Signal Transduction (Signal Transduct)

Publications in this journal

• Article: CD43 – One molecule, many tales to recount

  Gustavo Pedraza‐Alva, Yvonne Rosenstein
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  ABSTRACT: Immune cells functions are regulated through the orchestrated intervention of immune receptors that recognize non-self peptides or pathogen associated molecular patterns and of molecules that modulate the signals these receptors generate. These molecules, known as accessory or co-receptor molecules, sense the environment, setting the threshold for cell activation, as well as instructing the cells to ensure self-tolerance and homeostasis. CD43 is an abundant cell surface protein, expressed on nearly all lineages of hematopoietic cells. Multiple, and sometimes opposite functions, have been attributed to CD43: adhesion and anti-adhesion, locomotion, cellular activation, differentiation, proliferation and apoptosis. Here we will summarize recent developments in our understanding of the role this molecule plays in different cell types. In particular, we will illustrate the role of CD43 as a T cell accessory molecule, capable of generating intracellular signals, independently of or in coordination with the TCR, actively modulating T cell response. In addition, we review new functions for this molecule, in non-immune cells.
  Signal Transduction 01/2008; 7(5‐6):372 - 385.
• Article: The role of the Jak‐Stat pathway in chemokine‐mediated signaling in T lymphocytes

  Gloria Soldevila, Eduardo A. García‐Zepeda
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  ABSTRACT: Chemokines are low molecular weight soluble mediators that control leukocyte trafficking during lymphocyte homeostasis and inflammation. Chemokine-mediated signaling is triggered upon chemokine binding to seven transmembrane G protein-coupled receptors. Multiple signaling pathways are activated leading to cytoskeleton rearrangements, gene transcription and receptor internalization or degradation Among the signaling molecules involved in chemokine mediated signaling, the Jak-Stat pathway has been shown to be activated very early after chemokine stimulation. There is growing evidence showing the involvement of particular Jaks and Stats, in chemokine receptor signaling both in cell lines and primary cells. Jak/Stat phosphorylation is detected soon after chemokine receptor dimerization or in response to chemokines. Also, pharmacological inhibition of Jaks, or the use of Jak deficient lymphocytes results in inhibition of chemokine-mediated responses, such as chemotaxis or integrin-mediated adhesion. This review summarizes the current data describing the involvement of the Jak-Stat pathway in chemokine-mediated signaling in T lymphocytes and discusses the potential crosstalk with other TCR and cytokine-mediated signaling pathways.
  Signal Transduction 01/2008; 7(5‐6):427 - 438.
• Article: Fc receptor and integrin signaling in phagocytes

  Carlos Rosales
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  ABSTRACT: Specific receptors for antibodies, named Fc receptors, and for extracellular matrix proteins, named integrins, contribute to phagocyte activation. Because phagocyte activation is the mechanism whereby most of the potential pathogens are ultimately destroyed, there is a lot of interest to elucidate the biochemical signals that Fc receptors and integrins induce to activate phagocyte functions. This review describes the main signal transduction pathways that are initiated by Fc receptors and integrins in phagocytic leukocytes, with emphasis on the activation of phagocytosis and gene expression. New findings on the common signaling pathways used by Fc receptors and integrins are also discussed.
  Signal Transduction 01/2008; 7(5‐6):386 - 401.
• Article: Signaling through the high affinity IgE receptor and conditions able to modify IgE‐antigen responsiveness of mast cells

