Changes in Signal Transduction Pathways

8 Key excerpts on "Changes in Signal Transduction Pathways"

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  eBook - PDF

  Biomedical Science, Engineering and Technology

  • Dhanjoo N. Ghista(Author)
  • 2012(Publication Date)
  • IntechOpen

    (Publisher)

  Part 1 Biomedical Science: Disease Pathways, Models and Treatment Mechanisms 2 Cell Signalling and Pathways Explained in Relation to Music and Musicians John T. Hancock University of the West of England, Bristol, UK 1. Introduction Cell signalling is arguably the most important area of modern biology. The subject encompasses the control of cellular events, especially in response to extracellular factors. It has been suggested that the human body is one of the most complex machines ever produced (Dawkins, 1989) and the regulation of the activities within it are also equally complex. Interest in cell signalling does not simply stem from an academic viewpoint either. Certainly there is a vast resource of research which is focuses on the investigation of signalling pathways and the control which they bestow on a cell. However, there are tangible reasons to take an interest here too. The vast majority of new pharmaceutical compounds under development are aimed at the modulation of proteins involved in cell signalling events (Filmore, 2004). Such proteins may be G protein-coupled receptors (GPCRs) or perhaps kinases which are downstream of such receptors. Many anti-cancer studies are now focused on the development of compounds which modulate Mitogen Activated Protein Kinases (MAPKs) for example. Therefore, an understanding the working of the components of a signal transduction opens up avenues for the future modulation of such activities with the development of new therapies and pharmaceutical agents. The study of cell signalling can seem very daunting. Vast diagrams full of acronyms can put off the most ardent reader, but there are many basic principles which underpin the subject. In cell signalling compounds are made and initiate a response, and this is true whether the molecule originates outside the cell or is created inside.

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  Biochemistry

  An Integrative Approach with Expanded Topics

  • John T. Tansey(Author)
  • 2022(Publication Date)
  • Wiley

    (Publisher)

  This chapter looks beyond regulation of enzymatic activity to examine some other facets of cell signaling, particularly in growth and dif ferentiation of cells and tissues. One of the advantages of specializing tissue function into storage (adipose), movement (muscle), and collected metabolic pathways (liver) is that an organism can have dedicated systems for these dif ferent metabolic roles. A complex organism needs to first generate these tissues and systems, then orchestrate their growth and dif ferentiation, and finally coordinate their response to dif ferent metabolic states. Collectively, all this information is significant not only in terms of basic biochemistry but also in immunology, developmental biology, and the processes involved in diseases such as cancer.

  21.1.1 Signal transduction follows certain basic principles

  Signal transduction is generally accomplished through chemical signals, although some specialized cells can detect and respond to light. For communication to occur, three things need to be in place: a signal (a chemical compound released by other cells somewhere in the organism or by other organisms in the environment), a receptor for the signal, and a means by which the cell can respond (Figure 21.1 ). Signals are often hormones, and receptors are often transmembrane proteins.

  FIGURE 21.1 Fundamentals of signal transduction. In any signal transduction pathway, the binding of a signaling cell to a receptor initiates a cascade within the cell that ultimately results in alterations to enzyme activity or gene expression. Sometimes the signal is first propagated and amplified through a second messenger.

  The binding of the signal by the receptor on the extracellular side is specific, and it elicits a conformational change in the receptor that causes a change on the intracellular side of the protein. The change in the conformation typically activates enzymes such as kinases, and it can stimulate protein signaling pathways directly or be amplified by other enzymes and second messenger signaling molecules such as Ca2+ or cyclic AMP (cAMP). Recall that a second messenger

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  Bipolar Disorder

  Clinical and Neurobiological Foundations

  • Lakshmi N. Yatham, Mario Maj, Lakshmi N. Yatham, Mario Maj(Authors)
  • 2011(Publication Date)
  • Wiley

    (Publisher)

  Over the past 10 years, studies using animal models, postmortem brain tissue and lymphocytes samples have examined the intracellular signal transduction pathways linked to neurotransmitters to investigate the biological basis of BD. In this chapter, we will review the evidences for abnormalities in signal transduction pathways in BD. We will also discuss how these pathways may be relevant in the treatment of this illness with mood stabilizing medication.

  Signal transduction pathways

  Signal transduction pathways are uniquely responsible for coordinating the cellular response to information impinging on the cell from multiple sources and time frames [17]. These pathways follow a broadly similar course that can be viewed as a molecular circuit, which can detect, amplify and integrate diverse external signals to generate cellular response such as enzyme activity, stimulation of proliferation or cell death and lastly induced gene expression [17].

  Abnormalities in these pathways may lead to a functional imbalance in multiple neurotransmitter pathways, which could account for the diverse clinical features found in BD [18]. Most neurotransmitter receptors are coupled to guanine-nucleotide binding proteins (G-protein). These proteins link receptors to specific enzymes that activate second messengers, or alternatively, they link to specific ion channels. Now, the extracellular signals are integrated, amplified and transmitted to specific intracellular enzymes, called effectors, which catalyse the production of an extensive array of cascading second messengers. In turn, these messenger molecules act on various protein kinases [17]. The activation of these kinases is instrumental in regulating diverse intracellular processes, including gene expression, and in relating these to lasting neurobiological changes [17].

