type I↗
PubMed2000

Lipid rafts and signal transduction.

Signal transduction is initiated by complex protein-protein interactions between ligands, receptors and kinases, to name only a few. It is now becoming clear that lipid micro-environments on the cell surface -- known as lipid rafts -- also take part in this process. Lipid rafts containing a given set of proteins can change their size and composition in response to intra- or extracellular stimuli. This favours specific protein-protein interactions, resulting in the activation of signalling cascades.

Animals↗
PubMed2005

The G protein-coupled receptor kinase-2 is a TGFbeta-inducible antagonist of TGFbeta signal transduction.

Signaling from the activin/transforming growth factor beta (TGFbeta) family of cytokines is a tightly regulated process. Disregulation of TGFbeta signaling is often the underlying basis for various cancers, tumor metastasis, inflammatory and autoimmune diseases. In this study, we identify the protein G-coupled receptor kinase 2 (GRK2), a kinase involved in the desensitization of G protein-coupled receptors (GPCR), as a downstream target and regulator of the TGFbeta-signaling cascade. TGFbeta-induced expression of GRK2 acts in a negative feedback loop to control TGFbeta biological responses. Upon TGFbeta stimulation, GRK2 associates with the receptor-regulated Smads (R-Smads) through their MH1 and MH2 domains and phosphorylates their linker region. GRK2 phosphorylation of the R-Smads inhibits their carboxyl-terminal, activating phosphorylation by the type I receptor kinase, thus preventing nuclear translocation of the Smad complex, leading to the inhibition of TGFbeta-mediated target gene expression, cell growth inhibition and apoptosis. Furthermore, we demonstrate that GRK2 antagonizes TGFbeta-induced target gene expression and apoptosis ex vivo in primary hepatocytes, establishing a new role for GRK2 in modulating single-transmembrane serine/threonine kinase receptor-mediated signal transduction.

Active Transport, Cell Nucleus↗
PubMed2005

Casein kinase 1 gamma couples Wnt receptor activation to cytoplasmic signal transduction.

Signalling by Wnt proteins (Wingless in Drosophila) has diverse roles during embryonic development and in adults, and is implicated in human diseases, including cancer. LDL-receptor-related proteins 5 and 6 (LRP5 and LRP6; Arrow in Drosophila) are key receptors required for transmission of Wnt/beta-catenin signalling in metazoa. Although the role of these receptors in Wnt signalling is well established, their coupling with the cytoplasmic signalling apparatus remains poorly defined. Using a protein modification screen for regulators of LRP6, we describe the identification of Xenopus Casein kinase 1 gamma (CK1gamma), a membrane-bound member of the CK1 family. Gain-of-function and loss-of-function experiments show that CK1gamma is both necessary and sufficient to transduce LRP6 signalling in vertebrates and Drosophila cells. In Xenopus embryos, CK1gamma is required during anterio-posterior patterning to promote posteriorizing Wnt/beta-catenin signalling. CK1gamma is associated with LRP6, which has multiple, modular CK1 phosphorylation sites. Wnt treatment induces the rapid CK1gamma-mediated phosphorylation of these sites within LRP6, which, in turn, promotes the recruitment of the scaffold protein Axin. Our results reveal an evolutionarily conserved mechanism that couples Wnt receptor activation to the cytoplasmic signal transduction apparatus.

Amino Acid Motifs↗
PubMed1998

Determinants of specificity in TGF-beta signal transduction.

Signal transduction by the TGF-beta family involves sets of receptor serine/threonine kinases, Smad proteins that act as receptor substrates, and Smad-associated transcription factors that target specific genes. We have identified discrete structural elements that dictate the selective interactions between receptors and Smads and between Smads and transcription factors in the TGF-beta and BMP pathways. A cluster of four residues in the L45 loop of the type I receptor kinase domain, and a matching set of two residues in the L3 loop of the Smad carboxy-terminal domain establish the specificity of receptor-Smad interactions. A cluster of residues in the highly exposed alpha-helix 2 of the Smad carboxy-terminal domain specify the interaction with the DNA-binding factor Fast1 and, as a result, the gene responses mediated by the pathway. By establishing specific interactions, these determinants keep the TGF-beta and BMP pathways segregated from each other.

Activin Receptors, Type I↗
PubMed1993

Introduction: protein phosphorylation and signal transduction in bacteria.

A single type of reversible protein-phosphorylating system, the ATP-dependent protein kinase/phosphatase system, is employed in signal transduction in eukaryotes. By contrast, recent work has revealed that three types of protein-phosphorylating systems mediate signal transduction in bacteria. These systems are (1) classical protein kinase/phosphatase systems, (2) sensor-kinase/response-regulator systems, and (3) the multifaceted phosphoenolpyruvate-dependent phosphotransferase system. Physiological, structural, and mechanistic aspects of these three evolutionarily distinct systems are discussed in the papers of this written symposium.

Adenosine Triphosphate↗
PubMed1998

Thrombin signal transduction of the fibrinolytic system in human adult venous endothelium in vitro.

Thrombin can regulate the-fibrinolytic system by increasing the endothelial production of both tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type-1 (PAI-1). The thrombin receptor transducts signals through the GTP-binding protein system, the classical pathway being the Galpha q-protein. The purpose of the present study was to examine the roles of Galpha i-protein and tyrosine kinases in the thrombin signal transduction of t-PA and PAI-1 production from human adult vein endothelial cells (HAVEC). t-PA and PAI-1 antigen were analysed in conditioned medium from cultured HAVEC after 16 h incubation. Data are expressed as percentages of basal release (100%), means +/- 95% confidence intervals. Thrombin increased t-PA and PAI-1 production (234 +/- 42% and 211 +/- 42%, respectively). Pertussis toxin (PTX) (inhibiting Galpha i-pathway) reduced basal PAI-1 (66 +/- 8%), but had only a weak influence on basal t-PA production. Pertussis toxin and genistein (inhibiting tyrosine kinase) significantly reduced the thrombin induction of both t-PA and PAI-1 (PTX: 142 +/- 23% and 146 +/- 19%, respectively, genistein: 156 +/- 42% and 76 +/- 24%, respectively). The present study demonstrated that thrombin can increase the production of t-PA and PAI-1 by transducting signals through the Galpha i and tyrosine kinase pathway, in addition to the Galpha q/protein kinase C pathway as has been found previously.

Adult↗
PubMed2004

Life and death decisions: secondary complexes and lipid rafts in TNF receptor family signal transduction.

Signaling by receptors in the TNF receptor (TNFR) superfamily mediate biological outcomes ranging from inflammation to apoptosis and other forms of programmed cell death. How receptor signaling mediates these divergent responses is just beginning to be understood. Here, we discuss how receptor submembrane localization and the formation of alternate signaling complexes can alter the fate of cells stimulated through TNFRs with a death domain, also known as "death receptors."

Animals↗