V

Table of Contents 1 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8

2 2.1 2.2 2.3 2.4 2.5 2.6 2.7

Lipid Rafts, Caveolae, and Membrane Traffic 1 Doris Meder and Kai Simons Introduction 1 Basic Organization Principles of a Cell Membrane 1 Evidence for Phase Separation in Model Membrane Systems: Liquid-Ordered and Liquid-Disordered Phases 3 Evidence for Phase Separation in Cell Membranes: The “Raft Concept” 5 Raft Domains are Clustered to Exert their Function 8 The Apical Membrane of Epithelial Cells: A Percolating Raft Membrane at 25 °C 9 Caveolae: Scaffolded Membrane Domains Rich in Raft Lipids Caveolae and Lipid Rafts in Membrane Traffic 12 Abbreviations 17 References 17 The Forces that Shape Caveolae 25 Pierre Sens and Matthew S. Turner Introduction 25 Physical Modeling of Lipid Membranes 26 Caveolae as Invaginated Lipid Rafts 29 Membrane Inclusions 31 Caveolae as a Thermodynamic Phase Separation of Membrane Proteins 33 Caveolae and Membrane Tension: Mechano-Sensitivity and Mechano-Regulation 38 Conclusions 42 Abbreviations 42 References 43

Lipid Rafts and Caveolae. Christopher J. Fielding Copyright © 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 3-527-31261-7

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3 3.1 3.2 3.3 3.4 3.5 3.6 3.6.1 3.6.2 3.6.3 3.7 3.7.1 3.7.2 3.8

4

4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 4.10

5 5.1 5.2

The Biophysical Characterization of Lipid Rafts 45 Pranav Sharma, Rajat Varma, and Satyajit Mayor Introduction: The Fluid Mosaic Model and Membrane Domains The Origin of the Raft Hypothesis 45 The Role of Lipid-Anchored Proteins in the Development of the Membrane Raft Hypothesis 48 The Case For and Against DRMs as Evidence for “Rafts” in Cell Membranes 49 Why Are Biophysical Studies Useful for Understanding Lipid Rafts? 51 Diffusion-Based Measurements 52 Single-Molecule Studies 52 Fluorescence Recovery After Photobleaching 55 Fluorescence Correlation Spectroscopy 57 Proximity Measurements 59 Proximity Measurement Using Homo-FRET 60 Proximity Measurement Using Hetero-FRET 62 Conclusions 63 Abbreviations 64 References 64

45

The Role of Caveolae and Noncaveolar Rafts in Endocytosis 69 Bo van Deurs, Frederik Vilhardt, Maria Torgersen, Kirstine Roepstorff, Anette M. Hommelgaard, and Kirsten Sandvig Introduction 69 Caveolae are Largely Immobile, Nonendocytic Membrane Domains 71 Caveolae May Show Local, Short-Range Motility: A Role in Transendothelial Transport? 73 An Internalization Wave of Caveolae can be Stimulated by Virus 74 Role of Caveolae in Endocytosis of Cholera Toxin 75 A Small Fraction of Caveolae may become Constitutively Internalized 81 Caveosomes: Intracellular Caveolin-Associated Structures 82 The Role of Dynamin in Caveolar Function 83 Caveolin Immobilizes Rafts/Caveolar Invaginations 83 A 2005 Consensus Model for Caveolar Endocytosis 85 Acknowledgments 85 Abbreviations 86 References 86 Role of Cholesterol in Signal Transduction from Caveolae Christopher J. Fielding and Phoebe E. Fielding Introduction 91 Lipids of Caveolae 93

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5.3 5.4 5.4.1

5.5 5.6 5.7 5.8

6

6.1 6.2 6.2.1 6.2.2 6.2.3 6.2.4 6.2.5 6.2.6 6.2.7 6.3 6.3.1 6.3.2 6.3.3 6.3.4 6.3.5 6.3.6 6.3.7 6.3.8 6.3.9 6.3.10 6.4

