Structure and Function of the Neural Cell Adhesion Molecule NCAM (eBook)

Berezin_Frontmatter.pdf 1
Preface 5
Contributors 10
Berezin_Part-I.pdf 16
Berezin_Ch01.pdf 17
Structural Biology of NCAM 17
Introduction 17
NCAM Belongs to the Immunoglobulin Superfamily of CAMs 18
Architecture of NCAM 18
The Topology of Ig- and Fn3-homology Modules 19
Three-Dimensional Structure of NCAM Ig Modules 21
Three-Dimensional Structures of NCAM Fn3 Modules 24
Models of NCAM-Mediated Homophilic Binding 25
Surface Force Apparatus (SFA) and Atom Force Microscopy Experiments 29
Model of the Extracellular Part of NCAM 30
Perspectives 31
References 33
Berezin_Ch02.pdf 37
Extracellular Protein Interactions Mediated by the Neural Cell Adhesion Molecule, NCAM: Heterophilic Interactions Between NCAM 37
Introduction 38
NCAM Isoforms 38
NCAM Glycosylation 39
Extracellular Interactions between NCAM and other CAMs 40
Interactions between NCAM and the Prion Protein 40
Interactions between NCAM and TAG-1 42
Interactions between NCAM and L1 44
Interactions between NCAM and Extracellular Matrix Proteins 45
Structural Basis for Interactions between NCAM and Heparan Sulfate Proteoglycans 45
Biological Significance of Interactions between NCAM and Heparan Sulfate Proteoglycans 47
Modulation of Homophilic NCAM Interactions by Heparan Sulfate Proteoglycans 47
The Heparan Sulfate Proteoglycans Agrin and Collagen XVIII are NCAM Ligands 48
Structural Basis for NCAM Interactions with Chondroitin Sulfate Proteoglycans 50
The Chondroitin Sulfate Proteoglycans Neurocan and Phosphacan are Heterophilic NCAM Ligands 50
Biological Significance of NCAM Interactions with Chondroitin Sulfate Proteoglycans 52
NCAM Interactions with Collagen 53
NCAM and Laminin 54
Extracellular Interactions between NCAM and Viruses 54
Concluding Remarks 55
References 57
Berezin_Ch03.pdf 68
Intracelluar Ligands of NCAM 68
Introduction 68
Spectrin, the First Identified Intracellular NCAM-Associated Protein 69
Spectrin’s Function in Recruiting PKCb 70
Spectrin’s Function in Recruiting NMDA Receptor and CaMKIIa 70
NCAM Interacts with the Tyrosine-Kinase Fyn 71
NCAM Binds Not Only Spectrin, But Also Several Other Major Cytoskeletal Proteins 71
Interaction with Signaling Molecules 73
Direct Binding of LANP and PLCg to NCAM 75
MyoNAP, a Novel NCAM-Binding Molecule in Avians 76
Conclusion 76
References 77
Berezin_Ch04.pdf 80
NCAM and the FGF-Receptor 80
Structural Biology of NCAM 80
NCAM Functions 81
Mechanism of the NCAM Homophilic Binding 81
Interaction of NCAM with the FGF-Receptor 83
Mechanism of the FGF-Receptor Activation by NCAM 85
Conclusion 87
References 87
Berezin_Ch05.pdf 93
The Role of ATP in the Regulation of NCAM Function 93
Introduction 93
ATP as a Signaling Molecule in the Nervous System 94
NCAM ecto-ATPase Activity 95
NCAM–FGFR Interaction and ATP 96
ATP and NCAM Ectodomain Shedding 96
ATP and NCAM-Mediated Neurite Outgrowth 98
References 100
Berezin_Part-II.pdf 104
Berezin_Ch06.pdf 105
Polysialylation of NCAM 105
Introduction 105
Developmental Regulation of NCAM Polysialylation 106
Re-expression of Polysia in Tumors 107
PolySia Biosynthesis 108
Phenotype of Polysia-deficient Mice 112
Future Directions 113
References 114
Berezin_Ch07.pdf 120
