Biochemistry of signal transduction and regulation:
Gespeichert in:
| 1. Verfasser: | |
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| Format: | Buch |
| Sprache: | English |
| Veröffentlicht: |
Weinheim
Wiley-VCH
2014
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| Ausgabe: | 5., completely rev. ed. |
| Schlagworte: | |
| Online-Zugang: | Inhaltsverzeichnis |
| Beschreibung: | Hier auch später erschienene, unveränderte Nachdrucke |
| Beschreibung: | XXVIII, 815 S. Ill., graph. Darst. |
| ISBN: | 9783527333660 9783527667505 9783527667499 9783527667482 9783527667475 |
Internformat
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| 245 | 1 | 0 | |a Biochemistry of signal transduction and regulation |c Gerhard Krauss |
| 250 | |a 5., completely rev. ed. | ||
| 264 | 1 | |a Weinheim |b Wiley-VCH |c 2014 | |
| 300 | |a XXVIII, 815 S. |b Ill., graph. Darst. | ||
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Datensatz im Suchindex
| _version_ | 1804150632758640640 |
|---|---|
| adam_text | CONTENTS
PREFACE XXVII
1 BASICS OF CELL SIGNALING 1
1.1 CELL SIGNALING: WHY, WHEN, AND WHERE? 1
1.2 INTERCELLULAR SIGNALING 3
1.2.1 TOOLS FOR INTERCELLULAR SIGNALING 3
1.2.2 STEPS OF INTERCELLULAR SIGNALING 5
1.2.2.1 FORMATION OF A SIGNAL IN THE SIGNAL-PRODUCING CELL AS A
RESULT OF AN EXTERNAL TRIGGER 5
1.2.2.2 TRANSPORT OF THE SIGNAL TO THE TARGET CELL 6
1.2.2.3 REGISTRATION OF THE SIGNAL IN THE TARGET CELL 6
1.2.3 REGULATION OF INTERCELLULAR SIGNALING 7
1.3 HORMONES IN INTERCELLULAR SIGNALING 8
1.3.1 THE CHEMICAL NATURE OF HORMONES 8
1.3.2 HORMONE ANALOGS: AGONISTS AND ANTAGONISTS 11
1.3.2.1 ANTAGONISTS 11
1.3.2.2 AGONISTS 12
1.3.3 ENDOCRINE, PARACRINE, AND AUTOCRINE SIGNALING 13
1.3.3.1 ENDOCRINE SIGNALING 14
1.3.3.2 PARACRINE SIGNALING 15
1.3.3.3 AUTOCRINE SIGNALING 15
1.3.4 DIRECT PROTEIN MODIFICATION BY SIGNALING MOLECULES 15
1.4 INTRACELLULAR SIGNALING: BASICS 15
1.4.1 RECEPTION OF EXTERNAL SIGNALS 16
1.4.2 ACTIVATION AND DEACTIVATION OF SIGNALING PROTEINS 16
1.4.3 PROCESSING OF MULTIPLE SIGNALS 18
1.4.4 VARIABILITY OF SIGNALING PROTEINS 18
1.5 MOLECULAR TOOLS FOR INTRACELLULAR SIGNALING 18
1.5.1 RECEPTORS 19
1.5.1.1 RECEPTORS RECEIVE EXTERNAL SIGNALS AND TRIGGER INTRACELLULAR
SIGNALING 19
1.5.1.2 MEMBRANE-BOUND RECEPTORS 20
1.5.1.3 INTRACELLULAR RECEPTORS 21
HTTP://D-NB.INFO/1034511017
VI | CONTENTS
1.5.1.4 THE INTERACTION BETWEEN HORMONE AND RECEPTOR 21
1.5.1.5 REGULATION OF RECEPTOR ACTIVITY 22
1.5.2 SIGNALING ENZYMES 23
1.5.3 SCAFFOLDING PROTEINS 24
1.5.4 DIFFUSIBLE INTRACELLULAR MESSENGERS: SECOND MESSENGERS 25
2 STRUCTURAL PROPERTIES, REGULATION AND POSTTRANSLATIONAL
MODIFICATION OF SIGNALING PROTEINS 27
2.1 MODULAR STRUCTURE OF SIGNALING PROTEINS 27
2.1.1.1 CATALYTIC DOMAINS 28
2.1.1.2 TARGETING AND INTERACTION DOMAINS 28
2.1.1.3 REGULATORY DOMAINS 28
2.1.1.4 UNSTRUCTURED, FLEXIBLE SECTIONS 30
2.1.1.5 MULTIVALENCY 30
2.1.1.6 DIFFERENTIAL USE OF MODULES 31
2.1.1.7 MULTIPLE INPUTS, REGULATORY INFLUENCES, AND OUTPUTS 31
2.1.1.8 SUBTYPES OF SIGNALING MODULES 31
2.2 MODULAR SIGNALING COMPLEXES 31
2.2.1.1 SPECIFICITY 33
2.2.1.2 SIGNAL-DIRECTED ASSEMBLY 33
2.2.1.3 VARIABILITY 33
2.2.1.4 REGULATION 33
2.3 REGULATION OF SIGNALING ENZYMES BY EFFECTOR BINDING 34
2.3.1.1 ALLOSTERY IN SIGNALING ENZYMES 34
2.3.1.2 LOW-MOLECULAR-WEIGHT EFFECTORS 35
2.3.1.3 INHIBITOR PROTEINS 35
2.3.1.4 ACTIVATOR PROTEINS 36
2.3.1.5 METAL IONS 36
2.4 POSTTRANSLATIONAL MODIFICATIONS (PTMS) IN CELLULAR SIGNALING 36
2.4.1 CHEMICAL NATURE OF PTMS 37
2.4.1.1 ALLOSTERIC AND CONFORMATIONAL FUNCTIONS OF PTMS 38
2.4.1.2 RECOGNITION OF PTMS BY INTERACTION DOMAINS 38
2.4.1.3 DYNAMIC NATURE OF PTMS 38
2.4.1.4 EXAMPLES OF REGULATORY PTMS 38
2.4.2 RECOGNITION OF PROTEIN MODIFICATIONS BY MODIFICATION-SPECIFIC
INTERACTION DOMAINS 41
2.4.3 MULTISITE PROTEIN MODIFICATION 42
2.4.3.1 PTM PATTERNS ARE USED AS A BAR CODE 43
2.4.3.2 MULTIPLE MODIFICATIONS OFTEN SHOW COMBINATORIAL CHARACTERISTICS
43
2.4.4 BINDING PROPERTIES OF REGULATORY INTERACTION DOMAINS 43
2.4.4.1 VERSATILITY AND VARIABILITY OF INTERACTION DOMAINS 46
2.4.5 HOW INTERACTION DOMAINS READ PTM PATTERNS 47
2.4.5.1 INDUCIBLE INTERACTIONS 47
2.4.5.2 COOPERATIVE INTERACTIONS AND MULTISITE PTMS 47
2.4.5.3 SEQUENTIAL PTM-DEPENDENT INTERACTIONS AND
CROSS-REGULATION 47
CONTENTS I VII
2.4.5.4 MUTUALLY EXCLUSIVE PTMS AND INTERACTIONS 48
2.4.5.5 ANTAGONISTIC ACTION OF PTMS 49
2.4.5.6 REGULATION OF INTRAMOLECULAR INTERACTIONS BY PTMS 49
2.4.5.7 CONVERGENT RECOGNITION OF A PTM 50
2.5 REGULATION BY PROTEIN PHOSPHORYLATION 51
2.5.1 GENERAL ASPECTS OF PROTEIN PHOSPHORYLATION 51
2.5.1.1 PROPERTIES AND INTERACTIONS OF PHOSPHORYLATED PROTEINS 52
2.5.2 ALLOSTERIC FUNCTIONS OF PROTEIN PHOSPHORYLATION 53
2.5.3 ORGANIZATION OF SIGNALING PATHWAYS BY PROTEIN PHOSPHORYLATION 54
2.5.3.1 TYR-PHOSPHORYLATION 54
2.5.3.2 SER/THR PHOSPHORYLATION 54
2.6 REGULATION BY PROTEIN LYSINE ACETYLATION 55
2.6.1 GENERAL ASPECTS OF PROTEIN LYSINE ACETYLATION 55
2.6.2 ENZYMES OF PROTEIN LYSINE ACETYLATION 56
2.6.2.1 HATS 56
2.6.2.2 HDACS 56
2.6.2.3 CLEAVAGE MECHANISM 57
2.6.3 REGULATORY FUNCTIONS OF LYSINE ACETYLATION 57
2.7 REGULATION BY PROTEIN METHYLATION 58
2.7.1 PROTEIN LYSINE METHYLATION 58
2.7.1.1 LYSINE METHYL
TRANSFERASES 59
2.7.1.2 LYSINE DEMETHYLASES, KDMS 59
2.7.1.3 INTERACTION DOMAINS FOR METHYLATED LYSINE
61
2.7.2 PROTEIN ARGININE METHYLATION 61
2.7.2.1 ARGININE DEMETHYLATION/CITRULLINATION 61
2.7.2.2 INTERACTION DOMAINS 62
2.8 UBIQUITIN MODIFICATION OF PROTEINS 62
