Structure and function in cell signalling:
Gespeichert in:
| 1. Verfasser: | |
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| Format: | Buch |
| Sprache: | English |
| Veröffentlicht: |
Chichester
Wiley
2008
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| Schlagworte: | |
| Online-Zugang: | Inhaltsverzeichnis |
| Beschreibung: | Includes bibliographical references and index |
| Beschreibung: | XX, 389 S. zahlr. Ill. und graph. Darst. |
| ISBN: | 9780470025512 9780470025505 |
Internformat
MARC
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| 100 | 1 | |a Nelson, John |d 1953- |e Verfasser |0 (DE-588)135881803 |4 aut | |
| 245 | 1 | 0 | |a Structure and function in cell signalling |c John Nelson |
| 264 | 1 | |a Chichester |b Wiley |c 2008 | |
| 300 | |a XX, 389 S. |b zahlr. Ill. und graph. Darst. | ||
| 336 | |b txt |2 rdacontent | ||
| 337 | |b n |2 rdamedia | ||
| 338 | |b nc |2 rdacarrier | ||
| 500 | |a Includes bibliographical references and index | ||
| 650 | 4 | |a Amino Acid Sequence |x physiology | |
| 650 | 4 | |a Cellular signal transduction | |
| 650 | 4 | |a Intercellular Signaling Peptides and Proteins |x physiology | |
| 650 | 4 | |a Intracellular Signaling Peptides and Proteins |x physiology | |
| 650 | 4 | |a Signal Transduction |x physiology | |
| 650 | 0 | 7 | |a Zellkommunikation |0 (DE-588)4136131-3 |2 gnd |9 rswk-swf |
| 650 | 0 | 7 | |a Signaltransduktion |0 (DE-588)4318717-1 |2 gnd |9 rswk-swf |
| 650 | 0 | 7 | |a Zelle |0 (DE-588)4067537-3 |2 gnd |9 rswk-swf |
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| 999 | |a oai:aleph.bib-bvb.de:BVB01-016275119 | ||
Datensatz im Suchindex
| _version_ | 1804137315533062144 |
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| adam_text | Contents
Acknowledgments xvii
Preface xix
1 The components and foundations of signalling 1
1.1 Definition of terms used 2
1.1.1 First messengers 2
1.1.2 Glands and types of secretion 2
1.1.3 Ligands 4
1.1.4 Agonists 4
1.1.5 Antagonists 5
1.1.6 Receptors for first messengers 6
1.1.7 Second messengers 8
1.1.8 Soluble second messengers 9
1.1.9 Membrane-bound second messengers 9
1.2 Historical foundations 12
1.2.1 When did the discipline of cell signalling begin? 12
1.2.2 The discovery of hormones - Bayliss and Starling, 1902 13
1.2.3 The discovery of insulin and the beginning of endocrine
therapy - Banting and Best, 1921 14
1.2.4 Peptide sequencing - Fred Sanger, 1951 14
1.2.5 Discrimination of beta- and alpha-adrenergic responses -
Ahlquist, 1948 15
1.2.6 Acrasin = cAMP - the ancient hunger signal 15
1.3 Early milestones in signal transduction research 16
1.3.1 Cell-free experiments and the discovery of cAMP -
Sutherland, Rail and Berthet, 1957 16
1.3.2 Fluoride - a stimulator of G proteins 16
1.3.3 ATP and subcellular fractionation 17
1.3.4 Heat-stable factor - cAMP 17
1.3.5 The problem with rats 18
1.3.6 The discovery of hormonaUy regulated protein kinases -
phosphorylase kinase, serine phosphorylation and Ca2+ -
Krebs and Fischer, 1958-1968 18
1.3.7 Discovery of calcium as activator of phosphorylase
kinase 19
1.3.8 cAMP-dependent protein kinase 19
1.4 The discovery of receptors and G proteins 20
1.4.1 Radioligand receptor assays prove receptors are discrete
entities 20
vi CONTENTS
1.4.2 Oestrogen receptor directly detected by radioligand
binding assays - Jensen and Gorski, 1962 20
1.4.3 Purification of the (3-adrenergic receptor - Caron and
Lefkowitz, 1976 21
1.4.4 The discovery of G proteins. Guanine nucleotides, fluoride
and aluminium - Gilman and Rodbell, 1971-1983 21
1.4.5 Magnesium 21
1.4.6 High and low glucagon affinities 22
1.4.7 GTP (contaminant of ATP) lowers 7-pass receptor affinity 22
1.4.8 GTP analogues and adenylyl cyclase activation 23
1.4.9 cAMP toxicity and clonal mutants of S49 cells 24
1.4.10 Aluminium is needed for fluoride activation of G proteins 25
1.4.11 Use of bacterial toxins 25
1.4.12 The calcium signal 26
1.5 cAMP pathways 26
1.5.1 A simple mammalian signalling pathway - F-2,6-bisP as
a second messenger 26
1.5.2 PFK-1 and FBP-1 28
1.5.3 PFK-2/FBP-2 - a tandem enzyme 29
1.5.4 Control of PFK-2/FBP-2 by phosphorylation - liver 29
1.5.5 Control of PFK-2/FBP-2 by phosphorylation - heart 30
1.5.6 F-2,6-bisP in tumours 32
1.6 cAMP: ancient hunger signal - primitive signalling in
amoebazoans and prokaryotes 32
1.6.1 Slime moulds 32
1.6.2 cAMP and E. Coli 34
References 35
2 Enzymes and receptors - quantitative aspects 39
2.1 Enzyme steady state assays - Michaelian enzymes 39
2.1.1 How are enzymes assayed? 40
2.1.2 Steady state 40
2.1.3 KM - the Michaelis-Menten constant 42
2.1.4 Vmax is reached when the enzyme becomes saturated 42
2.1.5 What does the KM mean? 43
2.1.6 Non-Michealian enzymes - G proteins and Ras 45
2.1.7 Non-Michaelian enzymes - cooperativity and allostery 45
2.2 Receptor equilibrium binding assays 45
2.2.1 Equilibrium 45
2.2.2 Ko - the dissociation constant 47
2.2.3 Bmax - the maximum binding capacity is a count of the
receptors in a sample 47
2.2.4 The meaning of KD 49
2.2.5 Displacement assays 50
CONTENTS vii
2.3 The receptor s environment 51
2.3.1 Heterogeneity of binding sites - positive cooperativity 52
2.3.2 Binding site heterogeneity - two site models versus
negative cooperativity 53
2.3.3 Negative cooperativity of the insulin receptor or two
site model 55
2.3.4 Site heterogeneity of the EGF receptor - independent
two site model? 57
2.4 Guanine nucleotides and the agonist affinity-shift
of 7-pass receptors 59
2.4.1 The ternary complex equilibrium model 60
2.4.2 The empty pocket form of Ga 62
2.4.3 The thermodynamic catalytic or kinetic model 62
2.4.4 Constitutive signalling in the absence of ligand 64
2.4.5 The effect of limiting concentrations of G protein
on agonist binding 65