Proteins in Caveolae 95 The Caveolin Scaffold Hypothesis 98 Does the Scaffold Motif in Signaling Proteins that are Present in Caveolae Represent the Contact Site of these Proteins with Caveolin? 99 FC Binding by Proteins Including Caveolin 101 FC in Caveolae: Effects of Depletion and Loading 102 FC Changes in Caveolae: Effects of Signal Transduction 104 Summary 107 Abbreviations 107 References 107 Phosphorylation of Caveolin and Signaling from Caveolae 116 Cynthia Corley Mastick, Amy Sanguinetti, Haiming Cao, and Suhani Thakker Introduction 115 Signaling Pathways Leading to Caveolin Tyrosine Phosphorylation 116 Caveolins-1 and -2 are Phosphorylated in Response to Insulin in Adipocytes 116 The Caveolins are not Direct Substrates of the Insulin Receptor 117 Src-Family Kinases and Stress-Induced Caveolin Phosphorylation 118 Non-Receptor Tyrosine Kinases and Insulin-Induced Caveolin Phosphorylation 119 Abl is a Caveolin Kinase 120 Abl and Fyn Cooperate in the Caveolin Phosphorylation Signaling Pathway 121 Model of the Interaction of Fyn and Abl in Caveolin Phosphorylation 122 Signaling Pathways Downstream of Caveolin Tyrosine Phosphorylation 123 Csk Binds to Phosphocaveolin 124 Regulation of Src-Family Kinases by Csk 125 Feedback Inhibition of Fyn Through Activation of Csk 125 Phosphocaveolin in the Loop 126 Src-Family Kinases, Csk and Actin Remodeling 127 Phosphocaveolin is Enriched at Sites of Attachment of the Actin Cytoskeleton to the Plasma Membrane 127 Abl in the Loop 129 Abl and Actin Remodeling 130 Insulin-Induced Actin Remodeling, GluT4 Translocation, and Caveolae 131 The Role of Caveolin Phosphorylation in Cells 131 Summary 133 Abbreviations 133 References 134

VII

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7

7.1 7.1.1 7.1.2 7.2 7.2.1 7.2.2 7.2.3 7.2.4 7.2.5 7.3 7.4 7.5 7.6 7.7

8 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 8.9 8.10

Role of Lipid Microdomains in the Formation of Supramolecular Protein Complexes and Transmembrane Signaling 141 György Vámosi, Andrea Bodnár, György Vereb, János Szöllösi, and Sándor Damjanovich Introduction 141 Lateral organization of membrane proteins 142 Factors controlling the organization of membrane proteins 143 Biophysical Strategies for Studying the Lateral Organization of Membrane Proteins 144 Determination of Domain Size and Overlap between Fluorescence Distributions using Fluorescence Microscopy 144 Fluorescence Resonance Energy Transfer (FRET) 145 Fluorescence Cross-Correlation Spectroscopy: Analysis of Protein Co-Mobility 147 Atomic Force Microscopy (AFM) 149 Scanning Near-Field Optical Microscopy (SNOM) 149 The Immunological Synapse 150 Voltage-Gated K+ Channels in Lipid Rafts: Possible Involvement in Local Regulatory Processes 154 Cell Fusion as a Tool for Studying Dynamic Behavior of Protein Clusters 155 Lipid Rafts as Platforms for Cytokine Receptor Assembly and Signaling 156 Organization and Function of Receptor Tyrosine Kinases is Linked to Lipid Microdomains 162 Acknowledgments 166 Abbreviations 166 References 167 Caveolin and its Role in Intracellular Chaperone Complexes 175 William V. Everson and Eric J. Smart Caveolae and Caveolin-1 175 Caveolin Protein Structure, Domains, and Membrane Interactions 177 Caveolin Expression and Localization in the Cell 178 Caveolin Expression and Localization Varies Depending on the Physiological State of Cells in Culture 180 Caveolin-1 Expression Confers a New Level of Regulation 182 Caveolae Cholesterol and Caveolin Localization to Caveolae 182 Caveolin and Cholesterol Cross Membranes During Trafficking 183 Two Chaperone Complexes Regulate a Caveola-Cholesterol Trafficking Cycle 184 Caveolae Linked to Nongenomic Actions and Uptake of Estrogen 185 Protein Acylation and Caveolae 186