2.8.1 PATHWAYS OF PROTEIN DEGRADATION 63
2.8.1.1 LYSOSOMAL PATHWAY 64
2.8.1.2 AUTOPHAGOSOMAL PATHWAY 64
2.8.1.3 PROTEASOMAL PATHWAY 64
2.8.2 BASICS OF UBIQUITIN MODIFICATION 65
2.8.2.1 THE UB-CONJUGATION REACTIONS: EL, E2, AND E3 ENZYMES 66
2.8.2.2 EL: ACTIVATION OF UBIQUITIN
68
2.8.2.3 E2: TRANSACYLATION TO THE UBIQUITIN-CONJUGATING ENZYME E2 68
2.8.2.4 E3: UBIQUITIN TRANSFER TO THE TARGET 68
2.8.3 STRUCTURE AND REGULATION OF UB-PROTEIN LIGASES 69
2.8.3.1 HECT DOMAIN E3 ENZYMES 69
2.8.3.2 RING DOMAIN E3 ENZYMES 71
2.8.3.3 STRUCTURE AND REGULATION OF CULLIN-RING LIGASES 73
2.8.3.4 SUBSTRATE RECOGNITION BY CULLIN-RING LIGASES 74
2.8.3.5 N-END RULE 74
2.8.3.6 EXAMPLES OF CULLIN-RINGE3 LIGASES 75
2.8.3.7 SCF COMPLEX 75
2.8.3.8 ANAPHASE-PROMOTING COMPLEX (APC) 76
VIII
| CONTENTS
2.8.3.9 CBL PROTEINS 77
2.8.4 DEGRADATION IN THE PROTEASOME 78
2.8.4.1 THE 20S PROTEASOME 78
2.8.4.2 THE 19S ACTIVATOR 80
2.8.5 NONPROTEOLYTIC FUNCTIONS OF UBIQUITIN CONJUGATION 81
2.8.5.1 DEUBIQUITINATION 81
2.8.5.2 MULTIPLICITY OF UB CONJUGATION 81
2.8.5.3 UB-BINDING DOMAINS AND UB RECEPTORS 84
2.8.5.4 UB-CONJUGATION IN REGULATION OF THE NFKB PATHWAY 85
2.8.6 UBIQUITIN-LIKE PROTEINS: SUMO-MODIFICATION
88
2.9 LIPIDATION OF SIGNALING PROTEINS 90
2.9.1 MYRISTOYLATION 91
2.9.2 PALMITOYLATION 92
2.9.2.1 FUNCTIONS OF PALMITOYLATION 93
2.9.3 FAMESYLATION AND GERANYLATION 93
2.9.4 DUAL LIPIDATION 95
2.9.5 CHOLESTEROL MEMBRANE ANCHOR 95
2.9.6 THE SWITCH FUNCTION OF LIPID ANCHORS 96
2.9.7 THE GLYCOSYL-PHOSPHATIDYL-INOSITOL (GPI) ANCHOR 98
QUESTIONS 99
REFERENCES 100
3 ORGANIZATION OF SIGNALING 103
3.1 SCAFFOLD PROTEINS 103
3.1.1 GENERAL ASPECTS OF SCAFFOLD PROTEINS 103
3.1.2 SCAFFOLDS AS ORGANIZERS OF SIGNALING CIRCUITS 105
3.1.2.1 ORGANIZATION OF SEQUENTIAL SIGNALING AND SIGNALING
CIRCUITS 106
3.1.2.2 SCAFFOLDS ORGANIZE SIGNALING COMPLEXES AND ARE TARGETS OF
REGULATION 107
3.1.2.3 SCAFFOLDS ORGANIZE FEEDBACK LOOPS 107
3.1.2.4 SCAFFOLDS AS SIGNALING ENZYMES AND ALLOSTERIC REGULATORS 108
3.2 SIGNAL PROCESSING IN SIGNALING PATHS AND SIGNALING NETWORKS 108
3.2.1 SPECIFICITY OF SIGNALING 109
3.2.2 PTM-INDUCED FORMATION OF SIGNALING COMPLEXES 109
3.2.3 SIGNALING THROUGH PREASSEMBLED MULTIPROTEIN COMPLEXES 110
3.2.4 SIGNALING IN DEPENDENCE OF SUBCELLULAR LOCALIZATION: SPATIAL
ORGANIZATION 111
3.2.4.1 SPATIAL CONTROL BY SCAFFOLDING 111
3.2.4.2 SPATIAL CONTROL BY PHOSPHORYLATION 112
3.2.4.3 LIPID ANCHORS 112
3.2.4.4 CLUSTERING OF SIGNALING PROTEINS ON THE NANOSCALE 112
3.2.5 TEMPORAL CONTROL OF SIGNALING 113
3.3 ARCHITECTURE OF SIGNALING PATHWAYS 113
3.3.1 LINEARITY, BRANCHING, CROSSTALK, AND NETWORKS 114
CONTENTS I IX
3.3.1.1 LINEARITY 114
3.3.1.2 BRANCHING 114
3.3.1.3 CROSSTALK 114
3.3.1.4 NETWORKS 115
3.3.2 REGULATORY CIRCUITS AND RESPONSES IN BIOLOGICAL NETWORKS
116
3.3.2.1 CIRCUITS AND CASCADES
116
3.3.2.2 FEEDBACK LOOPS 117
3.3.2.3 NEGATIVE FEEDBACK 117
3.3.2.4 POSITIVE FEEDBACK 119
3.3.2.5 BISTABILITY 120
3.3.2.6 DYNAMIC BEHAVIOR OF RESPONSES 121
3.3.3 NETWORK STRUCTURES 121
3.3.3.1 INTERACTION NETWORKS: HUBS 122
3.3.3.2 LAYERED NETWORKS 124
3.3.3.3 MODULARITY 126
3.3.3.4 REDUNDANCY AND ROBUSTNESS 126
QUESTIONS 127
REFERENCES 127
4 THE REGULATION OF CENE EXPRESSION 129
4.1 THE BASIC STEPS OF GENE EXPRESSION 129
4.1.1 REGULATION OF TRANSCRIPTION 129
4.1.1.1 CONVERSION OF THE PRE-MRNA INTO THE MATURE MRNA 131
4.1.1.2 REGULATION AT THE LEVEL OF MRNA AND TRANSLATION 131
4.1.1.3 NATURE OF THE REGULATORY SIGNALS 131
4.2 THE COMPONENTS OF THE EUKARYOTIC TRANSCRIPTION MACHINERY 131
4.2.1 THE BASIC FEATURES OF EUKARYOTIC TRANSCRIPTION 132
4.2.2 ELEMENTARY STEPS OF EUKARYOTIC TRANSCRIPTION 135
4.2.3 THE EUKARYOTIC RNA POLYMERASES 135
4.2.4 THE CORE PROMOTER AND STRUCTURE OF THE TRANSCRIPTION
START SITE 137
4.2.5 GENERAL TRANSCRIPTION FACTORS AND THE BASAL TRANSCRIPTION
APPARATUS 139
4.2.5.1 TFIID 139
4.2.5.2 TFIIH 141
4.2.6 THE MEDIATOR COMPLEX 143
4.2.7 C-TERMINAL DOMAIN (CTD) OF RNA POLYMERASE II AND
THE ONSET OF TRANSCRIPTION 146
4.3 THE PRINCIPLES OF TRANSCRIPTION REGULATION 149
4.3.1 ELEMENTS OF TRANSCRIPTION REGULATION 149
4.3.2 REGULATION OF EUKARYOTIC TRANSCRIPTION BY SPECIFIC TRANSCRIPTION
FACTORS 151
4.3.2.1 ACTIVATION AND REPRESSION OF TRANSCRIPTION 152
4.3.3 COREGULATORS OFTRANSCRIPTION 153
4.3.4 DNA-BINDING OF SPECIFIC TRANSCRIPTION FACTORS 153
X | CONTENTS
4.3.4.1 DNA-BINDING DOMAINS 154
4.3.5 STRUCTURE OF THE RECOGNITION SEQUENCE AND QUATERNARY STRUCTURE OF
DNA-BINDING PROTEINS 155
4.3.5.1 PALINDROMIC ARRANGEMENT 155
4.3.5.2 DIRECT REPEATS OF THE RECOGNITION SEQUENCE 155
4.3.5.3 IDENTITY OF A RE 156
4.3.5.4 HOMODIMERS AND HETERODIMERS 156
4.3.6 COMMUNICATION WITH THE TRANSCRIPTION APPARATUS: TRANSACTIVATION
DOMAINS 157
4.3.7 CLUSTERING OFRES AND THE ENHANCEOSOME 159
4.3.8 DNA RECOGNITION AND SELECTIVITY OF TRANSCRIPTION ACTIVATION 161
4.3.8.1 SEQUENCE OF THE RE 161
4.3.8.2 ALLOSTERY IN TRANSCRIPTION FACTOR-RE INTERACTIONS 162
4.3.8.3 INFLUENCE OF NEIGHBORING SEQUENCES AND CHROMATIN
SURROUNDING 162
4.3.9 REPRESSION OF TRANSCRIPTION 163
4.4 THE CONTROL OF TRANSCRIPTION FACTORS 165
4.4.1 * CLASSIFICATION OF TRANSCRIPTION FACTORS BY THEIR FUNCTION IN
SIGNAL
TRANSDUCTION NETWORKS 165
4.4.1.1 CONSTITUTIVELY ACTIVE TRANSCRIPTION FACTORS 166
4.4.1.2 REGULATORY TRANSCRIPTION FACTORS 166
4.4.2 MECHANISMS FOR THE CONTROL OF THE ACTIVITY OF DNA-BINDING
PROTEINS 167
4.4.2.1 CHANGES IN THE CONCENTRATION OF REGULATORY DNA-BINDING
PROTEINS 169
4.4.2.2 REGULATION BY BINDING OF EFFECTOR MOLECULES 169