2.4.6 Agonist binding in membrane preparations where the
cognate G protein is in unlimited supply 65
2.4.7 In vivo GTP versus GDP concentrations 66
References 67
3 Modules and motifs in transduction 71
3.1 Src homology domains 72
3.1.1 Src-homology-1 (SHI) region represents the tyrosine
kinase domain 72
3.1.2 Src-homology-2 (SH2) modules are phosphotyrosine-
binding domains 73
3.1.3 Src-homology-3 (SH3) modules are polyproline-binding
domains 75
3.1.4 Src-homology-4 (SH4) motif and Src unique domain 78
3.1.5 The C-terminal Src regulatory motif and Src family
autoinhibition 82
3.2 PH superfold modules: PH-, PTB- and PDZ-domains 85
3.2.1 PH domains - phosphoinositide lipid-binding modules,
or Gp/y-interacting modules 86
3.2.2 PTB domains - phosphotyrosine binding modules 86
3.2.3 PDZ domains - C-terminal (and C-terminal-like)
peptide binding modules 88
3.3 Bcr-homology (BcrH) domains 88
3.4 Dbl homology (DH) domains - partners of PH domains 89
3.5 Bcl-2 homology (BH) domains 90
3.6 Ras binding domains 90
3.7 Phosphoserine/phosphothreonine-binding domains 92
3.7.1 14-3-3 proteins 93
viii CONTENTS
3.7.2 Forkhead-associated domains 95
3.8 EF-hands - calcium-sensing modules 95
3.9 Cl and C2 domains - a Ca2+-activated, lipid-binding, module 96
References 97
4 Protein kinase enzymes - activation and auto-inhibition 101
4.1 The protein kinase fold 102
4.1.1 Invariant residues 102
4.1.2 The phosphate-binding loop or p-loop 104
4.1.3 Critical differences between serine/threonine kinases
and tyrosine kinases 107
4.1.4 Closed and open conformations 108
4.1.5 The catalytic loop or C-loop 109
4.1.6 The activation segment/loop or A-loop 112
4.2 Protein kinases activated by A-loop phosphorylation 113
4.2.1 Phosphorylation of A-loop residues and assembly
of active site 114
4.2.2 The A-loop and catalysis - transition state and site closure 115
4.2.3 ATP binding 115
4.2.4 A-loop and autoinhibition 116
4.3 The insulin receptor kinase (IRK) - a gated kinase 116
4.4 Cyclin dependent kinases 119
4.4.1 Monomeric Cdk2 structures 120
4.4.2 Cyclin-bound unphosphorylated Cdk 123
4.4.3 Cyclin-bound phosphorylated Cdk 123
4.5 Secondary inhibition mechanisms - PKA 124
4.5.1 Substrate or pseudosubstrate binding to the catalytic
cleft of PKA 126
4.5.2 The extended binding surface of RSub 126
4.5.3 Effects on cAMP binding at CBD-A 129
References 131
5 7-pass receptors and the catabolic response 133
5.1 7-pass receptor phylogeny 134
5.2 Functional mechanisms of 7-pass receptors 134
5.2.1 Gas-coupling receptors - glucagon- and p-adrenergic
receptors - stimulation of cAMP production 135
5.2.2 Gaq-coupling receptors - bombesin- and al-adrenergic
receptors - stimulation of calcium release from the
endoplasmic reticulum 135
5.2.3 Gai-coupling receptors - somatostatin and a2-adrenergic
receptors - inhibition of adenylyl cyclase, activation of K+
ion channels, inhibition of Ca2+ channels, and activation
of phospholipase C(32 136
CONTENTS ix
5.2.4 Glucagon- and p-adrenergic-receptors - the catabolic
cAMP-dependent protein kinase (PKA) pathway leading
to glycogenolysis 137
5.3 Amplification 137
5.3.1 Stimulated changes in cytosolic cAMP concentration 139
5.3.2 Spare receptors - maximum signal transduction
from partial occupancy of receptors 139
5.3.3 Collision coupling versus pre-coupling 139
5.3.4 How much cAMP is needed? 139
5.3.5 The PKA cascade 140
5.4 Adenylyl cyclase - signal limitation 140
5.4.1 Adenylyl cyclase - signal termination and PDE isoforms 140
5.4.2 Crosstalk and negative feed back 141
5.5 Adenylyl cyclase isoforms 141
5.5.1 Transmembrane isoforms of adenylyl cyclase 141
5.6 G proteins and the adenylyl cyclase effector isoforms 143
5.6.1 Gs-coupling catabolic receptors 148
5.6.2 p-Adrenergic/glucagon-receptor stimulation of
glycogenolysis 148
5.6.3 p-Adrenergic/glucagon-receptor inhibition of glycogen
synthesis 148
5.6.4 al-adrenergic receptor stimulation of glycogenolysis 148
5.6.5 Diffusible cascade or scaffolded pathway 149
5.7 Regulatory subunits of PKA and A-Kinase Anchoring Proteins 149
5.7.1 RII regulatory subunits - reversible phosphorylation
and scaffolding 150
5.7.2 Segregation of pathways 153
5.7.3 PKA and its inhibitors 154
5.8 Phosphorylase kinase 155
5.8.1 PhK structure 155
5.8.2 The catalytic y-subunit of PhK 156
5.8.3 Regulatory subunits 156
5.8.4 PhK substrates and autophosphorylation sites 157
5.8.5 Possible mechanisms of activation and holoenzyme
conformation 157
5.9 Glycogen phosphorylase 160
5.9.1 Glycogen phosphorylase isoforms 160
5.9.2 Glycogen phosphorylase allosteric sites 161
5.9.3 Control by hormones or metabolite effectors - functional
differences between muscle and liver isoforms 162
5.9.4 How do these properties of GP isoforms fit with
metabolic necessities? 163
5.9.5 Structural changes induced by GP activating signals 165
5.9.6 T-state to R-state transition 165
x CONTENTS
5.9.7 Activation by phosphorylation 165
5.9.8 Activation by 5 -AMP 168
5.9.9 Inhibition by glucose 169
5.10 Glycogen synthase 169
5.10.1 GSK-3 - a multi-tasking enzyme 170
5.11 Remaining questions - scaffolds and alternate
second messenger receptors 171
5.11.1 Protein kinase C 171
5.11.2 Lipid activation of PKC - DAG-binding isoforms are also
activated by phorbol esters 172
5.11.3 Alternative DAG/phorbol ester receptors 172
5.11.4 PKC scaffolds 173
5.11.5 What does PKC actually do? 173
5.11.6 Alternate cAMP receptors 174
5.12 G protein coupled receptor kinases - downregulators,
signal integrators 174
References 175
6 Single pass growth factor receptors 179
6.1 Receptor tyrosine kinases - ligands and signal transduction 179
6.1.1 RTK ligands and receptors 180
6.2 The PDGFR family - signal transduction 181
6.2.1 PDGFR signal transduction particle 182
6.2.2 MAP kinases and MAPK kinases 184