Table of Contents

8.11 8.12 8.13 8.14 8.15

9

9.1 9.2 9.3 9.4 9.5 9.6 9.7

10

10.1 10.2 10.2.1 10.3 10.3.1 10.3.2 10.3.3 10.3.4 10.4 10.4.1 10.4.2 10.4.3 10.4.4 10.4.4.1

Scavenger Receptors Localize to Caveolae 187 Cholesterol Homeostasis Regulates Caveolin Localization and Organization of other Proteins in Caveolae 187 Chaperone Complexes Involved in Cholesterol Transport in Specialized Tissues 188 Caveolin is Linked to Additional Sterol and Lipid Uptake and Trafficking Pathways 188 Conclusions 189 Abbreviations 189 References 189 The Roles of Caveolae and Caveolin in Cell Shape, Locomotion, and Stress Fiber Formation 195 Sang Chul Park and Kyung A. Cho Introduction 195 Caveolin and Polarity 195 Caveolin and Rho-family GTPases 197 Caveolin and Focal Adhesion Complex 198 The Dynamics of Caveolin and Actin 199 Caveolae-Dependent Endocytosis via Actin Stress Fiber 200 Summary 201 Abbreviations 202 References 202 Lipid Rafts in Trafficking and Processing of Prion Protein and Amyloid Precursor Protein 205 Daniela Sarnataro, Vincenza Campana, and Chiara Zurzolo Introduction 205 Lipid Rafts and Caveolae 206 Biochemical Properties and Functions 206 PrPc and Prion Diseases 207 The Site of PrPc Conversion: The Role of Rafts in the Different Intracellular Compartments 208 Role of Lipid Rafts in PrPSc Formation 210 Mechanism of Raft Action in Prion Conversion 211 Role of Rafts in Proteolytic Attack on PrPc 214 Alzheimer’s Disease: The Role of Rafts in APP Trafficking and Processing 215 The “History” of APP Cleavage 215 Intracellular Compartments and Ab Generation: Involvement of Lipid Rafts 215 The Role of Rafts in b-Secretase Activity 217 The Role of Caveolae/Lipid Rafts in a-Secretase Activity 220 The Role of Lipid Rafts in this Event 221

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10.4.5 10.4.6 10.5

11 11.1 11.2 11.3 11.4 11.5 11.6 11.7 11.8

12

12.1 12.2 12.3 12.4 12.4.1 12.4.2 12.4.3 12.5 12.6 12.7 12.8

Index

The Role of Caveolae/Rafts in g-Secretase Activity 221 The Contribution of Cholesterol and Sphingolipids in APP Processing 222 Conclusions 222 Acknowledgments 223 Abbreviations 223 References 224 Caveolae and the Endothelial Nitric Oxide Synthase 233 Olivier Feron Introduction 233 Caveolin: A Scaffold for eNOS 235 The Caveolin-eNOS Regulatory Cycle 236 Lipoproteins and Caveolin-eNOS Interaction 239 Angiogenesis and Caveolin-eNOS Interaction 241 Vasodilation, Endothelial Permeability and Caveolin-eNOS Interaction 242 Caveolin-3-eNOS Interaction in Cardiac Myocytes 244 Conclusions 246 Abbreviations 246 References 247 The Role of Caveolin-1 in Tumor Cell Survival and Cancer Progression 249 Dana Ravid and Mordechai Liscovitch Introduction 249 The Caveolin-1 Gene and its Regulation During Differentiation and Transformation 250 Divergent Expression of Caveolin-1 in Human Cancer: The Case of Lung Cancer 251 Actions of Caveolin-1 in Cancer Cells: Effects of Heterologous Expression and Genetic or Functional Suppression 252 Anti-Proliferative Activity of Caveolin-1 252 Pro-Apoptotic Activity of Caveolin-1 253 Survival-Promoting Activity of Caveolin-1 253 Molecular Mechanisms Implicated in the Pro-Survival Action of Caveolin-1 254 The Role of Tyr14 Phosphorylation in Caveolin-1-Mediated Signaling 256 Stress-Induced Changes in Caveolin-1 Expression 257 Concluding Remarks 258 Acknowledgments 259 Abbreviations 259 References 260 265