Structural Basis for the Polysialylation of the Neural Cell Adhesion Molecule 120
Introduction 120
Polysialic Acid: An Important Regulator of NCAM-dependent and NCAM-independent Adhesion 120
Polysialylation of NCAM: A Protein Specific Modification 122
NCAM Domains Required for Polysialylation 123
The Unique b Sandwich Structure of NCAM FN1: The Role of an Acidic Surface Patch and Novel a-Helix in NCAM Polysialylatio 124
Are Interdomain Interactions Critical for Polysialylation of the Ig5 N-glycans? 127
Reconstitution of PolyST Recognition and Polysialylation of an Unpolysialylated NCAM-OCAM Chimeric Protein 128
A Model of PolyST-NCAM Interaction 130
Future Directions 130
References 131
Berezin_Ch08.pdf 136
The Role of PSA-NCAM in Adult Neurogenesis 136
Introduction 136
PSA-NCAM Expression in Adult Neurogenic Sites 137
Putative Functions of PSA-NCAM in Adult Neurogenesis 138
Neuronal Precursor Migration 138
Survival of Newly Generated Neurons 140
Neuronal Precursor Differentiation 141
Concluding Remarks 142
References 143
Berezin_Ch09.pdf 146
Use of PSA-NCAM in Repair of the Central Nervous System 146
Introduction 146
Polysialic Acid and Global Regulation of Cell Interactions 146
PSA-Induced Tissue Plasticity 147
PSA Promotes Precursor Cell Migration 148
PSA Facilitates Development of Neuronal Projections 148
Use of PSA Gain-of-Function to Promote Adult Tissue Repair 148
Regeneration of Damaged CNS Axons 149
Delivery of Neural Progenitors to a Brain Injury 151
Summary and Prospects 153
References 154
Berezin_Part-III.pdf 157
Berezin_Ch10.pdf 158
Signaling Pathways Involved in NCAM-Induced Neurite Outgrowth 158
Introduction 158
The MAPK Pathway 160
Fibroblast Growth Factor Receptor 160
Nonreceptor Tyrosine Kinases, Fyn and FAK 162
Rafts and Cytoskeletal Components 163
Intracellular Ca2+ and Activation of CaMKII 166
PKC 167
cAMP and PKA 168
The cGMP Pathway 168
PI3K and Akt 169
CREB 169
Concluding Remarks 170
References 171
Berezin_Ch11.pdf 176
Role of the Growth-Associated Protein GAP-43 in NCAM-Mediated Neurite Outgrowth 176
Introduction 176
Role of NCAM in the Nervous System 176
Role of GAP-43 in Remodeling of the Actin Cytoskeleton and Neurite Outgrowth 177
Involvement of GAP-43 in Neuronal Adhesion and NCAM-Mediated Neurite Outgrowth 178
Role of GAP-43 Phosphorylation in NCAM-Mediated Neurite Outgrowth 179
FGFR Function Is Required for NCAM-Stimulated GAP-43 Phosphorylation 180
PSA-NCAM and GAP-43 Are Coexpressed as Plasticity-Promoting Molecules: Possible Signaling Mechanisms Linking PSA-NCAM to GAP-43 180
Differential Role of NCAM Isoforms in GAP-43-Mediated Neurite Outgrowth 181
Functional Complex of NCAM-180 with GAP-43 and Spectrin 182
Open Question: Fyn/RPTPa Association with NCAM-180/Spectrin/GAP-43 Complex 183
NCAM and Growth-Associated Proteins BASP1 and MARCKS 183
References 185
Berezin_Ch12.pdf 190
The Neural Cell Adhesion Molecule NCAM and Lipid Rafts 190
Introduction 190
Lipid Rafts 191
Localisation of NCAM Inside and Outside Lipid Rafts 193
Localisation of NCAM Signalling Partners in Lipid Rafts and the Importance of Lipid Rafts for NCAM Signalling 195
The FGF Receptor 195
Fyn Kinase and RPTPa 195
Spectrin 197
Growth-Associated Protein-43 199
Conclusions and Perspectives 201
References 201
Berezin_Ch13.pdf 206