6.2.3 PDGFR kinase insert tyrosines - PI-3-kinase, and
Ras versus Rac 186
6.2.4 PDGFR, PI-3-kinase, Ras and mitosis 187
6.2.5 PDGFR, PI-3-kinase, Rac and motility 187
6.2.6 PDGFR insert phosphotyrosines and Ras regulators 188
6.2.7 Sos-1 - a bi-functional guanine nucleotide exchange
Tactor (GEF) 189
6.2.8 Sos - the switch from RasGEF to RacGEF 190
6.2.9 PDGFR C-terminal tail tyrosines 192
6.2.10 Alternative Grb-2 docking sites: SHP-2 and She 192
6.2.11 She 192
6.2.12 PLCy 193
6.2.13 PDGFR Juxtamembrane tyrosines 193
6.3 PDGFR family autoinhibition: juxtamembrane and A-loop
tyrosines 194
6.3.1 PDGFR juxtamembrane and A-loop tyrosines -»
phenylalanines 194
6.3.2 PDGFR juxtamembrane (Y-Y —» A-A) mutant unresponsive
to ligand 195
6.3.3 PDGFR Y579/581F is stuck in an autoinhibited state 195
CONTENTS xi
6.3.4 PDGFR A-loop (Y — F) mutant cannot bind exogenous
substrate polypeptides 195
6.3.5 PDGFR juxtamembrane and A-loop tyrosines — alanines 196
6.3.6 PDGFR Y579/581A is constitutively active 196
6.4 Crystal structure of kinase domain of PDGFR family-A member: Flt-3 197
6.4.1 Flt-3 juxtamembrane interactions and autoinhibition/
activation 197
6.5 The ErbB family 200
6.5.1 EGFR family members and ligands 200
6.6 ErbB-type receptor signal transduction particles 202
6.6.1 The epidermal growth factor receptor kinase - a
pre-assembled active site 204
6.7 Autoinhibition of EGFR and activation 205
6.7.1 Ligand binding, dimerisation and activation 206
6.7.2 The EGFR juxtamembrane domain - a nexus for crosstalk 207
6.7.3 EGFR activation and calcium 209
References 211
7 G proteins (I) - monomeric G proteins 215
7.1 Classification 216
7.2 ON and OFF states of Ras-like proteins 217
7.3 Raf - a multi-domain serine/threonine kinase family
of Ras effectors 218
7.3.1 Raf-Ras binding - translocation of Raf from cytosol to
membrane 219
7.3.2 cAMP inhibition of cell division wo sequestration of Raf 221
7.3.3 Raf activation by translocation 221
7.3.4 B-Raf is less stringently inhibited than C-Raf 222
7.3.5 Homologous or heterologous trans-autophosphorylation 223
7.3.6 Erk-l/2-type MAPK pathway activation 223
7.3.7 MAPK scaffolds 223
7.3.8 Signal termination 224
7.3.9 Other activating signals for Raf 225
7.4 Ras protein structure and function 225
7.4.1 The GTPase site of Ras: G-boxes and switch regions 226
7.4.2 The P-loop (G-l) 226
7.4.3 Switch I (G-2) 228
7.4.4 Switch II (G-3) 230
7.5 The switch mechanism: hydrolysis-driven conformational
change in Ras 231
7.6 GTP hydrolysis 232
7.6.1 Structural effects of loss of y-phosphate 234
7.7 Effector and regulator binding surfaces of Ras 234
7.7.1 RasGAP 234
xii CONTENTS
7.7.2 RasGEFs 236
7.7.3 The Ras effector region and Raf binding 239
7.7.4 Rapl and cAMP effects 240
References 241
8 G proteins (II) - heterotrimeric G proteins 245
8.1 Classification and structural relationship with Ras 246
8.2 Ga-subunits: the Ras-like core, G-boxes and switch regions 249
8.2.1 The P-loop 250
8.2.2 Switch I/G-2 250
8.2.3 Switch I/insert-1: a tethered GTPase-octivating
protein (GAP) 253
8.2.4 Switch II/G-3 253
8.2.5 Switch III 254
8.3 GTP exchange, hydrolysis and switch movements 254
8.3.1 GTP conformations 255
8.3.2 The transition state 256
8.4 p/y- and receptor-binding surfaces of a-subunits 256
8.4.1 The p/y binding site of GDP-occupied a 256
8.4.2 The receptor-binding interface of GDP-occupied G proteins 257
8.4.3 Receptor-induced GDP dissociation and nucleotide exchange 259
8.4.4 Switch II helix rotation 259
8.4.5 Switch II - the primary effector-binding surface of
a-subunits 262
8.5 Modulators of G protein activity - the RGS protein family 263
8.5.1 RGS proteins and GTPase activation 263
8.5.2 RGS proteins: inhibition of nucleotide exchange-
crosstalk with other pathways 264
8.5.3 God/o/q GEF proteins - unrelated to RGS 265
8.5.4 GRKs - RGS domain-containing S/T-kinases 265
8.6 Signal transduction by p/y subunits 266
References 268
9 The insulin receptor and the anabolic response 271
9.1 The insulin receptor - a pre-dimerised RTK with a unique substrate 271
9.1.1 Insulin receptor residues numbering 273
9.1.2 Three clusters of autophosphorylated tyrosines in the InsR
intracellular region 273
9.2 InsR and IGF-IR: differentiation leads differential tissue effects 275
9.3 Features of metabolic control in key tissues 276
9.4 InsR downstream signalling pathways 277
9.4.1 MAPK/p90Rsk pathway only mediates growth effects 277
9.4.2 PI-3-kinase is the prime anabolic effector - is there
a second (non-MAPK) anabolic pathway: (CAP-Cbl-Crk)? 278
CONTENTS xiii
9.5 The insulin receptor substrate - a surrogate signal transduction
particle 278
9.5.1 IRS protein targetting 279
9.5.2 IRS-interacting proteins - Class 1A PI-3-kinases 280
9.6 IRS-1/2 phosphorylation and PI-3-kinase activation 280
9.7 Protein phosphatase-1 (PP-1) 281
9.7.1 Glycogen granule targetting of PP-1 281
9.7.2 p70Rsk - inducer of GS dephosphorylation? 282
9.8 Insulin reverses effects of adrenaline and/or glucagon 283
9.8.1 Insulin s reversal of adrenaline-induced glycogenolysis
in muscle 283
9.8.2 Insulin s reversal of adrenaline- and glucoagon-induced
glycogenolysis in liver 283
9.8.3 Insulin s reversal of adrenalin/glucagon-induced lipolysis
in adipose tissue 285
9.9 PIP3 downstream effects - glycogen synthesis 285
9.9.1 PKB and GSK-3 inactivation 286
9.9.2 PKC-C - negative feedback control 287
9.9.3 PIP3 downstream effects - GLUT4 mobilisation 287
9.10 Many questions remain 289
9.10.1 Insulin activates the Erkl/2 MAPK pathway - why, then,
is the insulin receptor not as mitogenic as the
PDGF receptor 289
9.10.2 PDGR-(3 activates PI-3-kinase but does not exert anabolic
effects like the insulin receptor Why? 290
9.10.3 The insulin receptor and the IGF-I receptor are