  Claudia Gonzalez‐Espinosa, Jaciel Medina-Tamayo, Elizabeth Sanchez-Miranda, Juan Pablo Benitez-Garrido, Alejandro Martin Avila-Hernandez, Alejandro Padilla, Jonathan Garcia-Roman
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  ABSTRACT: Signaling through the high affinity receptor for IgE (FcεRI) on mast cells comprises an intricate network of protein-protein modifications and interactions leading to mast cell degranulation, lipid-derived mediator production and cytokine release. Depending on the tissue where mast cells are activated, mediator release can induce distinct allergy symptoms. FcεRI receptor mainly couples to at least two Src family kinases (Lyn and Fyn), which are responsible for the initiation of the signaling cascade. Distinct membrane bound adapters couple the initial signal to the formation of particular multi-molecular complexes that, in turn, will mediate a specific final response. In this review we summarize the molecular mechanisms initiated by the FcεRI receptor on mast cells that have been involved in cytokine expression. At the same time, some conditions where the main signal transduction mechanism is modified will be analyzed in order to understand how locally produced mediators could alter IgE-antigen-induced allergic responses.
  Signal Transduction 12/2007; 7(5‐6):402 - 414.
• Article: Histamine H3 receptors and their role in basal ganglia physiology and pathophysiology

  José‐Antonio Arias‐Montaño
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  ABSTRACT: Through interaction with G protein-coupled receptors, histamine regulates pre- and post-synaptically a number of brain functions such as wakefulness, locomotor activity, autonomic and vestibular functions, feeding, drinking, analgesia and memory. Four such receptors have been cloned to date, and three of them (H1, H2, and H3) are widely distributed in the central nervous system, which contains the great majority of histamine H3 receptors (H3Rs). These receptors are expressed at high densities in the basal ganglia, a group of subcortical neuronal nuclei intimately involved in the regulation of posture and movement. In this review the main characteristics of H3Rs (structure, isoforms, constitutive activity and signaling) are briefly described, to then summarize our own work regarding the H3R-mediated regulation of synaptic transmission in the basal ganglia. Finally, the possible participation of H3Rs in the pathophysiology of Parkinson's disease is discussed. Based on the information herein reviewed it is concluded that H3Rs play a relevant role in basal ganglia function both in normal and pathological conditions, and that H3R agonists and antagonists may have potential use in the treatment of both Parkinson's disease and the complications of the current pharmacological therapies of the disorder.
  Signal Transduction 12/2007; 7(5‐6):364 - 371.
• Article: Early biochemical events in leukocyte activation through receptors for IgG

  Enrique Ortega, Isabel Soto‐Cruz
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  ABSTRACT: Membrane receptors for the Fc portion of IgG antibodies (FcγR) are expressed by most cells of the immune system. Recent research has revealed that, besides their role in effector functions mediated by leukocytes, FcγR also participate in the antibody-mediated regulation of many phenomena in the afferent phase of immune responses and in the homeostasis of the immune system. Here, we review recent findings on the mechanisms of signal transduction by these receptors as well as on the modulation of FcγR signaling by signal regulators and/or by the activation state of the cell.
  Signal Transduction 12/2007; 7(5‐6):415 - 426.
• Article: Lysophosphatidic acid LPA1 receptor close‐up

  S. Eréndira Avendaño‐Vázquez, Alejandro Cabrera‐Wrooman, Christian C. Colín‐Santana, J. Adolfo García‐Sáinz
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  ABSTRACT: Lysophosphatidic acid is a local hormone / autacoid / growth factor, which induces a plethora of actions in the majority of cells in our organism. These actions include, among many others, the following: cell migration, proliferation and surviving, induction of gene transcription, platelet aggregation, smooth muscle contraction, myelinization, neurotransmitter release, cytoskeletal reorganization during the stress fiber formation, establishment of focal adhesions, neurite retraction, and cell rounding. The actions of lysophosphatidic acid are mediated through a family of G protein coupled receptors that includes five receptor subtypes, i.e. LPA1,–5 receptors. These receptors couple to different G proteins, mainly Gi, Gq and G12/13 and their signaling pathways, besides there is evidence that they can transactivate EGF receptors to mediate some of their actions. The LPA1 receptor was the first subtype to be cloned for this lysophospholipid. It plays an important role in development, is expressed in many cells and tissues and has been the most extensively studied. The present review presents current knowledge on the structure, function and regulation of this receptor subtype, its possible involvement in pathological conditions and suggests certain areas in which current knowledge is insufficient and further research is required.
  Signal Transduction 12/2007; 7(5‐6):351 - 363.
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  Available from: uni-erlangen.de