The Neural Cell Adhesion Molecule and Epidermal Growth Factor Receptor: Signaling Crosstalk 206
Introduction 206
Interactions Between NCAMs and the EGF Receptor in Drosophila 207
The Mammalian EGF Receptor: Regulation and Role in the Nervous System 208
Crosstalk Between Neuronal CAMs and EGF Receptor Signaling in Mammalian Cells 210
Conclusions and Perspectives 212
References 213
Berezin_Part-IV.pdf 217
Berezin_Ch14.pdf 218
Biosynthesis of NCAM 218
Introduction 218
Transcription of NCAM Gene 219
Alternative Splicing of NCAM Gene 219
Biosynthesis and Intracellular Transport of NCAM Molecule 220
Posttranslational Modifications: Glycosylation, Sulfation, Phosphorylation, and Palmitoylation 221
N-Linked Glycosylation of NCAM 222
O-Linked Glycosylation of NCAM 222
NCAM Polysialylation 222
The HNK-1/L2 Epitope on NCAM 223
NCAM Phosphorylation 223
NCAM Sulfation 223
NCAM Palmitoylation 224
Cellular Distribution of NCAM 224
NCAM Expression in Various Organs and Tissues During Development 224
Conclusions 226
References 226
Berezin_Ch15.pdf 231
Soluble NCAM 231
Introduction 231
Characterization of Soluble NCAM 232
The Source of Soluble NCAM 233
Secretion 233
Enzymatic Cleavage of the Extracellular Domain 233
Detached NCAM-Containing Membrane Fragments 235
Biological Effect of Soluble NCAM 235
In Vitro 235
In Vivo 237
Soluble NCAM in Disease 238
Schizophrenia 240
Mood Disorders 240
Neurodegenerative Disorders 241
Cancer 241
Others Disorders 242
Summary 242
References 243
Berezin_Part-V.pdf 247
Berezin_Ch16.pdf 248
Role of NCAM in Spine Dynamics and Synaptogenesis 248
Introduction 248
Adhesion Molecules and Synaptogenesis 249
Role of NCAM and PSA-NCAM in Synaptic Function and Plasticity 250
Role of PSA-NCAM in Synaptogenesis 251
Dynamic Aspect of Spine Turnover and Synapse Formation 252
Regulation of Spine Stability and Function by PSA-NCAM/NCAM Ratio 255
Conclusion 256
References 256
Berezin_Ch17.pdf 260
NCAM in Long-Term Potentiation and Learning 260
Introduction 260
NCAM in Learning and LTP 262
NCAM Expression and Localization in Synaptic Plasticity 265
PSA-NCAM in Synaptic Plasticity 266
Synaptic Plasticity in NCAM-Deficient Mice 267
NCAM in Synaptogenesis 268
Concluding Remarks 269
References 270
Berezin_Ch18.pdf 274
Role of NCAM in Emotion and Learning 274
Introduction 274
General Features of NCAM in the Central Nervous System: Molecular Structure and Function 274
NCAM and Emotion 275
NCAM in Learning: Functional Studies 281
NCAM in Learning: Correlative Studies 283
PSA-NCAM in Learning 284
NCAM and PSA-NCAM: Sensitive Indices of “Emotional Learning” 285
Mechanisms Related to NCAM Actions on Learning 293
References 294
Berezin_Part-VI.pdf 300
Berezin_Ch19.pdf 301
NCAM in Neuropsychiatric and Neurodegenerative Disorders 301
Introduction 301
Schizophrenia 304
Mood Disorders: Bipolar Disorder 306
Mood Disorders: Depression 307
Anxiety Disorders 309
Alzheimer’s Disease 310
Future Directions 311
References 312
Berezin_Ch20.pdf 320
Neural Cell Adhesion Molecule in Cancer: Expression and Mechanisms 320
Introduction 320
NCAM in Human Cancer: An Overview 321
Brain Tumors 322
Myeloma 322
Acute Myeloid Leukemia 323
Gastrointestinal Cancers 323
Thyroid Cancer 324
Small Cell Lung Cancer 325
How Does NCAM Modulate Tumor Development? 325