homologues - why is one anabolic and the other mitogenic? 290
9.10.4 Do differing C-terminal tails cause differing regulation
of growth responses in InsR versus IGF-IR? 291
9.10.5 IFG-II, insulin receptor-A and half receptors 292
References 293
10 Mitogens and cell cycle progression 297
10.1 The mitogenic response and the cell division cycle 298
10.1.1 Large scale biophysical events in the cell division cycle 298
10.1.2 The cyclin model 298
10.1.3 Summary of the budding yeast cell cycle 301
10.1.4 Mammalian cyclin cycle model 301
10.1.5 Embryonic cell cycle has no gaps 302
10.2 GO, competency, and the point of no return in Gl - the
R-point 303
10.2.1 What is GO? 303
10.2.2 The commitment point and competency factors 304
10.2.3 Growth factors and the fibroblast cell cycle 304
xiv CONTENTS
10.3 Oncogene products derived from growth factor pathway
components 305
10.4 Transcription and cyclins 306
10.5 Cyclin dependent kinases 307
10.5.1 Activating and inactivating phosphorylations 307
10.5.2 Inactivating phosphorylations of Cdks 307
10.5.3 Activating dephosphorylations of Cdks 309
10.5.4 DNA damage prevents dephosphorylation of Cdks 309
10.6 Deactivation by cyclin destruction 309
10.6.1 APC/cyclosome (APC/C) and SCF - E3 ubiquitin ligase
complexes 309
10.6.2 APC/C 310
10.6.3 SCF 310
10.7 Cyclin dependent kinases - activation through cyclin synthesis 311
10.7.1 Two sets of early genes - immediate and delayed 311
10.8 Mitogenic pathway downstream of single pass tyrosine kinase
receptors 311
10.8.1 Transcription factor families involved in triggering
the mitogenic response 311
10.8.2 Myc 311
10.8.3 Induction of Fos by serum response element binding 312
10.8.4 The Ets family of ternary complex transcription
factors - Elk-1, Sap-1/2 312
10.8.5 The serum response factor - MADS box-containing
transcrition factors 312
10.8.6 Signalling sequence of single-pass tyrosine kinase
receptors leading to cyclin D induction - serum
response element 313
10.8.7 Activation of Jun (and Myc) by inactivation of
glycogen synthase kinase-3 (GSK-3) 313
10.8.8 AP-1 complexes - bZip transcription factors 315
10.8.9 AP-1 response elements on DNA 318
10.8.10 AP-1 and cyclin Dl induction 319
10.9 CyclinD/Cdk-4/6 - only important substrate is RB 319
10.10 Retinoblastoma-related pocket proteins - negative
modulators of E2F 319
10.10.1 Phosphorylation/inactivation mechanism 321
10.10.2 The E2F family of transcription factors - the targets
of the pocket proteins 323
10.10.3 RB - a DNA-binding, E2F protein-binding tumour
suppressor 324
10.10.4 E2F targets - genes for DNA replication and licensing,
delayed early response genes (cyclin E and A),
and NPAT 324
CONTENTS xv
10.11 De-repression of the cyclin E gene by cyclin D/Cdk-4/6 325
10.11.1 Cyclin E/Cdk-2 substrates - RB, NPAT, nucleophosmin 325
10.11.2 Cyclin E - licensing and loading of helicase 326
10.12 Cyclin A/Cdk-2 - S-phase progression and termination 327
10.12.1 Cyclin A/Cdk-2 - prevention of origin re-firing 327
10.12.2 Terminating S-phase - cyclin A effects 327
10.13 The controlled process of mammalian DNA replication 328
10.13.1 How does a cell know when to dvivide? 328
10.13.2 DNA replication 328
10.13.3 Pre-replicative complex formation begins in Gl 328
10.13.4 Helicase loading 330
10.13.5 Geminin control of helicase loading and licensing 331
10.13.6 Origin firing - Ddk and Cdc45 331
10.14 Cyclin B translocations and M-phase 332
10.14.1 What triggers mitosis? 332
10.14.2 POLO - the ultimate mitotic trigger? 333
10.15 Cdk inhibitors 334
10.15.1 The INK proteins 334
10.15.2 The Cip/WAF family 335
10.16 p53 cell cycle arrest and apoptosis 336
10.16.1 p53 and Cip/WAF 336
10.16.2 Mdm2 and pl9Arf - control of p53 337
10.16.3 Apoptosis 338
10.16.4 Apoptosis or cell cycle arrest - majority verdict by a
jury of Cdk inhibitors, survival factors, and
pro-apoptotic factors 338
10.16.5 BH domain proteins and mitochondrial outer
membrane permeabilisation 339
10.16.6 p53 and apoptosis 339
10.16.7 Survival factors opposing induction of apoptosis 340
10.17 7-pass receptors and mitosis 340
10.17.1 The Gsp oncogene 340
10.17.2 Wnt/P-catenin 341
10.18 Concluding remarks and caveats 345
References 347
Appendix 1: Worked examples 355
A.I Enzyme and receptor assays worked out from raw data examples 355
A.I.I An alkaline phosphatase assay 355
Appendix 2: RasMol: installation and use 365
Index 377
|
| adam_txt |
Contents
Acknowledgments xvii
Preface xix
1 The components and foundations of signalling 1
1.1 Definition of terms used 2
1.1.1 First messengers 2
1.1.2 Glands and types of secretion 2
1.1.3 Ligands 4
1.1.4 Agonists 4
1.1.5 Antagonists 5
1.1.6 Receptors for first messengers 6
1.1.7 Second messengers 8
1.1.8 Soluble second messengers 9
1.1.9 Membrane-bound second messengers 9
1.2 Historical foundations 12
1.2.1 When did the discipline of cell signalling begin? 12
1.2.2 The discovery of 'hormones' - Bayliss and Starling, 1902 13
1.2.3 The discovery of insulin and the beginning of endocrine
therapy - Banting and Best, 1921 14
1.2.4 Peptide sequencing - Fred Sanger, 1951 14
1.2.5 Discrimination of beta- and alpha-adrenergic responses -
Ahlquist, 1948 15
1.2.6 'Acrasin' = cAMP - the ancient hunger signal 15
1.3 Early milestones in signal transduction research 16
1.3.1 Cell-free experiments and the discovery of cAMP -
Sutherland, Rail and Berthet, 1957 16
1.3.2 Fluoride - a stimulator of G proteins 16
1.3.3 ATP and subcellular fractionation 17
1.3.4 Heat-stable factor - cAMP 17
1.3.5 The problem with rats 18
1.3.6 The discovery of hormonaUy regulated protein kinases -
phosphorylase kinase, serine phosphorylation and Ca2+ -
Krebs and Fischer, 1958-1968 18
1.3.7 Discovery of calcium as activator of phosphorylase
kinase 19
1.3.8 cAMP-dependent protein kinase 19
