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Chapter 1 -2 -3 -4 -5 -6 -7 -8 -9 -10 -11 -12 -13 -14 -15 -
16 -17 -18 -19 -20 -21 -22 -23 -24
Preface
Chapter 1 Prologue: Signal Transduction, Origins, and Ancestors (p1)
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
Chapter 2 First Messengers (p21)
Hormones
Growth factors
Cytokines
Vasoactive agents
Neurotransmitters and neuropeptides
Lipophilic messengers
Common aspects
Intracellular messengers
Binding of ligands to receptors
Binding heterogeneity
Measurement of binding affi nity
KD and EC50: receptor binding and functional consequences
Spare receptors
Down-regulation of receptors
Discovery of the fi rst second messenger, cAMP
Adrenaline (again) 
α-and β-adrenergic receptors
Adrenergic receptor agonists and antagonists
Acetylcholine receptors
Acetylcholine
Cholinergic receptor subtypes
Nicotinic receptors
Muscarinic receptors
Nicotinic receptors are ion channels
Architecture of the nicotinic receptor
Other ligand-gated ion channels
The 7TM superfamily of G-protein-linked receptors
Categories of 7TM receptor
Receptor diversity: variation and specialization
Binding of low-molecular-mass ligands
Calcium sensors and metabotropic receptors
Proteinase-activated receptors (PARs)
The adhesion receptor subfamily
Frizzled
Receptor– ligand interaction and receptor activation
Receptor dimerization
Transmitting signals into cells
Intracellular 7TM receptor domains and signal transmission
Adrenaline (yet again)
Chapter 4 GTP-binding Proteins and Signal Transduction (p81)
Nucleotides as metabolic regulators
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
α -Subunits
α-Subunits determine G protein diversity
Sites on α-subunits that interact with the membrane and with other proteins
β γγ-Subunits
βγ-Subunits as signalling proteins
The G protein receptor kinase family
Receptor phosphorylation, down-regulation and pathway switching
Receptor mechanisms obviating G proteins 
Monomeric GTP-binding proteins
Subfamilies of Ras
Structure
Post-translational modifications
GTPases everywhere!
Mutations of Ras that promote cancer
Functions of Ras
Ras-GAPs
Ras-GAP
Mechanism of GTPase activation
Guanine nucleotide exchange factors (GEFs)
Essay: Activation of G proteins without subunit unit dissociation
Pheromone-induced mating response in yeast
Monitoring subunit interactions in living cells by FRET
Constructing the mammalian β-adrenergic transduction system in insect cells
Chapter 5 Effector Enzymes Coupled to GTP Binding Proteins: Adenylyl Cyclase and Phospholipase C (p131)
Adenylyl cyclase
cAMP is formed from ATP
Adenylyl cyclase and its regulation
Structural organization of adenylyl cyclases
Regulation of adenylyl cyclase
ADP-ribosylation of βγ-subunits
Phospholipase C
The phospholipase family
The isoenzymes of PLC
PLCδ:a prototype
Regulation of PLC
Chapter 6 The Regulation of Visual Transduction and Olfaction (p159)
Phototransduction
Sensitivity of photoreceptors
Photoreceptor mechanisms
Photoreceptor cells
Adaptation: calcium acts as a negative regulator
Photo-excitation of rhodopsin 
Switching off the mechanism
Retinal, an inverse agonist?
Note on phototransduction in invertebrates
Olfaction
Olfactory receptor cells
Olfactory receptors
Transduction of olfactory signals
Chapter 7 Intracellular Calcium (p185)
A new second messenger is discovered
Calcium and evolution
Distinguishing Ca2+ and Mg2+
Free, bound, and trapped Ca2+
Cytosol Ca2+ is kept low
Extracellular calcium and activation
Using Ca2+ ionophores to impose a rise in Ca2+
Sensing changes in intracellular Ca2+ concentration
Ca2+-sensitive photoproteins
Fluorescent Ca2+ indicators
Monitoring cytosol Ca2+ in individual cells
Detecting and imaging subcellular Ca2+ changes
Mechanisms that elevate cytosol Ca2+ concentration
Ca2+ release from intracellular stores, IP3 and ryanodine receptors
Elevation of Ca2+ by cyclic ADP-ribose and NAADP
Elevation of Ca2+ by sphingosine-1-phosphate
Ca2+ influx through plasma membrane channels
Replenishing depleted stores
Ca2+ microdomains and global cellular signals
Ca2+ signals in electrically excitable cells
Calcium signals in non-excitable cells
Chapter 8 Calcium Eff ectors (p221)
Calcium-binding by proteins
Polypeptide modules that bind Ca2+
Decoding Ca2+ signals
Calmodulin and troponin C
Kinases regulated by calmodulin
Other Ca2+-calmodulin dependent enzymes
Calcium-dependent enzymes that are not regulated by calmodulin
Paradigms of calcium signalling
Initiation of contraction in skeletal muscle
Smooth muscle contraction
Chapter 9 Phosphorylation and Dephosphorylation: Protein kinases A and C (p243)
Protein phosphorylation as a switch in cellular functioning 
Cyclic AMP and the amplifi cation of signals
Protein kinase A
Protein kinase A and the regulation of transcription
Attenuation of the cAMP response elements by dephosphorylation
Protein kinase A and the activation of ERK
Actions of cAMP not mediated by PKA
Epac, a guanine nucleotide exchange factor directly activated by cAMP