  Article: The pre‐B cell receptor and its ligands – it takes two to tango

  Harald Bradl, Christian Vettermann, Wolfgang Schuh, Silke Meister, Hans‐Martin Jäck
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  ABSTRACT: The development of early precursor B cells is governed by the surface-bound pre-B cell receptor consisting of the immunoglobulin μ heavy chain, the surrogate light chain components λ5 and VpreB, and the signal transducing subunits immunglobulin /immunglobulin β. The pre-B cell receptor controls clonal expansion, survival and efficient differentiation of functional B lymphoid precursors; however, it is still controversial how signals from this receptor are initiated. Recent studies with Abelson murine leukemia virus (Abl-MuLV)-transformed pre-B cell lines suggest that the N-terminal non-immunoglobulin portion of λ5, the so-called unique tail, is required to initiate cell-autonomous signals by mediating self-aggregation of the pre-B cell receptor (pre-BCR). Strikingly however, the λ5 unique tail also controls the interaction with two different groups of stroma cell-derived pre-BCR ligands, namely heparan sulfate glycosaminoglycans and surface-associated galectin-1. Even though these findings are not mutually exclusive, they refresh the discussion about potential modes of pre-BCR signal initiation. In this review, we discuss recent key findings and propose an integrative model for ligand dependent and independent initiation of pre-BCR signals during selection of functional B cell precursors.
  Signal Transduction 07/2007; 7(4):299 - 310.
• Article: Clustering of membrane proteins in the pre‐stimulation stage is required for signal transduction: a computer analysis

  Hiroshi Kobayashi, Ryuzo Azuma, Akihiko Konagaya
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  ABSTRACT: The physiological significance of membrane protein clustering for signal transduction was examined theoretically using a Monte Carlo computer simulation. Simulation results revealed that pre-stimulation clustering of membrane proteins enhanced signal transduction. Membrane protein clustering induced by the binding of external stimuli provided no kinetic advantage in terms of formation rate or maximum quantity of active membrane receptor complexes. These data suggested that membrane proteins associate weakly in the clustering areas of non-stimulated cells, and that their association is strengthened upon binding of extracellular stimuli to the membrane receptor. Additionally, the number of cytosolic proteins recruited to membrane receptor complexes was not increased by the membrane complex clustering, except when cytosolic signal proteins were localized to a narrow area such as a tunnel that ran from the membrane cluster to the nucleus. Simulations were carried out on a conventional personal computer under Windows XP or 2000 operating systems. Since neither special computing hardware nor special training is required, our simulation procedure could be easily adapted for kinetic analysis of any signal transduction pathway.
  Signal Transduction 07/2007; 7(4):329 - 339.
• Article: Novel monoclonal antibodies for the investigation of PCH family proteins

  Marcus Lettau, Alyn Beyer, Ottmar Janssen
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  ABSTRACT: The pombe Cdc15 homology (PCH) protein family (also termed FCH/SH3 family) comprises 5 subgroups of structurally related polypeptides. The protein kinase C and casein kinase substrate in neurons 1 (PACSIN1), the CD2-binding protein 1 (CD2BP1) and the Cdc42-interacting protein 4 (CIP4) represent members of three individual subgroups. PCH proteins in general are supposed to link cytoskeletal elements to membrane trafficking machineries. In various cellular systems, PCH proteins are involved in lysosomal targeting, vesicular transport, and endocytotic as well as exocytotic processes. However, the specific molecular networks around individual PCH proteins and their localization in different cell populations need to be identified. We have recently reported that several members of the PCH family interact with the death factor FasL (CD178). This interaction is mediated via the SH3 domains of PCH proteins binding to the proline-rich cytoplasmatic region of FasL. To analyze the role of endogenous PCH proteins in the context of FasL or other interactors, novel molecular tools are needed. We developed a set of monoclonal antibodies against three individual PCH family members. These novel reagents will help to analyze the presence and function of endogenous PCH proteins in lymphocytes and other cell types.
  Signal Transduction 06/2007; 7(4):320 - 328.
• Article: Protein and lipid signaling in membrane fusion: nuclear envelope assembly

