Signal Transduction

Signal Transduction

Third Edition

IJsbrand M. Kramer

University of Bordeaux, European Institute of Chemistry and Biology, INSERM U1045, Talence, France

Table of Contents

Cover image

Title page

Copyright

Biography

Preface

Chapter 1. Prologue: Signal Transduction from an Historical Perspective

Transduction, the word and its meaning

Irritability, a vital phenomenon

Protoendocrinologists

Hormones and neurotransmitters

The receptive substance

Proto-messengers and -receptors

Growth factors: setting the framework

Problems with nomenclature

Chapter 2. An Introduction to Signal Transduction

Cells need ways to create symbolic representations of their (changing) environment

First messengers

First-messenger signals are ambiguous: their meaning is embedded in context

The plasma membrane barrier, membrane receptors, and signal transduction

Receptors and their ligands

Five types of receptors

Signaling mechanisms

Wired allostery and thoughtful decisions

Posttranslational modifications involved in signaling events

Focus on nucleotide exchange

A brief definition of effectors

Focus on protein phosphorylation

Protein kinases catalyze the phosphate transfer

Protein domains, their folds, and their graphic representations

Which amino acids are susceptible to phosphorylation?

Bacterial exceptions: phosphoenolpyruvate as phosphate donor and histidine kinases as environmental sensors

Substrate phosphorylation motifs and distal docking sites

Protein kinase activation mechanisms

Protein phosphatases

PPP1R12A (MYPT1) as an example of how a regulatory subunit controls substrate selectivity (of PP1CC)

Regulation by intramolecular domain interaction, the example of PTPN6 (SHP-1)

Decision-making in glycogen synthesis and breakdown: concerted action of kinases and phosphatases

Signal termination

Chapter 3. Regulation of Muscle Contraction by Adrenoceptors

Catecholamines

α- and β-adrenoceptors

Adrenaline-binding and G-protein-coupling mechanisms

Adrenoceptor agonists, antagonists, and inverse agonists

How do ligand-binding characteristics translate into signaling effects?

Adenylyl cyclase

cAMP-binding proteins

Phospholipase C

Muscle contraction: striated versus smooth muscle

Contraction waves in the heart

Adrenaline as a cardiac ino- and chronotrope messenger

Arresting the β-adrenoreceptor signal: pathway switching and the role of G-protein receptor kinase and arrestin

α1-adrenoceptors and visceral vasoconstriction

Adrenaline (again)

Chapter 4. Cholinergic Signaling and Muscle Contraction

Acetylcholine

Cholinergic receptor subtypes; nicotinic and muscarinic

Nicotinic acetylcholine receptors

Muscarinic acetylcholine receptors

Type IV nicotinic AChR induces skeletal muscle contraction

Acetylcholine, acting on the M2-receptor, reduces force and slows down the heart rate

Phosphodiesterases

Acetylcholine, acting on the M3 receptor, causes airway constriction and mucus secretion

Acetylcholine and the induction of nitric oxide, a potent vasodilator

Neurotransmitters that function with both ionotropic and metabotropic signaling mechanisms