1.4 The discovery of receptors and G proteins 20
1.4.1 Radioligand receptor assays prove receptors are discrete
entities 20
vi CONTENTS
1.4.2 Oestrogen receptor directly detected by radioligand
binding assays - Jensen and Gorski, 1962 20
1.4.3 Purification of the (3-adrenergic receptor - Caron and
Lefkowitz, 1976 21
1.4.4 The discovery of G proteins. Guanine nucleotides, fluoride
and aluminium - Gilman and Rodbell, 1971-1983 21
1.4.5 Magnesium 21
1.4.6 High and low glucagon affinities 22
1.4.7 GTP (contaminant of ATP) lowers 7-pass receptor affinity 22
1.4.8 GTP analogues and adenylyl cyclase activation 23
1.4.9 cAMP toxicity and clonal mutants of S49 cells 24
1.4.10 Aluminium is needed for fluoride activation of G proteins 25
1.4.11 Use of bacterial toxins 25
1.4.12 The calcium signal 26
1.5 cAMP pathways 26
1.5.1 A simple mammalian signalling pathway - F-2,6-bisP as
a second messenger 26
1.5.2 PFK-1 and FBP-1 28
1.5.3 PFK-2/FBP-2 - a 'tandem' enzyme 29
1.5.4 Control of PFK-2/FBP-2 by phosphorylation - liver 29
1.5.5 Control of PFK-2/FBP-2 by phosphorylation - heart 30
1.5.6 F-2,6-bisP in tumours 32
1.6 cAMP: ancient hunger signal - primitive signalling in
amoebazoans and prokaryotes 32
1.6.1 Slime moulds 32
1.6.2 cAMP and E. Coli 34
References 35
2 Enzymes and receptors - quantitative aspects 39
2.1 Enzyme steady state assays - Michaelian enzymes 39
2.1.1 How are enzymes assayed? 40
2.1.2 Steady state 40
2.1.3 KM - the Michaelis-Menten constant 42
2.1.4 Vmax is reached when the enzyme becomes saturated 42
2.1.5 What does the KM mean? 43
2.1.6 Non-Michealian enzymes - G proteins and Ras 45
2.1.7 Non-Michaelian enzymes - cooperativity and allostery 45
2.2 Receptor equilibrium binding assays 45
2.2.1 Equilibrium 45
2.2.2 Ko - the dissociation constant 47
2.2.3 Bmax - the maximum binding capacity is a 'count' of the
receptors in a sample 47
2.2.4 The meaning of KD 49
2.2.5 Displacement assays 50
CONTENTS vii
2.3 The receptor's environment 51
2.3.1 Heterogeneity of binding sites - positive cooperativity 52
2.3.2 Binding site heterogeneity - two site models versus
negative cooperativity 53
2.3.3 Negative cooperativity of the insulin receptor or two
site model 55
2.3.4 Site heterogeneity of the EGF receptor - independent
two site model? 57
2.4 Guanine nucleotides and the agonist 'affinity-shift'
of 7-pass receptors 59
2.4.1 The ternary complex 'equilibrium' model 60
2.4.2 The 'empty pocket' form of Ga 62
2.4.3 The thermodynamic 'catalytic' or 'kinetic' model 62
2.4.4 Constitutive signalling in the absence of ligand 64
2.4.5 The effect of limiting concentrations of G protein
on agonist binding 65
2.4.6 Agonist binding in membrane preparations where the
cognate G protein is in unlimited supply 65
2.4.7 In vivo GTP versus GDP concentrations 66
References 67
3 Modules and motifs in transduction 71
3.1 Src homology domains 72
3.1.1 Src-homology-1 (SHI) region represents the tyrosine
kinase domain 72
3.1.2 Src-homology-2 (SH2) modules are phosphotyrosine-
binding domains 73
3.1.3 Src-homology-3 (SH3) modules are polyproline-binding
domains 75
3.1.4 Src-homology-4 (SH4) motif and Src 'unique domain' 78
3.1.5 The C-terminal Src regulatory motif and Src family
autoinhibition 82
3.2 PH superfold modules: PH-, PTB- and PDZ-domains 85
3.2.1 PH domains - phosphoinositide lipid-binding modules,
or Gp/y-interacting modules 86
3.2.2 PTB domains - phosphotyrosine binding modules 86
3.2.3 PDZ domains - C-terminal (and C-terminal-like)
peptide binding modules 88
3.3 Bcr-homology (BcrH) domains 88
3.4 Dbl homology (DH) domains - partners of PH domains 89
3.5 Bcl-2 homology (BH) domains 90
3.6 Ras binding domains 90
3.7 Phosphoserine/phosphothreonine-binding domains 92
3.7.1 14-3-3 proteins 93
viii CONTENTS
3.7.2 Forkhead-associated domains 95
3.8 EF-hands - calcium-sensing modules 95
3.9 Cl and C2 domains - a Ca2+-activated, lipid-binding, module 96
References 97
4 Protein kinase enzymes - activation and auto-inhibition 101
4.1 The protein kinase fold 102
4.1.1 Invariant residues 102
4.1.2 The phosphate-binding loop or 'p-loop' 104
4.1.3 Critical differences between serine/threonine kinases
and tyrosine kinases 107
4.1.4 Closed and open conformations 108
4.1.5 The catalytic loop or 'C-loop' 109
4.1.6 The activation segment/loop or 'A-loop' 112
4.2 Protein kinases activated by A-loop phosphorylation 113
4.2.1 Phosphorylation of A-loop residues and assembly
of active site 114
4.2.2 The A-loop and catalysis - transition state and site closure 115
4.2.3 ATP binding 115
4.2.4 A-loop and autoinhibition 116
4.3 The insulin receptor kinase (IRK) - a 'gated' kinase 116
4.4 Cyclin dependent kinases 119
4.4.1 Monomeric Cdk2 structures 120
4.4.2 Cyclin-bound unphosphorylated Cdk 123
4.4.3 Cyclin-bound phosphorylated Cdk 123
4.5 Secondary inhibition mechanisms - PKA 124
4.5.1 Substrate or pseudosubstrate binding to the catalytic
cleft of PKA 126
4.5.2 The extended binding surface of RSub 126
4.5.3 Effects on cAMP binding at CBD-A 129
References 131
5 7-pass receptors and the catabolic response 133
5.1 7-pass receptor phylogeny 134
5.2 Functional mechanisms of 7-pass receptors 134
5.2.1 Gas-coupling receptors - glucagon- and p-adrenergic
receptors - stimulation of cAMP production 135
5.2.2 Gaq-coupling receptors - bombesin- and al-adrenergic
receptors - stimulation of calcium release from the
endoplasmic reticulum 135
5.2.3 Gai-coupling receptors - somatostatin and a2-adrenergic
receptors - inhibition of adenylyl cyclase, activation of K+
ion channels, inhibition of Ca2+ channels, and activation
of phospholipase C(32 136
CONTENTS ix
5.2.4 Glucagon- and p-adrenergic-receptors - the catabolic
cAMP-dependent protein kinase (PKA) pathway leading
to glycogenolysis 137
5.3 Amplification 137