4.4.3 PTM OF TRANSCRIPTION REGULATORS 170
4.4.3.1 REGULATION BY PHOSPHORYLATION 171
4.4.3.2 REGULATION BY ACETYLATION 175
4.5 CHROMATIN STRUCTURE AND TRANSCRIPTION REGULATION 175
4.5.1 CHROMATIN ARCHITECTURE AT PROMOTERS 177
4.5.1.1 HISTONE VARIANTS 180
4.5.1.2 CHROMATIN REMODELING 180
4.5.1.3 CHROMATIN MODIFICATION 182
4.5.2 HISTONE ACETYLATION 182
4.5.2.1 HISTONE ACETYLTRANSFERASES 184
4.5.2.2 HISTONE DEACETYLATION 185
4.5.3 HISTONE METHYLATION 186
4.5.3.1 ENZYMES OF HISTONE LYSINE METHYLATION 188
4.5.3.2 ENZYMES OF HISTONE LYSINE DEMETHYLATION 189
4.5.3.3 HISTONE ARGININE METHYLATION 189
4.5.4 HISTONE PHOSPHORYLATION 190
4.5.5 HISTONE UBIQUITINATION 192
4.5.6 RECOGNITION OF HISTONE MODIFICATIONS BY PROTEIN DOMAINS 192
4.5.7 HISTONE MODIFICATION CROSSTALK 193
CONTENTS IXI
4.5.7.1 CROSSTALK MECHANISMS 194
4.5.7.2 IS THERE A HISTONE MODIFICATION CODE ? 196
4.5.8 HISTONE MODIFICATION AND EPIGENETICS 197
4.5.9 DNA METHYLATION 197
4.5.9.1 DNA METHYLTRANSFERASES 200
4.5.9.2 COUPLING DNA METHYLATION TO GENE REPRESSION 200
4.5.9.3 LINKING DNA METHYLATION AND HISTONE METHYLATION 201
4.5.9.4 BIOLOGICAL FUNCTIONS OF DNA METHYLATION 202
4.5.10 SUMMARY OF THE REGULATORY STEPS IN TRANSCRIPTION 203
QUESTIONS 205
REFERENCES 206
5 RNA PROCESSING, TRANSLATIONAL REGULATION, AND RNA INTERFERENCE 209
5.1 PRE-MRNA PROCESSING 209
5.1.1 CAPPING AND POLYADENYLATION 210
5.1.1.1 CAPPING 210
5.1.1.2 POLYADENYLATION 210
5.1.2 ALTERNATIVE SPLICING 210
5.1.3 REGULATION OF ALTERNATIVE SPLICING 211
5.1.3.1 SR PROTEINS 213
5.1.3.2 HNRNPS 214
5.1.4 CHROMATIN STRUCTURE AND SPLICING 214
5.1.5 COUPLING OF PRE-MRNA PROCESSING, TRANSCRIPTION, AND
TRANSLATION 215
5.1.5.1 RNA POL II POISED FOR TRANSCRIPTION 215
5.1.5.2 FORMATION OF 5 CAP 215
5.1.5.3 CHROMATIN MODIFICATION AND START OF PRODUCTIVE ELONGATION 215
5.1.5.4 TRANSCRIPTION AND NUCLEAR PORES 216
5.1.5.5 SPLICING DURING TRANSCRIPTION ELONGATION 216
5.1.5.6 RNA POL II TERMINATION 216
5.1.5.7 LINKAGE TO CYTOPLASMIC EVENTS 216
5.2 REGULATION AT THE LEVEL OF TRANSLATION 217
5.2.1 OVERVIEW OF TRANSLATION INITIATION 217
5.2.2 THE GENERAL MECHANISMS OF TRANSLATIONAL CONTROL 218
5.2.2.1 MRNA-SPECIFIC CONTROL OF TRANSLATION 219
5.2.2.2 GLOBAL CONTROL OF TRANSLATION 219
5.2.3 MRNA-SPECIFIC REGULATION BY 5 -SEQUENCES: CONTROL OF
FERRITIN MRN A TRANSLATION BY IRON 220
5.2.4 MRNA-SPECIFIC TRANSLATIONAL REGULATION BY PROTEIN
BINDING TO 3 -UTRS 222
5.2.5 GLOBAL TRANSLATIONAL REGULATION OF MRNAS BY TARGETING EIF-4E 222
5.2.5.1 4E-BP1 PHOSPHORYLATION 224
5.2.5.2 S6 KINASE PHOSPHORYLATION 226
5.2.6 REGULATION OF TRANSLATION VIA EIF-2 226
5.3 REGULATION BY RNA SILENCING 229
XII
| CONTENTS
5.3.1 BASICS OF RNA SILENCING 230
5.3.2 THE MIRNAS 233
5.3.2.1 MIRNA BIOGENESIS 233
5.3.2.2 FORMATION OF MIRISC 235
5.3.2.3 POSTTRANSCRIPTIONAL REPRESSION AND MRNA DECAY 235
5.3.2.4 REGULATION OF MIRNAS 238
5.3.2.5 REGULATORY FUNCTIONS OF MIRNAS 240
5.3.2.6 MIRNAS AND CANCER 243
5.3.3 SIRNAS 243
5.3.3.1 SOURCES AND PROCESSING OF SIRNAS 243
5.3.3.2 POSTTRANSCRIPTIONAL SILENCING BY SIRNAS 246
5.3.3.3 FUNCTIONS AND APPLICATIONS OF SIRNAS 246
QUESTIONS 247
REFERENCES 248
6 SIGNALING BY NUCLEAR RECEPTORS 251
6.1 IIGANDS OF NUCLEAR RECEPTORS (NRS) 252
6.2 PRINCIPLES OF SIGNALING BY NUCLEAR RECEPTORS (NRS) 254
6.3 STRUCTURE OF NUCLEAR RECEPTORS (NRS) 257
6.3.1 DNA-BINDING ELEMENTS OF NRS: HRES 258
6.3.2 THE DNA-BINDING DOMAIN OF NRS 260
6.3.3 LIGAND-BINDING DOMAIN 261
6.3.3.1 LIGAND BINDING 262
6.3.3.2 LIGAND BINDING AND AF-2 FUNCTION 263
6.3.3.3 SWITCH FUNCTION OF LIGAND BINDING 264
6.3.3.4 PROMISCUOUS LIGAND BINDING 265
6.3.4 TRANSACTIVATION FUNCTIONS OF THE NRS 265
6.3.5 STRUCTURE OF AN INTACT NR COMPLEX ON DNA 266
6.3.6 ORPHAN NUCLEAR RECEPTORS 268
6.4 TRANSCRIPTIONAL REGULATION BY NRS 268
6.4.1 COREGULATORS IN NR FUNCTION 269
6.4.2 NR COACTIVATORS 271
6.4.2.1 SRC/PL60 FAMILY OF COACTIVATORS 271
6.4.2.2 TRAP COMPLEX, MEDIATOR 273
6.4.2.3 VARIABILITY OF COACTIVATOR RECRUITMENT 273
6.4.3 COREPRESSORS OF NRS 274
6.5 REGULATION OF SIGNALING BY NUCLEAR RECEPTORS 274
6.5.1 REGULATION AT THE LEVEL OF LIGAND CONCENTRATION 275
6.5.2 REGULATION BY PTM 276
6.5.2.1 REGULATION BY PHOSPHORYLATION 276
6.5.3 UBIQUITINATION AND SUMOYLATION OF NRS 278
6.5.4 COMPOSITE DNA ELEMENTS, INTERACTION WITH OTHER TRANSCRIPTION
FACTORS, AND LONG-RANGE EFFECTS 278
6.5.4.1 CROSSTALK WITH OTHER TRANSCRIPTION FACTORS 279
6.5.4.2 LONG-RANGE ACTIONS OF NRS 279
CONTENTS | XIII
6.5.5 DETERMINANTS OF CELL-AND GENE-SPECIFICITY OF NR ACTION 280
6.6 SUBCELLULAR LOCALIZATION OF NRS 280
6.6.1 NUCLEAR AND CYTOPLASMIC POOLS 281
6.6.2 OTHER SUBCELLULAR POOLS 281
6.6.3 LIGAND-DEPENDENT TRANSLOCATION OF NUCLEAR RECEPTORS 281
6.6.4 NUCLEAR TRANSLOCATION 283
6.7 NONGENOMIC FUNCTIONS OF NRS AND THEIR LIGANDS 284
6.7.1 NUCLEAR RECEPTOR FUNCTIONS OUTSIDE OF THE NUCLEUS 284
6.7.1.1 CYTOPLASMIC FUNCTIONS 284
6.7.1.2 ER ACTIONS AT THE CELL MEMBRANE 285
6.7.1.3 NR ACTION AT THE MITOCHONDRION 288
6.7.2 HORMONE BINDING TO OTHER RECEPTOR TYPES 288
QUESTIONS 289
REFERENCES 289
7 C PROTEIN-COUPLED SIGNAL TRANSMISSION PATHWAYS 291
7.1 TRANSMEMBRANE RECEPTORS: GENERAL STRUCTURE AND
CLASSIFICATION 291
7.1.1 SIGNALING VIA TRANSMEMBRANE RECEPTORS 291
7.1.2 SIGNALING VIA LIGAND- OR VOLTAGE-GATED ION CHANNELS 292
7.2 STRUCTURAL PRINCIPLES OF TRANSMEMBRANE RECEPTORS 294
7.2.1 THE EXTRACELLULAR DOMAIN OF TRANSMEMBRANE RECEPTORS 294
7.2.2 THE TRANSMEMBRANE DOMAIN 296
7.2.2.1 STRUCTURE OF TRANSMEMBRANE ELEMENTS 296
7.2.3 THE INTRACELLULAR DOMAIN OF MEMBRANE RECEPTORS 298