  Banafshé Larijani, Dominic Poccia
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  ABSTRACT: Membrane fusion is important in many cell processes including membrane trafficking, mitotic reconstitution of organelles, viral infection and fertilization. Several fusion events occur just prior and subsequent to fertilization in the sea urchin, including the sperm acrosomal reaction, fusion of sperm and egg plasma membranes, exocytosis of cortical granules, reassembly of the sperm nuclear envelope and fusion of the male and female pronuclear envelopes leading to the zygote nucleus of the one-cell embryo. The study of male pronuclear membrane dynamics with cell-free extracts of fertilized sea urchin eggs has revealed several novel features, in particular a structural role arising from altering phospholipids prior to nuclear membrane formation. Fusion of chromatin-bound membrane vesicles in vitro can be triggered by either GTP hydrolysis or exogenous phosphatidyl inositol phospholipase C (PI-PLC). Recent data strongly implicate a role for diacylglycerol in nuclear envelope formation as a structural destabilizing lipid in membrane fusion. Moreover, the endogenous enzyme, PI-PLCγ, is >100-fold enriched in a nuclear envelope precursor vesicle population (MV1) that is required for nuclear envelope assembly. NMR and mass spectrometry analyses show that MV1 contains high levels of phosphoinositides, including the substrate of PLCγ, compared to the other nuclear envelope precursor membranes. MV1 exists in eggs as vesicles in the cortex distinct from the endoplasmic reticulum which contributes most of the nuclear envelope membrane. PLCγ is activated by a tyrosine kinase in response to GTP hydrolysis at an early stage of nuclear envelope formation suggesting a role in initiation of fusion and revealing aspects of a signaling mechanism leading to fusion. The binding of MV1 to two poles of the sperm nucleus offers spatial as well as temporal control of the initiation phase.
  Signal Transduction 04/2007; 7(2):142 - 153.
• Article: Secondary axis specification in sea urchin embryos

  Cynthia A. Bradham, David R. McClay
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  ABSTRACT: Secondary axis specification is a process that relies on asymmetric nuclearization of transcription factors in flies and vertebrates, such that the crucial factor is nuclear and therefore functional only in cells along one side of the embryo. In vertebrates, this transcription factor is β-catenin, which is canonically activated downstream from Wnt signals. However, the sea urchin uses asymmetric β-catenin nuclearization during specification of the primary animal-vegetal axis, rather than the secondary oral-aboral (OA) axis. OA specification relies instead on the asymmetric localization of p38 MAPK, a signaling kinase that directly modulates transcription factor activity. A number of genes are expressed in the oral territory downstream from p38, including Nodal and Goosecoid, both of which are associated with secondary axis specification in vertebrate embryos. Because the p38 asymmetry is the earliest known event in the specification of the OA axis, an outstanding question concerns identifying the apparatus upstream from p38 that regulates its asymmetrical activity. Intriguingly, this may be controlled by reactive oxygen species released from the mitochondria, which are asymmetrically distributed about the OA axis.
  Signal Transduction 04/2007; 7(2):181 - 186.
• Article: Integrin signaling in early sea urchin development