Chapter 5. Sensory Signal Processing; Visual Transduction and Olfaction

Visual transduction

Ocular photoreceptor cells

Photoreceptor mechanisms

Electric activity of rod cells

Sensitivity of photoreceptors and adaptation to changing light intensities

Note on phototransduction in invertebrates

Olfaction

Olfactory epithelium

Odorant receptor signaling

Other signaling pathways involved in chemosensing

Pheromone reviews

The GPCR superfamily

Chapter 6. Intracellular Calcium

A new second messenger is discovered

Free, bound, and trapped Ca²+

Cytosolic Ca²+ is kept low

Ca²+-binding proteins

Ca²+ receptors

Ca²+/calmodulin-mediated regulation of protein activity

Tools to study the role of Ca²+ in cellular processes

Mechanisms that elevate cytosol Ca²+ concentration

Decoding Ca²+ oscillations

Mobilizing Ca²+ through cyclic ADP ribose, NAADP, and sphingosine-1-phosphate

Ca²+ in action

Michael Abercrombie a pioneer in cell migration

Chapter 7. Bringing the Signal into the Nucleus: Regulation of Gene Expression

Gluconeogenesis

Glucagon and glucocorticoids augment gluconeogenesis

Signaling through the glucagon receptor

Protein kinase A

AKAP, anchoring and scaffolding

Activation of PKA by cAMP

PKA substrates involved in gluconeogenesis

CREB, a nuclear target of PKA

CREB is member of the basic leucine zipper (bZIP) family of proteins

Transcription and transcription factors

Ser133-phosphorylated CREB recruits coactivators CREBBP, PE300, and CRTC2

CREB stimulates the gluconeogenic program

Glucagon and cortisol (glucocorticoid) cooperate

Insulin causes disassembly of the CREB-mediated PIC

Diabetes and enhanced gluconeogenesis

Chapter 8. Nuclear Receptors

Steroid hormones

Steroids accumulate in the nucleus

Steroids regulate gene transcription

A superfamily of nuclear receptors

Domain architecture and general structure of the DNA–protein complex

Nuclear receptors in context: cross-talk with other transcription factors

Non-genomic signaling modes of nuclear receptors

Three precise descriptions of steroids in action in the context of pregnancy

Chapter 9. Protein Kinase C in Oncogenic Transformation and Cell Polarity

Discovery of a phosphorylating activity independent of cAMP

The protein kinase C family

Structural composition of protein kinase C

Priming and activation of conventional and novel protein kinase C

Priming and activation of atypical protein kinase C

Multiple sources of diacylglycerol and other lipids to regulate protein kinase C

Differential localization of protein kinase C isoforms

Different types of protein kinase C-binding proteins

Holding back the PKC response

Protein kinase C in the context of oncogenic transformation

Atypical protein kinase C and the regulation of cell polarity

Atypical protein kinase C in cell migration and axonal outgrowth

Chapter 10. Regulation of Cell Proliferation by Receptor Tyrosine Protein Kinases

Introduction

Spotting phosphotyrosine

v-Src and other protein tyrosine kinases

Focus on the ERBB receptor family, their ligands, and their dimer partners

Cross-linking of receptors causes activation

Oncogenenic mutations

Protein domains that bind phosphotyrosines and the assembly of signaling complexes

Branching of the signaling Pathway

Fine tuning the RAS–MAP-kinase pathway: scaffold proteins

Termination of the ERK1/2 response

A family of MAP-kinase-related proteins

MAP kinases in other organisms

Other branches of the EGFR signaling pathways

Chapter 11. Signal Transduction to and from Adhesion Molecules

Adhesion molecules

Naming names

Immunoglobulin superfamily

Claudins

Occludins

Integrins

Cadherins

Selectins

Cartilage link proteins

Integrins, cell survival, and cell proliferation

Signaling from cadherin clusters

Chapter 12. WNT Signaling and the Regulation of Cell Adhesion and Differentiation

Destabilization of adherens junctions causes cellular dedifferentiation

The discovery of the Wnt family of cytokines

Wnt signals through β-catenin

Switching TCF from a repressor to an activator

Adenomatous polyposis coli and the regulation of subcellular localization of β-catenin

Take your partner: which way β-catenin?

WTN signaling disables the AXIN–APC destruction complex

Regulation of gene transcription by β-catenin

More about the TCF family

Wnt target genes with a Wnt-enhancer element

Extracellular inhibitors of Wnt and its receptors

Contribution of different species to the elucidation of the WNT signal transduction pathway

Wnt signaling and stem cell self-renewal

WNT and planar cell polarity

Mutations of CTNNB1, AXIN, and APC in human cancers

Chapter 13. Activation of the Innate Immune System: The Toll-Like Receptor-4 and Signaling through Ubiquitinylation

Introduction

Sensing the microbial universe

Signaling through the TLR4 receptor

The IRF family of transcription factors

Negative feedback control of the TLR4 pathway

Some consequences of TLR4-induced gene transcription

Essay: Ubiquitinylation and Sumoylation

Chapter 14. Chemokines and Traffic of White Blood Cells

Inflammation and leukocytes

Inflammatory mediators

Tumor necrosis factor: potential antitumor agent or inflammatory cytokine?