7.2.3.1 RECRUITMENT OF DOWNSTREAM SIGNALING PROTEINS 298
7.2.3.2 TRIGGERING OF ENZYME ACTIVITY 299
7.2.4 REGULATION OF RECEPTOR ACTIVITY 300
7.2.4.1 RECEPTOR PHOSPHORYLATION AND RECEPTOR RECYCLING 300
7.2.4.2 UBIQUITINATION AND DEGRADATION 301
7.3 G PROTEIN-COUPLED RECEPTORS 301
7.3.1 CLASSIFICATION OF GPCRS 304
7.3.2 STRUCTURE OF G PROTEIN-COUPLED RECEPTORS 305
7.3.2.1 OVERALL STRUCTURE 307
7.3.2.2 LIGAND BINDING AND EFFECTOR ACTIVATION 309
7.3.2.3 BINDING OF ACTIVATED GPCR TO G PROTEIN 310
7.3.2.4 LIGAND-SELECTIVE GPCR SIGNALING 311
7.3.3 REGULATION OF GPCRS 312
7.3.3.1 PHOSPHORYLATION OF GPCRS 314
7.3.3.2 DESENSITIZATION AND DOWNREGULATION OF GPCRS 315
7.3.3.3 GPCR PHOSPHORYLATION BY GRKS 316
7.3.3.4 BINDING OF ARRESTIN 317
7.3.3.5 SIGNAL SWITCHING 319
7.3.3.6 COUPLING TO OTHER SIGNALING PATHWAYS 319
7.3.4 OLIGOMERIZATION OF GPCRS 319
XIV
| CONTENTS
7.4 REGULATORY GTPASES 320
7.4.1 THE GTPASE SUPERFAMILY: GENERAL FUNCTIONS 321
7.4.2 SWITCH FUNCTIONS OF GTPASES AND THE GTPASE CYCLE 321
7.4.2.1 MODULATION AND REGULATION OF THE SWITCH FUNCTION 323
7.4.3 INHIBITION OF GTPASES BY GTP ANALOGS 324
7.4.4 THE G-DOMAIN AS A COMMON STRUCTURAL ELEMENT
OF THE GTPASES 325
7.4.5
THE GTPASE FAMILIES 326
7.5 THE HETEROTRIMERIC G PROTEINS 327
7.5.1 CLASSIFICATION OF THE HETEROTRIMERIC G PROTEINS 328
7.5.1.1
G
S
SUBFAMILY 331
7.5.1.2 GJ SUBFAMILY 331
7.5.1.3 G
Q
SUBFAMILY 332
7.5.1.4
G12 SUBFAMILY 332
7.5.2 TOXINS AS TOOLS
IN THE CHARACTERIZATION OF HETEROTRIMERIC G
PROTEINS 332
7.5.3 THE FUNCTIONAL CYCLE OF HETEROTRIMERIC G PROTEINS 334
7.5.3.1
INACTIVE GROUND STATE 334
7.5.3.2
ACTIVATION 334
7.5.3.3 TRANSMISSION OF THE SIGNAL 336
7.5.3.4 TERMINATION OF THE SIGNAL AND GTPASE-ACTIVATING PROTEINS 336
7.5.3.5 HETEROTRIMERIC G PROTEINS IN SUPRAMOLECULAR COMPLEXES 337
7.5.4
STRUCTURAL AND MECHANISTIC ASPECTS OF THE SWITCH FUNCTION OF G
PROTEINS 337
7.5.4.1 COUPLING OF THE ACTIVATED RECEPTOR TO THE G PROTEIN 337
7.5.4.2 STRUCTURE OF THE G
A
-SUBUNIT 337
7.5.4.3 STRUCTURE OF THE HETEROTRIMER 339
7.5.4.4 CONFORMATIONAL CHANGES UPON ACTIVATION BY GTP 339
7.5.4.5
MECHANISM OF GTP HYDROLYSIS 340
7.5.4.6 ACCELERATION OF GTP HYDROLYSIS BY GTPASE-ACTIVATING PROTEINS 342
7.5.5 STRUCTURE AND FUNCTION OF THE GP^-COMPLEX 342
7.5.5.1
STRUCTURE OF THE GP-Y-COMPLEX 343
7.5.5.2 SPECIFICITY OF G(}-Y SIGNALING 343
7.5.5.3 SIGNALING BY THE (3-Y-COMPLEX 344
7.5.6 MEMBRANE ASSOCIATION OF THE G PROTEINS 345
7.5.7 REGULATORS OF G PROTEINS: PHOSDUCIN AND RGS PROTEINS 346
7.5.7.1 PHOSDUCIN 347
7.5.7.2 RGS PROTEINS 347
7.5.7.3 NON-G PROTEIN SIGNALING BY RGS PROTEINS 349
7.6
RECEPTOR-INDEPENDENT FUNCTIONS OF HETEROTRIMERIC G PROTEINS 350
7.6.1
NOVEL G PROTEIN CYCLE 350
7.7 EFFECTOR MOLECULES OF G PROTEINS 352
7.7.1 ADENYLYL CYCLASE AND CAMP AS SECOND MESSENGER 352
7.7.1.1 STRUCTURE OF ADENYLYL CYCLASE 354
7.7.1.2 REGULATION OF ADENYLYL CYCLASE 355
CONTENTS J XV
7.7.2 PHOSPHOLIPASE C 357
7.7.2.1 PHOSPHOLIPASE C-(I 360
IH.2.2 PHOSPHOLIPASE C--Y 362
7.7.2.3 PHOSPHOLIPASES C-8 362
7.7.2.4 PHOSPHOLIPASE C-E 362
7.8 GPCR SIGNALING VIA ARRESTIN 363
QUESTIONS 365
REFERENCES 366
8 INTRACELLULAR MESSENGER SUBSTANCES: SECOND MESSENGERS 369
8.1 GENERAL PROPERTIES OF INTRACELLULAR MESSENGER SUBSTANCES 369
8.2 CYCLIC AMP 371
8.2.1 FORMATION AND DEGRADATION OF CAMP 371
8.2.1.1 FORMATION BY ACS 371
8.2.1.2 PHOSPHODIESTERASES AND CAMP BREAKDOWN 372
8.2.2 TARGETS OF CAMP 372
8.2.3 COMPARTMENTALIZATION OF CAMP SIGNALING 374
8.3 CGMP AND GUANYLYL CYCLASES 375
8.3.1 GUANYLYL CYCLASES 375
8.3.1.1 GUANYLYL CYCLASE RECEPTORS 376
8.3.1.2 SOLUBLE GUANYLYL CYCLASES 377
8.3.2 TARGETS OF CGMP 377
8.4 METABOLISM OF INOSITOL PHOSPHOLIPIDS AND INOSITOL
PHOSPHATES 378
8.4.1 OTHER INOSITOL MESSENGERS 380
8.4.2 ACTIVATION OF PLC AND INOSITOL PHOSPHATE FORMATION 381
8.5 STORAGE AND RELEASE OF CA
2+
383
8.5.1 RELEASE OF CA
2+
FROM CA
2+
STORAGE 384
8.5.1.1 THE INSP
3
RECEPTOR 384
8.5.1.2 THE RYANODINE RECEPTOR 387
8.5.1.3 CADP-RIBOSE AND NAADP 387
8.5.1.4 CA
2+
CHANNELS AND APOPTOSIS 388
8.5.1.5 TOOL KIT FOR CA
2+
RELEASE 389
8.5.2 INFLUX OF CA
2+
FROM THE EXTRACELLULAR REGION 390
8.5.3 REMOVAL AND STORAGE OF CA
2+
390
8.5.4 TEMPORAL AND SPATIAL CHANGES IN CA
2+
CONCENTRATION 391
8.5.4.1 CALCIUM OSCILLATIONS 392
8.6 FUNCTIONS OF PHOSPHOINOSITIDES 392
8.6.1 THE MESSENGER FUNCTION OF PTDLNS(3,4,5)P3 393
8.6.2 FUNCTIONS OF PTINS(4,5)P
2
AND OTHER PHOSPHOINOSITIDES 393
8.7 CA
2+
AS A SIGNAL MOLECULE 394
8.7.1 THE EF HAND: A CA
2+
-BINDING MODULE 396
8.7.2 CALMODULIN AS A CA
2+
SENSOR 398
8.7.3 TARGET PROTEINS OF CA
2+
/CALMODULIN 399
8.7.4 OTHER CA
2+
SENSORS 399
CONTENTS
8.8 DIACYLGLYCEROL AS A SIGNAL MOLECULE 401
8.9 OTHER LIPID MESSENGERS: CERAMIDE, SPHINGOSINE,
AND LYSOPHOSPHATIDIC ACID 401
8.9.1 CERAMIDE 402
8.9.2 SPHINGOSINE 403
8.9.3 LYSOPHOSPHATIDIC ACID (LPA) 404
8.10 THE NO SIGNALING MOLECULE 404
8.10.1 REACTIVITY OF NO 405
8.10.2 SYNTHESIS OF NO 407
8.10.2.1 NNOS 408
8.10.2.2 ENOS 408
8.10.2.3 INOS 409
8.10.3 PHYSIOLOGICAL FUNCTIONS OF NITROSYLATION 409
8.10.4 NITROSYLATION OF METAL CENTERS 409
8.10.4.1 NO-SENSITIVE GUANYLYL CYCLASE 409
8.10.4.2 NITROSYLATION OF HEMOGLOBIN 410
8.10.5 REGULATORY FUNCTIONS OF PROTEIN S-NITROSYLATION 411
8.10.5.1 SELECTIVITY OF PROTEIN S-NITROSYLATION 411
8.10.5.2 TRANSNITROSYLATION 412
8.10.5.3 DENITROSYLATION 412
8.10.5.4 TARGET PROTEINS FOR S-NITROSYLATION 413
8.10.6 TOXIC ACTION OF NO AND NITROSATIVE STRESS 413
QUESTIONS 414
REFERENCES 415