5.3.1 Stimulated changes in cytosolic cAMP concentration 139
5.3.2 'Spare receptors' - maximum signal transduction
from partial occupancy of receptors 139
5.3.3 Collision coupling versus pre-coupling 139
5.3.4 How much cAMP is needed? 139
5.3.5 The PKA 'cascade' 140
5.4 Adenylyl cyclase - signal limitation 140
5.4.1 Adenylyl cyclase - signal termination and PDE isoforms 140
5.4.2 Crosstalk and negative feed back 141
5.5 Adenylyl cyclase isoforms 141
5.5.1 Transmembrane isoforms of adenylyl cyclase 141
5.6 G proteins and the adenylyl cyclase effector isoforms 143
5.6.1 Gs-coupling catabolic receptors 148
5.6.2 p-Adrenergic/glucagon-receptor stimulation of
glycogenolysis 148
5.6.3 p-Adrenergic/glucagon-receptor inhibition of glycogen
synthesis 148
5.6.4 al-adrenergic receptor stimulation of glycogenolysis 148
5.6.5 Diffusible cascade or scaffolded pathway 149
5.7 Regulatory subunits of PKA and A-Kinase Anchoring Proteins 149
5.7.1 RII regulatory subunits - reversible phosphorylation
and scaffolding 150
5.7.2 Segregation of pathways 153
5.7.3 PKA and its inhibitors 154
5.8 Phosphorylase kinase 155
5.8.1 PhK structure 155
5.8.2 The catalytic y-subunit of PhK 156
5.8.3 Regulatory subunits 156
5.8.4 PhK substrates and autophosphorylation sites 157
5.8.5 Possible mechanisms of activation and holoenzyme
conformation 157
5.9 Glycogen phosphorylase 160
5.9.1 Glycogen phosphorylase isoforms 160
5.9.2 Glycogen phosphorylase allosteric sites 161
5.9.3 Control by hormones or metabolite effectors - functional
differences between muscle and liver isoforms 162
5.9.4 How do these properties of GP isoforms fit with
metabolic necessities? 163
5.9.5 Structural changes induced by GP activating signals 165
5.9.6 T-state to R-state transition 165
x CONTENTS
5.9.7 Activation by phosphorylation 165
5.9.8 Activation by 5'-AMP 168
5.9.9 Inhibition by glucose 169
5.10 Glycogen synthase 169
5.10.1 GSK-3 - a multi-tasking enzyme 170
5.11 Remaining questions - scaffolds and alternate
second messenger 'receptors' 171
5.11.1 Protein kinase C 171
5.11.2 Lipid activation of PKC - DAG-binding isoforms are also
activated by phorbol esters 172
5.11.3 Alternative DAG/phorbol ester receptors 172
5.11.4 PKC scaffolds 173
5.11.5 What does PKC actually do? 173
5.11.6 Alternate cAMP receptors 174
5.12 G protein coupled receptor kinases - downregulators,
signal integrators 174
References 175
6 Single pass growth factor receptors 179
6.1 Receptor tyrosine kinases - ligands and signal transduction 179
6.1.1 RTK ligands and receptors 180
6.2 The PDGFR family - signal transduction 181
6.2.1 PDGFR signal transduction particle 182
6.2.2 MAP kinases and MAPK kinases 184
6.2.3 PDGFR kinase insert tyrosines - PI-3-kinase, and
Ras versus Rac 186
6.2.4 PDGFR, PI-3-kinase, Ras and mitosis 187
6.2.5 PDGFR, PI-3-kinase, Rac and motility 187
6.2.6 PDGFR insert phosphotyrosines and Ras regulators 188
6.2.7 Sos-1 - a bi-functional guanine nucleotide exchange
Tactor (GEF) 189
6.2.8 Sos - the switch from RasGEF to RacGEF 190
6.2.9 PDGFR C-terminal tail tyrosines 192
6.2.10 Alternative Grb-2 docking sites: SHP-2 and She 192
6.2.11 She 192
6.2.12 PLCy 193
6.2.13 PDGFR Juxtamembrane tyrosines 193
6.3 PDGFR family autoinhibition: juxtamembrane and A-loop
tyrosines 194
6.3.1 PDGFR juxtamembrane and A-loop tyrosines -»
phenylalanines 194
6.3.2 PDGFR juxtamembrane (Y-Y —» A-A) mutant unresponsive
to ligand 195
6.3.3 PDGFR Y579/581F is stuck in an autoinhibited state 195
CONTENTS xi
6.3.4 PDGFR A-loop (Y — F) mutant cannot bind exogenous
substrate polypeptides 195
6.3.5 PDGFR juxtamembrane and A-loop tyrosines — alanines 196
6.3.6 PDGFR Y579/581A is constitutively active 196
6.4 Crystal structure of kinase domain of PDGFR family-A member: Flt-3 197
6.4.1 Flt-3 juxtamembrane interactions and autoinhibition/
activation 197
6.5 The ErbB family 200
6.5.1 EGFR family members and ligands 200
6.6 ErbB-type receptor signal transduction particles 202
6.6.1 The epidermal growth factor receptor kinase - a
pre-assembled active site 204
6.7 Autoinhibition of EGFR and activation 205
6.7.1 Ligand binding, dimerisation and activation 206
6.7.2 The EGFR juxtamembrane domain - a nexus for crosstalk 207
6.7.3 EGFR activation and calcium 209
References 211
7 G proteins (I) - monomeric G proteins 215
7.1 Classification 216
7.2 ON and OFF states of Ras-like proteins 217
7.3 Raf - a multi-domain serine/threonine kinase family
of Ras effectors 218
7.3.1 Raf-Ras binding - translocation of Raf from cytosol to
membrane 219
7.3.2 cAMP inhibition of cell division wo sequestration of Raf 221
7.3.3 Raf activation by translocation 221
7.3.4 B-Raf is less stringently inhibited than C-Raf 222
7.3.5 Homologous or heterologous trans-autophosphorylation 223
7.3.6 Erk-l/2-type MAPK pathway activation 223
7.3.7 MAPK scaffolds 223
7.3.8 Signal termination 224
7.3.9 Other activating signals for Raf 225
7.4 Ras protein structure and function 225
7.4.1 The GTPase site of Ras: G-boxes and switch regions 226
7.4.2 The P-loop (G-l) 226
7.4.3 Switch I (G-2) 228
7.4.4 Switch II (G-3) 230
7.5 The switch mechanism: hydrolysis-driven conformational
change in Ras 231
7.6 GTP hydrolysis 232
7.6.1 Structural effects of loss of y-phosphate 234
7.7 Effector and regulator binding surfaces of Ras 234
7.7.1 RasGAP 234
xii CONTENTS
7.7.2 RasGEFs 236
7.7.3 The Ras effector region and Raf binding 239
7.7.4 Rapl and cAMP effects 240
References 241
8 G proteins (II) - heterotrimeric G proteins 245
8.1 Classification and structural relationship with Ras 246
8.2 Ga-subunits: the Ras-like core, G-boxes and switch regions 249
8.2.1 The P-loop 250
8.2.2 Switch I/G-2 250
8.2.3 Switch I/insert-1: a tethered GTPase-octivating
protein (GAP) 253
8.2.4 Switch II/G-3 253
8.2.5 Switch III 254