  The number of findings for abnormalities in signal transduction systems in samples obtained directly from patients is growing. Indeed, animal and cell culture studies have demonstrated pharmacological effects of mood stabilizers, especially lithium, suggesting its role in neuroprotection, which range from reducing excitotoxicity through increased glutamate uptake, to regulation of a number of second messenger systems, such as adenylate cyclase (cyclic adenosine monophosphate, cAMP), phosphoinosi-tide (PI), protein kinase C (PKC), protein kinase A (PKA), protein kinase B (AKT) and glycogen synthase kinase-3 (GSK-3) [19].

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  Karp's Cell Biology

  • Gerald Karp, Janet Iwasa, Wallace Marshall(Authors)
  • 2018(Publication Date)
  • Wiley

    (Publisher)

  Virtually every activity in which a cell is engaged is regulated by signals originating at the cell surface. This overall process in which information carried by extracellular messenger molecules is translated into changes that occur inside a cell is referred to as signal transduction. Finally, signaling has to be terminated. This is important because cells have to be responsive to additional messages that they may receive. The first order of business is to eliminate the extracellular messenger molecule. To do this, certain cells Active Inactive Protein kinase 2 P Protein kinase 2 Active Protein kinase 1 Active Protein kinase 3 Inactive Protein kinase 3 P Active Transcription factor Inactive Transcription factor P DNA mRNA P FIGURE 15.3 Signal transduction pathway consisting of protein kinases and protein phosphatases whose catalytic actions change the conformations, and thus the activities, of the proteins they modify. In the example depicted here, protein kinase 2 is activated by protein kinase 1. Once activated, protein kinase 2 phosphorylates protein kinase 3, activating the enzyme. Protein kinase 3 then phospho- rylates a transcription factor, increasing its affinity for a site on the DNA. Binding of a transcription factor to the DNA affects the transcription of the gene in question. Each of these activation steps in the pathway is reversed by a phosphatase. 628 CHAPTER 15 • Cell Signaling Pathways FIGURE 15.4 A comparison in the frequency of tyrosine phosphorylation in two different types of breast cancer cells. The panels on the left side of the figure show the frequency of phosphoty- rosine (pTyr) residues in certain proteins (named on the right side of the figure) in triple‐negative breast cancer cell lines. Triple‐negative cells do not express three major molecular signatures of many breast cancer cells–estrogen receptor, progesterone receptor, and the growth factor receptor HER2.

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  Developmental Toxicology

  • Deborah K. Hansen, Barbara D. Abbott(Authors)
  • 2008(Publication Date)
  • CRC Press

    (Publisher)

  2 Signal Transduction Pathways as Targets for Teratogens Barbara D. Abbott Reproductive Toxicology Division (MD67), National Health and Environmental Effects Research Laboratory (NHEERL), Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, U.S.A. INTRODUCTION Control of morphogenetic processes is critical for embryonic development. These processes include proliferation, cell death, extracellular matrix (ECM) and cytoskeletal remodeling, cell–cell and cell–ECM adhesion, cell motility, cell shape modifications, and differentiation to tissue/organ specific cellular phenotypes. Sig-naling pathways provide the regulation necessary to control these processes during development allowing the critical events to occur at the right time and at the spe-cific locations necessary for an organ to form, mature, and become functional. These signaling events are tightly regulated during development, and disruption of the signaling pathways by exogenous agents can be catastrophic for the embryo. This chapter provides an introduction to signal transduction pathways essential for development and presents examples of teratogenic modes of action that involve disrupting signal transduction. Signal transduction pathways can be described and grouped by their cellular location (membrane bound, cytoplasmic, and nuclear), ligands, cofactors or signaling intermediates utilized, kinase activities, or targeted genes. The National Research Council evaluated the mechanisms of action of developmental toxicants and focused on identifying signaling pathways that impact development and may be targets of teratogens. Their report “Scientific Frontiers in Developmental 43 44 Abbott Toxicology and Risk Assessment” [1] listed 17 signaling pathways as important regulators of development.

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  Gene Control

  • David Latchman(Author)
  • 2020(Publication Date)
  • Garland Science

    (Publisher)

  Figure 8.4 ). The mechanisms by which cellular signaling pathways regulate transcription factor activity are considered in this chapter.

  FIGURE 8.3 The post-translational activation of transcription factor A (a) allows a much more rapid response than the de novo transcription of the gene encoding transcription factor B (b), which requires multiple stages before transcription factor protein is produced.

  FIGURE 8.4 Production of a biological effect by a specific signal can occur by the signal activating a transcription factor. The transcription factor then activates its target genes, resulting in enhanced levels of the proteins they encode, thereby producing the appropriate change in cellular phenotype.