The family of TNF proteins and receptors

TNF and regulation of adhesion molecule expression in endothelial cells

Chemokines and activation of integrins on leukocytes

Cellular protrusions aid in probing permissive sites on the endothelial surface

Migration within the tissue

The three-step process of leukocyte adhesion to endothelial cells

Chapter 15. Activating the Adaptive Immune System: Role of Non-receptor Tyrosine Kinases

The family of non-receptor protein tyrosine kinases

T-cell receptor signaling

Down-regulation of the TCR response

The lipid raft hypothesis

Signaling through the interferon receptors

Oncogenes, malignancy, and signal transduction

Essay: non-receptor PTKs and their regulation

Chapter 16. Signaling through the Insulin Receptor: Phosphoinositide 3-Kinases and AKT

Insulin receptor-signaling: it took a little time to work out the details

Signaling through phosphoinositides

Phosphatidyl inositol 3-kinase

Studying the role of PI3-kinase with inhibitors

Pathways of activation for PI3-kinase

AKT and activation through PI-3,4,5-P3

Insulin: the role of IRS, PI3-kinase and AKT in the regulation of glycogen synthesis

The role of PI3-kinase in activation of protein synthesis

RHEB and TSC

Integration of growth factor and nutrient signaling

PI3-kinase, regulator of cell size, proliferation, and transformation

Other processes mediated by the 3-phosphorylated inositol phospholipids

Chapter 17. TGFβ and Signaling through Receptor Serine/Threonine Protein Kinases

The TGFβ family of growth factors

TGFβ receptors, type-I and type-II

TGFβ-mediated receptor activation

Accessory and pseudo-receptors: TGFBR3, ENG, TDGF1, and BAMBI

Downstream signaling: Drosophila, Caenorhabditis, and Smad

SMAD proteins have multiple roles in signal transduction

Regulation of Transcription by SMAD Proteins

Cooperation with other pathways and other transcription factors

Holding the TGFβ pathway in check

TGFβ: tumor suppressor and metastatic promoter?

Noncanonical pathways

Chapter 18. Protein Phosphatases

Introduction

Protein tyrosine phosphatases

Protein serine/threonine phosphatases

Chapter 19. Cell Fate Determination by Notch

Notched wings, Morgan, and the gene theory

One gene, many alleles

Membrane components of the Notch pathway

Activation of NOTCH1

Destruction of the NOTCH1-intracellular domain, Nicd

Both receptor and ligand trafficking are essential for NOTCH signaling

NOTCH in drosophila development

Notch in the maintenance of an intestinal stem compartment

Cross-talk with other signal transduction pathways

Notch and disease

Index

Copyright

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Biography

IJsbrand Kramer is a professor at the University of Bordeaux, working in the European Institute of Chemistry and Biology (IECB). He holds a bachelors and masters degree in biomedicine from the University of Utrecht, the Netherlands, with a one year research-excursion in the Department of Cell Biology at the University of Liverpool, the UK. He did his PhD at the University of Amsterdam, in the Central Laboratory of Blood Transfusion Services (Stichting Sanquin) and worked as a postdoctoral fellow at the Hubrecht Laboratory in Utrecht and at the University of Washington in Seattle. He then took a lecturer position at the Department of Pharmacology at University College London, where he taught signal transduction (with Bastien Gomperts and Peter Tatham) and pharmacology. Both teaching activities have been documented in textbooks: Signal Transduction (three editions) and Receptor Pharmacology (CRC Press/Taylor Francis Group, three editions). Most of his research centers on the theme of inflammation, starting with neutrophils and the NADPH oxidase, synovial fibroblasts and destruction of the joint and more recently podosomes formation and extracellular matrix destruction in vascular endothelium. He moved to the University of Bordeaux for family reasons and switched from pharmacology to cell biology, with a strong contribution to an introductory course for first-year university students. Given the important teaching load and the general low level of student engagement in higher education, he started to investigate the reasons for student failure (finding out about their expectations and attitudes) and the role of images and animations in comprehension. Scientific publications, Web-based multimedia resources, and dramatically enhanced retention rates (from 33% to 85%) are the fruits of these activities. At the same time, he organized with University College London and Universitat Pompeu Fabra, Barcelona, summer schools on Receptor and Signaling Mechanism. He has been codirector of two European Programmes (Interbio and Transbio) that aimed at enhancing industrial innovation in the biomedical sector in the South West European region (SUDOE). More information about his teaching and pedagogical-research activities can be found at www.cellbiol.net.