Protein kinase C
The protein kinase C family
Structural domains and activation of protein kinase C
Activation of protein kinase C
Multiple sources of diacylglycerol and other lipids activate protein kinase C
Differential localization of PKC isoforms
Different types of PKC-binding proteins
Holding back the PKC response
A matter of life or death: PKC signalling complexes in the evasion of the fly-swat
Phorbol ester and infl ammation
Chapter 10 Nuclear Receptors (p273)
First steps in the isolation of steroid hormones 
Beginning again
The discovery of intracellular hormone receptors
Evidence for intracellular receptors
A superfamily of nuclear receptors
Orphan receptors and evolution
Nomenclature of nuclear receptors
Receptor structure and ligand binding
Ligand-binding domains are molecular switches
Activation of cytosol-resident receptors
DNA binding
Recognizing response elements
Activation and repression of transcription
Coactivators
Corepressors
Transrepression
Regulatory networks
Interaction with other signalling pathways
Phosphorylation
Phosphorylation may up- or down-regulate transcription
Ligand-independent activation
Non-transcriptional actions of nuclear receptors and their ligands
Chapter 11 Growth Factors: Setting the Framework (p297)
Viruses and tumours 
The discovery of NGF … and EGF
Platelet-derived growth factor (PDGF)
Transforming growth factors (TGFα and TGF β )
Problems with nomenclature
Essay: Cancer and transformation
Alterations dictating malignancy
Genetic alterations at the basis of malignancy
Constructing cancer in a dish
Chapter 12 Signalling Pathways Operated by Receptor Protein Tyrosine Kinases (p315)
Introduction
Spotting phosphotyrosine
v-Src and other protein tyrosine kinases
Processes mediated through tyrosine phosphorylation
Tyrosine kinase-containing receptors
Cross-linking of receptors causes activation
Assembly of receptor signalling complexes
Protein domains that bind phosphotyrosines and the assembly of signalling complexes
Branching of the signalling pathway 
The PLCγ–PKC signal transduction pathway
The Ras signalling pathway
From Ras to MAP kinase and the activation of transcription
Raf genes
Beyond ERK
Activation of protein kinases by ERKs 1 and 2
Activation of early response genes
Regulation of the cell cycle
Fine tuning the Ras-MAP kinase pathway: scaff old proteins
MAP kinase scaff old proteins discovered in yeast
KSR, a mammalian scaff old protein that regulates MAP kinase signalling
Other proteins that regulate MAP kinase pathways
Why are the signalling pathways so complicated?
Termination of the ERK response
The Ca2+–calmodulin pathway
Activation of PI3-kinase
Direct phosphorylation of STAT transcription factors
A switch in receptor signalling: activation of ERK by 7TM receptors
Pathway switching by transactivation
Pathway switching, transactivation, and metastatic progression of colorectal cancer
Chapter 13 Signal Transduction to and From Adhesion Molecules (p375)
Adhesion molecules 
Naming names
Immunoglobulin superfamily
ICAM
SIGLEC
Junctional adhesion molecules (JAMs)
Claudins
Occludin
Integrins
Cadherins
Selectins
Cartilage link proteins
Integrins, cell survival, and cell proliferation
Outside-in signalling from integrin adhesion complexes
Integrins and cell survival
Integrins and cell proliferation
Chapter 14 Adhesion Molecules in the Regulation of Cell Differentiation: Mainly About Wnt (p417)
Destabilization of adherens junctions causes cellular de-diff erentiation
Signalling through the canonical WNT pathway
Adenomatous polyposis coli (APC) and the localization of β-catenin
Take your partner: which way β-catenin?
The (β-catenin-dependent) canonical Wnt pathway
Wnt organizes the villous epithelium of the small intestine
Mutations of β-catenin, Axin, and APC in human cancers
Non-canonical signal transduction pathways
A role for cadherin in contact inhibition
Other examples of signalling through adhesion molecules
JAM and the regulation of diff erentiation
Occludin interacts with the TGFβ type I receptor
Occludin prevents Raf-1-mediated cell transformation
Chapter 15 Activation of the Innate Immune System: theToll-like Receptor 4 and
Signalling through Ubiquitylation (p541)
Sensing the microbial universe 
The toll receptor in Drosophila
Signalling through the TLR4 receptor
The TIRAP/MyD88 pathway
From TRAF6 to activation of NF-κB
From TRAF6 to activation of IRF-5
The IRF family of transcription factors
Some consequences of TLR4-induced gene transcription
Essay: Ubiquitylation and SUMOylation
Ubiquitylation: a process involving three activities (but not necessarily three proteins)
63K or 48K conjugation
Two classes of E3-ubiquitin ligases
Ubiquitin-binding proteins
SUMO and sumoylation
Essay: The proteasome complex
The proteasome
20S particle
Proteasome activator (PA) subunits
Chapter 16 Traffic of White Blood Cells (p483)
Infl ammation and leucocytes
Infl ammatory mediators
Tumour necrosis factor-α, potential anti-tumour agent or inflammatory cytokine?