8.3 GTP exchange, hydrolysis and switch movements 254
8.3.1 GTP conformations 255
8.3.2 The transition state 256
8.4 p/y- and receptor-binding surfaces of a-subunits 256
8.4.1 The p/y binding site of GDP-occupied a 256
8.4.2 The receptor-binding interface of GDP-occupied G proteins 257
8.4.3 Receptor-induced GDP dissociation and nucleotide exchange 259
8.4.4 Switch II helix rotation 259
8.4.5 Switch II - the primary effector-binding surface of
a-subunits 262
8.5 Modulators of G protein activity - the 'RGS' protein family 263
8.5.1 RGS proteins and GTPase activation 263
8.5.2 RGS proteins: inhibition of nucleotide exchange-
crosstalk with other pathways 264
8.5.3 God/o/q GEF proteins - unrelated to RGS 265
8.5.4 GRKs - RGS domain-containing S/T-kinases 265
8.6 Signal transduction by p/y subunits 266
References 268
9 The insulin receptor and the anabolic response 271
9.1 The insulin receptor - a pre-dimerised RTK with a unique substrate 271
9.1.1 Insulin receptor residues numbering 273
9.1.2 Three clusters of autophosphorylated tyrosines in the InsR
intracellular region 273
9.2 InsR and IGF-IR: differentiation leads differential tissue effects 275
9.3 Features of metabolic control in key tissues 276
9.4 InsR downstream signalling pathways 277
9.4.1 MAPK/p90Rsk pathway only mediates growth effects 277
9.4.2 PI-3-kinase is the prime anabolic effector - is there
a second (non-MAPK) anabolic pathway: (CAP-Cbl-Crk)? 278
CONTENTS xiii
9.5 The insulin receptor substrate - a surrogate signal transduction
particle 278
9.5.1 IRS protein targetting 279
9.5.2 IRS-interacting proteins - Class 1A PI-3-kinases 280
9.6 IRS-1/2 phosphorylation and PI-3-kinase activation 280
9.7 Protein phosphatase-1 (PP-1) 281
9.7.1 Glycogen granule targetting of PP-1 281
9.7.2 p70Rsk - inducer of GS dephosphorylation? 282
9.8 Insulin reverses effects of adrenaline and/or glucagon 283
9.8.1 Insulin's reversal of adrenaline-induced glycogenolysis
in muscle 283
9.8.2 Insulin's reversal of adrenaline- and glucoagon-induced
glycogenolysis in liver 283
9.8.3 Insulin's reversal of adrenalin/glucagon-induced lipolysis
in adipose tissue 285
9.9 PIP3 downstream effects - glycogen synthesis 285
9.9.1 PKB and GSK-3 inactivation 286
9.9.2 PKC-C - negative feedback control 287
9.9.3 PIP3 downstream effects - GLUT4 mobilisation 287
9.10 Many questions remain 289
9.10.1 Insulin activates the Erkl/2 MAPK pathway - why, then,
is the insulin receptor not as mitogenic as the
PDGF receptor 289
9.10.2 PDGR-(3 activates PI-3-kinase but does not exert anabolic
effects like the insulin receptor Why? 290
9.10.3 The insulin receptor and the IGF-I receptor are
homologues - why is one anabolic and the other mitogenic? 290
9.10.4 Do differing C-terminal tails cause differing regulation
of growth responses in InsR versus IGF-IR? 291
9.10.5 IFG-II, insulin receptor-A and 'half receptors' 292
References 293
10 Mitogens and cell cycle progression 297
10.1 The mitogenic response and the cell division cycle 298
10.1.1 Large scale biophysical events in the cell division cycle 298
10.1.2 The cyclin model 298
10.1.3 Summary of the budding yeast cell cycle 301
10.1.4 Mammalian cyclin cycle model 301
10.1.5 Embryonic cell cycle has no 'gaps' 302
10.2 GO, competency, and the point of no return in Gl - the
'R-point' 303
10.2.1 What is GO? 303
10.2.2 The commitment point and competency factors 304
10.2.3 Growth factors and the fibroblast cell cycle 304
xiv CONTENTS
10.3 Oncogene products derived from growth factor pathway
components 305
10.4 Transcription and cyclins 306
10.5 Cyclin dependent kinases 307
10.5.1 Activating and inactivating phosphorylations 307
10.5.2 Inactivating phosphorylations of Cdks 307
10.5.3 Activating dephosphorylations of Cdks 309
10.5.4 DNA damage prevents dephosphorylation of Cdks 309
10.6 Deactivation by cyclin destruction 309
10.6.1 APC/cyclosome (APC/C) and SCF - E3 ubiquitin ligase
complexes 309
10.6.2 APC/C 310
10.6.3 SCF 310
10.7 Cyclin dependent kinases - activation through cyclin synthesis 311
10.7.1 Two sets of early genes - immediate and delayed 311
10.8 Mitogenic pathway downstream of single pass tyrosine kinase
receptors 311
10.8.1 Transcription factor families involved in triggering
the mitogenic response 311
10.8.2 Myc 311
10.8.3 Induction of Fos by 'serum response element' binding 312
10.8.4 The Ets family of 'ternary complex transcription
factors' - Elk-1, Sap-1/2 312
10.8.5 The 'serum response factor' - MADS box-containing
transcrition factors 312
10.8.6 Signalling sequence of single-pass tyrosine kinase
receptors leading to cyclin D induction - serum
response element 313
10.8.7 Activation of Jun (and Myc) by inactivation of
glycogen synthase kinase-3 (GSK-3) 313
10.8.8 AP-1 complexes - bZip transcription factors 315
10.8.9 AP-1 response elements on DNA 318
10.8.10 AP-1 and cyclin Dl induction 319
10.9 CyclinD/Cdk-4/6 - only important substrate is RB 319
10.10 Retinoblastoma-related 'pocket proteins' - negative
modulators of E2F 319
10.10.1 Phosphorylation/inactivation mechanism 321
10.10.2 The E2F family of transcription factors - the targets
of the 'pocket proteins' 323
10.10.3 RB - a DNA-binding, E2F protein-binding tumour
suppressor 324
10.10.4 E2F targets - genes for DNA replication and licensing,
delayed early response genes (cyclin E and A),
and NPAT 324
CONTENTS xv
10.11 De-repression of the cyclin E gene by cyclin D/Cdk-4/6 325
10.11.1 Cyclin E/Cdk-2 substrates - RB, NPAT, nucleophosmin 325
10.11.2 Cyclin E - licensing and loading of helicase 326
10.12 Cyclin A/Cdk-2 - S-phase progression and termination 327
10.12.1 Cyclin A/Cdk-2 - prevention of origin re-firing 327
10.12.2 Terminating S-phase - cyclin A effects 327
10.13 The controlled process of mammalian DNA replication 328