Preface

The third edition differs considerably from the earlier editions in that the book is no longer separated in two parts, the first providing the nuts and bolts of what might be termed classical signal transduction. In fact, this classification does not really apply for two reasons. First, for students everything is as new as the latest scientific article is for a teacher and dividing between classical or nonclassical is not really making the subject clearer and might even pretend that cells employ classical (important) and not-so classical (less important) mechanisms that bring about changes in their metabolism, gene expression, secretion rate, contraction state, and so on. Second, with the recent structural revelations of G protein-coupled receptor and the action of biased agonists, classical signal transduction has suddenly lost its classical touch and has become very modern. Instead, an introductory chapter has been added in which a number of principles are outlined common to many signal transduction events, and these are placed in the context of the most Nobel, the most classic, of all pathways: adrenaline to glycogen phosphorylase. While the previous editions were written by three authors and rewritten by Bastien Gomperts, so that it appeared as written by one mind, one hand, this edition also differs in that it has been written by one hand only (or, less poetically, typed by two hands on a keyboard). The two greybeards have pulled out after publication of the second edition and, very sadly, Bastien Gomperts has passed away in October 2013. If, from the previous editions, you appreciate the writing style, the wit, and the anecdotes, bearing from some unusual sources, much of the credit goes to him. He was an inspiring mentor indeed.

With a few exceptions, for instance the chapter on protein phosphatases, each chapter now has a theme of its own, around which specific aspects of signal transduction pathways are developed. For teaching purposes, Table 1-1 attempts to give a short overview of each chapter’s subjects and highlights, so that, depending on the pathway to be explored, a relevant (suitable) context can be selected. Although there still is a gradual build-up of the subject, where later chapters make reference to earlier chapters, each chapter could stand on its own. Naturally, the signaling aspects highlighted are not necessarily unique to the context in which they are developed, but it allows teachers (and students) to tell a story rather than just listing a sequence of signaling events (Kramer and Thomas, 2006). As a consequence, this edition contains more on cell biology, physiology, pathology, and immunology. By providing precise examples, embedded in precise contexts, the book offers the possibility to integrate signalingknowledge into the above-mentioned disciplines and, therefore, facilitates a constructive approach to teaching (for more information, see http://www.cellbiol.net/docs/Constructive_teachingKramer.pdf).

Again, there has been no attempt to be comprehensive and certain important topics that well qualify for inclusion in this book, such as signals initiated by damaged DNA or unfolded proteins, are conspicuous only by their absence. Although the book touches the leading edges of the subject, it also endeavors to provide an elementary basis with some historical background to all the topics covered. The prologue has been extended considerably with new information about the first observations of irritability, a phenomenon that qualifies as an essential element of the living (besides template replication and metabolism). Historical background not only provides a broader insight into the subject and pays tribute to the wisdom of our forebears, whose freedom of thought and sometimes serendipitous discoveries in the nineteenth and early twentieth centuries led to the creation of the modern sciences, for certain people it may also provide meaning to the numerous odd names, abbreviations, and acronyms (collectively named symbols) that riddle the book. For unexplained symbols the reader is encouraged to consult UniProt (paragraphs function and names & taxonomy) or relevant Wikipedia articles. Besides the chapter about intracellular calcium, the book does not reveal a good deal of experimental techniques. A lack of time and a growing complexity of technology are to blame. Moreover, experience tells that explaining technology is revealing for learners who already master the cellular context and signaling events but tend to mystify matters, because of a substantial increase in cognitive burden, when learners are still struggling with the molecular mechanisms that drive the pathways.

In preparing the book, I have had the benefit of advice and opinions from many friends and colleagues. These include (in order of their first name) Alan Hall (New York), Alasdair Gibb (London), Bob Weinberg (Cambridge, USA), Bob Lefkowitz (Durham, USA), Bruno Klaholz (Illkirch), Carsten Hoege (Dresden), Chris de Graaf (Amsterdam), Christopher Glass (San Diego), David Armstrong (Durham, USA), David Strutt (Sheffield), Filip van Petegem (Vancouver), Geerten Vuister (Leicester), George Mosialos (Thessaloniki), Graham Dunn (London), Jean Dessolin (Bordeaux), Jeff Saucerman (Charlottesville), Jennifer Lippincott-Schwartz (Bethesda), Jürgen Knoblich (Vienna), Karin Rittinger (London), Karl Matter (London), Maria Schumacher (Durham, USA), Marian Joëls (Utrecht), Marina Gloukova (Paris), Mark Dell’Acqua (Aurora), Matthew Gold (London), Michel Laguerre (Bordeaux), Miho Lijima (Baltimore), Mingjie Zhang (Hong Kong), Peter van Haastert (Groningen), Purna Joshi (Toronto), Roel Sterckx (Cambridge, UK), Romuald Nargeot (Bordeaux), Sander van den Heuvel (Utrecht), Shiva Malek (South San Francisco), Stuart Firestein (New York), Yohanns Bellaiche (Paris), Vadim Asharvsky (Durham, USA), Wai Leong (Singapore), and Wei-Min Shen Los Angeles. Special gratitude also goes to all authors, curators, Website developers, andtechnicians who contributed and continue to contribute to an increasing number of outstanding annotated databases (UniProt, PubMed, OMIM, UniGene, GenomeNet, HGNC, PhosphoSite, and so on) and Wikis. These databases have become key sources of information for research as well as education. I encourage students to go out on the web!