  Multiple mechanisms regulate transcription factor activity

  As indicated in Figure 8.5 , a number of different mechanisms allow the regulation of transcription factor activity. In the case of signaling molecules that can enter the cell, direct binding of the ligand to the transcription factor is a frequently used mechanism for transcription factor activation. The regulation of transcription factors by such intracellular ligands is therefore discussed in Section 8.1 (Figure 8.5a ). Conversely, signaling molecules that bind to cell surface receptors and cannot enter the cell frequently act by inducing enzymes that can post-translationally modify proteins, for example, by phosphorylation (Figure 8.5b ). The post-translational modification of transcription factors by phosphorylation is therefore discussed in Section 8.2 and other post-translational modifications that regulate transcription factor activity are discussed in Section 8.3

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  Karp's Cell and Molecular Biology

  Concepts and Experiments

  • Gerald Karp, Janet Iwasa, Wallace Marshall(Authors)
  • 2016(Publication Date)
  • Wiley

    (Publisher)

  A quick look at Figure 15.15 or 15.25 b, c illustrates how a single stimulus—a ligand binding to a GPCR or an insulin receptor—sends signals out along a variety of different pathways. 3. Cross‐talk. In previous sections, we examined a number of sign- aling pathways as if each operated as an independent, linear chain of events. In fact, the information circuits that operate in cells are more likely to resemble an interconnected web in which components produced in one pathway can participate in events occurring in other pathways. The more that is learned about information signaling in cells, the more cross‐talk between sign- aling pathways that is discovered. Rather than attempting to cata- log the ways that information can be passed back and forth within a cell, we will look at an example involving cAMP that illustrates the importance of this type of cross‐talk. Cyclic AMP was depicted earlier as an initiator of a reaction cascade leading to glucose mobilization. However, cAMP can also inhibit the growth of a variety of cells, including fibroblasts and fat cells, by blocking signals transmitted through the MAP kinase cas- cade. Cyclic AMP is thought to accomplish this by activating PKA, the cAMP‐dependent kinase, which can phosphorylate and inhibit Ras PIP 2 PDGF, EGF, etc. Tyrosine kinase-linked receptors G Protein-coupled receptors IP 3 Ca 2+ IP 3 R DAG PLCβ PLCγ Cellular activity & mitogenesis R Acetylcholine, histamine NA, 5-HT, ATP, PAF, TXA2, Glutamate, Angiotensin II, Vasopressin, Bradykinin, Substance P, Bombesin, Neuropeptide Y, Thrombin, Cholecystokinin, Endothelin, Neuromedin, TRH, GnRH, PTH Odorants, Light I II III P P PKC PI3K PIP 3 Raf MAP kinase GAP G FIGURE 15.33 Examples of convergence, divergence, and cross‐talk among various signal‐transduction pathways. This drawing shows the outlines of signal‐transduction pathways initiated by receptors that act by means of both heterotrimeric G proteins and receptor protein‐tyrosine kinases.

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  Identification of Neural Markers Accompanying Memory

  • Alfredo Meneses(Author)
  • 2013(Publication Date)
  • Elsevier

    (Publisher)

  8

  Basic Elements of Signal Transduction Pathways Involved in Chemical Neurotransmission

  Claudia González-Espinosa and Fabiola Guzmán-Mejía,    Pharmacobiology Department, Center for Research and Advanced Studies (Cinvestav), South Campus, Mexico City, México

  Distinct process of signal transduction triggered in neurons by receptors to neurotransmitters and neuromodulators have been recognized as responsible for long-term changes on synapse function. Some of those biochemical modifications to the metabolism of information inside neurons are thought related to memory formation and consolidation. Basic notions of signal transduction are, then, necessary for the understanding of current literature and hypothesis on the neurotransmitter systems involved in prolonged alterations to neuronal function. This chapter briefly summarizes some fundamental concepts and elements of the signal transduction systems involved in synaptic chemical transmission.

  Keywords

  Signal transduction; chemical neurotransmission; G-protein-coupled receptors.

  Introduction

  Research on cellular and molecular mechanisms involved in learning and memory constitutes a leading area in neuroscience that started long time ago. Since the mid-twentieth century, researchers have been concerned not only in finding the neurotransmitter systems involved in the transmission of electrical stimuli between nerve cells, but also in determining the long-term molecular changes that lead to long-term modifications to neural activity due to the neurotransmission process. One of the underlying hypothesis of molecular approaches to neurotransmission is that specific characteristics on the neuron-to-neuron communication (such as the intensity, duration, and composition of the signal) induce particular and sometimes irreversible modifications on neuron physiology leading to learning and memory consolidation. Description of the main neurotransmitter systems came together with the discovery of important changes in the postsynaptic terminals after the learning process. Those findings contributed to the late recognition of the importance of signal transduction events on the generation and maintenance of long-term changes on neural function, and allowed researchers to propose that abnormalities on particular signaling cascades could lead to modifications on the learning and memory processes.

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