10.13.1 How does a cell know when to dvivide? 328
10.13.2 DNA replication 328
10.13.3 Pre-replicative complex formation begins in Gl 328
10.13.4 Helicase loading 330
10.13.5 Geminin control of helicase loading and licensing 331
10.13.6 Origin firing - Ddk and Cdc45 331
10.14 Cyclin B translocations and M-phase 332
10.14.1 What triggers mitosis? 332
10.14.2 POLO - the ultimate mitotic trigger? 333
10.15 Cdk inhibitors 334
10.15.1 The INK proteins 334
10.15.2 The Cip/WAF family 335
10.16 p53 cell cycle arrest and apoptosis 336
10.16.1 p53 and Cip/WAF 336
10.16.2 Mdm2 and pl9Arf - control of p53 337
10.16.3 Apoptosis 338
10.16.4 Apoptosis or cell cycle arrest - majority verdict by a
jury of Cdk inhibitors, survival factors, and
pro-apoptotic factors 338
10.16.5 BH domain proteins and mitochondrial outer
membrane permeabilisation 339
10.16.6 p53 and apoptosis 339
10.16.7 Survival factors opposing induction of apoptosis 340
10.17 7-pass receptors and mitosis 340
10.17.1 The Gsp oncogene 340
10.17.2 Wnt/P-catenin 341
10.18 Concluding remarks and caveats 345
References 347
Appendix 1: Worked examples 355
A.I Enzyme and receptor assays worked out from raw data examples 355
A.I.I An alkaline phosphatase assay 355
Appendix 2: RasMol: installation and use 365
Index 377 |
| any_adam_object | 1 |
| any_adam_object_boolean | 1 |
| author | Nelson, John 1953- |
| author_GND | (DE-588)135881803 |
| author_facet | Nelson, John 1953- |
| author_role | aut |
| author_sort | Nelson, John 1953- |
| author_variant | j n jn |
| building | Verbundindex |
| bvnumber | BV023071980 |
| callnumber-first | Q - Science |
| callnumber-label | QP517 |
| callnumber-raw | QP517.C45 |
| callnumber-search | QP517.C45 |
| callnumber-sort | QP 3517 C45 |
| callnumber-subject | QP - Physiology |
| classification_rvk | WE 5320 |
| classification_tum | BIO 200f BIO 220f |
| ctrlnum | (OCoLC)154798414 (DE-599)BSZ271437316 |
| dewey-full | 571.7/4 |
| dewey-hundreds | 500 - Natural sciences and mathematics |
| dewey-ones | 571 - Physiology & related subjects |
| dewey-raw | 571.7/4 |
| dewey-search | 571.7/4 |
| dewey-sort | 3571.7 14 |
| dewey-tens | 570 - Biology |
| discipline | Biologie |
| discipline_str_mv | Biologie |
| format | Book |
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| id | DE-604.BV023071980 |
| illustrated | Illustrated |
| index_date | 2024-07-02T19:33:23Z |
| indexdate | 2024-07-09T21:10:21Z |
| institution | BVB |
| isbn | 9780470025512 9780470025505 |
| language | English |
| lccn | 2007040695 |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-016275119 |
| oclc_num | 154798414 |
| open_access_boolean | |
| owner | DE-703 DE-29 DE-91G DE-BY-TUM DE-20 DE-355 DE-BY-UBR DE-29T DE-634 DE-11 DE-188 DE-578 |
| owner_facet | DE-703 DE-29 DE-91G DE-BY-TUM DE-20 DE-355 DE-BY-UBR DE-29T DE-634 DE-11 DE-188 DE-578 |
| physical | XX, 389 S. zahlr. Ill. und graph. Darst. |
| publishDate | 2008 |
| publishDateSearch | 2008 |
| publishDateSort | 2008 |
| publisher | Wiley |
| record_format | marc |
| spelling | Nelson, John 1953- Verfasser (DE-588)135881803 aut Structure and function in cell signalling John Nelson Chichester Wiley 2008 XX, 389 S. zahlr. Ill. und graph. Darst. txt rdacontent n rdamedia nc rdacarrier Includes bibliographical references and index Amino Acid Sequence physiology Cellular signal transduction Intercellular Signaling Peptides and Proteins physiology Intracellular Signaling Peptides and Proteins physiology Signal Transduction physiology Zellkommunikation (DE-588)4136131-3 gnd rswk-swf Signaltransduktion (DE-588)4318717-1 gnd rswk-swf Zelle (DE-588)4067537-3 gnd rswk-swf Zelle (DE-588)4067537-3 s Signaltransduktion (DE-588)4318717-1 s DE-604 Zellkommunikation (DE-588)4136131-3 s HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=016275119&sequence=000006&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Nelson, John 1953- Structure and function in cell signalling Amino Acid Sequence physiology Cellular signal transduction Intercellular Signaling Peptides and Proteins physiology Intracellular Signaling Peptides and Proteins physiology Signal Transduction physiology Zellkommunikation (DE-588)4136131-3 gnd Signaltransduktion (DE-588)4318717-1 gnd Zelle (DE-588)4067537-3 gnd |
| subject_GND | (DE-588)4136131-3 (DE-588)4318717-1 (DE-588)4067537-3 |
| title | Structure and function in cell signalling |
| title_auth | Structure and function in cell signalling |
| title_exact_search | Structure and function in cell signalling |
| title_exact_search_txtP | Structure and function in cell signalling |
| title_full | Structure and function in cell signalling John Nelson |
| title_fullStr | Structure and function in cell signalling John Nelson |
| title_full_unstemmed | Structure and function in cell signalling John Nelson |
| title_short | Structure and function in cell signalling |
| title_sort | structure and function in cell signalling |
| topic | Amino Acid Sequence physiology Cellular signal transduction Intercellular Signaling Peptides and Proteins physiology Intracellular Signaling Peptides and Proteins physiology Signal Transduction physiology Zellkommunikation (DE-588)4136131-3 gnd Signaltransduktion (DE-588)4318717-1 gnd Zelle (DE-588)4067537-3 gnd |
| topic_facet | Amino Acid Sequence physiology Cellular signal transduction Intercellular Signaling Peptides and Proteins physiology Intracellular Signaling Peptides and Proteins physiology Signal Transduction physiology Zellkommunikation Signaltransduktion Zelle |
| url | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=016275119&sequence=000006&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| work_keys_str_mv | AT nelsonjohn structureandfunctionincellsignalling |