  Robert Douglas Burke, Elizabeth Brothers, Andrea Matviw
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  ABSTRACT: The eggs and cleavage stage embryos of many animals express integrins and signal transduction components, yet comparatively little is known of the signaling complexes formed or the role of integrin signaling in early development. Genomic approaches have revealed the complement of integrin signaling components expressed in early sea urchin development. We review what is known about the distribution and function of integrins, integrin ligands, and integrin signal transduction proteins expressed during this critical phase of development. Immediately after fertilization integrins are expressed on the apical surface of the egg where the receptors interact with several potential ligands in the hyaline layer. The apical integrin complex is essential for reorganization of the egg cortex. During cleavage the blastocoel forms and a second integrin complex forms on the basal surface of blastomeres interacting with basal lamina components of the extracellular matrix. The integrin subunits of the apical and basal complexes differ and localization data indicate the apical and basal complexes may contain different scaffolding proteins and different kinases. We propose that there are two independent integrin-based signaling complexes formed during cleavage and blastula formation that may have distinct and essential functions in early development. The sea urchin is an excellent model for studies of these pathways and a number of approaches are available to determine their roles in early development.
  Signal Transduction 04/2007; 7(2):207 - 215.
• Article: “Birth of the cool”: Using sea urchin zygotes to study centrosome duplication, cell division, and cytokinesis

  Elizabeth S. Halpin, Edward H. Hinchcliffe
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  ABSTRACT: The successful division of the cell depends on several morphological events that must be coordinated in a cell cycle dependent fashion. Crucial to this process is the remodeling of the cytoskeleton to both establish the bipolar spindle during mitosis, and cleave the cell into two daughters during cytokinesis. From the standpoint of the cytoskeleton, this process begins during interphase with the duplication of the centrosome; it is the two daughter centrosomes that will assemble the poles of the mitotic spindle and establish its necessary bipolarity. Following the cell cycle transition into mitosis, the spindle must assemble in order to properly align the sister chromatids at the center of the cell, and release the “wait anaphase checkpoint”. As the spindle transports the disjoined sister chromatids to the spindle poles, the cell must rapidly undergo cytokinesis, cleaving the cell into two – the plane of cleavage being established by the spindle itself. Understanding the temporal regulation and molecular basis for these events has come from extensive experiments using a variety of model systems, and has benefited from cell biological, molecular genetic, and biophysical approaches. One of the earliest and most important model systems for studying mitosis is the sea urchin zygote. With their large size, rapid/synchronous cell cycles, and advantages for conduct of biochemical and cytological investigations on the same system, fertilized sea urchin eggs have revealed many of the fundamental properties of centrosome duplication, cell division and cytokinesis. Here we review several key studies that have utilized the sea urchin zygote to explore mechanisms that coordinate and drive two of the major cytoskeletal events of mitotic division – centrosome duplication and cytokinesis.
  Signal Transduction 04/2007; 7(2):154 - 163.
• Article: Signal transduction mechanisms regulating ion fluxes in the sea urchin sperm

  Carmen Beltrán, Blanca Estela Galindo, Esmeralda Rodríguez-Miranda, Daniel Sánchez
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  ABSTRACT: Ion permeability changes involving ion channels and transporters are essential for fertilization, since they are key elements in sperm-egg signaling and environmental sensing. Changes modulated by external factors and components from the outer layer of the homologous egg, like the sperm-activating peptides and the fucose-sulfate glycoconjugate, trigger complex signaling systems in the sperm that modulate how sperm swim, find the egg and fertilize it. These signaling systems depend on plasma membrane ion permeability and involve an alteration of second messenger levels, changes of membrane potential and intracellular Ca2+, Na+ and pH, along with changes in sperm morphology in the case of the acrosome reaction (AR). New procedures to elucidate the signaling pathways implicated in sperm ion transport have expanded the opportunities to dissect sperm-egg signaling revealing how sperm ion channels participate in activation, motility, chemotaxis, and the AR. The sperm signaling pathways involve a large variety of ion channels and transporters, which are discretely localized and finely orchestrated to play specific roles that define the elaborate performance of sperm and allow a successful fertilization. In this review we will focus on the signaling molecules involved in the final aim of the sperm, to reach and fertilize the egg.
  Signal Transduction 03/2007; 7(2):103 - 117.
• Article: Specification and patterning of the animal‐vegetal axis in sea urchins by the canonical Wnt signaling pathway

