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Chapter1 -2 -3 -4 -5 -6 -7 -8 -9 -10 -11 -12 -13 -14 -15 -16 -17 -18
Preface
Chapter 1 Prologue: Signal Transduction, origins and personalities
Transduction, the Word and its Meaning: One dictionary, different points of view.
Hormones, evolution and history
The plasma membrane barrier
Protohormones
Protoendocrinologists
Hormones: a definition.
What's in a name?
Neurotransmitters
Ergot
Receptors and ligands
First messengers
Hormones
Growth factors
Cytokines
Vasoactive agents
Neurotransmitters and neuropeptides
Lipophilic hormones
Intracellular messengers
Binding of ligands to receptors
Binding heterogeneity
K D and EC 50 : Receptor binding and functional consequences
Spare Receptors
Down-regulation of receptors
Discovery of the first second messenger, cyclic AMP
Adrenaline (again)
a -and b -adrenergic receptors
Adrenergic receptor agonists and antagonists
Acetylcholine receptors
Cholinergic receptor subtypes
Nicotinic receptors
Muscarinic receptors
Receptor desensitization
Other receptor-linked ion channels
The 7TM superfamily of G-protein linked receptors
Categories of 7TM receptor
Receptor diversity: variation and specialization
Receptor-ligand interaction and receptor activation
A two state equilibrium description of receptor activation
Receptor dimerization
Transmitting signals into cells
The receptor and the effector: one and the same, or are they separate entities?
Mixing and matching receptors and effectors
Intracellular 7TM receptor domains and signal transmission
Chapter 4 GTP-binding proteins and signal transduction
Introduction
ATP is not quite what it seems
GTP-binding proteins, G-proteins or GTPases
G-proteins
The GTPase cycle: A monostable switch
Switching off activity: Switching on GTPase
a -subunits
a -subunits determine G-protein diversity
Sites on ?-subunits that interact with the membrane and with other proteins
bg Subunits
b and g subtypes
bg subunits as signalling proteins
Receptor phosphorylation, down-regulation and pathway switching
Ras proteins
Monomeric GTP-binding proteins discovered as oncogene products
Subfamilies of Ras
Structure
Post-translational modifications
GTPases everywhere!
Mutations of Ras promoting cancer
Functions of Ras
Ras-GAPs
p120 GAP
Mechanism of GTPase activation
Organization of the active site of Ras and its interaction with RasGAP
GEFs: Guanine nucleotide exchange factors
Activation of G-proteins without subunit unit dissociation.
Constructing the mammalian b -adrenergic transduction system in insect cells
Chapter 5 Effector enzymes coupled to GTP binding proteins: Adenylyl Cyclase and Phospholipase C
Adenylyl cyclase
Cyclic AMP: the first second messenger
Cyclic AMP is formed from ATP
Adenylyl cyclase and its regulation
Structural organisation of adenylyl cyclases
Regulation of adenylyl cyclase
Phospholipase C
First hints of a signalling role for inositol phospholipids
The phospholipase family
The isoenzymes of PLC
PLC d: a prototype
Regulation of PLC
Chapter 6 The regulation of visual transduction
Sensitivity of photoreceptors
Photoreceptor mechanisms
Photoreceptor cells
Rod cells
Adaptation: Calcium acts as a negative regulator
Photo-excitation of rhodopsin
Switching off the mechanism
Retinal, an inverse agonist?
A note on phototransduction in invertebrates
Chapter 7 Calcium and signal transduction
A new second messenger is discovered
Calcium and evolution
Distinguishing Ca 2+ and Mg 2+
Free, bound and trapped Ca 2+
Cytosol Ca 2+ is kept low
Detecting changes in cytosol Ca 2+
Using Ca 2+ ionophores to impose a rise in Ca 2+
Sensing changes in Ca 2+ concentration
Mechanisms that elevate cytosol Ca 2+ concentration
Two sources of Ca 2+
The pattern of cytosol Ca 2+ changes in single cells
Temporal aspects
Resolving the spatial detail
Miniature calcium release events and global cellular signals
Ca 2+ signals in electrically excitable cells
Calcium signals in non-excitable cells
Localisation of intracellular second messengers
Box 1 Graded responses and Ca 2+ -induced Ca 2+ release
Calcium-binding by proteins
Polypeptide modules that bind Ca 2+
Effects of elevated calcium
Calmodulin and troponin C
Ca 2+ /Calmodulin-dependent kinases
Other Ca 2+ /calmodulin dependent enzymes
Calcium-dependent enzymes that are not regulated by calmodulin
Paradigms of calcium signalling
Example 1. Triggering neurotransmitter secretion
Example 2. Initiation of contraction in striated muscle
Example 3. Smooth muscle contraction
Example 4. Adrenergic control of contraction in the heart?
Chapter 9 Phosphorylation and dephosphorylation: protein kinases A and C
Protein phosphorylation as a switch in cellular functioning
Cyclic AMP and the Amplification of signals
Protein Kinase A
Protein kinase A and the regulation of transcription
Activation of the CREB transcription factor
Attenuation of the cyclic AMP response elements by dephosphorylation
Protein kinase A and the activation of ERK.
Actions of cyclic AMP not mediated by PKA
Regulation of ion channels by cyclic nucleotides
Epac, a guanine nucleotide exchange factor directly activated by cyclic AMP
Protein kinase C
Discovery of a phosphorylating activity independent cyclic AMP
The protein kinase C family
Structural domains and activation of protein kinase C
The C1 to C4 regions
Pseudo substrate
Activation
Multiple sources of diacylglycerol and other lipids to activate protein kinase C
Differential localization of PKC isoforms
PKC anchoring proteins, STICKs, PICKs and RACKs
Drosophila leads the way in revealing PKC signalling complexes.