In acknowledgment of their contribution I offer the following quotation by one of the pioneers of signal transduction (Figure 1-1; Ringer and Murrell, 1878).

Figure 1-1

Of course, the authors of this paper would themselves never have recognized the expression signal transduction, and it would be a further 100  years before it made its appearance in the biological literature. The sensations brought about by pituri, an alkaloid that Ringer and Murrell described as sharing some of the pharmacological properties of atropine (courage, infuriation, frustration, and headaches), are not dissimilar to those experienced in the writing of this book. Indeed, they will be familiar to many students and investigators in this and other fields of research. However, we should not take this too far. When Ringer (1879) tested the effects of the application of pituri on four men, he noted that it also causes drowsiness, faintness, pallor, giddiness, hurried and superficial breathing, dilates the pupil, produces general weakness with convulsive twitchings, and antagonizes the action of muscarin on the heart. Unlike atropine, it produces sickness and increases the salivary secretion in large doses copiously, the breathing becomes quick and shallow, and general weakness ensues. Reading all this, it leads one to wonder who, among their students, colleagues, and servants, may have offered themselves up as willing, or less than willing, guinea pigs in the furtherance of scientific research. Ringer and his friends apparently preferred to eschew membership of the very honorable brotherhood of self-experimenters, of which the more famous members include Sir, Humphry Davey, who breathed nitrous oxide as well as other more noxious gases, John Scott Haldane, who too inhaled lethal gases; and more recently Barry Marshall, who has swallowed a culture of Helicobacter pylori to show that it caused stomach ulcers and who with Robin Warren was awarded the Nobel Prize in Physiology or Medicine in 2005. Another member of this fraternity, Charles Eduard Brown-Sequard, figures prominently in prologue chapter.

Notes

For web-support of this book

See the companion website: http://booksite.elsevier.com/9780123948038

For protein structural data we have made use of

The Protein Data Bank: Berman et al. (2000).

Protein structures have been generated using PyMol (education version), a molecular visualization system on open source foundation, maintained and distributed by Schrodinger.

References

We have tried to provide original text sources to nearly all the statements, experiments, and discoveries discussed. The main reason for thisis that we ourselves have necessarily had to extend the treatment of nearly all the topics presented far beyond the areas of our own experience or expertise. Thus, comprehensive lists are there to provide us with some sort of reassurance that what we have written has not simply been conjured out of the air. Also, because we have made a particular feature of presenting original historical source material by quotation, which necessarily required referencing, it seemed logical also to include literature references to modern sources as well. Thus we hope that this book may serve as a valuable resource, in the manner of a basic literature review, for anyone wanting to explore further.

Protein symbols (gene products)

We have named proteins according to the symbols agreed upon in the HUGO gene nomenclature database (HGNC) (www.genenames.org). Similar symbols have been adopted by protein databases such as UniProt. Some of the new symbols are simply awkward, so different from conventional names that they are even not recognized by scientists who made major contributions to the field, and when they really are uncommon alternative more conventional names are provided, but from a pedagogical point of view it is vital that students can search the web with unique (unambiguous) symbols and find out about the relevant proteins (and genes) themselves. And remember, certain symbols may be more familiar to experts in the field, for students they are all the same: new and often gruesome.

References

Kramer I.M, Thomas G. Meeting report: teaching signal transduction. CBE Life Sci. Educ. Spring 2006;5:19–26.

Ringer S, Murrell W. On pituri. J. Physiol. 1878:377–383.

Ringer S. On the action of pituri on man. Lancet. 1879:290–291.

Berman H.M, Westbrook J, Feng Z, Gilliland G, Bhat T.N, Weissig H, Shindyalov I.N, Bourne P.E. The protein data bank. Nucleic Acids Res. 2000;28:235–242. http://www.rcsb.org/pdb/.

Table 1-1

Contexts, pathways, subjects, and proteins/molecules elaborated in different chapters