9 SER/THR-SPECIFIC PROTEIN KINASES AND PROTEIN PHOSPHATASES 417
9.1 CLASSIFICATION, STRUCTURE, AND CHARACTERISTICS OF PROTEIN KINASES
417
9.2 STRUCTURE AND REGULATION OF PROTEIN KINASES 420
9.2.1 THE PROTEIN KINASE REACTION 421
9.2.2 MAIN STRUCTURAL ELEMENTS OF PROTEIN KINASES 422
9.2.3 SUBSTRATE BINDING AND RECOGNITION 425
9.2.4 CONTROL OF PROTEIN KINASE ACTIVITY 427
9.2.5 REGULATION OF PROTEIN PHOSPHORYLATION BY SUBCELLULAR LOCALIZATION
AND SPECIFIC TARGETING SUBUNITS 430
9.3 PROTEIN KINASE A 431
9.3.1 STRUCTURE AND SUBSTRATE SPECIFICITY OF PKA 432
9.3.2 REGULATION OF PKA 435
9.3.3 A-KINASE ANCHOR PROTEINS (AKAPS) 436
9.3.3.1 AKAPS AS MULTIVALENT SCAFFOLDS 436
9.4 THE PI3 KINASE/AKT PATHWAY 439
9.4.1 PI3K 440
9.4.1.1 CLASSIFICATION AND PROPERTIES OF PI3K 440
9.4.1.2 ACTIVATION OF PI3K 441
9.4.2 AKT KINASE (PKB) 442
9.4.2.1 ACTIVATION OF AKT KINASE 443
9.4.2.2 SIGNALING BY AKT KINASE 444
9.4.2.3 PHOSPHATASE AND TENSIN HOMOLOG PTEN PHOSPHATASE 446
9.5 PROTEIN KINASE C 447
9.5.1 CLASSIFICATION AND STRUCTURE OF PKC 447
9.5.2 THE PROTEIN KINASE C FAMILY 447
9.5.2.1 STIMULATION BY PHORBOL ESTERS 449
9.5.3 ACTIVATION OF PKC 449
9.5.4 REGULATION OF PROTEIN KINASE C 450
9.5.4.1 REGULATION BY CA
2+
AND DAG 451
9.5.4.2 REGULATION BY PHOSPHORYLATION: PDK1 452
9.5.4.3 PROTEIN KINASE C-INTERACTING PROTEINS AND REGULATION BY
LOCALIZATION 453
9.5.5 RECEPTORS FOR PROTEIN KINASE C, RACK PROTEINS 453
9.5.6 FUNCTIONS AND SUBSTRATES OF PKC 454
9.6 CA
2+
/CALMODULIN-DEPENDENT PROTEIN KINASES, CAM KINASES 455
9.6.1 GENERAL FUNCTION OF CAM KINASES 455
9.6.2 CAM KINASE II 456
9.6.2.1 STRUCTURE AND ACTIVATION OF CAM
KII 457
9.6.2.2 MEMORY FUNCTION OF CAMKII 460
9.7 SER/THR-SPECIFIC PROTEIN PHOSPHATASES 461
9.7.1 CLASSIFICATION AND STRUCTURE OF SER/THR PROTEIN PHOSPHATASES 462
9.7.2 FUNCTION AND REGULATION OF SER/THR PROTEIN PHOSPHATASES 462
9.7.3 PROTEIN PHOSPHATASE I, PPI 464
9.7.4 PROTEIN PHOSPHATASE 2A, PP2A 465
9.7.5 PROTEIN PHOSPHATASE 2B, CALCINEURIN 467
QUESTIONS 469
REFERENCES 470
10 SIGNAL TRANSMISSION VIA TRANSMEMBRANE RECEPTORS
WITH TYROSINE-SPECIFIC PROTEIN KINASE ACTIVITY 473
10.1 STRUCTURE AND FUNCTION OF RTKS 474
10.1.1 GENERAL STRUCTURE AND CLASSIFICATION 475
10.1.2 LIGAND BINDING AND RECEPTOR DIMERIZATION 477
10.1.2.1 RECEPTOR HETERODIMERIZATION 481
10.1.3 STRUCTURE AND ACTIVATION OF THE TK DOMAIN 481
10.1.3.1 AUTOINHIBITION BY THE ACTIVATION LOOP: THE INSULIN RECEPTOR 483
10.1.3.2 JUXTAMEMBRANE AUTOINHIBITION 484
10.1.3.3 AUTOINHIBITION BY C-TERMINAL SEQUENCES 484
10.1.3.4 ALLOSTERIC MECHANISM OF ACTIVATION 485
10.1.4 RTK ACTIVATION AND DOWNSTREAM SIGNALING 485
10.1.4.1 NUCLEATION OF SIGNALING COMPLEXES 485
10.1.5 RECRUITMENT OF EFFECTORS VIA INTERACTION DOMAINS 490
10.1.5.1 SH2 DOMAINS 491
10.1.5.2 P-TYROSINE-BINDING (PTB) DOMAIN 493
10.1.5.3 C2 DOMAINS 493
XVIIII CONTENTS
10.2 DOWNSTREAM EFFECTOR PROTEINS OF RTKS 494
10.2.1 ADAPTER PROTEINS IN RTK SIGNALING 494
10.2.1.1 INSULIN RECEPTOR SUBSTRATE (IRS) 495
10.2.1.2 TYR-PHOSPHORYLATION: EFFECTOR RECRUITMENT 495
10.2.1.3 SER/THR PHOSPHORYLATION: SIGNAL DAMPENING 496
10.2.2 ADAPTOR PROTEINS: FRS, GRB2, GAB, SHE, LAT, AND PL30 CAS 497
10.2.2.1 FIBROBLAST GROWTH FACTOR RECEPTOR SUBSTRATE (FRS) 497
10.2.2.2 GRB2 497
10.2.2.3 GAB 499
10.2.2.4 SHE 499
10.2.2.5 PDZ-CONTAINING ADAPTER PROTEINS 500
10.2.2.6 LAT 500
10.2.2.7 PL30CAS 500
10.2.3 DOWNSTREAM EFFECTORS OF RTK SIGNALING 500
10.2.4 RTKS AS PART OF SIGNALING NETWORKS 501
10.2.5 ATTENUATION AND FEEDBACK REGULATION IN RTK SIGNALING 504
10.2.5.1 ANTAGONISTIC LIGANDS, HETERODIMERIZATION 505
10.2.5.2 INHIBITION BY INHIBITOR PROTEINS 505
10.2.6 ENDOCYTOSIS AND TRAFFICKING OF RTKS 506
10.2.6.1 UBIQUITINATION 506
10.2.7 RTK DYSFUNCTION IN DISEASE 506
10.3 NONRECEPTOR TYROSINE-SPECIFIC PROTEIN KINASES, NON-RTKS 507
10.3.1 STRUCTURE AND GENERAL FUNCTION OF NON-RTKS 507
10.3.1.1 FUNCTIONS OF NON-RTKS 508
10.3.2 SRC TYROSINE KINASE 508
10.3.2.1 STRUCTURE OF INACTIVE SRC 509
10.3.2.2 INACTIVE STATE OF SRC 511
10.3.2.3 ACTIVATION OF SRC 511
10.3.3 ABL TYROSINE KINASE 513
10.3.3.1 STRUCTURE OF ABL 513
10.3.3.2 ACTIVATION OF ABL 515
10.3.3.3 SUBSTRATE SELECTION AND INTERACTION PARTNERS OF ABL 515
10.3.3.4 REGULATION OF ABL 517
10.3.3.5 CELLULAR FUNCTIONS OF ABL 517
10.3.3.6 ONCOGENIC ACTIVATION OF ABL 518
10.4 PROTEIN TYROSINE PHOSPHATASES 519
10.4.1 GENERAL FUNCTIONS OF PTPS 519
10.4.2 CLASSIFICATION, STRUCTURE, AND MECHANISM OF PTPS 520
10.4.3 CATALYTIC MECHANISM OF PTPS 520
10.4.3.1 RECEPTOR PROTEIN TYROSINE PHOSPHATASES (PTPRS) 521
10.4.3.2 NONRECEPTOR PROTEIN TYROSINE PHOSPHATASES (PTPNS) 523
10.4.3.3 AUTOINHIBITION OF PTPN ENZYMES 523
10.4.4 REGULATION OF CELL SIGNALING BY PTPS 525
10.4.4.1 NEGATIVE REGULATION BY PTPS, AND TUMOR SUPPRESSION 526
10.4.4.2 POSITIVE REGULATION BY PTPS, AND ONCOGENIC FUNCTIONS 526
CONTENTS | XIX
10.4.5 REGULATION OF PTP ACTIVITY 527
10.4.6 OXIDATION OF PTPS 528
10.4.7 SUBCELLULAR LOCALIZATION OF PTPS 532
QUESTIONS 532
REFERENCES 533
11 SIGNAL TRANSMISSION VIA RAS PROTEINS 535
11.1 THE RAS SUPERFAMILY OF MONOMERIC GTPASES 535
11.1.1 CROSSTALK AMONG RAS SUPERFAMILY MEMBERS 538
11.2 GTPASE-ACTIVATING PROTEINS (GAPS) OF THE MONOMERIC GTPASES 539
11.3 GUANINE NUCLEOTIDE EXCHANGE FACTORS (GEFS) OF THE MONOMERIC
GTPASES 541
11.3.1 CATALYTIC DOMAINS 541
11.3.1.1 MECHANISM OF NUCLEOTIDE EXCHANGE 542
11.3.1.2 MULTIVALENCY OF GEFS 542
11.3.1.3 GEFS CAN ACTIVATE TWO DIFFERENT GTPASES 543
11.3.1.4 GEFS AS EFFECTORS OF GTPASES: LINKAGE OF AND CROSSTALK BETWEEN
GTPASES 543