  Shalika Kumburegama, Athula H. Wikramanayake
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  ABSTRACT: Pattern formation along the sea urchin A-V axis is initiated by the selective activation of the canonical Wnt signaling pathway in vegetal blastomeres. Activation of this pathway is essential for deployment of the endomesoderm gene regulatory network (EGRN), and for pattern formation along the entire A-V axis. During early embryogenesis the canonical Wnt signaling pathway is selectively activated by Dishevelled (Dsh), a critical activator of the Wnt pathway. Dsh is highly enriched in vesicular structures at the vegetal pole in eggs and early embryos, and selective activation of this protein leads to the nuclearization of β-catenin in the endomesoderm. Following activation of canonical Wnt signaling by Dsh, signaling by β-catenin and the Lef/Tcf transcription factors regulates endomesoderm specification by activating the EGRN. One critical early target of nuclear β-catenin is Wnt8, which is selectively expressed in the micromeres at the 16-cell stage and in the macromeres one cleavage division later. Wnt8 signaling is not required for the endomesoderm-inducing activity of the micromeres, but this protein regulates primary mesenchyme cell differentiation. Within the endomesodermal domain Wnt8 regulates the later specification of endoderm and mesoderm. These results have highlighted the important role of the canonical Wnt signaling pathway in patterning the A-V axis in the sea urchin embryo, and have strongly suggested that this axis is initially specified by a cytoplasmic/cytoarchitectural mechanism to activate Dsh in vegetal blastomeres. Additionally, this work along with work in vertebrates and cnidarians has shown that the canonical Wnt pathway plays a conserved role in early pattern formation in metazoan embryos.
  Signal Transduction 03/2007; 7(2):164 - 173.
• Article: Dlk/ZIP kinase, a novel Ser/Thr‐specific protein kinase with multiple functions

  Karl Heinz Scheidtmann
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  ABSTRACT: Dlk/ZIP kinase is a member of the DAP kinase family which has been implicated in apoptosis. However, Dlk/ZIP kinase does not induce apoptosis per se. Rather, downregulation of Dlk/ZIP kinase by siRNA results in apoptosis and multinucleated cells suggesting that Dlk/ZIP kinase fulfills a vital function in processes other than apoptosis. Indeed, Dlk/ZIP kinase interacts with several transcription and splicing factors pointing to a role in transcription, presumably via chromatin modification. Moreover, it appears to participate in regulation of cell polarity and contractile processes in non-muscle or smooth muscle cells. Finally, Dlk/ZIP kinase seems to play a role in mitosis, particularly cytokinesis. Thus, rather than being a proapoptotic kinase, Dlk/ZIP kinase participates in diverse and vital processes.
  Signal Transduction 03/2007; 7(3):248 - 259.
• Article: Signal transduction in vestibular adaptation to microgravity – A still unsolved problem

  Eberhard R. Horn
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  ABSTRACT: In men and monkeys as well as adult and developing fish (Fundulus heteroclictus, Opsanus tau, Xiphophorus helleri), amphibian (Rana catesbeiana, Xenopus laevis) and rodents, microgravity cause significant behavioral, physiological and psychophysical sensitivity changes within the vestibular system. Some of these observations point to sensitization of the vestibular system during exposure to weightlessness. The review presents mechanisms that might contribute to vestibular sensitization during microgravity adaptation. They include (1) stimulus transduction within vestibular hair cells, (2) activation of immediate early genes within central afferent and efferent vestibular nuclei, and (3) modifications of cellular transcription factors' activity during early development.
  Signal Transduction 03/2007; 7(3):240 - 247.