The family of TNF proteins and receptors
TNF-α and regulation of adhesion molecule expression in endothelial cells
Signalling via NF-κB
Chemokines and activation of integrins on leucocytes
The three-step process of leucocyte adhesion to endothelial cells
Chapter 17 Tyrosine Protein Kinases and Adaptive Immunity:TCR, BCR,
Soluble Tyrosine Kinases and NFAT (p513)
The family of non-receptor protein tyrosine kinases
T-cell receptor signalling
More than one lymphocyte receptor must be engaged to ensure activation
PLC-γ1 to NFAT 
The PLC-γ1 to NF-κB pathway
Down-regulation of the TCR response
Signalling through interferon receptors
Interferon-α receptor and STAT proteins
Alternative signalling pathways
Down-regulation of the JAK-STAT pathway
Oncogenes, malignancy, and signal transduction
Non-viral oncogenes
Essay: Non-receptor protein tyrosine kinases and their regulation
Chapter 18 Phosphoinositide 3-Kinases, Protein Kinase B, and Signalling through the Insulin Receptor (p543)
Insulin receptor signalling; it took a little time to work out the details through phosphoinositides
PI 3-kinase and PI(3,4,5)P3
A family of PI 3-kinases
Studying the role of 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 PKB to glycogen synthase
The role of PI 3-kinase in activation of protein synthesis
Other processes mediated by the 3-phosphorylated inositol phospholipids
Chapter 19 Protein Kinase C Revisited (p577)
PKC in cell transformation
The search for transcription factors that mediate phorbol ester eff ects
Regulation of cell polarity
Chapter 20 Signalling Through Receptor Serine/Threonine Kinases (p599)
The TGF β family of growth factors
TGFβ receptors, type I and type II
TGFβ-mediated receptor activation
Accessory and pseudo receptors: betaglycan, endoglin, cripto, and BAMBI
Downstream signalling: Drosophila, Caenorhabitidis , and Smad
SMAD proteins have multiple roles in signal transduction
Hetero-oligomeric complex formation
Nuclear import and export
Holding the TGFβ pathway in check
TGFβ: tumour suppressor and metastatic promoter?
Chapter 21 Protein Dephosphorylation and Protein Phosphorylation (p641)
Protein tyrosine phosphatases 
Cytosolic PTPs
Transmembrane receptor-like PTPs
Tyrosine specifi city and catalytic mechanism
PTPs in signal transduction
PTP1B, diabetes, and obesity
Redox regulation of PTP1B: reactive oxygen species as second messengers
SHP-1 and SHP-2
CD45 and the regulation of immune cell function
Regulating receptor PTPs
Dual specificity phosphatases
Regulation of MAP kinases by dual-specificity protein phosphatases (DS-MKP)
Physiological role of the dual-specifi city MAP kinase phosphatases
PTEN, a dual-specifi city phosphatase for phosphatidyl inositol lipids Serine/threonine phosphatases
Classifi cation of the serine/threonine phosphatases
Regulation of PPPs
PP1 in the regulation of glycogen metabolism
PP2B (calcineurin)
Dephosphorylation of NFAT: immunophilins show the way
Notched wings, Morgan, and the gene theory
One gene, many alleles
Membrane components of the Notch pathway
Notch receptors
Glycosylation of ligands and receptor
Activation of Notch
Both receptor and ligand traffi cking are essential for Notch signalling
Notch and sensory progenitor cells of Drosophila ; the importance of endocytosis
Development of mechanoreceptors on thorax and wing
Notch and the development of the bristle-containing sensory organ
Notch in the maintenance of an intestinal stem compartment
Cross-talk with other signal transduction pathways
Chapter 23 Targeting Transduction Pathways for Research and
Medical Intervention (p735)
Chemotherapy 
Cytotoxic antibiotics and antimetabolites
The purine pathway to chemotherapy
Good drugs and bad
Combination chemotherapy
Alternative targets for cancer therapy: towards a scientifi c rationale
Inhibiting the EGF family of receptor kinases
The antibody approach: trastuzumab
The tyrosine kinase inhibitor approach
Other signal transduction components targeted for therapeutic intervention
Towards a different approach in testing cancer drugs?
Chapter 24 Protein Domains and Signal Transduction (p763)
Modular structure of proteins
Structural domains
The evolution and shuffl ing of domains
Sequence homology and the acquisition of function
Domain function
The inventory of domains
Classification
Examples of domains with roles in signalling
Domains that bind oligopeptide motifs
Phosphoinositide-binding domains
Polypeptide modules that bind Ca2+
Zinc finger domains
Protein kinase domains
Signal Transduction 2nd edition
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