11.4 GUANINE NUCLEOTIDE DISSOCIATION INHIBITORS (GDIS) 544
11.5 THE RAS FAMILY OF MONOMERIC GTPASES 545
11.5.1 GENERAL PROPERTIES OF THE RAS PROTEIN 545
11.5.2 STRUCTURE OF THE GTP- AND GDP-BOUND FORMS OF RAS PROTEIN 547
11.5.3 GTP HYDROLYSIS MECHANISM AND STIMULATION BY GAPS 548
11.5.4 STRUCTURE AND BIOCHEMICAL PROPERTIES OF TRANSFORMING
MUTANTS OF RAS PROTEIN 550
11.5.5 MEMBRANE LOCALIZATION OF RAS PROTEIN 551
11.5.5.1 RAS NANOCLUSTERS 551
11.5.6 GAPS IN RAS SIGNAL TRANSDUCTION 552
11.5.7 GUANINE NUCLEOTIDE EXCHANGE FACTORS (GEFS) IN RAS SIGNAL
TRANSDUCTION 553
11.5.7.1 STRUCTURE AND ACTIVATION 553
11.5.7.2 REGULATION 554
11.6 RAF KINASE AS AN EFFECTOR OF SIGNAL TRANSDUCTION BY RAS PROTEINS
555
11.6.1 STRUCTURE OF RAF KINASE 557
11.6.2 MECHANISM OF ACTIVATION AND REGULATION OF RAF KINASE 557
11.6.2.1 FORMATION OF HOMODIMERS AND HETERODIMERS 559
11.6.2.2 NEGATIVE FEEDBACK BY INHIBITORY PHOSPHORYLATIONS 560
11.6.3 ONCOGENIC ACTIVATION OF RAF 561
11.7 FURTHER RAS FAMILY MEMBERS: R-RAS, RAL, AND RAP 561
11.8 RECEPTION AND TRANSMISSION OF MULTIPLE SIGNALS BY RAS PROTEIN 562
11.8.1 MULTIPLE INPUT SIGNALS OF RAS PROTEIN 562
11.8.2 MULTIPLE EFFECTOR MOLECULES OF RAS PROTEINS 564
11.8.3 THE RAS SIGNALING NETWORK 566
11.9 THE FURTHER BRANCHES OF THE RAS SUPERFAMILY 568
11.9.1 THE RHO/RAC FAMILY 568
XX | CONTENTS
11.9.2 THE RAB FAMILY 569
11.9.3 THE RAN FAMILY 570
11.9.4 THE ARF FAMILY 570
QUESTIONS 570
REFERENCES 571
12 INTRACELLULAR SIGNAL TRANSDUCTION: THE MAP KINASE PATHWAYS 573
12.1 ORGANIZATION AND COMPONENTS OF MAPK PATHWAYS 575
12.1.1 MAPKS 577
12.1.2 MAPK KINASES (MAP2KS, MEKS) 577
12.1.3 MEK KINASES (MAPKK KINASES, MAP3KS) 579
12.2 REGULATION OF MAPK PATHWAYS BY PROTEIN PHOSPHATASES
AND INHIBITOR PROTEINS 579
12.2.1 FEEDBACK LOOPS IN MAPK REGULATION 580
12.2.2 REGULATION BY MAPK PHOSPHATASES 581
12.2.3 MAPK REGULATION BY INHIBITORY PROTEINS 583
12.3 SCAFFOLDING IN MAPK SIGNALING 583
12.4 THE MAJOR MAPK PATHWAYS OF MAMMALS 586
12.4.1 THE ERK PATHWAY 586
12.4.1.1 INPUT SIGNALS 586
12.4.1.2 SUBSTRATES OF ERKS 587
12.4.2 THE JNK AND P38 MAPK PATHWAYS 588
12.4.2.1 INPUT SIGNALS AND SIGNAL ENTRY POINTS OF THE JNK AND P38
PATHWAYS 589
12.4.2.2 SUBSTRATES OF THE JNK AND P38 PATHWAYS 590
12.4.2.3 THE JNK MODULE 591
12.4.2.4 THE P38 MODULE 591
QUESTIONS 592
REFERENCES 592
13 MEMBRANE RECEPTORS WITH ASSOCIATED TYROSINE KINASE ACTIVITY 593
13.1 CYTOKINES AND CYTOKINE RECEPTORS 593
13.1.1 CYTOKINES 594
13.1.1.1 CYTOKINE STRUCTURE 595
13.1.1.2 GENERAL FUNCTIONS OF CYTOKINES 595
13.1.2 STRUCTURE AND ACTIVATION OF CYTOKINE RECEPTORS 596
13.1.2.1 CLASSIFICATION AND GENERAL FEATURES 596
13.1.2.2 STRUCTURAL DOMAINS 597
13.1.2.3 OLIGOMERIC STRUCTURE 598
13.1.2.4 CYTOKINE BINDING AND ACTIVATION 599
13.1.2.5 GPL30 RECEPTORS 601
13.1.2.6 SHARED -YC-CHAIN RECEPTORS 603
13.1.2.7 SHARED FI-CHAIN RECEPTORS 603
13.1.3 ACTIVATION OF CYTOPLASMIC TYROSINE KINASES 604
13.2 THE JAK-STAT PATHWAY 608
CONTENTS IXXI
13.2.1 THE JANUS KINASES 609
13.2.1.1 KINASE REGULATION 609
13.2.1.2 COUPLING TO OTHER RECEPTOR TYPES 610
13.2.1.3 NUCLEAR FUNCTIONS OF JAKS 610
13.2.2 THE STAT PROTEINS 611
13.2.2.1 STRUCTURE OF STATS 612
13.2.2.2 ACTIVATION OF STATS 612
13.2.2.3 SIGNALING FUNCTION OF STATS 614
13.2.2.4 SIGNALING BY UNPHOSPHORYLATED STATS 615
13.2.2.5 ACETYLATION OF STATS 615
13.2.3 REGULATION OF CYTOKINE RECEPTOR SIGNALING 615
13.2.3.1 PROTEIN TYROSINE PHOSPHATASES 617
13.2.3.2 SOCS PROTEINS 617
13.2.3.3 PIAS (PROTEIN INHIBITORS OF ACTIVATED STATS) 617
13.3 T- AND B-CELL RECEPTORS 618
13.3.1 IMMUNORECEPTOR STRUCTURE 618
13.3.1.1 T-CELL RECEPTOR STRUCTURE 618
13.3.1.2 B-CELL RECEPTOR STRUCTURE 619
13.3.2 ACTIVATION AND SIGNALING OF THE T-CELL ANTIGEN RECEPTORS 621
13.3.2.1 INITIATION OF SIGNALING 621
13.3.2.2 ZAP70 621
13.3.2.3 LAT (LINKER FOR ACTIVATION OF T LYMPHOCYTES) 623
13.4 SIGNAL TRANSDUCTION VIA INTEGRINS 623
13.4.1.1 TALIN AND KINDLIN AS KEY ACTIVATORS 625
13.4.1.2 DOWNSTREAM SIGNALING 626
13.4.1.3 FOCAL ADHESION KINASE (FAK) 627
QUESTIONS 628
REFERENCES 629
14 OTHER TRANSMEMBRANE RECEPTOR CLASSES: SIGNALING BY TGF-P
RECEPTORS, TNF RECEPTORS, TOLL RECEPTORS, AND NOTCH 631
14.1 RECEPTORS WITH INTRINSIC SER/THR KINASE ACTIVITY; THE TGF-P
RECEPTOR
AND SMAD PROTEIN SIGNALING 631
14.1.1 THE FAMILY OF TGF-P CYTOKINES 633
14.1.2 TGF-P RECEPTOR 634
14.1.2.1 TGF-P RECEPTOR STRUCTURE 635
14.1.2.2 TGF-P RECEPTOR ACTIVATION 635
14.1.2.3 NON-SMAD SIGNALING PATHWAYS 636
14.1.3 SMAD PROTEINS 636
14.1.3.1 SMAD ACTIVATION 638
14.1.3.2 DNA BINDING AND TRANSCRIPTIONAL REGULATION BY SMADS 640
14.1.4 REGULATION OF TGF-P AND SMAD SIGNALING 640
14.1.4.1 INHIBITION BY I-SMADS 641
14.1.4.2 UBIQUITINATION AND SUMOYLATION 641
14.1.4.3 PHOSPHORYLATION 641
XXIII CONTENTS
14.1.4.4 ACTIVATION OF SMAD EXPRESSION 641
14.1.4.5 GROWTH REGULATORY EFFECTS OFTGF-(3 SIGNALING 642
14.2 RECEPTOR REGULATION BY INTRAMEMBRANE PROTEOLYSIS:
THE NOTCH RECEPTOR 642
14.2.1 NOTCH: GENERAL FUNCTION, STRUCTURE, AND LIGANDS 643
14.2.1.1 REGULATED INTRAMEMBRANE PROTEOLYSIS 643
14.2.1.2 DOMAIN ORGANIZATION OF NOTCH 644
14.2.1.3 NOTCH LIGANDS 644
14.2.2 PROCESSING AND ACTIVATION OF NOTCH 644
14.2.2.1 TRANSCRIPTION ACTIVATION 648
14.3 TUMOR NECROSIS FACTOR RECEPTOR (TNFR) SUPERFAMILY 648
14.3.1 BIOLOGICAL FUNCTIONS OFTNFR SIGNALING 650
14.3.2 TNFR STRUCTURE 650
14.3.3 TNF CYTOKINES 651
14.3.4 RECEPTOR ACTIVATION AND DOWNSTREAM SIGNALING 652
14.3.4.1 DOWNSTREAM SIGNALING 652
14.3.4.2 RECRUITMENT OF ADAPTER PROTEINS AND ACTIVATION OF NFKB
PATHWAYS 652