PKC and cell transformation
The search for transcription factors that mediate phorbol ester effects
Over-expression of PKC isoforms and cellular transformation
PKC and inflammation
Phorbol ester and activation of endothelial cells and leukocytes
The role of PKC in the regulation of the respiratory burst
Chapter 10 Growth Factors: setting the framework.
Viruses and tumours
The discovery of NGF .... and EGF
Platelet derived Growth Factor, PDGF
Transforming Growth Factors, TGF a and TGF b
Problems with Nomenclature
Box: The cell cycle
Stages of the cell cycle and random transitions
Molecules that drive the cell cycle
Policing the drivers of the cell cycle
Box: Cancer and transformation
Definitions
The essence of cancer
Alterations dictating malignancy
Genetic alterations at the basis of malignancy
Constructing cancer in a dish
Chapter 11 Signalling pathways operated by receptor protein tyrosine kinases
Introduction
Spotting phosphotyrosine
v-Src and other protein tyrosine kinases
Other processes mediated through tyrosine phosphorylation
Tyrosine kinase-containing receptors
Cross-linking of receptors causes activation
Assembly of receptor signalling complexes
Src homology domains and the formation of receptor signalling complexes
Branching of the signalling pathway
1. The PLC?-protein kinase C signal transduction pathway
2. The Ras signalling pathway
3. The Ca 2+ /Calmodulin pathway
4. Activation of PI 3-kinase
5. Direct phosphorylation of transcription factors
A switch in receptor signalling: activation of ERK by 7TM receptors
Pathway switching mediated by receptor phosphorylation
Pathway switching by transactivation
Chapter 12 Signalling pathways operated by non-receptor protein tyrosine kinases
T cell receptor signalling
The IgE receptor and a signal for exocytosis
Interferons and their effects
Oncogenes, malignancy and signal transduction
Viral oncogenes
Non-viral oncogenes
BOX 12.1 Non-receptor protein tyrosine kinases and their activation
Chapter 13 Phosphoinositide 3-kinases, protein kinase B and signalling through the insulin receptor
Insulin receptor signalling; it took some time to discover
PI 3-kinase
A family of PI 3-kinases
Studying the role of PI 3-kinase
Pathways of activation for PI 3-kinase
Protein kinase B and activation through PI-3,4,5-P3
Insulin: the role of IRS, PI 3-kinase and PKB in the regulation of glycogen synthesis
From the insulin receptor to PKB
From PKB to glycogen synthase
The role of PI 3-kinase in activation of glucose transport and protein synthesis
Other processes mediated by the 3-phosphorylated inositol phospholipids
Multiple kinases and multiple phosphorylation sites, PDK1 as an integrator of multiple inputs
So, who did discover insulin?
Chapter 14 Signal transduction to and from adhesion molecules
Adhesion molecules
Naming names
Immunoglobulin superfamily
Integrins
Cadherins
Selectins
Cartilage Link proteins
Adhesion molecules and cell survival
Jun-N-terminal kinase (JNK) induces apoptosis in detached epithelial cells
Scatter factor rescues endothelial cells from apoptosis
Adhesion molecules and regulation of the cell cycle
Adhesion molecules as tumour suppressors
Adherens junctions and desmosomes in endothelial and epithelial cells.
Loss of adherent junctions induces de-differentiation
b -catenin plays a crucial role in the de-differentiation of epithelial cells
Mutations of b -catenin and APC in human cancers
A role of cadherin in contact inhibition?
BOX: Apoptosis
Introduction 
Characteristics of an apoptotic cell
Caspases, cellular proteases cause apoptosis
Cellular targets of caspases
Regulation of caspases
Regulation by Bcl-2
Induction of apoptosis by Fas-ligand
Activation of caspases by cell damage
Chapter 15 Adhesion molecules and trafficking of leukocytes
Introduction to inflammation and its mediators
Tumour Necrosis Factor- a ; potential anti-tumour agent or inflammatory cytokine?
TNF- a and regulation of adhesion molecule expression in endothelial cells
Chemokines and activation of integrins on leukocytes
The three-step process of leukocyte adhesion to endothelial cells
Chapter 16 Signalling through Receptor Bound Protein Serine/Threonine Kinases
The TGF b family of growth factors
Two signalling receptors for TGF b ; type I and type II
Accessory Receptors: betaglycan and endoglin
Downstream signalling; Drosophila, Caenorhabitidis and Smad
SMADs have multiple roles in signal transduction
Receptor-binding proteins involved in modulation of receptor function
Transcriptional regulation by Smads
Role of Smads in tumour suppression
Chapter 17 Protein dephosphorylation and protein phosphorylation
Introduction
Protein tyrosine phosphatases
Transmembrane receptor-like PTPs
Cytosolic PTPs
The role of PTPs in signal transduction
Positive regulation through phosphotyrosine dephosphorylation
CD45
SHP-2
Negative regulation through dephosphorylation
MKP-1, Dual specific protein phosphatases and regulation of MAP kinase by tyrosine protein phosphatases
SHP-1, Epo-R, STAT5 and JAK2
PTEN, a phosphatase for phosphoproteins and phospholipids
Serine/Threonine Phosphatases
The role of PP1 in the regulation of glycogen metabolism
The role of PP2B (calcineurin) in regulation of T-cell proliferation
Chapter 18 Protein domains and signal transduction
Structurally conserved protein modules
Identification of domains
Domain function
Domains that bind oligopeptide motifs
SH2 domains
PTB/PID domains
SH3 domains
Domains that bind proteins and lipids
PH domains
Polypeptide modules that bind Ca 2+
The EF-hand motif
C2 domains
Protein kinase domains
Protein kinases share a common domain Structural elements that regulate kinase activity
The regulatory domains of Src control protein kinase activity
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