NCAM and Tumor–Microenvironment Interactions: The Rip1Tag2 Model 325
NCAM and Tumor Angiogenesis 327
The NCAM–FGFR Crosstalk 328
Perspectives 330
References 330
Berezin_Part-VII.pdf 335
Berezin_Ch21.pdf 336
NCAM Mimetic Peptides: An Update 336
Introduction 336
Ectodomain Structure of NCAM and Natural Extracellular Interaction Partners 342
Artificial NCAM-Binding Peptides 342
C3 342
NBP10 343
ENFIN2 and ENFIN11 344
Synthetic NCAM-Derived Peptides Targeting NCAM 344
P2 344
P1-B 345
P-3-G 345
P-3-DE 345
Synthetic NCAM-Derived Peptides Targeting Heterophilic Ligands of NCAM 345
FGL 346
FRM 347
DekaCAM 347
BCL 347
Encamin Peptides 348
HBP 348
Conclusions 348
References 349
Berezin_Ch22.pdf 353
Synthetic NCAM-Derived Ligands of the Fibroblast Growth Factor Receptor 353
Introduction 353
NCAM Interactions with FGFR 354
Structural Basis for the Interaction Between NCAM and FGFR 355
FGL, a Synthetic FGFR-Ligand Derived from the Second NCAM FN3 Module 356
FGL-Induced Intracellular Signaling 357
Cellular Responses to FGL In Vitro 358
Effects of FGL In Vivo 359
BCL, a Synthetic FGFR Ligand Derived from the Second NCAM FN3 Module 360
FRM, a Synthetic FGFR Ligand Derived from the First NCAM FN3 Module 361
DekaCAM, a Synthetic NCAM and FGF10-Derived FGFR Ligand 362
Mechanism of FGFR Activation by the Peptides 363
Different NCAM-Derived FGFR Ligands Induce Differential Responses 364
Conclusions and Future Directions 366
References 366
Berezin_Ch23.pdf 371
Dendritic Spine and Synapse Morphological Alterations Induced by a Neural Cell Adhesion Molecule Mimetic 371
Introduction 371
NCAM Involvement in Synapse Formation 371
NCAM Involvement in Memory 372
What Is the Mode of Action of NCAM at the Cellular/Synaptic Level? 372
How Does NCAM Influence Synaptic and Dendritic Morphology? 373
Aged Rats 373
Spine Volume, and Percentage Distribution of Synapse on Spine Types 373
Curvature Changes 374
Volume and Surface Area of Endososmes/Multivesicular Bodies 375
Does FGL Exert a Similar Effect on Younger Animals? 377
The Mechanism of NCAM Action at the Synaptic Level? 377
Multivesicular Bodies and Clathrin Coated Pits 378
References 379
Berezin_Part-VIII.pdf 382
Berezin_Ch24.pdf 383
Fasciclin II: The NCAM Ortholog in Drosophila melanogaster 383
Introduction 383
Alternative Splicing and Posttranslational Modifications 385
Fasciclin II Expression 386
Cell Adhesion Mechanism 387
Proneural Functions 387
Axon Growth and Guidance 388
Activation of EGFR and FGFR 388
Synaptic Functions 390
References 392
Berezin_Ch25.pdf 398
The Neural Cell Adhesion Molecule NCAM2/OCAM/RNCAM, a Close Relative to NCAM 398
Cell Adhesion Molecules in the Nervous System 399
The Identification of NCAM2 399
Isoforms and Protein Structure of NCAM2 400
Extracellular Posttranslational Modifications of NCAM2 403
Glycosylation 403
Intracellular Posttranslational Modifications of NCAM2 406
Acetylation 406
Phosphorylation 407
Expression of NCAM2 407
Homophilic NCAM2 Interactions 408
Heterophilic Binding Partners of NCAM2 408
Functions 409
NCAM2 in the Olfactory System 409
NCAM2 in Down Syndrome, Autism, and Cancer 410
Concluding Remarks 411
References 412
Berezin_Part-IX.pdf 416
Berezin_Ch26.pdf 417
Honoring Dr. Elisabeth Bock 417
References 419
Berezin_Backmatter.pdf 421