14.4 TOLL-LIKE RECEPTOR SIGNALING 653
14.4.1 TLR STRUCTURE 654
14.4.1.1 LIGAND BINDING AND ACTIVATION 655
14.4.1.2 TLR ADAPTORS AND FURTHER SIGNALING 656
14.4.1.3 ADAPTER-MEDIATED DOWNSTREAM SIGNALING 657
QUESTIONS 658
REFERENCES 659
15 CELL-CYCLE CONTROL BY EXTERNAL SIGNALING PATHWAYS 661
15.1 PRINCIPLES OF CELL-CYCLE CONTROL 661
15.1.1 INTRINSIC CONTROL MECHANISMS 663
15.1.2 EXTERNAL CELL CYCLE CONTROL 664
15.1.2.1 MITOGENIC SIGNALS 664
15.1.2.2 ANTIMITOGENIC SIGNALS DURING CELL-CELL COMMUNICATION 665
15.1.3 CELL-CYCLE CHECKPOINTS 665
15.2 KEY ELEMENTS OF THE CELL-CYCLE APPARATUS 666
15.2.1 CYDIN-DEPENDENT PROTEIN KINASES (CDKS) 666
15.2.1.1 CDKS INVOLVED IN CELL-CYCLE REGULATION 667
15.2.1.2 OTHER CDKS 667
15.2.2 CYCLINS 667
15.2.2.1 REGULATION OF CYCLIN CONCENTRATION 670
15.2.3 INHIBITORS OF CDKS: THE CKIS 671
15.2.3.1 REGULATION AND FUNCTION OF CKIS 672
15.2.3.2 THE CIP/KIP FAMILY 672
15.2.3.3 INK4 PROTEINS 674
15.2.4 STRUCTURAL BASIS OF CDK REGULATION 674
15.2.4.1 CDK-CYDIN COMPLEXES 674
CONTENTS I XXIII
15.2.4.2 PHOSPHORYLATION OF CDKS 676
15.2.4.3 STRUCTURAL BASIS OF INHIBITION BY P27
KIP1
677
15.2.5 MULTIPLE REGULATION OF CDKS 678
15.2.6 SUBSTRATES OF CDKS 679
15.2.6.1 SUBSTRATES IN GJ/S PHASE 679
15.2.6.2 SUBSTRATES IN G
2
/M PHASE 680
15.3 REGULATION OF THE CELL CYCLE BY PROTEOLYSIS 681
15.3.1 PROTEOLYSIS MEDIATED BY THE SCF COMPLEX 682
15.3.2 PROTEOLYSIS MEDIATED BY THE APC/CYDOSOME 684
15.4 GI PROGRESSION AND S PHASE ENTRY 684
15.4.1 CDK4/6 AND THE D-TYPE CYCLINS 685
15.4.1.1 REGULATION OF CDK4*CYCLIN D1 685
15.4.2 FUNCTION OF CDK2-CYCLIN E IN S PHASE ENTRY 687
15.4.3 FUNCTION OF THE RETINOBLASTOMA PROTEIN (RB) IN THE CELL CYCLE 687
15.4.3.1 DOMAIN STRUCTURE OF RB 689
15.4.3.2 CONTROL OF RB BY PHOSPHORYLATION 690
15.4.4 THE E2F TRANSCRIPTION FACTORS AND THEIR CONTROL BY RB 691
15.4.4.1 CONTROL OF E2FS BY RB 692
15.4.5 SUMMARY OF GI PROGRESSION 694
15.4.6 MITOGENIC SIGNALS REGULATING GJ ENTRY AND PROGRESSION 694
15.4.6.1 TRANSCRIPTIONAL CONTROL OF CYCLIN D1 695
15.4.6.2 CONTROL OF CYCLIN D1 TRANSLATION AND STABILITY 696
15.4.7 NEGATIVE REGULATION OF THE GJ/S TRANSITION 697
15.4.8 INTEGRATION OF MITOGENIC SIGNALS FOR CONTROL OF CELL
PROLIFERATION, CELL
GROWTH, AND SURVIVAL 697
15.5 TRANSIT THROUGH S PHASE AND M PHASE 699
15.5.1 DNA REPLICATION DURING S PHASE 699
15.5.2 G
2
/M TRANSITION AND PROGRESSION THROUGH M PHASE 700
15.5.2.1 CDK1 CONTROL AT G
2
/M 700
15.5.2.2 PROGRESSION THROUGH M PHASE 702
15.6 DNA DAMAGE AND DNA REPLICATION CHECKPOINTS 702
15.6.1 COMPONENTS AND ORGANIZATION OF DNA DAMAGE CHECKPOINTS 703
15.6.1.1 RECOGNITION OF DNA DAMAGE OR SENSING OF REPLICATION STRESS 707
15.6.1.2 FUNCTIONS OF ATM 708
15.6.1.3 FUNCTIONS OF ATR 709
15.6.1.4 CHKL, CHK2, AND DOWNREGULATION OF CDC25 PHOSPHATASE 709
15.6.2 THE MAMMALIAN GIDNA DAMAGE CHECKPOINT 710
15.6.3 THE G
2
/M CHECKPOINT 712
QUESTIONS 712
REFERENCES 713
16 MALFUNCTION OF SIGNALING PATHWAYS AND TUMORIGENESIS:
ONCOGENES AND TUMOR SUPPRESSOR GENES 715
16.1 BASIC CHARACTERISTICS OF TUMOR CELLS 715
16.2 MUTATIONS IN CANCER CELLS 715
XXIV I CONTENTS
16.2.1 GENETIC CHANGES IN CANCER CELLS 716
16.2.1.1 SMALL-SCALE CHANGES 717
16.2.1.2 LARGE-SCALE CHANGES AND GENETIC INSTABILITY 717
16.2.2 EPIGENETIC CHANGES IN TUMOR CELLS 717
16.2.2.1 ALTERED DNA METHYLATION 718
16.2.2.2 ALTERED HISTONE MODIFICATIONS IN CANCER 720
16.2.2.3 MICRO RNAS AND CANCER 720
16.2.3 CANCER GENES: DRIVERS AND PASSENGERS 721
16.2.3.1 ONCOGENES VERSUS TUMOR SUPPRESSOR GENES 722
16.2.4 CARCINOGENESIS AS AN EVOLUTIONARY PROCESS 722
16.3 COMMON PHYSIOLOGIC CHANGES IN TUMOR CELLS: THE HALLMARKS
OF CANCER 725
16.3.1 SELF-SUFFICIENCY IN GROWTH SIGNALS 727
16.3.2 INSENSITIVITY TO ANTIGROWTH SIGNALS 728
16.3.3 EVASION OF PROGRAMMED CELL DEATH (APOPTOSIS) 729
16.4 SIGNALING PROTEINS MUTATED IN CANCER ONCOGENES 729
16.4.1 MECHANISMS OF ONCOGENE ACTIVATION 730
16.4.1.1 ONCOGENIC ACTIVATION BY STRUCTURAL CHANGES 730
16.4.1.2 ONCOGENIC FUSION PROTEINS 731
16.4.1.3 ACTIVATION BY PROTEIN CONCENTRATION INCREASE 732
16.4.2 EXAMPLES OF THE FUNCTIONS OF ONCOGENES 733
16.4.2.1 ONCOGENIC RECEPTOR TYROSINE KINASES: THE ERBB2/NEU RECEPTOR 734
16.4.2.2 ONCOGENIC NONRECEPTOR TYROSINE KINASES 735
16.4.2.3 ONCOGENIC ACTIVATION OF RAS SIGNALING PATHWAYS 737
16.4.2.4 ONCOGENIC ACTIVATION OF CYCLINS 737
16.4.2.5 ONCOGENIC TRANSCRIPTION FACTORS: MYC 737
16.5 TUMOR SUPPRESSOR GENES: GENERAL FUNCTIONS 741
16.6 TUMOR SUPPRESSORS: RB AND ARF PROTEINS 743
16.6.1 RB IN CANCER 743
16.6.1.1 RB AND APOPTOSIS 744
16.6.2 THE PL6
INK4A
GENE LOCUS AND ARF 746
16.7 TUMOR SUPPRESSOR PROTEIN P53 747
16.7.1 OVERVIEW OF P53 FUNCTION 749
16.7.1.1 COUSINS OF P53 751
16.7.2 STRUCTURE AND BIOCHEMICAL PROPERTIES OF THE P53 PROTEIN 751
16.7.3 STRUCTURE OF P53 752
16.7.4 PTMS OF P53 753
16.7.4.1 PHOSPHORYLATION 753
16.7.4.2 ACETYLATION 755
16.7.4.3 METHYLATION 755
16.7.4.4 UBIQUITINATION 756
16.7.4.5 NEDDYLATION, SUMOYLATION 756
16.7.5 CONTROL OF P53 BY MDM2 756
16.7.5.1 MDM2 IS AN ONCOGENE 757
16.7.5.2 NEGATIVE FEEDBACK BETWEEN P53 AND MDM2 757
CONTENTS | XXV
16.7.5.3 OTHER CONTROLS OF MDM2 FUNCTION 759
16.7.5.4 P53-INDEPENDENT FUNCTIONS OF MDM2 759
16.7.6 GENES REGULATED BY P5 3 760
16.7.6.1 SELECTION OF TARGET GENES 760
16.7.7 PATHWAYS INVOLVED IN THE ACTIVATION OF P53 762
16.7.7.1 ACTIVATION OF P53 BY DNA DAMAGE 762
16.7.7.2 ACTIVATION OF P53 BY ONCOGENIC STRESS 762
16.7.7.3 ACTIVATION OF P53 BY NONGENOTOXIC STRESS 763
16.7.8 CLASSIFICATION OF P53 TARGET GENES 763
16.7.8.1 P53 TARGETS ACTIVATED IN UNSTRESSED CELLS AND UNDER
LOW INTRINSIC STRESS 764
16.7.8.2 P5 3 TARGETS ACTIVATED BY MODERATE STRESSES 764
16.7.8.3 P53
TARGETS ACTIVATED BY SUSTAINED OR SEVERE STRESS 766
16.7.8.4 P53-MEDIATED REPRESSION 767
16.7.9 METABOLIC REGULATION BY P53 767
16.7.10 P53-MEDIATED INDUCTION OF MIRNA 768
16.7.11 SUMMARY OF TUMOR SUPPRESSION BY P53 768
16.8 WNT/P-CATENIN SIGNALING AND THE TUMOR SUPPRESSOR APC 770
16.8.1 APC 770
16.8.1.1 DOWNREGULATION OF P-CATENIN 772
16.8.1.2 ACTIVATION OF P-CATENIN 772
QUESTIONS 773
REFERENCES 774
17 APOPTOSIS 777
17.1 OVERVIEW OF APOPTOTIC PATHWAYS 778
17.2 CASPASES: DEATH BY PROTEOLYSIS 779
17.2.1 INITIATOR AND EFFECTOR CASPASES 780
17.2.1.1 INITIATOR CASPASES 781
17.2.1.2 EFFECTOR CASPASES 781
17.2.2 MECHANISM OF CASPASES 781
17.2.3 CASPASE ACTIVATION AND REGULATION 783
17.2.3.1 DEATH PLATFORMS 783
17.2.3.2 ACTIVATION OF INITIATOR CASPASES 785
17.2.3.3 ACTIVATION OF EFFECTOR CASPASES 785
17.2.3.4 CONTROL BY INHIBITOR PROTEINS 785
17.2.3.5 CASPASE SUBSTRATES 786
17.3 THE FAMILY OF BCL-2 PROTEINS: GATEKEEPERS OF APOPTOSIS 786
17.4 THE MITOCHONDRIAL PATHWAY OF APOPTOSIS 789
17.4.1 PERMEABILIZATION OF THE MITOCHONDRIAL OUTER MEMBRANE 789
17.4.2 FORMATION OF THE APOPTOSOME AND TRIGGERING OF A CASPASE
CASCADE 791
17.4.2.1 OTHER APOPTOGENIC PROTEINS RELEASED FROM MITOCHONDRIA 792
17.5 DEATH RECEPTOR-TRIGGERED APOPTOSIS 792
17.5.1 THE FAS/CD95 SIGNALING PATHWAY 794
XXVI
| CONTENTS
17.5.2 TUMOR NECROSIS FACTOR-RECEPTOR 1 AND APOPTOSIS 795
17.6 LINKS OF APOPTOSIS TO CELLULAR SIGNALING PATHWAYS 795
17.6.1 PI3 KINASE/AKT KINASE AND APOPTOSIS 796
17.6.2 THE PROTEIN P53 AND APOPTOSIS 797
17.6.2.1 APOPTOTIC GENES ACTIVATED BY P53 798
17.6.2.2 TRANSCRIPTION-INDEPENDENT INDUCTION OF APOPTOSIS BY P53 799
QUESTIONS 799
REFERENCES 799
INDEX 801
|
| any_adam_object | 1 |
| author | Krauss, Gerhard 1943- |
| author_GND | (DE-588)133839915 |
| author_facet | Krauss, Gerhard 1943- |
| author_role | aut |
| author_sort | Krauss, Gerhard 1943- |
| author_variant | g k gk |
| building | Verbundindex |
| bvnumber | BV041204448 |
| classification_rvk | WD 4000 WD 4010 WE 5300 WE 5320 |
| classification_tum | BIO 200f CHE 800f BIO 220f |
| ctrlnum | (OCoLC)877912163 (DE-599)BVBBV041204448 |
| dewey-full | 571.74 |
| dewey-hundreds | 500 - Natural sciences and mathematics |
| dewey-ones | 571 - Physiology & related subjects |
| dewey-raw | 571.74 |
| dewey-search | 571.74 |
| dewey-sort | 3571.74 |
| dewey-tens | 570 - Biology |
| discipline | Biologie Chemie |
| edition | 5., completely rev. ed. |
| format | Book |
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| genre | (DE-588)4123623-3 Lehrbuch gnd-content |
| genre_facet | Lehrbuch |
| id | DE-604.BV041204448 |
| illustrated | Illustrated |
| indexdate | 2024-07-10T00:42:01Z |
| institution | BVB |
| isbn | 9783527333660 9783527667505 9783527667499 9783527667482 9783527667475 |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-026179265 |
| oclc_num | 877912163 |
| open_access_boolean | |
| owner | DE-20 DE-11 DE-B768 DE-703 DE-188 DE-19 DE-BY-UBM DE-29T |
| owner_facet | DE-20 DE-11 DE-B768 DE-703 DE-188 DE-19 DE-BY-UBM DE-29T |
| physical | XXVIII, 815 S. Ill., graph. Darst. |
| publishDate | 2014 |
| publishDateSearch | 2014 |
| publishDateSort | 2014 |
| publisher | Wiley-VCH |
| record_format | marc |
| spelling | Krauss, Gerhard 1943- Verfasser (DE-588)133839915 aut Biochemistry of signal transduction and regulation Gerhard Krauss 5., completely rev. ed. Weinheim Wiley-VCH 2014 XXVIII, 815 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Hier auch später erschienene, unveränderte Nachdrucke Regulation (DE-588)4049075-0 gnd rswk-swf Signaltransduktion (DE-588)4318717-1 gnd rswk-swf Molekularbiologie (DE-588)4039983-7 gnd rswk-swf (DE-588)4123623-3 Lehrbuch gnd-content Signaltransduktion (DE-588)4318717-1 s Regulation (DE-588)4049075-0 s Molekularbiologie (DE-588)4039983-7 s 1\p DE-604 b DE-604 DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=026179265&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis 1\p cgwrk 20201028 DE-101 https://d-nb.info/provenance/plan#cgwrk |
| spellingShingle | Krauss, Gerhard 1943- Biochemistry of signal transduction and regulation Regulation (DE-588)4049075-0 gnd Signaltransduktion (DE-588)4318717-1 gnd Molekularbiologie (DE-588)4039983-7 gnd |
| subject_GND | (DE-588)4049075-0 (DE-588)4318717-1 (DE-588)4039983-7 (DE-588)4123623-3 |
| title | Biochemistry of signal transduction and regulation |
| title_auth | Biochemistry of signal transduction and regulation |
| title_exact_search | Biochemistry of signal transduction and regulation |
| title_full | Biochemistry of signal transduction and regulation Gerhard Krauss |
| title_fullStr | Biochemistry of signal transduction and regulation Gerhard Krauss |
| title_full_unstemmed | Biochemistry of signal transduction and regulation Gerhard Krauss |
| title_short | Biochemistry of signal transduction and regulation |
| title_sort | biochemistry of signal transduction and regulation |
| topic | Regulation (DE-588)4049075-0 gnd Signaltransduktion (DE-588)4318717-1 gnd Molekularbiologie (DE-588)4039983-7 gnd |
| topic_facet | Regulation Signaltransduktion Molekularbiologie Lehrbuch |
| url | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=026179265&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| work_keys_str_mv | AT kraussgerhard biochemistryofsignaltransductionandregulation |